Calcium channel modulators and methods of using thereof

Abstract

The present disclosure provides compounds, compositions, and methods for modulating plasma membrane Cav1.3 calcium channels and treating diseases or disorders (e.g., Parkinson's disease, aldosteronism) with the compounds or compositions thereof. In particular, disclosed herein are modified pyrimidine-2,4,6-triones and modified dihydropyridines that have elevated potency and selectivity for Cav1.3 Ca2+ channels, and compositions and formulations thereof.

Description

Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02CALCIUM CHANNEL MODULATORS AND METHODS OF USING THEREOFCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 718,968, filed November 11, 2024, which is incorporated by reference herein in its entirety.FIELD

[0002] The present disclosure provides compounds, compositions, and methods for modulating plasma membrane Cav 1.3 calcium channels and treating diseases or disorders (e.g., Parkinson's disease, aldosteronism) with the compounds or compositions thereof.BACKGROUND

[0003] Parkinson’s disease (PD) is the second most common neurodegenerative disorder. In the United States alone, more than one million Americans are living with PD and this number is projected to increase to 1.2 million by 2030 due to the aging population. PD is characterized as a progressive neurological disorder that primarily affects movement, causing tremors, stiffness, and difficulty with balance and coordination.[0004| Over 20 years of study suggest that mitochondrial dysfunction in vulnerable brain neurons is critical to PD pathogenesis. Preclinical studies have shown that Cavl.3 calcium channels increase mitochondrial oxidant stress and mitophagy in neurons at-risk in Parkinson's disease. Epidemiological and clinical studies suggest that inhibiting these channels slows the progression of Parkinson's disease, but current pharmacotherapies are limited by the off-target inhibition of Cavl .2 calcium channels found throughout the brain and cardiovascular system. Dihydropyridines (DHPs) are the only orally deliverable, small-molecule inhibitors of Cavl Ca2+channels in human use. However, all available DI IPs have a higher affinity for the more common Cav1.2 Ca2+channel, limiting their dosing and utility as a disease- modifying agent. Thus, there is a need for a small molecule, selective inhibitor of Cav 1.3 calcium channels as an effective therapeutic for PD as well as other diseases and disorders mediated by Cavl.3 calcium channels.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02SUMMARY

[0005] In one aspect, disclosed herein are compounds of formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1, R2, and R3are each independently selected from hydrogen and Ci-6 alkyl; n is 1, 2, 3, or 4; m is 1, 2, 3, or 4; and each R4is halo.

[0006] In some embodiments, R1and R2are each independently selected from methyl and ethyl.

[0007] In some embodiments, R3is a Cj alkyl. In some embodiments, R3is methyl.

[0008] In some embodiments, n is 2 or 3.

[0009] In some embodiments, m is 1. In some embodiments, m is 2.

[0010] In some embodiments, each R4is chloro.

[0011] In some embodiments, the compound of formula (I) is selected from:; or S, R, racemic mixutres, or other stereoisomric mixtures thereof.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02[0012| In one aspect, disclosed herein are compounds of formula (II)or a pharmaceutically acceptable salt thereof, wherein: p and q are each 0 or 1 , wherein at least one of p and q is 1 ;R5and R6are each C(O)Ra, wherein when p and q are each 1, R5and R6are taken together with the atoms to which they are attached to form a six-membered ring;Rais hydrogen, C1-C3 alkyl, or aryl-Ci-Cb-alkyl; w is 1, 2, or 3; and each R7is independently selected from Ci-C& alkyl, C3-C8 cycloalkyl, haloalkyl, or nitro, wherein when R3and R6are taken together R7is C3-C8 cycloalkyl, wherein each cycloalkyl or aryl is independently unsubstituted or substituted with1, 2, or 3 substituents independently selected from Ci-Ce alkyl, haloalkyl, halo, and nitro.

[0013] In some embodiments, p is 1 and q is 0. In some embodiments, R5is odiments, p is 0 and q is 1. In some embodiments, is

[0015] In some embodiments, w is 1. In some embodiments, R7is methyl.

