Radiolabeled amino amide compounds and uses thereof

Abstract

The present disclosure relates to radiolabeled amino amide compounds, particularly radiolabeled compounds that can bind to (e.g., block) Navs and can be used for imaging, and pharmaceutically acceptable salts and pharmaceutical compositions of the same. The present disclosure also relates to methods of using the radiolabeled amino amide compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, and methods of preparing the same.

Description

RADIOLABELED AMINO AMIDE COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0000] This application claims the benefit of U.S. Provisional Application No. 63 / 663,238, filed June 24, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND

[0001] Voltage gated sodium channels (Navs) encompass a family of transmembrane proteins, including isoforms Navl. l, Navi.2, Navi.3, Navi.4, Navi.5, Navi.6, Navi.7, Navi.8, Navi.9, and Nax, which conduct sodium currents across membranes in response to changes in membrane voltage (see e.g., Kwong et al. Curr Opin. Pharmacol. (2015) 22: 131-139). Navs are responsible for neuronal excitability and the generation and propagation of action potentials in neurons, among other functions. For example, Navs play a role in fast electrical communication by initiating and propagating action potential firing (see e.g., Bean, B. P. Nat. Rev. Neurosci.(2007) 8:451-465). Neurons of the central nervous system (CNS) and peripheral nervous system contain different populations of Nav isoforms, while Navi.5 is found in the myocardium (see e.g., Gellens et al, Proc. Natl. Acad. Set. USA (1992) 89:554-558), and is the initiator of cardiac electrical signaling that controls heart rate and contraction. Several small-molecule inhibitors have been developed that can be used as a blockade of Navs, such as for local anesthesia.

[0002] While many compounds that can block Navs and be used for the prevention or relief of pain are known, there is a lack of compounds suitable for imaging Navs that are effective for visualizing and / or examining Navs, or the tissues, cells, organs, tumors, and the like, that express Navs. As such, there is a need for new compounds that can bind to Navs and also be used for imaging.SUMMARY

[0003] This disclosure relates to radiolabeled amino amide compounds that are useful for imaging techniques, and in particular, radiolabeled amino amide compounds that can bind to and / or image Navs, as well as pharmaceutical compositions of the same. In particular, the present disclosure relates to radiolabeled analogs of ropivacaine, bupivacaine, levobupivacaine,mepivacaine, an A-alkyl pipecholyl xylidine, and the like, including any pharmaceutically acceptable salt thereof. Also disclosed herein are methods of using the radiolabeled amino amide compounds or pharmaceutical compositions thereof, such as for binding to and / or inhibitingNavs, for imaging tissues, cells, organs, tumors, and the like, that express Navs, for monitoring diseases or disorders that are associated with Navs, and for monitoring the treatment of diseases or disorders that are associated with Navs. Also disclosed herein are methods of preparing radiolabeled amino amide compounds that can bind to Navs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0004] For example, the present disclosure relates to compound of Formula (A):pharmaceutically acceptable salt thereof, wherein: each R1is independently halo, (C1-C6)-alkyl, or (C1-C6)-haloalkyl; R1Ais hydrogen or a radionuclide, R4is (C1-C6)-alkyl, (C1-C6)-heteroalkyl, or (C1-C6)-haloalkyl; and n is an integer of 1-5; wherein the compound of Formula (A) comprises at least one radionuclide (e.g.,18F). It will be understood that the R4group can bind to any substitutable ring atom of the piperidine ring, and that each R1group can bind to any substitutable ring atom of the benzene ring.

[0005] In some embodiments, each R1is independently (C1-C6)-alkyl (e.g., methyl).

[0006] In some embodiments, R4is (C1-C6)-haloalkyl.

[0007] In some embodiments, n is an integer of 2.

[0008] In some embodiments, R1Ais hydrogen.

[0009] The present disclosure also relates radiolabeled compounds comprising a structure selected from the group consistingcomprises a radionuclide that is covalently bonded to a substitutable atom (e.g., a substitutable carbon atom or heteroatom) of the compound. It will be understood that the non-radiolabeled forms of the above compounds are not encompassed by the radiolabeled compounds of the present disclosure (e.g., compounds of Formula (A)).

[0010] Compounds of the present disclosure, and pharmaceutically acceptable salts thereof, comprise a radionuclide selected from the group consisting ofnC,13N,15O,18F,34mCl,38K,45Ti, 51Mn,52mMn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,66Ga,67Ga,68Ga,71As,72As,74As,75Br,76Br,In some embodiments, the radionuclide is selected from the group consisting of18F,34mCl,75Br, 76Br,120I,121I,122I,123I,124I,124I, and131I. In some embodiments, the radionuclide is18F.

[0011] The present disclosure also relates to radiolabeled compounds comprising (e.g., consisting essentially of, e.g., consisting of) a structure selected from the group consisting ofpharmaceutically acceptable salts thereof.

[0012] The present disclosure also relates to radiolabeled compounds comprising (e.g., consisting essentially of, e.g., consisting of) a structure selected from the group consisting ofpharmaceutically acceptable salts thereof.

[0013] For example, the present disclosure relates to compound that comprises (e.g., consists essentially of, e.g., consists of) the structure pharmaceuticallyacceptable salt thereof.

[0014] The present disclosure further relates to pharmaceutical compositions comprising (e.g., consisting essentially of, e.g., consisting of) a compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, optionally comprising one or more pharmaceutically acceptable excipients (e.g., an excipient disclosed herein). For example, a pharmaceutical composition of the present disclosure may comprise (e.g., consist essentially of, e.g., consist of) a compound with the structurepharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients (e.g., an excipient disclosed herein).

[0015] The present disclosure further relates to a method of blocking a voltage gated sodium channel (Nav) in a subject, comprising (e.g., consisting essentially of, e.g., consisting of)administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, a method of the present disclosure for blocking a voltage gated sodium channel (Nav) in a subject may comprise (e.g., consist essentially of, e.g., consist of) administering to the subject a compound with the structurepharmaceutically acceptable salt thereof.

[0016] The present disclosure further relates to a method of imaging a voltage gated sodium channel (Nav), or an organ (e.g., heart), a tissue, a tumor, or at least a portion of a central nervous system (e.g., spinal cord), in a subject, comprising (e.g., consisting essentially of, e.g., consisting of): i) administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and ii) imaging the subject with an imaging technique (e.g., an imaging technique disclosed herein, e.g., positron emission tomography (PET)). For example, a method of the present disclosure for imaging a voltage gated sodium channel (Nav), or an organ (e.g., heart), a tissue, a tumor, or at least a portion of a central nervous system (e.g., spinal cord), in a subject, may comprise (e.g., consist essentially of, e.g., consist of): i) administering to the subject a compound with the structure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and ii) imaging the subject with an imaging technique (e.g., an imaging technique disclosed herein, e.g., positron emission tomography (PET)).

[0017] The present disclosure further relates to a method of monitoring treatment of a disease or disorder, or imaging a disease or disorder, in a subject (e.g., a disease or disorder associated with abnormal expression levels or abnormal activity of a voltage gated sodium channel), comprising (e.g., consisting essentially of, e.g., consisting of): i) imaging the subject with an imaging technique (e.g., an imaging technique disclosed herein, e.g., PET); ii) administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A), a radionuclidecontaining analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; iii) imaging the subject with an imaging technique (e.g., an imaging technique of the present disclosure, e.g., PET); and iv) comparing the image of step i) and the image of step iii). For example, a method of the present disclosure for monitoring treatment of a disease or disorder, or imaging a disease or disorder, in a subject (e.g., a disease or disorder associated with abnormal expression levels or abnormal activity of a voltage gated sodium channel), may comprise (e.g., consist essentially of, e.g., consist of): i) imaging the subject with an imaging technique (e.g., an imaging technique disclosed herein, e.g., PET); ii) administering to the subject a compound with the structurepharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; iii) imaging the subject with an imaging technique (e.g., an imaging technique of the present disclosure, e.g., PET); and iv) comparing the image of step i) and the image of step iii).

