Methods of treating epilepsy using the same

Abstract

To provide a method for treating or preventing seizures, epilepsy, or epilepsy-related syndrome in a subject.SOLUTION: The present invention provides a method comprising administering to the subject a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 896,116, filed September 5, 2019, which is incorporated herein by reference in its entirety.

[0002] Embodiments disclosed herein relate, in part, to compounds, or pharmaceutically acceptable salts thereof, for modulating S1P1 receptor activity, and / or methods for treating and / or preventing epilepsy, epilepsy-related syndromes, and the like, as described herein. [Background technology]

[0003] Epilepsy is a widespread chronic neurological disorder affecting 2.2 million people in the United States and over 65 million people worldwide (Hirtz et al., 2007). Currently available antiepileptic drugs suffer from a variety of side effects, and there is a significant group of patients, accounting for approximately 20-30% of cases, who are resistant to currently available treatments. Thus, there is a need for new compounds and compositions for treating and / or preventing epilepsy. The compounds and compositions described herein meet these and other needs. Summary of the Invention

[0004] Methods for treating or preventing a seizure, epilepsy, or epilepsy-related syndrome, such as those described herein, in a subject described herein are provided. In some embodiments, the method comprises administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound described herein partially modulates the activity of the S1P1 receptor. In some embodiments, the method comprises administering to the subject one or more compounds described herein.

[0005] In some embodiments, there is provided a method of treating or preventing seizures, epilepsy, or epilepsy-related syndromes, etc., described herein in a subject, the method comprising administering to the subject a compound of Formula I or Formula II [ka] or a pharmaceutically acceptable salt thereof, wherein AA, B1, B2, B3, B4, D1, V, R 30 , and R 31 are as provided herein and may, for example, be selected from each group of chemical moieties described herein. Processes for preparing these compounds are also provided.

[0006] In some embodiments, methods are provided for treating or preventing seizures, epilepsy, or epilepsy-related syndromes, etc., described herein in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising one or more compounds described herein, which may also include a pharmaceutically acceptable carrier. In some embodiments, the compounds described herein may be provided in any form, such as a solid or a solution (e.g., an aqueous solution), as described herein. The compounds described in can be obtained and used, for example, alone or in lyophilized form together with suitable additives. DETAILED DESCRIPTION OF THE INVENTION

[0007] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0008] As used herein, the terms "a" or "an" mean "at least one" or "one or more" unless the context clearly indicates otherwise.

[0009] As used herein, the term "about" means that a numerical value is approximate and that small variations do not significantly affect the practice of the disclosed embodiments. When numerical limitations are used, unless the context dictates otherwise, "about" means that the numerical value can vary by ±10% and remain within the range of the disclosed embodiments.

[0010] As used herein, the term "acylamino" refers to an amino group substituted with an acyl group (e.g., -OC(=O)-H or -OC(=O)-alkyl). Examples of acylamino are -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" refers to a lower acyl group (e.g., -OC(=O)-H or -OC(=O)-C 1-6 An example of lower acylamino is -NHC(=O)H or -NHC(=O)CH3.

[0011] As used herein, the term "alkenyl" means a straight or branched chain alkyl group having one or more double carbon-carbon bonds and 2 to 20 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In some embodiments, the alkenyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0012] As used herein, the terms "antiepileptic drug(s)" (also commonly known as anticonvulsants or antiseizure drugs) or "AED(s)" generally encompass pharmacological agents that reduce the frequency or likelihood of seizures. There are many drug classes that comprise the set of antiepileptic drugs (AEDs), and many different mechanisms of action are represented. For example, some drugs are thought to increase the seizure threshold, thereby making the brain less likely to initiate a seizure. Other drugs tend to slow the spread of neuronal firing activity, preventing the propagation or spread of seizure activity. Some AEDs, such as benzodiazepines, act through GABA receptors to globally suppress neural activity. However, other AEDs may act by modulating neuronal calcium channels, neuronal potassium channels, neuronal NMDA channels, neuronal AMPA channels, neuronal metabotropic channels, neuronal sodium channels, and / or neuronal kainite channels. As used herein, the phrases "antiepileptic drug that blocks sodium channels" and "sodium channel-blocking AEDs" refer to antiepileptic drugs that block sodium channels. The sodium channel-blocking AED may be selected from the group consisting of carbamazepine, clonazepam, eslicarbazepine, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, vigabatrin, valproate (valproic acid), and zonisamide, as well as other existing or new AEDs that may be identified in the future to block sodium channels.