[0016] In some embodiments, w is 2. In some embodiments, each R7is haloalkyl or nitro.

[0017] In some embodiments, the grouphas a structure selected from

[0018] In some embodiments, p and q are each 1 , R5and R6are taken together with the atoms to which they arc attached to form a six-membered ring, and R7is C5 cycloalkyl.

[0019] In some embodiments, the compound of formula (II) is selected from:Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02

[0020] In another aspect disclosed herein are pharmaceutical compositions comprising an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.

[0021] In further aspects disclosed herein are methods of treating or preventing a disease or disorder comprising administering an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof) or a composition disclosed herein (e.g., a composition comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof), to a subject in need thereof. In some embodiments, the disease or disorder is a neurological or neurodegenerative disease or disorder. In some embodiments, the disease or disorder is Parkinson's disease. In some embodiments, the disease or disorder is an adrenal disease or disorder.

[0022] In another aspect, disclosed herein is a use of compound disclosed herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for the treatment or prevention a disease or disorder. In some embodiments, the disease or disorder is a neurological or neurodegenerative disease or disorder. In some embodiments, the disease or disorder is Parkinson’s disease. In some embodiments, the disease or disorder is an adrenal disease or disorder.

[0023] In some embodiments, provided herein are methods of modulating plasma membrane Cavl .3 calcium channel activity comprising contacting the plasma membrane Cavl.3 calcium channel with a compound described herein (e.g., a compound of formula (I) or formula (II)). In some embodiments, the plasma membrane Cavl.3 calcium channel activity is inhibited. In some embodiments, methods further comprise contacting a plasmaAttorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02 membrane Cavl.2 calcium channel with the compound described herein (e.g., a compound of formula (I) or formula (II)), wherein the compound is selective for the plasma membrane Cavl.3 calcium channel over the plasma membrane Cavl.2 calcium channel.

[0024] Other aspects and embodiments of the disclosure will be apparent in light of the following detailed description.BREIF DESCRIPTION OF THE DRAWINGSFigure 1. Isradipine is a more potent inhibitor of Cavl.2 channels, whereas (S)-C40 is a more potent inhibitor of Cavl.3 channels.Figure 2. Racemic C40 is a selective inhibitor of Cavl.3 channels.Figure 3. ADME assays and in vivo PK results.Figure 4. At relevant concentrations, (S)-C40 produced no off-target effects were detected.Figure 5. At relevant concentrations, (S)-C40 selectively inhibits calcium entry into mouse SNc dopaminergic neurons.DETAILED DESCRIPTION

[0025] Described herein are negative allosteric modulators of plasma membrane Cavl.3 calcium channels that have a higher affinity for channels with a Cav1.3 pore-forming subunit than those with a Cav1.2 subunit. Currently available drugs have the opposite affinity profile, limiting their disease- modifying utility in prodromal and early-stage Parkinson’s disease patients. Using a combination of medicinal chemistry and high-throughput, planar patch clamp drag screening of heterologously expressed channels, a number of modified pyrimidine-2, 4,6- triones (mPYTs) and modified dihydropyridines (niDHPs) were identified that have nanomolar IC50s and elevated selectivity for Cav1.3 Ca2+channels.

[0026] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.Definitions

[0027] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, some preferred methods, compositions, devices, and materials are described herein. However, before the present materials and methods are described, it is to be understood that this invention is not limited to the particular compounds, compositions, methodologies, or protocols hereinAttorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02 described, as these may vary in accordance with routine experimentation and optimization. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of the embodiments described herein.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of conflict, the present specification, including definitions, will control. Accordingly, in the context of the embodiments described herein, the following definitions apply.