[0018] The present disclosure further relates to the use of a radiolabeled compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in a method of blocking a voltage gated sodium channel (Nav) in a subject, comprising (e.g., consisting essentially of, e.g., consisting of) administering to the subject the radiolabeled compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] The present disclosure also relates to the use of a radiolabeled compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in a method of imaging a voltage gated sodium channel (Nav), or an organ (e.g., heart), a tissue, a tumor, or at least a portion of a central nervous system (e.g., spinal cord), in a subject, comprising (e.g., consisting essentially of, e.g., consisting of): i) administering to the subject the radiolabeled compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and ii) imaging the subject with an imaging technique (e.g., an imaging technique disclosed herein, e.g., positron emission tomography (PET)).

[0020] The present disclosure further relates to the use of a radiolabeled compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in a method of monitoring treatment of a disease or disorder, or imaging a disease or disorder, in a subject (e.g., a disease or disorder associated with abnormal expression levels or abnormal activity of a voltage gated sodium channel), comprising (e.g., consisting essentially of, e.g., consisting of): i) imaging the subject with an imaging technique (e.g., an imaging technique disclosed herein, e.g., PET); ii) administering to the subject the radiolabeled compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; iii) imaging the subject with an imaging technique (e.g., an imaging technique of the present disclosure, e.g., PET); and iv) comparing the image of step i) and the image of step iii).

[0021] The present disclosure also relates to the use of a radiolabeled compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for blocking a voltage gated sodium channel (Nav) in a subject.

[0022] The present disclosure also relates to the use of a radiolabeled compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament forimaging a voltage gated sodium channel (Nav), an organ (e.g., heart), a tissue, a tumor, or at least a portion of a central nervous system (e.g., spinal cord), in a subject.

[0023] The present disclosure further relates to the use of a radiolabeled compound of the present disclosure (e.g., a compound of Formula (A), a radionuclide-containing analog of a compound listed in Table 1, or a radiolabeled compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for monitoring treatment of a disease or disorder, or imaging a disease or disorder, in a subject (e.g., a disease or disorder associated with abnormal expression levels or abnormal activity of a voltage gated sodium channel).

[0024] In some embodiments, the disease or disorder is selected from the group consisting of cardiovascular disease, neurological disease, and cancer.

[0025] The cardiovascular disease may be selected from the group consisting of cardiomyopathy, ventricular fibrillation, atrial fibrillation, tachycardia, myocardial infarction, long QT syndrome, Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, hypertension, myocarditis, and heart failure.

[0026] The neurological disease may be selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, diabetic pain, cancer pain, and trigeminal neuralgia.

[0027] The cancer may be selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, mesothelioma, uterine cancer, gastrointestinal cancer (e.g., esophageal cancer, colon cancer, rectal cancer, and stomach cancer), pancreatic cancer, bladder cancer, kidney cancer, liver cancer, head and neck cancer, brain cancer, thyroid cancer, skin cancer, prostate cancer, and testicular cancer. For example, the cancer may be breast cancer, prostate cancer, lung cancer, or brain cancer.

[0028] The present disclosure also relates to a process of preparing a compound of Formula (A):pharmaceutically acceptable salt thereof, comprising (e.g., consisting essentially of, e.g., consisting of): reacting a compound of Formula (Q-I):suitable solvent (e.g., a polar aprotic solvent), optionally with a base (e.g., potassium carbonate), and optionally at an elevated temperature, wherein R1, R1A, R4, and n are as defined herein for a compound of Formula (A), and LG denotes a leaving group (e.g., mesyl, tosyl, Br, or I), and wherein the compound of Formula (A) comprises at least one radionuclide (e.g.,18F).

[0029] In some embodiments, the compound of Formula (Q-II) comprises a radionuclide (e g.,18F). In some embodiments, the compound of Formula (Q-II) comprises the structure:or a pharmaceutically acceptable salt thereof, where LG denotes a leaving group (e.g., mesyl, tosyl, Br, or I), in some embodiments, the compound of Formula (Q-I) comprises the structure:pharmaceutically acceptable salt thereof.

[0030] For example, a process of the present disclosure may comprise (e.g., consist essentially of, e.g., consist of) reacting a compound with the structurecompound that has the structure, in a suitable solvent (e.g., a polar aprotic solvent), optionally with a base (e.g., potassium carbonate), and optionally at an elevated temperature, to provide a compound with the structureDETAILED DESCRIPTION

[0031] The present disclosure relates to radiolabeled amino amide compounds, pharmaceutical compositions of the same, methods of using the same, and processes for preparing the same. The compounds of the present disclosure, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are useful for imaging techniques. For example, methods of the present disclosure comprise administering radiolabeled amino amide compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to a subject or a sample, for binding to and or inhibiting Navs, for imaging tissues, cells, organs, tumors, and the like, that express Navs, for monitoring diseases or disorders that are associated with Navs, or for monitoring the treatment of diseases or disorders that are associated with Navs. Also disclosed herein are methods of preparing radiolabeled amino amide compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0032] All publications (e.g., scientific journal articles, patent publications, and the like) cited in this disclosure are incorporated by reference in their entireties. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. The citation of any references herein is not an admission that such references are prior art to the present disclosure. Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0033] Chemical Definitions

[0034] As used herein, the term “alkyl” refers to a radical of a saturated hydrocarbon group. An alkyl group can be a straight chain or a branched chain saturated hydrocarbon group. An alkyl disclosed herein can have 1 to 18 carbon atoms (Ci-i8-alkyl), such as 1 to 12 carbon atoms (C1-12- alkyl), or 1 to 6 carbon atoms (Ci-6-alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, Ao-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. Throughout this disclosure, abbreviations that are well known in the art to describe various alkyl groups or their derivatives may be used, such as Me (methyl), Et (ethyl), Pr (propyl), Bu (butyl), and the like. Each instance of an alkyl group may be unsubstituted (an “unsubstituted alkyl”), orsubstituted (a “substituted alkyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] As used herein, the term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds, and no triple bonds. An alkenyl group can have from 2 to 18 carbon atoms, for example, an alkenyl group may have 2 to 8 carbon atoms (C2-8-alkenyl), 2 to 6 carbon atoms (C2-6-alkenyl), 2 to 5 carbon atoms (C2-5- alkenyl), 2 to 4 carbon atoms (C2-4-alkenyl), or 2 to 3 carbon atoms (C2-3-alkenyl). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2- butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like. Each instance of an alkenyl group may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted alkenyl”), or substituted (a “substituted alkenyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] As used herein, the term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 18 carbon atoms, and one or more carbon-carbon triple bonds. The alkynyl group may have 2 to 8 carbon atoms (C2-8-alkynyl), 2 to 6 carbon atoms (C2- 6-alkynyl), 2 to 5 carbon atoms (C2-5-alkynyl), 2 to 4 carbon atoms (C2-4-alkynyl), or 2 to 3 carbon atoms (C2-3-alkynyl). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of alkynyl groups include ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. Each instance of an alkynyl group may be unsubstituted (an “unsubstituted alkynyl”), or substituted (a “substituted alkynyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent

[0037] As used herein, the term “heteroalkyl” refers to a non-cyclic, stable, straight or branched chain, that comprises at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen (N) and sulfur (S) atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. A heteroalkyl disclosed herein can have 1 to 18 carbon atoms (Ci-i8-heteroalkyl), such as 1 to 12 carbon atoms (Ci-12-heteroalkyl), or 1 to 6 carbon atoms (Ci-6-heteroalkyl). The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group, including at the terminus. Where “heteroalkyl” is recited in this disclosure together with recitations of specific heteroalkyl groups, such as -(CH2)-C(O)-OH, -NH-CH3, or the like, it will be understood thatthe terms heteroalkyl and recitations of specific heteroalkyl groups are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding the specific heteroalkyl groups, such as -(CH2)-C(0)-0H, -NH-CH3, or the like. Each instance of a heteroalkyl group may be unsubstituted (an “unsubstituted heteroalkyl”), or substituted (a “substituted heteroalkyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] As used herein, the term “haloalkyl” refers to a radical of a saturated or unsaturated hydrocarbon group, that may be straight or branched chain, and that includes at least one halogen atom (e.g., F, Cl, Br, or I, including all isotopes thereof, e.g.,18F and34mCl). A haloalkyl disclosed herein can have 1 to 18 carbon atoms (Ci-is-haloalkyl), such as 1 to 12 carbon atoms (Ci-12-haloalkyl), or 1 to 6 carbon atoms (Ci-6-haloalkyl). The halogen atom(s) may be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CCI3, -CH2-CF3, -CH2-CCI3, -CH2-CI, -CH2-I, -(CH2)-F, -(CH2)2-F, -(CH2)3-F, or - (CH2)4-F. It will be understood that haloalkyl can include a particular isotope of the halogen atom, including unstable isotopes, e.g., haloalkyl may refer to -(CH2)2-18F. Each instance of a haloalkyl may be unsubstituted (an “unsubstituted haloalkyl”), or substituted (a “substituted haloalkyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] As used herein, the term “aryl,” refers to a stable aromatic ring system, that may be monocyclic or polycyclic, of which all the ring atoms are carbon. The aromatic ring system may have, for example, six, ten, or fourteen ring carbon atoms. Examples include phenyl (Ph), naphthyl, anthracyl, and the like, which may be referred to herein as benzene, naphthalene, or anthracene, respectively. Each instance of an aryl group may be unsubstituted (an “unsubstituted aryl”), or substituted (a “substituted aryl”) with one or more substituents. For example, a phenyl may be substituted with 1, 2, 3, 4, or 5 substituents.