[0013] "Alkoxy", "phenyloxy", "benzoxy" and "pyrimidinyloxy" The term "alkoxy" refers to an alkyl, phenyl, benzyl, or pyrimidinyl group, each optionally substituted and attached through an oxygen atom. For example, the term "alkoxy" refers to a straight or branched chain -O-alkyl group of 1 to 20 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain is 1 to 10 carbon atoms in length, 1 to 8 carbon atoms in length, 1 to 6 carbon atoms in length, 1 to 4 carbon atoms in length, 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0014] As used herein, the term "alkyl" refers to a saturated hydrocarbon group that is straight-chained or branched. The alkyl group can contain 1 to 20, 2 to 20, 1 to 10, 2 to 10, 1 to 8, 2 to 8, 1 to 6, 2 to 6, 1 to 4, 2 to 4, 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1-propyl ... 2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and the like.

[0015] As used herein, the term "arylamino" refers to an amino group substituted with an alkyl group having 1 to 6 carbon atoms. An example of an alkylamino is -NHCH2CH3.

[0016] As used herein, the terms "alkylene" or "alkylenyl" refer to a divalent alkyl linking group. Examples of alkylene (or alkylenyl) groups are methylene and methylenenyl (-CH-).

[0017] As used herein, the term "alkylthio" refers to an -S-alkyl group having 1 to 6 carbon atoms. An example of an alkylthio group is -SCH2CH3.

[0018] As used herein, the term "alkynyl" means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2 to 20 carbon atoms, including, but not limited to, acetylene, 1-propylene, 2-propylene, etc. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0019] As used herein, the term "amidino" means -C(=NH)NH2.

[0020] As used herein, the term "amino" means --NH.sub.2.

[0021] As used herein, the term "aminoalkoxy" refers to an alkoxy group substituted with an amino group. An example of an aminoalkoxy is -OCH2CH2NH2.

[0022] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group. It refers to an alkyl group. An example of an aminoalkyl is -CH2CH2NH2.

[0023] As used herein, the term "aminosulfonyl" means -S(=O)2NH2.

[0024] As used herein, the term "aminoalkylthio" refers to an alkylthio group substituted with an amino group. An example of an aminoalkylthio is -SCH2CH2NH2.

[0025] As used herein, the term "amphiphilic" refers to a three-dimensional structure having distinct hydrophobic and hydrophilic regions. Amphiphilic compounds preferably have both hydrophobic and hydrophilic elements present.

[0026] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.

[0027] As used herein, the terms "antagonize" or "antagonizing" mean to reduce or completely eliminate the effect, such as activity, of the S1P1 receptor.

[0028] As used herein, the phrase "anti-receptor effective amount" of a compound can be measured by the anti-receptor efficacy of the compound. In some embodiments, an anti-receptor effective amount inhibits receptor activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. In some embodiments, an "anti-receptor effective amount" is also a "therapeutically effective amount" whereby the compound reduces, eliminates, or modulates at least one effect of the S1P1 receptor. In some embodiments, the effect is a beta-arrestin effect. In some embodiments, the effect is a G protein-mediated effect.

[0029] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon. In some embodiments, an aryl group has 6 to 20 carbon atoms or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include, but are not limited to, the following: [ka] [ka]

[0030] As used herein, the term "arylalkyl" refers to an aryl-substituted C 1-6 It means alkyl.

[0031] As used herein, the term "arylamino" refers to an amino group substituted with an aryl group. An example of an arylamino is -NH (phenyl).

[0032] As used herein, the term "arylene" means an aryl linking group, ie, an aryl group that links one group to another group within a molecule.

[0033] As used herein, the term "carbamoyl" means -C(=O)-NH2.

[0034] As used herein, the term "carbocycle" means a 5- or 6-membered, saturated or unsaturated cyclic ring that optionally contains an O, S, or N atom as part of the ring. Examples of heterocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the above heterocycles.