[0029] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0030] As used herein, the term “comprise” and linguistic variations thereof denote the presence of recited feature(s), element(s), method step(s), etc. without the exclusion of the presence of additional fcaturc(s), clcmcnt(s), method stcp(s), etc. Conversely, the term “consisting of’ and linguistic variations thereof, denotes the presence of recited feature(s), element(s), method step(s), etc. and excludes any unrecited feature(s), element(s), method step(s), etc., except for ordinarily-associated impurities. The phrase “consisting essentially of’ denotes the recited feature(s), element(s), method step(s), etc. and any additional feature(s), element(s), method step(s), etc. that do not materially affect the basic nature of the composition, system, or method. Many embodiments herein are described using open “comprising” language. Such embodiments encompass multiple closed “consisting of’ and / or “consisting essentially of’ embodiments, which may alternatively be claimed or described using such language.

[0031] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0032] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications,Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0033] As used herein, “treat,” “treating,” and the like means a slowing, stopping, or reversing of progression of a disease or disorder when provided a compound or composition described herein to an appropriate control subject. The term also means a reversing of the progression of such a disease or disorder to a point of eliminating or greatly reducing the symptoms. As such, “treating” means an application or administration of the compositions described herein to a subject, where the subject has a disease or a symptom of a disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or symptoms of the disease.

[0034] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (c.g., children). Moreover, patient may mean any living organism, preferably a mammal (c.g., humans and non-humans) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0035] As used herein, the terms “providing,” “administering,” and “introducing,” are used interchangeably herein and refer to the placement of the compounds or compositions of the disclosure into a subject by a method or route which results in at least partial localization of the compounds or composition to a desired site. The compounds or compositions can be administered by any appropriate route which results in delivery to a desired location in the subject.

[0036] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, University Science Books, Sausalito, 2006; Smith, March's Advanced Organic Chemistry:Attorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0037] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4- dimethylpentan-2-yl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl.

[0038] As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero hctcroatoms (“Cg-Ci4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl,” i.e., phenyl).

[0039] The term “cycloalkyl,” as used herein, refers to a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0040] The term “halogen” or “halo,” as used herein, means F, Cl, Br, or I.

[0041] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen. Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2- trifluoroethyl, and 3,3,3-trifluoropropyl.

[0042] As used herein, the term “nitro” refers to an -NO2 group.

[0043] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groupsAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.

[0044] As used herein, the term “substituent” refers to a group substituted on an atom of the indicated group.

[0045] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogen atoms on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkcnyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamide, thiol, thione, thioxo, or combinations thereof.

[0046] As used herein, in chemical structures the indication:represents a point of attachment of one moiety to another moiety.

[0047] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl alkenyl) is indicated by the prefix “Cx-Cy”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C3 alkyl” refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0048] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0049] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- is intended to encompass -OCH2-, and -C(O)NH- is intended to encompass -NHC(O)-.Attorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02

[0050] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein arc illustrative only and not intended to be limiting.Compounds

[0051] In some embodiments, disclosed herein is a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1, R2, and R3are each independently selected from hydrogen and Ci-6 alkyl; n is 1, 2, 3, or 4; m is 1, 2, 3, or 4; and each R4is halo.

[0052] In some embodiments, R1and R2are each independently selected from methyl and ethyl. In some embodiments, R1and R2are each methyl. In some embodiments, R1is ethyl and R2is methyl.[0053| In some embodiments, R3is a C3 alkyl. In some embodiments, R3is n-propyl. In some embodiments, R3is isopropyl. In some embodiments, R3is methyl.

[0054] In some embodiments, n is 2. In some embodiments, n is 3.

[0055] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, each R4is chloro.

[0056] In some embodiments, the compound is selected from:Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02or a pharmaceutically acceptable salt thereof, wherein: p and q are each 0 or 1, wherein at least one of p and q is 1;R5and R6are each C(O)Ra, wherein when p and q are each 1 , R5and R6are taken together with the atoms to which they are attached to form a six-membered ring;Rais hydrogen, C1-C3 alkyl, or aryl-Ci-Cj-alkyl; w is 1, 2, or 3; and each R7is independently selected from Ci-Ce alkyl, C3-C8 cycloalkyl, haloalkyl, or nitro, wherein when R5and R6are taken together R7is C3-C.8 cycloalkyl, wherein each cycloalkyl or aryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from Ci-C& alkyl, haloalkyl, halo, and nitro.

[0058] At least one of p and q is 1.