[0040] As used herein, the term “heteroaryl” refers to an aryl group that includes one or more ring heteroatoms. For example, a heteroaryl can include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, or 9-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms, and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted. Examples of heteroaryl groups include pyrrole, furan, indole, thiophene, thiazole, isothiazole, imidazole,triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phthalazine, 1,2,3-triazine, 1,2,4- triazine, 1,3,5-triazine, acridine, and the like.

[0041] As used herein, the term “cycloalkyl” refers to a radical of a cyclic hydrocarbon group having from three to ten carbon atoms and no heteroatoms in the cyclic structure. Cycloalkyl can include cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The cycloalkyl group can be either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted cycloalkyl”), or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0042] As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered cyclic structure comprising one or more carbon atoms and one or more heteroatoms in the ring or rings (a radical of a heterocyclic ring). The heteroatom may be selected from nitrogen, oxygen, sulfur, boron, phosphorous, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can be either monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Each instance of heterocyclyl may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. Additional reference is made to: Oxford Dictionary of Biochemistry and MolecularBiology, Oxford University Press, Oxford, 1997 as evidence that heterocyclic ring is a term well- established in field of organic chemistry.

[0043] The terms “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” or “haloalkylene,” alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl, respectively. For instance, the term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl. In the case of heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). No orientation of the group is implied by the direction in which the formula is written. For example, the formula -C(O)OR’- may represent both -C(O)OR’- and-R’OC(O)-. Each instance of an alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene may be unsubstituted or substituted with one or more substituents. Each instance of alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene can have 1 to 18 carbon atoms (e.g., Ci is-alkylene), such as 1 to 6 carbon atoms (e.g., Ci-6-alkylene), or 1 to 3 carbon atoms (e.g., C 1-3 -alkylene). Examples of alkylene include methylene, ethylene, propylene, butylene, and the like.

[0044] As used herein, the terms “cycloalkylene,” “heterocyclylene,” “arylene,” and “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively. Each instance of a cycloalkylene, heterocyclylene, arylene, or heteroarylene may be unsubstituted or substituted with one or more substituents.

[0045] As used herein, the term “cyano” or “-CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C=N.

[0046] As used herein, the term “halo” or “halogen” refers to F, Cl, Br, or I, including any isotope thereof, including unstable isotopes, e.g.,18F and34mCl.

[0047] As used herein, the term “hydroxy” refers to a group of formula -OH.

[0048] As used herein, the term “leaving group” refers to a molecular fragment of a compound (e.g., a precursor compound) which, upon reaction of the compound with an appropriate reactant, undergoes heterolytic bond cleavage. The leaving group may be an anionic leaving group (i.e., the molecular fragment generated upon the heterolytic bond cleavage is an anionic group).Exemplary anionic leaving groups include, but are not limited to, halo groups (e.g., chloride, bromide, or iodide), sulfonate esters (e.g., tosylate or mesylate, which may be referred to herein as tosyl (Ts) or mesyl (Ms), respectively). The leaving group may be a neutral leaving group (i.e., the molecular fragment generated upon the heterolytic bond cleavage is a neutral group). Exemplary neutral leaving groups include, but are not limited to, water and ammonia.

[0049] As used herein, the term “nitro” refers to a substituent having two oxygen atoms bound to a nitrogen atom, e.g., -NO2.

[0050] As used herein, the term “oxo” refers to an oxygen group which is double bonded to another atom, e.g., carbon. For example, “oxo” refers to the =0 in a carbonyl group (C=O) or the oxygen substituent in -CH2-C(O)-CH3.

[0051] As used herein, the phrase “optionally substituted” means unsubstituted or substituted, and the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A “substitutable atom” means any atom bound to one or more hydrogen atoms, such as the nitrogen in -NH-, or the carbon in -CH- or -CH2-, that can be substituted by replacing the one or more hydrogen atoms with a substituent. It is to be understood that substitution at a given atom is limited by valency. For example, the term “substituted” may be in reference to a substituted alkyl, substituted alkylene, substituted alkenyl, substituted alkenylene, substituted alkynyl, substituted alkynylene, substituted heteroalkyl, substituted heteroalkylene, substituted heteroalkenyl, substituted heteroalkenylene, substituted heteroalkynyl, substituted heteroalkynylene, substituted haloalkyl, substituted haloalkenyl, substituted cycloalkyl, substituted cycloalkylene, substituted heterocyclyl, substituted heterocyclylene, substituted aryl, substituted arylene, substituted heteroaryl, substituted heteroarylene, and the like, i.e., an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, heteroalkenyl, heteroalkenylene, heteroalkynyl, heteroalkynylene, haloalkyl, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, heteroarylene moieties, and the like, having substituents replacing one or more hydrogen atoms on one or more carbon atoms or heteroatoms of the moiety. In general, the term substituted means that at least one hydrogen present on a group (e.g., a hydrogen bonded to carbon or nitrogen atom of said group) is replaced with a suitable substituent, such as a substituent described herein, including, but not limited to, radionuclides disclosed herein (e.g.,18F). Substituents can be any suitable substituent including, for example, alkyl (e.g., C1-C6alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl),heteroalkyl (e g., C1-C6heteroalkyl), haloalkyl (e.g., C1-C6haloalkyl, e.g., -CF3, where the halo can be any isotope, including unstable isotopes, for example a haloalkyl group can be -(CH2)18F, -(CH2)218F, -(CH2)318F, -(CH2)418F, or -(CH2)S18F), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-C8 heterocyclyl), alkylaryl (e.g., benzyl), aryl (e.g., phenyl), heteroaryl (e.g., pyrrolyl, imidazolyl, quinolinyl, or indolyl), halo (e.g., -F, -Cl, -Br, or -I, including any isotope thereof, including an unstable isotope, e.g.,18F or34mCl), hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., -OMe, - OEt, or -OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O- heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, - C(O)NH2, -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., - NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl)2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl)2, -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, - N(alkyl)C(O)N(alkyl)2, -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl)2, - N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl, or a radionuclide disclosed herein. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0052] As used herein, the term “protecting group” refers to a group that acts to temporarily block a particular functional moiety, e.g., -OH, -SH, or -NH2, so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. It will be appreciated by one of ordinary skill in the art that the synthetic methods and compounds described herein may utilize a variety of protecting groups. Protecting groups may be introduced and removed at appropriate stages during the synthesis of a compound using methods that are known to one of ordinary skill in the art. The protecting groups are applied according to standard methods oforganic synthesis as described in the literature (Theodora W. Greene and Peter G. M. Wuts (2007) Protecting Groups in Organic Synthesis, 4thedition, John Wiley and Sons, incorporated by reference in its entirety). Exemplary protecting groups include, but are not limited to, oxygen, sulfur, nitrogen and carbon protecting groups. For example, oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMB (p-methoxybenzyl), optionally substituted ethyl ethers, optionally substituted benzyl ethers, silyl ethers (e.g., TMS (trimethyl silyl ether), TES (triethylsilylether), TIPS (triisopropyl silyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, di chloroacetate), carbonates, cyclic acetals and ketals. In addition, nitrogen or amino protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Boc or Troc), amides, cyclic imide derivatives, N-alkyl and N-aryl amines, imine derivatives, and enamine derivatives, fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), acetamide, trifluoroacetamide, etc. It will be appreciated that the present disclosure is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups may be utilized according to methods known to one skilled in the art.