[0035] As used herein, the term "carrier" refers to a diluent, adjuvant, or excipient with which a compound is administered. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Pharmaceutical carriers can also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary substances, stabilizers, thickeners, lubricants, and coloring agents can be used.

[0036] As used herein, the term "compound" refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0037] As used herein, the term "complex partial seizure" refers to one of the symptoms associated with intractable epilepsy, a partial seizure accompanied by impaired consciousness, similar to seizures traditionally referred to as psychomotor seizures or seizures associated with temporal lobe epilepsy. The International Classification of Epilepsy (1981) defines a complex partial seizure as a seizure accompanied by impaired consciousness, characterized by unilateral or bilateral electroencephalographic discharges, diffuse or due to lesions in the temporal or frontal regions.

[0038] As used herein, the terms "comprising" (and any form of "comprising", such as "comprise", "comprises", and "comprised"), "having" (and any form of "having", such as "have" and "has"), "including" (and any form of "including", such as "includes" and "include"), or "containing" (and any form of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0039] As used herein, the term "contacting" refers to bringing two elements together in an in vitro system or in vivo system. For example, "contacting" an S1P1 receptor compound with an S1P1 receptor in an individual, patient, or cell includes administering the compound to an individual or patient, such as a human, and introducing the compound into a sample containing, for example, a cell preparation or purified preparation containing the S1P1 receptor.

[0040] As used herein, the term "cortical epilepsy" refers to a type of intractable epilepsy, which has a lesion in the cerebral cortex and is classified as a localization-related (focal) epilepsy and a symptomatic epilepsy belonging to a syndrome in the International Classification of Epilepsy. In the International Classification of Epilepsy, seizures associated with cortical epilepsy are classified as simple partial seizures, which are partial seizures without reduced consciousness. Therefore, electroencephalograms (EEGs) taken during seizures associated with cortical epilepsy (not always recorded on the scalp) show focal contralateral discharges from the corresponding cortical area. Cortical epilepsy is classified as temporal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy.

[0041] As used herein, the term "cyano" means --CN.

[0042] As used herein, the term "cycloalkyl" refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl, alkenyl, and alkynyl groups, containing up to 20 ring-forming carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic ring systems, including fused, bridged, and spirocyclic ring systems. In some embodiments, polycyclic ring systems contain 2, 3, or 4 fused rings. Cycloalkyl groups can contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused (having a common bond) to the cycloalkyl ring, e.g., benzo derivatives such as pentane, pentene, hexane, or thienyl derivatives (e.g., 2,3-dihydro-1H-inden-1-yl, or 1H-inden-2(3H)-on-1-yl).

[0043] As used herein, the term "cycloalkylalkyl" refers to a C substituted with cycloalkyl. 1-6 It means alkyl.

[0044] As used herein, the term "dialkylamino" means an amino group substituted with two alkyl groups, each having from 1 to 6 carbon atoms.

[0045] As used herein, the term "diazamino" means -N(NH2)2.

[0046] As used herein, the terms "epilepsy," "epileptic seizure," and "epileptic syndrome" are meant to include all known types of epileptic seizures and syndromes, including simple, complex, and partial seizures that progress to generalized tonic-clonic convulsions, generalized seizures, both convulsive and non-convulsive, and unclassified epileptic seizures.

[0047] As used herein, the term "facially amphiphilic" or "facially amphiphilic" refers to a compound having polar (hydrophilic) and non-polar (hydrophobic) side chains that adopt a conformation(s) that results in the separation of the polar and non-polar side chains onto opposite sides or distinct regions of the structure or molecule.

[0048] As used herein, the term "guanidino" means -NH(=NH)NH2.

[0049] As used herein, the term "halo" means a halogen radical, including, but not limited to, fluoro, chloro, bromo, and iodo.

[0050] As used herein, the term "haloalkoxy" means an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0051] As used herein, the term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1-6 It refers to an alkyl group. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.

[0052] As used herein, the term "heteroaryl" refers to an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, heteroaryl The heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which is independently sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, 3 to 6 ring-forming atoms, or 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group has 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (e.g., indol-3-yl), pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and pyranyl. , oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolidinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl groups and the like. Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.