[0059] In some embodiments, wherein p is 1 and q is 0. In some embodiments, R3isAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02

[0060] In some embodiments, p is 0 and q is 1. In some embodiments, is

[0061] In some embodiments, w is 1. In some embodiments, R7is methyl.

[0062] In some embodiments, w is 2. In some embodiments, each R7is haloalkyl or nitro.In some embodiments, one R7is haloalkyl and the other R7is nitro.

[0063] In some embodiments, the grouphas a structure selected from

[0064] In some embodiments, p and q are each 1 and R5and R6are taken together with the atoms to which they are attached to form a six-membered ring. In some embodiments, R7is cyclopentyl.

[0065] In some embodiments, the compound is selected from:

[0066] The compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution arc exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Fumiss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or more recent versions thereol), or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.|0067] It should be understood that the compounds may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0068] The present disclosure also includes isotopically-labeled compounds, which is identical to those recited in formula (1) and formula (II), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes include those for hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Substitution with heavier isotopes such as deuterium, for example,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) and formula (II) arenC,13N,15O, and18F. Isotopically-labeled compounds of formula (I) and formula (II) can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically- labeled reagent in place of non-isotopically-labeled reagent.

[0069] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation andAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stcaryl and the like.

[0070] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, di cyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1 -ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0071] Compounds may be synthesized according to a variety of methods, including those illustrated in the Examples. Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials usingAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0072] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the disclosure can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0073] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0074] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0075] It can be appreciated that the synthetic schemes and specific examples as described are illuslrati ve and are not to be read as limiting the scope of the disclosure as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02Compositions

[0076] The disclosed compounds may be incorporated into compositions that may be suitable for administration to a subject (such as a patient, which may be a human or nonhuman).

[0077] The disclosed compounds may be incoiporated into pharmaceutically acceptable compositions. The pharmaceutical compositions may include a “therapeutically effective amount’’ or a “prophylactically effective amount’’ of the compound(s). A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I) or formula (II)) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0078] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrins or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, com starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; surfactants such as, but not limited to, cremophor EL, cremophor RH 60, Solutol HS 15 and polysorbate 80; cyclodextrins such as, but not limited to, alpha-CD, beta-CD, gamma-CD, HP-beta-CD, SBE-beta-CD; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free waler; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0079] The route by which the disclosed compounds arc administered, and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral injections) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). In some embodiments, the composition is for oral administration. In some embodiments, the composition is for subcutaneous administration. In some embodiments, the composition is for intravenous administration.

[0080] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, cyclodextrins combinations thereof, and others. All carriers are optional in the compositions.

[0081] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0082] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic composition is typically about 5 to about 10%.

[0083] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0084] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02

[0085] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0086] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of prcscrvativc(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0087] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, dimethyl sulfoxide, N-methyl-2- pyrrolidone, dimethylacetamide and phosphate (or other suitable buffer). The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0088] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, Pa.) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0089] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Del. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592;Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0. 1 % to about 5%.

[0090] Suitable cyclodextrins include alpha-CD, beta-CD, gamma-CD, hydroxypropyl betadex (HP-beta-CD), sulfobutyl-ether P-cyclodextrin (SBE-beta-CD). The amount of cyclodextrins in the systemic or topical composition is typically about 0% to about 40%.

[0091] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I) for formula (II)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0092] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02

[0093] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film- coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0094] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0095] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0096] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0097] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02

[0098] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl mcthylccllulosc. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0099] Any of the above compositions or formulations disclosed herein may further comprise at least one additional therapeutic agent.Methods of Use

[0100] The disclosed compounds and pharmaceutical compositions may be used in methods for treatment of diseases and disorders, such as a disease or disorder characterized or mediated by Cav 1.3 calcium channels, and methods for selectively inhibiting a Cavl .3- calcium ion channel.

[0101] In some embodiments, the methods comprise contacting a Cav 1.3 -calcium ion channel with an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof).

[0102] In some embodiments, the methods comprise administration of an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof) to a subject in need thereof. In some embodiments, the subject is a human.