[0053] The compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to: cis- and trans- forms; E- and Z-forms; endo- and exo- forms; R-, S-, and meso-forms; D- and L-forms; d- and 1- forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and P-forms; axial and equatorial forms; boat-, chair-, twist-, envelope- and half chair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

[0054] Compounds described herein may comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In an embodiment, the stereochemistry depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquidchromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. This disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0055] Compounds disclosed herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), or3H (T or tritium); C may be in any isotopic form, including12C,13C, or14C; O may be in any isotopic form, including16O or18O; N may be in any isotopic form, including14N or13N; F may be in any isotopic form, including18F or19F.

[0056] The term “pharmaceutically acceptable salt” as used herein refers to a salt of the compound prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the respective compound. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable solvent (e.g., an inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable solvent (e.g., an inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic (acetate), propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, pamoic (pamoate), phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic (mesylate), and the like. For example, a pharmaceutically acceptable salt disclosed herein may be a hydrochloride salt. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like. Certain compounds of the present disclosure can contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptablesalts known to those of skill in the art are suitable for pharmaceutical compositions the present disclosure relates to.

[0057] The term “solvate” as used herein refers to forms of a compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. Compounds of the present disclosure may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates.Representative solvates include hydrates, ethanolates, and methanolates.

[0058] The term “hydrate” as used herein refers to a compound which is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R’xFbO, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e g., hemihydrates (R*0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R»2H2O) and hexahydrates (R*6H2O)).

[0059] The term “tautomer” as used herein refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7t electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0060] The term “radionuclide” as used herein, refers to an unstable isotope that can undergo radioactive decay, and may be referred to herein as a “radioactive nuclide,” “radioisotope,” or “radioactive isotope.” A radionuclide may be present in a compound of the present disclosure asa substituent. A radionuclide of the present disclosure may be a positron emitter, e.g., a radionuclide wherein a proton is converted to a neutron, thereby releasing a positron and an electron neutrino. Examples of radionuclides include, but are not limited to,nC,13N,15O,18F,34mCl,38K,45Ti,51Mn,52mMn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,66Ga,67Ga,68Ga,71As,72As,74AS,75Br,76Br,82Rb,86Y,89Zr,90Nb,94mTc, "mTc,110mIn,111In,118Sb,120I,121I,122I,123I,124I,124I,131I, and201Tl.

[0061] Other Definitions

[0062] Throughout this disclosure, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

[0063] The articles “a” and “an” are used herein to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0064] The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or less, or in some instances ±15% or less, or in some instances ±10% or less, or in some instances ±5% or less, or in some instances ±1% or less, or in some instances ±0.1% or less, from the specified value, as such variations are appropriate.

[0065] The phrase “and / or” as used herein should be understood to mean “either or both” of the elements so conjoined, e.g., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, e.g., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0066] The term “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a compound, or a pharmaceutical composition , described herein which is sufficient to achieve a desired result under the conditions of administration. For example, a therapeutically effective amount can refer to the amount of compound that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. A skilled clinician can determine appropriate dosing based on a variety of considerations including the severity of the disease or disorder, the subject’s age, weight, general health, and other considerations.

[0067] The term “pharmaceutically acceptable excipient” as used herein refers to a non-toxic material that may be formulated with a compound disclosed herein to provide a pharmaceutical composition. Preferably, the pharmaceutically acceptable excipient is inert and does not interfere with the pharmacological activity of a compound which it is formulated with. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions disclosed herein are any of those well known in the art, and include without limitation, diluents, dispersing agents, granulating agents, surface active agents, emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, ion exchangers, salts, electrolytes, waxes, and / or oils. For example, a pharmaceutically acceptable excipient may be alumina, aluminum stearate, lecithin, a serum protein (e.g., human serum albumin), a phosphate, glycine, sorbic acid, potassium sorbate, a glyceride mixture (e.g., saturated vegetable fatty acids), water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, a zinc salt, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose or a derivative thereof, polyethylene glycol or a derivative thereof (e.g., PEG-300), sodium carboxymethylcellulose, a polyacrylate, a polyethylene-polyoxypropylene-block polymer, wool fat, a cyclodextrin (e.g., CAPTISOL®), dimethylacetamide (DMA), a polysorbate (e g., a TWEEN®, e.g., TWEEN-20®), ethylenediaminetetraacetic acid (EDTA) or a salt thereof, and any combination thereof.

[0068] The term “subject” as used herein refers to any animal, such as any mammal, including but not limited to, humans, non-human primates, rodents, dogs, and the like. Non-human primates include chimpanzees, cynomolgus monkeys, spider monkeys, baboons, and macaques (e.g., Rhesus). Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species (e.g., domesticcat), canine species (e.g., dog, fox, wolf), avian species, and fish. In some embodiments, the subject is a mammal (e.g., a human, a rat, or a mouse). The subject can be male or female. The subject may be of any age, including an elderly human subject (e.g., 65 years or older), a human subject that is not elderly (e.g., less than 65 years old), or a human pediatric subject (e.g., 18 years old or less). In preferred aspects, the subject is a human.

[0069] As used herein, the terms “treat,” “treatment,” “treating,” or grammatically related terms, refer to a method of reducing the effects of a disease or disorder. As is readily appreciated in the art, full eradication of the disease, disorder, or symptoms thereof is preferred but not a requirement for treatment. Desirable effects of treatment include, but are not limited to, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease or disorder, or other improvement of any sign, symptom, or consequence of the disease or disorder, such as prolonged survival, less morbidity, and / or a lessening of side effects.

[0070] Throughout this disclosure, various embodiments can be presented in a range format (e.g., from X - Y). It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 5, from 1 to 4, from 1 to 3, from 2 to 6, from 2 to 4, from 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.8, 3, 3.6, 4, 5, 5.4, and 6. As another example, a range such as 95-99% includes 95%, 96%, 97%, 98%, or 99% and all subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98%, etc. This applies regardless of the breadth of the range.

[0071] Various embodiments of the compounds, pharmaceutical compositions, and methods herein are described in further detail below, and additional definitions may be provided throughout the specification.

[0072] Compounds

[0073] Disclosed herein are radiolabeled compounds, including radiolabeled compounds that can bind to and / or block a Nav. It will be understood that the compounds of the present disclosure comprise a radionuclide (e.g.,18F), and may therefore be referred to as radiolabeled compounds.

[0074] Unless specified otherwise, compounds disclosed herein, or pharmaceutically acceptable salts thereof, can include any isotope of an atom occurring in the compounds or intermediates used to prepare the compounds, including unstable isotopes.

[0075] A compound of the present disclosure may be a compound with a structure of Formula(A): or a pharmaceutically acceptable salt thereof, wherein:each R1is independently halo, (C1-C6)-alkyl, or (C1-C6)-haloalkyl; R1Ais hydrogen or a radionuclide, R4is (C1-C6)-alkyl, (C1-C6)-heteroalkyl, or (C1-C6)-haloalkyl; and n is an integer of 1-5; wherein the compound of Formula (A) comprises at least one radionuclide (e.g.,18F). The radionuclide may be present in one or more of the variable groups (e.g., as the haloalkyl group at R4), and / or as a substituent at any substitutable atom of the compound.

[0076] In a compound of the present disclosure (e.g., a compound of Formula (A)), each R1can, independently, be halo, (C1-C6)-alkyl, or (C1-C6)-haloalkyl. For example, R1may be halo, e.g., F, Cl, Br, or I, including any isotope thereof, including an unstable isotope, such as18F or34mCl. R1may be (C1-C6)-alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl. R1may be (C1-C6)- haloalkyl, e.g., trifluoromethyl, wherein one or more halo groups in the haloalkyl can be any isotope, including an unstable isotope, e.g.,18F or34mCl. It will be understood that where more than one R1is present in a compound, each R1may be the same or different, e.g., in a compound of the present disclosure comprising two R1groups, each may be independently (C1-C6)-alkyl; or alternatively, for example, one may be (C1-C6)-alkyl and the other may be (C1-C6)-haloalkyl. In some embodiments, two R1groups are present and each are independently methyl. It will be understood that each R1group can bind to any substitutable ring atom of the benzene ring of the compound in Formula (A).

[0077] In a compound of the present disclosure (e.g., a compound of Formula (A), R1 Acan be hydrogen or a radionuclide. For example, in a compound of the present disclosure (e.g., a compound of Formula (A), R1Ais hydrogen. Alternatively, for example, in a compound of the present disclosure (e.g., a compound of Formula (A), R1Ais a radionuclide, such as a radionuclide disclosed herein, e.g.,18F.

[0078] In a compound of the present disclosure (e.g., a compound of Formula (A), R4can be (C1-C6)-alkyl, (C1-C6)-heteroalkyl, or (C1-C6)-haloalkyl. For example, R4can be (C1-C6)-alkyl,e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl. R4can be (C1-C6)-heteroalkyl. R4can be (Ci- C6)-haloalkyl, e.g., -(CH2)-18F, -(CH2)2-18F, -(CH2)3-18F, -(CH2)4-18F, -(CH2)5-18F, or -(CH2)6-18F. In some embodiments, R4is -(CH2)-18F. In some embodiments, R4is -(CH2)2-18F. In some embodiments, R4is -(CH2)3-18F. In some embodiments, R4is -(CH2)4-18F. In some embodiments, R4is -(CH2)s-18F. In some embodiments, R4is-(CH2)e-18F. It will be understood that the R4group can bind to any substitutable ring atom of the piperidine ring in the compound of Formula (A).

[0079] In a compound of the present disclosure (e.g., a compound of Formula (A)), n can be an integer of 1-5. For example, in a compound of the present disclosure (e.g., a compound of Formula (A)), n can be an integer of 1. In a compound of the present disclosure (e.g., a compound of Formula (A)), n can be an integer of 2. In some embodiments, n is an integer of 2, and each R1is independently (C1-C6)-alkyl (e.g., methyl).

[0080] It will be understood that a compound of the present disclosure (e g., a compound of Formula (A) comprises at least one radionuclide, and the radionuclide can be present at any position of the compound, valency permitting, and / or as a substituent of the compound (e.g., at a substitutable atom), and / or comprised by any one or more variable groups of the compound (e.g., R1, R1A, or R4). For example, the radionuclide may be encompassed by R4, when R4is haloalkyl, e.g., -(CH2)418F. Or, for example, the radionuclide may be encompassed by R1, when R1is halo, e.g.,18F. In some embodiments, the radionuclide (e.g.,18F) is bonded to a terminal carbon of an alkyl group (e g., providing a haloalkyl group).

[0081] Exemplary compounds that can be modified to include a radionuclide (e.g.,18F) at any substitutable atom (e.g., a carbon atom, such as a methyl group, e.g., the terminal carbon of an alkyl group) to provide a compound of the present disclosure are presented in Table 1, including any pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds that can be modified to include a radionuclide.

[0082] Exemplary compounds that can be modified to include a radionuclide (e.g.,18F) at any substitutable atom (e.g., a carbon atom, e.g., a methyl group) to provide a compound of the present disclosure also include ropivacaine, bupivacaine, levobupivacaine, mepivacaine, an A- alkyl pipecholyl xylidine, and the like, including any pharmaceutically acceptable salt thereof.

[0083] Compounds that can be modified to include a radionuclide (e.g.,18F) may be modified at a terminal carbon atom to include the radionuclide. For example, a compound of Table 1 that comprises an alkyl group may be modified at the terminal carbon of the alkyl group (a methyl) to form a covalent bond between the radionuclide and the carbon atom, thereby providing a radiolabeled compound of the present disclosure. In another example, a compound of Table 1 that comprises an alkyl group may be modified at the terminal carbon of the alkyl group (amethyl) to form a covalent bond between18F and the carbon atom (i.e., providing a haloalkyl group), thereby providing a radiolabeled compound of the present disclosure. For example, the terminal carbon of the butyl group of bupivacaine can be modified to be attached to18F, thereby providing compound A2-10 of the present disclosure.

[0084] The radionuclide on the compound can be any one of1 1C,13N,15O,18F,34mCl,38K,45Ti,51Mn,52mMn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,66Ga,67Ga,68Ga,71As,72As,74As,75Br,76Br,82Rb,86Y,89Zr,90Nb,94mTc, "mTc,110mIn,111In,118Sb,120I,121I,122I,123I,124I,124I,131I, and2O1T1. In some embodiments, the radionuclide is selected from18F,34mCl,75Br,76Br,120I,121I,122I,123I,124I,124I, and131I. In some embodiments, the radionuclide is18F.

[0085] Exemplary compounds of the present disclosure (e.g., a compound of Formula (A)) include the compounds listed in Table 2, and any pharmaceutically acceptable salt thereof, and any stereoisomer thereof.Table 2. Exemplary radiolabeled amino amide compounds.

[0086] Pharmaceutical Compositions

[0087] The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein (e.g., a Compound of Formula (A), or a radionuclide-containing analog of a compound listed in Table 1, or a compound listed in Table 2), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0088] In some aspects, a pharmaceutical composition described herein comprises a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In some aspects, a pharmaceutical composition described herein comprises a compound that is a radionuclide-containing analog of a compound listed in Table 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In some aspects, a pharmaceutical composition described herein comprises a compound listed in Table 2 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0089] A pharmaceutical composition of the present disclosure may be prepared by any suitable method known in the art. Such methods can involve a step of bringing the compound (the “active ingredient,” e.g., a compound of Formula (A), or a compound that is a radionuclidecontaining analog of a compound listed in Table 1, or a compound listed in Table 2, or a pharmaceutically acceptable salt thereof, into association with one or more pharmaceutically acceptable excipients (e.g., a carrier or binding agent), and may further involve a step of shaping and / or packaging the composition into a single- or multi-dose unit.

[0090] Relative amounts of the compound, and the one or more pharmaceutically acceptable excipients, in a pharmaceutical composition of the present disclosure will vary depending on several factors, including the identity, size, and / or condition of the subject or sample to be administered the compound, and also depending on the route by which the composition is to be administered. For example, the pharmaceutical composition may comprise between about 0.1 wt% and about 100 wt% of the compound.

[0091] Compounds or pharmaceutical compositions of the present disclosure may be administered orally, parenterally (including, without limitation, subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation (e.g., oral inhalation), topically, rectally, nasally, buccally, vaginally, or by an implanted reservoir. In some embodiments, the compound, pharmaceutical salt thereof, or pharmaceutical composition thereof, is administered intravenously.

[0092] Pharmaceutical compositions of the present disclosure may be intravenously administered in any acceptable dosage form including, without limitation, aqueous solutions. Intravenous dosage forms can include a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable excipient disclosed herein), e.g., carriers, diluents, or the like.

[0093] The descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions which are suitable for administration to humans, but it will be understood that such compositions are generally suitable for administration to other animals. It will also be well understood that modifications of pharmaceutical compositions are possible to render the compositions suitable for administration to various animals, and the ordinarily skilled person can design and / or perform such modification with ordinary experimentation.

[0094] Compounds and pharmaceutical compositions disclosed herein can be formulated in a dosage unit form, e.g., a single unit dosage form, for ease of administration or uniformity of dosage. However, it will be understood that the dosage of the compounds or compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0095] A compound or pharmaceutical composition disclosed herein may be formulated or administered to provide a total dose of between about 1 mCi and about 30 mCi (e.g., about 1 mCi, about 2 mCi, about 4 mCi, about 6 mCi, about 8 mCi, about 10 mCi, about 15 mCi, about 20 mCi, about 25 mCi, or about 30 mCi). A compound or pharmaceutical composition disclosed herein may be administered as a bolus dose, as an infusion, or a combination thereof. For example, a compound or pharmaceutical composition disclosed herein may be administered as a bolus dose of between about 1 mCi and about 15 mCi (e.g., about 1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi, about 7 mCi, about 8 mCi, about 9 mCi, about 10 mCi, about 11 mCi, about 12 mCi, about 13 mCi, about 14 mCi, or about 15 mCi), followed by an infused dose of between about 1 mCi and about 10 mCi (e.g., about 1 mCi, about 2 mCi,about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi, about 7 mCi, about 8 mCi, about 9 mCi, or about 10 mCi). It will be understood that the term “mCi” refers to “millicurie,” a unit of radioactivity.