[0103] In some embodiments, the disease or disorder is a neurological or neurodegenerative disease or disorder.

[0104] Neurological disorders may be any disease affecting neuronal network connectivity, synaptic function and activity. A neurodegenerative disease refers to a central nervous system disease characterized by progressive, normally gradual, loss of functional neural tissue. Non-limiting examples of neurodegenerative diseases include frontotemporal dementia (FTD), Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Multiple sclerosis, Niemann-Pick disease, Huntington's disease, transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, dementia with Lewy bodies (DLB), corticobasal degeneration, progressive supranuclear palsy, Bell’sAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 palsy, neuronal ceroid lipofuscinoses, and hereditary spastic paraparesis. In select embodiments, the disease or disorder is Parkinson’s disease.

[0105] In some embodiments, a subject has one or more risk factors for a neurological or neurodegenerative disease or disorder. In some embodiments, risk factors for a ncurodcgcncrativc disorder include increased age (c.g., >40, >50, >60, >70, >80, etc.), genetic polymorphisms linked to neurodegenerative disorders, environmental factors, gender, education, endocrine conditions, oxidative stress, inflammation, stroke, hypertension, diabetes, smoking, head trauma, depression, infection, tumors, vitamin deficiencies, immune and metabolic conditions, and chemical exposure.

[0106] In some embodiments, the disease or disorder is an endocrine disease or disorder. In some embodiments, the disease or disorder is an adrenal disease or disorder. In particular embodiments, the adrenal disease or disorder is at least one of: aldosteronism, primary aldosteronism, secondary aldosteronism, hyperaldosteronism, primary hypcraldostcronism, secondary hypcraldostcronism and adrenal hypertension. In some embodiments, the subject has congential hyperinsulinemic hypoglycemia and primary hyperaldosteronism.

[0107] The compounds and compositions disclosed herein may be administered to a subject by a variety of methods. In any of the uses or methods described herein, administration may be by various routes known to those skilled in the art, including without limitation oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof.

[0108] The amount of the compounds of the present disclosure required for use in the disclosed methods will vary not only with the particular compound selected but also with the route of administration, the nature and / or symptoms of the disease and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages can be determined by comparing their in vitro activity, and in vivo activity in animal models.

[0109] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend onAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0110] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions.Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the symptoms to be treated and the route of administration. Further, the dose, and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0111] fhe compounds and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of the compounds sharing certain chemical moieties, or a composition thereof, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs, or monkeys, may be determined using known methods. Efficacy may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.

[0112] A wide range of second therapies may be used in conjunction with the compounds of the present disclosure. The second therapy may be administration of an additional therapeutic agent or may be a second therapy not connected to administration of another agent.

[0113] The second therapy may be administered at the same time as the initial therapy, either in the same composition or in a separate composition administered at substantially the same time as the first composition. In some embodiments, the second therapy may precede or follow the treatment of the first therapy by time intervals ranging from hours to months.Attorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02

[0114] In some embodiments, a therapeutically effective amount of a compound disclosed herein, or compositions thereof, is administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, effective combination therapy is achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time or separated by a time interval, wherein one composition includes a compound of this invention, and the other includes the at least one additional therapeutic agent.

[0115] In some embodiments, the at least one additional therapeutic agent comprises dopamine agonists. Monoamine oxidase B (MAO B) inhibitors, anti-tremor agents (e.g., anticholinergics, amantadine), anti-hallucinogens, and / or antidepressants.

[0116] In some embodiments, methods are provided herein for the treatment or prevention of diseases or disorders (e.g., Parkinson's disease, aldosteronism) with the compounds (e.g., of formula (I) or formula (II)) or compositions herein. In some embodiments, the compounds herein are co-administered with one or more therapies or therapeutics for the treatment, prevention, and / or symptom reduction related to a disease or disorder described herein (e.g., Parkinson's disease). Any agents or therapies understood for the treatment, prevention, and / or symptom reduction of PD may find use for coadministration with the compounds herein.