[0096] A compound or composition of the present disclosure can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which can be useful, e.g., to monitor treatment with the one or more additional pharmaceutical agents. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and / or at a time determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved.

[0097] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). The kits may comprise a compound or composition disclosed herein and a container (e g., a blister pack, vial, bottle, ampule, dispenser package, syringe, or other suitable container). In some embodiments, kits may further include a second container comprising a pharmaceutical excipient, e.g., for dilution or suspension of the compound or composition. In some embodiments, the compound or composition provided in the container, and the second container, are combined to form one unit dosage form, or a multi-unit dosage form.

[0098] Methods of Use

[0099] The present disclosure also relates to methods of using compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0100] For example, disclosed herein are methods of blocking a Nav in a subject, comprising administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A), or a compound that is a radionuclide-containing analog of a compound listed in Table 1, or a compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0101] Also disclosed herein are methods of blocking a Nav in a sample (e.g., a cell sample or tissue sample), and / or imaging a Nav in the sample, comprising contacting the sample with acompound of the present disclosure (e.g., a compound of Formula (A), or a compound that is a radionuclide-containing analog of a compound listed in Table 1, or a compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof

[0102] Also disclosed herein are methods of imaging aNav, an organ (e.g., heart), a tissue, a tumor, or at least a portion of a central nervous system (CNS) (e.g., spinal cord), in a subject, comprising i) administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A), or a compound that is a radionuclide-containing analog of a compound listed in Table 1, or a compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and ii) imaging the subject with an imaging technique (e.g., positron emission tomography (PET)). The tissue, tumor, or portion of the CNS may express one or more isoforms of Nav. The tumor may be caused by or associated with a cancer disclosed herein (e.g., a tumor in the brain, caused by brain cancer).

[0103] Also disclosed herein are methods of monitoring treatment of a disease or disorder, or imaging a disease or disorder, in a subject (e.g., a disease associated with abnormal expression levels or abnormal activity of a Nav), comprising: i) imaging the subject with an imaging technique (e.g., PET); ii) administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A), or a compound that is a radionuclide-containing analog of a compound listed in Table 1, or a compound listed in Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; iii) imaging the subject with an imaging technique (e g., PET); and iv) comparing the image of step i) and the image of step iii).

[0104] A method of the present disclosure may comprise imaging an organ in a subject, such as the heart, or a portion thereof, or imaging the spinal cord in a subject, or a portion thereof, or a tumor in a subject, or a portion thereof.

[0105] The disease or disorder involved in a method of the present disclosure may be associated with abnormal expression levels of one or more Nav isoforms in a subject. The disease or disorder may be associated with reduced or increased total expression levels of one or more Nav isoforms in a subject. For example, the disease or disorder, or its treatment, may be associated with increased total expression levels of one or more Nav isoforms in a subject.

[0106] The disease or disorder, or its treatment, may be associated with abnormal activity of one or more Nav isoforms in a subject. The disease or disorder, or its treatment, may be associated with increased or decreased functional activity (e.g., opening frequency) of one or more Navisoforms in a subject. For example, the disease or disorder, or its treatment, may be associated with increased functional activity of one or more Nav isoforms in a subject.

[0107] More than one isoform of Nav can be involved in a method disclosed herein (e.g., (Navl.l, Navi.2, Navi.3, Navi.4, Navi.5, Navi.6, Navi.7, Navi.8, Navi.9). For example, a method disclosed herein may comprise blocking Navi .1. A method disclosed herein may comprise blocking Navi.2. A method disclosed herein may comprise blocking Navi.3. A method disclosed herein may comprise blocking Navi.4. A method disclosed herein may comprise blocking Navi.5. A method disclosed herein may comprise blocking Navi.6. A method disclosed herein may comprise blocking Navi.7. A method disclosed herein may comprise blocking Navi .8. A method disclosed herein may comprise blocking Navi .9. A method disclosed herein may comprise blocking Nax. Blocking can comprise binding and / or occluding an intracellular or extracellular pore opening of the Nav, thereby causing decreased conductivity of sodium ions through the blocked Nav compared to a Nav that is not blocked.

[0108] A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of one or more Navs in a subject. For example, a method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi .1. A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.2. A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.3. A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.4. A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.5. Amethod disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.6. A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.7. Amethod disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.8. A method disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Navi.9. Amethod disclosed herein may comprise evaluating the functional activity (e.g., opening frequency), and / or expression level, of Nax.

[0109] A disease or disorder involved in a method disclosed herein may be associated with abnormal expression levels (e.g., low or high expression levels) or abnormal activity (e.g., opening frequency) of one or more Navs in a subject, compared to Navs in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.1 in the subject, compared to the expression or activity of Navi.1 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.2 in the subject, compared to the expression or activity of Navi.2 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.3 in the subject, compared to the expression or activity of Navi.3 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi .4 in the subject, compared to the expression or activity of Navi .4 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.5 in the subject, compared to the expression or activity of Navi.5 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.6 in the subject, compared to the expression or activity of Navi.6 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.7 in the subject, compared to the expression or activity of Navi.7 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.8 in the subject, compared to the expression or activity of Navi.8 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Navi.9 in the subject, compared to the expression or activity of Navi.9 in a control subject. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression or activity of Nax in the subject, compared to the expression or activity of Nax in a control subject.

[0110] A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of a gene selected from SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN6A, SCN7A, SCN8A, SCN9A, SCN10A, and SCN11A. For example, a disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN1A. A disease or disorder involved in a method disclosed herein may be associated with abnormalexpression of SCN2A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN3A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN4A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN5A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN6A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN7A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN8A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN9A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN10A. A disease or disorder involved in a method disclosed herein may be associated with abnormal expression of SCN11A.

[0111] The disease or disorder may be a cardiovascular disease, neurological disease, or cancer. For example, the cardiovascular disease may be selected from the group consisting of cardiomyopathy, ventricular fibrillation, atrial fibrillation, tachycardia, myocardial infarction, long QT syndrome, Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, hypertension, myocarditis, and heart failure. The neurological disease can be selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, diabetic pain, cancer pain, and trigeminal neuralgia. The cancer can be selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, mesothelioma, uterine cancer, gastrointestinal cancer (e.g., esophageal cancer, colon cancer, rectal cancer, and stomach cancer), pancreatic cancer, bladder cancer, kidney cancer, liver cancer, head and neck cancer, brain cancer, thyroid cancer, skin cancer, prostate cancer, and testicular cancer.

[0112] A method disclosed herein that provides an image (e.g., a step of imaging the subject administered a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof) may further comprise comparing the image to a database of images, e.g., a database comprising images selected from the group consisting of images of the heart of one or more healthy subjects, images of the heart of one or more control subjects, images of the heart of one or more subjects determined to have about 10% to 90% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, forexample, about 10% to 90% risk, about 10% to 75% risk, about 10% to 50% risk, about 10% to40% risk, about 10% to 25% risk, about 25% to 90% risk, about 25% to 75% risk, about 25% to50% risk, about 25% to 40% risk, about 40% to 90% risk, about 40% to 75% risk, about 40% to50% risk, about 50% to 90% risk, about 50% to 75% risk, about 75% to 90% risk, images of the heart of one or more subjects determined to have a greater than about 5% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 10% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 20% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 30% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 40% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 50% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 60% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 70% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 80% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 90% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, images of the heart of one or more subjects determined to have a greater than about 95% risk of developing cardiovascular disease or symptoms associated with cardiovascular disease, or any combination thereof.

[0113] Exemplary imaging techniques that can be used in a method disclosed herein include, but are not limited to, magnetic resonance imaging (MRI), ultrasound imaging, tomographic imaging, positron emission tomography (PET) imaging, computed tomography (CT) (e.g.,single-photon emission CT), PET with CT imaging, and PET with MRI. For example, the imaging technique used in a method of the present disclosure can be PET imaging.

[0114] Methods of Preparation

[0115] It will be understood that the compounds of the present disclosure, including pharmaceutically acceptable salts thereof, can be prepared using known techniques, and can be synthesized according to any of numerous possible synthetic routes. The synthetic route described below is exemplary.