[0117] In some embodiments, a compound herein is co-administered with an additional pharmacological therapy, including but not limited to: dopaminergic replacement agents such as levodopa and carbidopa / levodopa (immediate-release, controlled-release and other oral formulations), inhaled levodopa formulations, and levodopa-carbidopa intestinal gel (LCIG / Duopa); dopamine receptor agonists including pramipexole, ropinirole, rotigotine (transdermal), apomorphine (subcutaneous bolus and continuous infusion) and other ergoline and non-ergoline agonists; monoamine oxidase B (MAO-B) inhibitors including selegiline, rasagiline and safinamide; catechol-O-methyltransferase (COMT) inhibitors including entacapone, tolcapone and opicapone; N-methyl-D-aspartate (NMDA) receptor antagonists and related agents such as amantadine (immediate and extended-release formulations) for motor symptoms and dyskinesia; anticholinergic agents such as trihexyphenidyl and benztropine for tremor-predominant presentations; agents for non-motor symptoms including antidepressants (SSRIs, SNRIs, tricyclics), anxiolytics, sleep agents, cholinesterase inhibitors for Parkinson’s disease dementia (e.g., rivastigmine), and drugs for autonomic dysfunction (e.g., droxidopa for orthostatic hypotension), as well as combination products (e.g., carbidopa / levodopa / entacapone) and rescue formulations designed for “off’ episodes.Attorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02

[0118] In some embodiments, a compound herein is co-administered with a device-based, procedural and surgical therapy, including but not limited to: implantable neurostimulation systems such as deep brain stimulation (DBS) targeting subthalamic nucleus (STN), globus pallidus interna (GPi) or ventral intermediate nucleus (VIM), including both continuous and scnsing / closcd-loop adaptive DBS systems; MR-guidcd focused ultrasound (non-invasivc thalamotomy and emerging pallidal / pallidothalamic tract targets) and other lesioning approaches; traditional stereotactic lesioning such as pallidotomy and thalamotomy; infusion therapies including levodopa-carbidopa intestinal gel (LCIG / Duopa) administered via percutaneous enteral systems and continuous subcutaneous apomorphine infusion; and other neuromodulation technologies and implantable devices under development or recently approved.

[0119] In some embodiments, a compound herein is co-administered with rehabilitative and non-pharmacologic interventions, including but not limited to: multidisciplinary rehabilitation comprising physical therapy (gait training, balance and cueing strategics), occupational therapy (activities of daily living training and adaptive devices), speechlanguage therapy (including LSVT LOUD / LSVT BIG programs), exercise programs (aerobic exercise, resistance training), dance, Tai Chi, speech and swallowing interventions, cognitive behavioral therapy and structured exercise regimens shown to improve motor and non-motor function.

[0120] In some embodiments, a compound herein is co-administered with adjunctive, complementary and supportive measures, including but not limited to: dietary and nutritional approaches, management of constipation and sleep disorders, pain management, respiratory therapies, bladder and sexual dysfunction treatments, psychosocial support, caregiver education, palliative care approaches, and complementary therapies such as acupuncture, massage and mind-body practices.

[0121] In some embodiments, a compound herein is co-administered with advanced biological therapies, including but not limited to: cell-based and stem cell-derived dopaminergic neuron replacement therapies; viral-vector gene therapies (for example, AAV or lentiviral delivery of enzymes, trophic factors or corrective genes such as AADC, GDNF- related approaches); small-molecule disease-modifying strategies directed to alpha-synuclein aggregation, LRRK2 inhibitors, GCase (GBA) modulators, immune-based (passive and active) anti-alpha-synuclein approaches, and programs employing antisense oligonucleotides or RNA-based therapeutics; gene-editing strategies (e.g., CRISPR / Cas systems) directed toAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 monogenic forms of PD; and other neuroprotective and pathway-targeted approaches currently in preclinical and clinical trials.Kits

[0122] Compounds and / or compositions disclosed herein may be assembled into kits or pharmaceutical systems. Kits or pharmaceutical systems according may include a carrier or package such as a box, carton, tube or the like, having in close confinement therein one or more containers, such as vials, tubes, ampoules, or bottles, which contain a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof.

[0123] The kits can also comprise other agents and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another agent for delivery to a patient.

[0124] The kits or pharmaceutical systems can also comprise instructions for using the components of the kit or pharmaceutical systems. The instructions are relevant materials or methodologies pertaining to the kit or pharmaceutical system. The materials may include any combination of the following: background information, list of components, brief or detailed protocols for using the compositions, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or pharmaceutical system or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0125] It is understood that the disclosed kits or pharmaceutical systems can be employed in connection with the disclosed methods. The kit or pharmaceutical system may further contain containers or devices for use with the methods disclosed herein.EXAMPLES

[0126] The following Examples are offered as illustrative as a partial scope and particular embodiments of the disclosure and are not meant to be limiting of the scope of the disclosure.Example 1

[0127] Medicinal chemistry approaches were used to alter pyrimidine-2, 4, 6-triones and the dihydropyridine isradipine to better align with the binding pocket of the Cavl.3 calciumAttorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02 channel. Over 250 candidate compounds were synthesized and screened for cellular activity against Cav1.3 channels and counter screened a subset against Cav1.2 channels. All compounds were screened against Cav1.3 channels expressed in HEK293 cells using a planar patch clamp assay, which can assess the ability of compounds to inhibit channels at physiologically relevant depolarized membrane potentials. Briefly, compounds were applied and peak channel currents evoked by a brief step to 0 mV from holding potentials of -80 or - 50 mV. Compounds were initially screened at a single concentration, and compounds showing strong inhibition were re-screened at multiple concentrations to establish a doseresponse relationship; data were be fitted with an isotherm to estimate IC50 values and efficacy. Potent compounds were counter screened against Cav1.2 channels to determine selectivity. The cellular assay, as described, is the only way to determine the functional inhibition of Cavl channels, which are transmembrane proteins. The potency of compounds in cellular assays tend to be lower than in biochemical assays because the activity of compounds in cell assays depend several additional factors, including the ability of compounds to partition into the cell membrane and to gain access to the allosteric binding site on the channel protein. Thus, in this screening paradigm, compounds that have activity at concentrations at or below one micromolar are considered potent.

[0128] The screening effort identified two modified dihydropyridines (mDHPs) and three modified pyrimidine-2, 4, 6-triones (mPYTs) that exhibited high selectivity and reasonable potency, sub- micromolar activity, against Cav1.3 channels were identified. Several compounds had equal or better potency at Cav1.3 channels than Cav1.2 channels. As mentioned above, isradipine has 12-fold greater potency at Cav1.2 channels compared to Cav1.3 channels, and thus a compound with equal potency against both channels constituted a significant improvement in selectivity compared to isradipine. Table 1 includes representative compounds with sub-micromolar activity and improved selectivity towards Cav1.3 channels, as compared to isradipine.Table 1.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02Example 2Experiments were conducted during development of embodiments herein to examine the effects of exemplary compounds described herein on human Cavl.3 / Cavl.2 and PD progression. Cell lines that stably express human Cavl.3 or human Cavl.2 channels were obtained. Assays were performed in automated, high-throughput planar patch clamp instrument SynchroPatch 384i. 384-well recording chips with four-holes and medium resistance (2-4MQ) were used. The external solution contained 120 mM NaCl, 20 mM CsCl, 10 mM BaC12, 1 mM MgC12, 15 mM HEPES, and 5 mM glucose (pH 7.4, 310 mOsm / L), and the internal solution contained 80 mM CsF, 50 mM NMDG, 10 mM HEPES, 5 mM BAPTA, 10 mM phosphocrcatinc, 2 mM MgATP, 0.5 mM Na2GTP, and 0.1 mM leupcptin, (pH 7.2-7.3, 290 mOsm / L). Calcium currents were measured in whole-cell mode. Cells were depolarized from a holding potential of -60 mV to 0 mV. Only gallium-sensitive bariumAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02 currents were measured. Experiments confirmed isradipine preferentially inhibits hCavl.2, while C40 preferentially inhibits hCavl.3 (Figure 1). Racemic C40 is a selective inhibitor of Cavl.3 channels (Figure 2). (R / S)-C40 are rapidly metabolized by liver microsomes (like isradipine), has a brain to plasma ratio of -0.15, exhibits low free drug availability (high protein binding) (Figure 3). At relevant concentrations, (S)-C40 produced no off-target effects (Figure 4) and selectively inhibits calcium entry into mouse SNc dopaminergic neurons (Figure 5).