[0116] Compounds of the present disclosure can be prepared, for example, according to the procedure shown in Scheme 1, wherein variable groups R1, R1A, R4, and n are as defined herein for compounds of Formula (A), and LG is a leaving group (e.g., a tosylate group, a mesylate group, a halo, or the like). For example, as depicted in Scheme 1, precursor compound (Q-I) can be reacted with precursor compound (Q-II) in a suitable solvent (e.g., a polar aprotic solvent), optionally with a base (e.g., potassium carbonate), and optionally at an elevated temperature, to afford a compound of Formula (A). It will be understood that the compound of Formula (A) comprises at least one radionuclide (e.g.,18F), which may be present in either one of, or both of, the precursor compounds (Q-I) and (Q-II).

[0117] Scheme 1 An exemplary process for preparing a compound of the present disclosure.

[0118] Precursor compound (Q-I) may be a compound with the structure

[0119] Precursor compound (Q-II) may be a compound with the structurewhere x is an integer of 1 to 6, e.g., 1, 2, 3, 4, 5, or 6, and LG is a leaving group (e.g., mesyl or tosyl). For example, precursor compound (Q-II) may be a compound with the structureis preferred, the equivalent precursor compound will be used with the desired radionuclide instead of18F.

[0120] The optional base used in a method of preparation may be a carbonate base, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or ammonium carbonate. Alternatively, other types of bases could be used, such as amines (e.g., triethylamine), lithium hydroxide, sodium hydroxide, potassium hydroxide, alkoxides (e.g., lithium, sodium, or potassium salts of methyl, ethyl and t-butyl oxides), metal amides (e.g., sodium amide, potassium amide, or lithium amide), metal hydrides (e.g., sodium hydride, potassium hydride, or lithium hydride), metal dialkylamides (e g., lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, trimethylsilyl and cyclohexyl substituted amides), or arylamines.

[0121] Optionally, a synthetic method disclosed herein can be performed at an elevated temperature, such as a temperature of about 50° C to about 150° C, for example, about 50° C to about 130° C, about 50° C to about 110° C, about 50° C to about 90° C, about 50° C to about 70° C, about 70° C to about 150° C, about 70° C to about 130° C, about 70° C to about 110° C, about 70° C to about 90° C, about 90° C to about 150° C, about 90° C to about 130° C, about 90° C to about 110° C, about 110° C to about 150° C, about 110° C to about 130° C, or about 110° C to about 130° C.

[0122] The synthetic processes disclosed herein may be performed in a solvent, such as a polar aprotic solvent or a polar protic solvent. Exemplary polar aprotic solvents include, but are not limited to, tetrahydrofuran (THF), ethyl acetate (EtOAc) acetone, dimethylformamide (DMF),acetonitrile, and dimethyl sulfoxide (DMSO). Exemplary polar protic solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, iso-propanol, butanol, and the like), nitromethane, and water.

[0123] Additional synthetic methods for incorporating radionuclides into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize other methods applicable for preparing the radiolabeled compounds or the present disclosure, and pharmaceutically acceptable salts thereof.EXEMPLIFICATION

[0124] Example 1. Preparation of exemplary Compound A2-10

[0125] A-(2,6-Dimethylphenyl)piperidine-2-carboxamide (2 mmol), or a salt thereof, will be dissolved in DMF, and l-((4-(fluoro-18F)butyl)sulfonyl)-4-methylbenzene (2.4 mmol) will be added to the mixture, followed by potassium carbonate (4.2 mmol). The resulting mixture will be stirred at 90° C, until such time as the starting material has been substantially converted to product, e.g., as determined by thin layer chromatography, e.g., for a period of 3-18 hours. The mixture will then be cooled to room temperature and worked up, e.g., by diluting with ethyl acetate and washing the organic phase with a IM sodium hydroxide solution, followed by brine, and collecting the organic layer and drying it using sodium sulfate, and concentrating the dried organic layer using rotary evaporation. The residue will be purified, e.g., using flash chromatography and / or HPLC, and characterized, e.g., by nuclear magnetic resonance (NMR) and / or mass spectrometry, or a combination thereof.

[0126] Example 2. Ex vivo autoradiography.

[0127] Sections of tissue, e.g., heart tissue (myocardium) or tumor, from an animal subject (e.g., mouse, rat, non-human primate, or human) will be prepared using a -20° C cryostat and thawmounted onto gelatin-coated slides. The slides will be stored at -20° C, and immediately prior touse the slides will be incubated at room temperature in a bath containing 10 mM Tris-HCl. Approximately 100 Ci of the test compound (e.g., Compound A2-10 prepared in Example 1) will be added to the bath and incubated for 15 minutes at room temperature. The slides will then be dipped 3* in a fresh bath containing 10 mM Tris-HCl, and subsequently washed for 1 min in an additional bath of 10 mM Tris-HCl. Slides will be dried and then exposed to a multi sensitive phosphorscreen developed using, for example, a Cyclone Plus phosphorimager (PerkinElmer) and the resulting parent image will be evaluated using, for example, ImageJ software (NIH), and F-18 autoradiography. The extent of compound binding and its association and dissociation time course will be measured.

[0128] Competition experiments will also be carried out by incubating the slide in a bath containing 10 mM Tris-HCl and the competition compound, prior to exposure to the radiolabeled compound. The competition compound can be a non-radiolabeled counterpart of the test compound, e g., a compound shown in Table 1 that is not derivatized to comprise a radionuclide).

[0129] Example 3. PET studies in animal models.

[0130] The radiolabeled compound of Example 1 will be purified by semipreparative HPLC, and then diluted with 10*PBS buffer and filtered through a sterile 22 pm filter into sterile injection vials, to provide an injectable stock solution that may be diluted with sterile saline as needed to adjust for the desired volume and amount of radioactivity. For example, concentrations of 2 mCi / mL and volumes of 1 mL / kg will be used for studies in rats (e g., 0.5 mCi in 0.25 mL for a 250 g animal). For non-human primate imaging, doses of about 5 mCi will be injected in volumes of 4-6 mL.

[0131] Studies in Rats

[0132] Sprague-Dawley rats will be anesthetized and catheterized for intravenous injection of the test compound, and placed in a PET / CT / SPECT scanner (e.g., Triumph Trimodality by Gamma Medica, Northridge, Calif., or a MicroPET P4 scanner). Rats will then be injected with saline about 5 minutes before the start of PET acquisition and injection of the test compound (e.g., Compound A2-10 of Example 1). Dynamic PET acquisition will be performed over 45 min, followed by computed tomography (CT) for anatomic coregistration and attenuation correction. PET data will be reconstructed, e.g., using a 3D-MLEM method resulting in a full width at half-maximum (fwhm) resolution of 1 mm. Reconstructed images will be exported fromthe scanner, e.g., in DICOM format along with an anatomic CT for rodent studies, and will be imported to AMIDE and Gaussian fdtered (kernel size=15, fwhm=1.5 mm). Regions of interest (ROIs) will be drawn manually at the lung and myocardium guided by high-resolution CT structural images and summed PET data. Time-activity-curves (TACs) will be exported in terms of decay corrected activity per unit volume at specified time points with gradually increasing intervals. In vivo mPET imaging experiments in healthy rats will be used to determine the extent of specific binding and the signal to background ratio for comparison to autoradiography.

[0133] A single bolus injection of the test compound (e.g., A2-10 of Example 1) is expected to provide a full representation of the target organ of interest (e.g., heart) or tumor, or other parameter. Baseline signals will be obtained to show the time-course of radiotracer binding, which may be correlated to the ex vivo experiments described in Example 2. Comparisons of the target organ (e.g., heart) will be made to other organs (e.g., lung) to assess clearance of the radiolabeled compound from the blood pool and signal to background ratio. Specificity of the signal will be evaluated by intravenously administering to the rat a non-radiolab eled NaV binder, e.g., a compound of Table 1 that has not been modified to incorporate a radionuclide, e.g., nonradiolabeled bupivacaine, 5 minutes prior to injection of the radiolabeled compound, to preoccupy potential binding sites. The ratio of target organ (e.g., heart) to non-target organ (e.g., lung) signal will be used as a measurement to assess the signal to background ratio as a function of drug occupancy. Signal will also be compared to vehicle injection.

[0134] Bolus-infusion experiments will also be performed to investigate the radiolabeled compound signal at equilibrium conditions, and non-radiolabeled compound challenges will be performed during the dynamic scan. For example, applying an intravenous bolus of -150 pCi Compound A2-10, followed by a constant infusion of -300 pCi through the same vein over the course of 60 min is expected to provide a stable baseline signal after 20 min. Injection of vehicle through an additional i.v. line is not expected to provide a change in signal. However, injections of a non-radiolabeled compound (e.g., a compound of Table 1 that has not been modified to incorporate a radionuclide, e.g., non-radiolabled bupivacaine) are expected to reduce the signal in a dose-dependent manner.

[0135] Studies in Non-Human Primates.

[0136] Baboons (Papio anubis) will be fasted for 12 h, then anesthetized and endotracheally intubated. The baboons will also be catheterized for injection of the radiolabeled compound(e g., Compound A2-10). Vital signs, including heart rate, respiration rate, blood pressure, O2 saturation, and end tidal CO2, will be monitored continuously. Simultaneous PET / MR data will be acquired, e.g., using a Siemens Biograph mMR system (Siemens Healthcare, Erlangen, Germany). Each animal will undergo a baseline and a blocking scan on two separate days. MR body imaging will be performed. PET data will be acquired dynamically for 60 min (bolus injection of Compound A2-10) or 90 min (bolus / infusion of Compound A2-10) after intravenous administration of the test compound (5.0 mCi bolus or 4 mCi bolus + 4 mCi infusion). PET data will be stored in list mode, and reconstruction will be performed, e.g., using a 3D-OSEM method with detector efficiency, decay, dead time, attenuation, and scatter corrections applied. The extent of signal specificity and background clearance will be measured.

[0137] Single bolus injection of the radiolabeled compound (e.g., Compound A2- 10) in a healthy baboon is expected to provide a full representation of the target organ of interest (e.g., heart) and at early time points (e.g., 30-150 s), a thoracic PET scan is expected to show the blood-filled heart and lungs. After 2-3 min, the blood background is expected to have cleared and the left myocardium should appear as a strong signal. Differences between the right and left myocardial signals in the same animal will be used as an indicator for the expected change in radiolabeled compound signal that may be observed in cardiomyopathies.

[0138] Abolus+infusion paradigm will be carried out by injecting a baboon with a bolus of 4 mCi test compound (Compound A2-10), followed by continuous administration of 4 mCi over 90 min scan. A dose of a non-radiolabled Nav-blocking compound (5 mg / kg), e.g., one of the compounds of Table 1 not modified to include a radionuclide, e.g., non-radiolabeled bupivacaine, will be administered (through a second i.v. line) after equilibrium conditions are reached. Within 10 minutes, the myocardial signal is expected to reach the background level of the ventricle. The overall time-course of binding in both bolus and bolus+infusion experiments will be longer in baboons than in rats, but scan-times of 20-30 min are expected to be sufficient to capture the majority binding kinetics which is representative for human imaging, in particular with the ventricle or the lungs as an internal quantitative reference.

Claims

We claim:

1. A compound of Formula (A):or a pharmaceutically acceptable salt thereof, wherein: each R1is independently halo, (C1-C6)-alkyl, or (C1-C6)-haloalkyl;R1Ais hydrogen or a radionuclide,R4is (C1-C6)-alkyl, (C1-C6)-heteroalkyl, or (C1-C6)-haloalkyl; and n is an integer of 1-5; wherein the compound of Formula (A) comprises at least one radionuclide (e.g.,18F).

2. The compound of claim 1, wherein each R1is independently (C1-C6)-alkyl (e.g., methyl).

3. The compound of claim 1 or 2, wherein R4is (C1-C6)-haloalkyl.

4. The compound of any one of the preceding claims, wherein n is an integer of 2.

5. The compound of any one of the preceding claims, wherein R1Ais hydrogen.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofpharmaceutically acceptable salts thereof, with the proviso that the compound comprises a radionuclide that is covalently bonded to a substitutable atom (e.g., a substitutable carbon atom or heteroatom) of the compound.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is selected from the group consisting ofnC,13N,13O,18F,34mCl,38K,45Ti,51Mn,52mMn,52Fe,55Co,60Cu,61Cu,62Cu,64Cu,66Ga,67Ga,68Ga,71As,72As,74AS,75Br,76Br,82Rb,86Y,89Zr,90Nb,94mTc, "mTc,110mIn,inIn,118Sb,120I,121I,122I,123I,124I,124I,131I, and2O1T1.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is selected from the group consisting of18F,34mCl,73Br,76Br, 120J, i2ij, i22j, 123J, i24j, i24j,ancj i3ij,eg ,wherejnthe radionuclide is18F.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofpharmaceutically acceptable salts thereof.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofpharmaceutically acceptable salts thereof.

11. The compound of any one of the preceding claims, wherein the compound ispharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, optionally comprising one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition of claim 12, wherein the compound ispharmaceutically acceptable salt thereof.

14. A method of blocking a voltage gated sodium channel in a subject, comprising administering to the subject a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12.

15. The method of claim 14, wherein the compound ipharmaceutically acceptable salt thereof.

16. A method of imaging a voltage gated sodium channel, an organ (e.g., heart), a tissue, a tumor, or at least a portion of a central nervous system (e.g., spinal cord), in a subject, comprising: i) administering to the subject a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12; and ii) imaging the subject with an imaging technique (e.g., positron emission tomography (PET)).

17. The method of claim 16, wherein the compound ipharmaceutically acceptable salt thereof18. A method of monitoring treatment of a disease or disorder, or imaging a disease or disorder, in a subject (e.g., a disease or disorder associated with abnormal expression levels or abnormal activity of a voltage gated sodium channel), comprising: i) imaging the subject with an imaging technique (e.g., PET); ii) administering to the subject a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12; iii) imaging the subject with an imaging technique (e.g., positron emission tomography); and iv) comparing the image of step i) and the image of step iii).

19. The method of claim 18, wherein the compound ipharmaceutically acceptable salt thereof20. The method of claim 18 or 19, wherein the disease or disorder is selected from the group consisting of cardiovascular disease, neurological disease, and cancer.

21. The method of claim 20, wherein the cardiovascular disease is selected from the group consisting of cardiomyopathy, ventricular fibrillation, atrial fibrillation, tachycardia, myocardial infarction, long QT syndrome, Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, hypertension, myocarditis, and heart failure.

22. The method of claim 20, wherein the neurological disease is selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, diabetic pain, cancer pain, and trigeminal neuralgia.

23. The method of claim 20, wherein the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, mesothelioma, uterine cancer, gastrointestinal cancer (e.g., esophageal cancer, colon cancer, rectal cancer, and stomach cancer), pancreatic cancer, bladder cancer, kidney cancer, liver cancer, head and neck cancer, brain cancer, thyroid cancer, skin cancer, prostate cancer, and testicular cancer.

24. The method of claim 20, wherein the cancer is breast cancer, prostate cancer, lung cancer, or brain cancer.

25. A process of preparing a compound of Formula (A):or a pharmaceutically acceptable salt thereof, comprising: reacting a compound of Formula (Q-I):with a compound of Formula (Q-II) :LG R4(Q-II), in a suitable solvent (e g., a polar aprotic solvent), optionally with a base (e.g., potassium carbonate), and optionally at an elevated temperature, wherein R1, R1A, R4, and n are as defined in claim 1, and LG denotes a leaving group (e g., mesyl, tosyl, Br, or I), and wherein the compound of Formula (A) comprises at least one radionuclide (e.g.,18F).

26. The process of claim 25, wherein the compound of Formula (or a pharmaceutically acceptable salt thereof.

27. The process of claim 25 or 26, wherein the compound of Formula (Q-II) comprises a radionuclide (e.g.,18F).

28. The process of any one of claim 25-27, wherein the compound of Formula (Q-II) comprises the structure:, or a pharmaceutically acceptable salt thereof, whereLG denotes a leaving group (e.g., mesyl, tosyl, Br, or I).

29. The process of any one of claims 25-28, wherein the compound of Formula (Q-I) comprises the structure:pharmaceutically acceptable salt thereof.

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