Claims

Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02CLAIMS1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:R1, R2, and R3are each independently selected from hydrogen and Ci-6 alkyl; n is 1, 2, 3, or 4; m is 1, 2, 3, or 4; and each R4is halo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from methyl and ethyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3is a C3 alkyl.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3is methyl.

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein m is 1.

7. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein m is 2.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R4is chloro.

9. The compound of claim 1, wherein the compound is selected from:Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-02; or S, R, racemic mixutres, or other stereoisomric mixtures thereof.

10. A compound of formula (II)or a pharmaceutically acceptable salt thereof, wherein: p and q are each 0 or 1 , wherein at least one of p and q is 1 ;R’ and R6are each C(O)Ra, wherein when p and q are each 1, R’ and R6are taken together with the atoms to which they are attached to form a six-membered ring;Rais hydrogen, C1-C3 alkyl, or aryl-Ci-C3-alkyl; w is 1, 2, or 3; andAttorney Docket No. NWEST-43763.601 Client Ref. No. NU 2024-179-02 each R7is independently selected from Ci-C& alkyl, Cj-Cs cycloalkyl, haloalky 1, or nitro, wherein when R5and R6are taken together R7is C3-C8 cycloalkyl, wherein each cycloalkyl or aryl is independently unsubstituted or substituted with 1,2, or 3 substituents independently selected from Ci-Ce alkyl, haloalkyl, halo, and nitro.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein p is 1 and q is 0.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R3is13. The compound of claim 10, or a pharmaceutically acceptable salt thereof, herein p is 0 and q is 1.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R6is15. The compound of any of claims 11-14, or a pharmaceutically acceptable salt thereof, wherein w is h16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

17. The compound of any of claims 11-14, or a pharmaceutically acceptable salt thereof, wherein w is 2.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each R7is haloalkyl or nitro.

19. The compound any of claims 15-18, wherein the grouphas a structure selected fromAttorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-0220. The compound of claim 10, wherein p and q are each 1, R5and R6are taken together with the atoms to which they are attached to form a six-membered ring, and R7is C.s cycloalkyl.

21. The compound of claim 10, wherein the compound is selected from:

22. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A method of treating or preventing a disease or disorder comprising administering an effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22, to a subject in need thereof.

24. The method of claim 23, wherein the disease or disorder is a neurological or neurodegenerative disease or disorder.

25. The method of claim 23 or 24, wherein the disease or disorder is Parkinson’s disease.

26. The method of claim 23, wherein the disease or disorder is an adrenal disease or disorder.

27. Use of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a composition of claim 22 in the manufacture of a medicament for the treatment or prevention of a disease or disorder.

28. Use of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a composition of claim 22 for the treatment or prevention of a disease or disorder.Attorney Docket No. NWEST-43763.601Client Ref. No. NU 2024-179-0229. The use of claim 27 or 28, wherein the disease or disorder is a neurological or neurodegenerative disease or disorder or an adrenal disease or disorder.

30. The use of any of claims 27-29, wherein the disease or disorder is Parkinson’s disease.

31. A method of modulating plasma membrane Cavl.3 calcium channel activity comprising contacting the plasma membrane Cavl.3 calcium channel with a compound of any one of claims 1-21.

32. The method of claim 31, wherein the plasma membrane Cavl.3 calcium channel activity is inhibited.

33. The method of claim 31 or 32, further comprising contacting a plasma membrane Cavl.2 calcium channel with the compound of any one of claims 1-21, wherein the compound is selective for the plasma membrane Cavl.3 calcium channel over the plasma membrane Cavl.2 calcium channel.

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