[0053] As used herein, the term "heteroarylalkyl" refers to a C substituted with a heteroaryl group. 1-6 It means an alkyl group.

[0054] As used herein, the term "heteroarylamino" refers to an amino group substituted with a heteroaryl group. An example of a heteroarylamino is -NH-(2-pyridyl).

[0055] As used herein, the term "heteroaryl" refers to a heteroaryl linking group, i.e., a heteroaryl group that links one group to another group within a molecule.

[0056] As used herein, the term "heterocycle" or "heterocyclic ring" refers to a 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated and consists of carbon atoms and one to three heteroatoms selected from N, O, and S, where the N and S heteroatoms may be optionally oxidized and the N heteroatom may be optionally quaternized, including any bicyclic group in which any of the above-defined heterocycles is fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur in combination with one or two nitrogen atoms. The heterocycle may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, iso-, thiazolyl ... Examples of thiazolidinyl include, but are not limited to, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

[0057] As used herein, the term "heterocycloalkyl" refers to a non-aromatic heterocycle having up to 20 ring-forming atoms, including cyclized alkyl, alkenyl, and alkynyl groups, in which one or more of the ring-forming carbon atoms is replaced by a heteroatom, such as an O, N, or S atom. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spiro). In some embodiments, heterocycloalkyl groups have 1 to 20 carbon atoms, or 3 to 20 carbon atoms. In some embodiments, heterocycloalkyl groups have 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, etc. Furthermore, ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally substituted with oxo or sulfido. For example, ring-forming S atoms can be substituted with one or two oxo atoms (forming S(O) or S(O)2). In another example, ring-forming C atoms can be substituted with oxo (forming carbonyl).The definition of heterocycloalkyl also includes moieties having one or more aromatic rings fused (having a common bond) to a non-aromatic heterocycle, including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally substituted with oxo or sulfido.

[0058] As used herein, the term "heterocycloalkylalkyl" refers to a C substituted with heterocycloalkyl. 1-6 refers to alkyl.

[0059] As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0060] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl group substituted with a hydroxyl group. Examples of hydroxylalkyl include, but are not limited to, -CHOH and -CHCHOH.

[0061] As used herein, the terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, such as humans.

[0062] As used herein, the phrase "inhibitory activity" of an enzyme or receptor activity, etc. means reducing the activity of an enzyme or receptor, such as an S1P1 receptor, by any measurable amount.

[0063] As used herein, the phrase "activating activity," such as enzyme activity or receptor activity, means increasing the activity of an enzyme or receptor, such as an S1P1 receptor, by any measurable amount.

[0064] As used herein, the phrase "in need thereof" means that an animal or mammal has been identified as having a need for a particular method or treatment. In some embodiments, identification can be by any diagnostic means. The animal or mammal can be in need of any of the methods and treatments described herein. In some embodiments, the animal or mammal is in or will move to an environment where a particular disease, disorder, or condition is prevalent. In some embodiments, a subject or patient "in need thereof" is a subject who has been diagnosed with or is suspected of having epilepsy or an epilepsy syndrome. In some embodiments, a subject or patient "in need thereof" has suffered a seizure. In some embodiments, a subject or patient "in need thereof" is currently suffering from a seizure when a compound or composition provided herein is administered or used in the methods described herein.

[0065] As used herein, the phrase "in situ gelling" is meant to encompass not only low viscosity liquids that form gels upon contact with the eye or lacrimal fluid outside the eye, but also more viscous liquids, such as semi-fluid and thixotropic gels, that exhibit substantially increased viscosity or gel stiffness upon administration to the eye.

[0066] As used herein, the phrase "an integer between X and Y" means any integer, including the endpoints. For example, the phrase "an integer between X and Y" means 1, 2, 3, 4, or 5.

[0067] As used herein, the phrase "refractory epilepsy" refers to epilepsy or related seizures that correspond to the following four types of epilepsy or related seizures: (1) Refractory epilepsy, where the associated seizures cannot be controlled through conventional pharmaceutical treatment (Masako WATANABE, et al., Igaku-no Ayumi, 183(1):103-108, 1997), (2) epilepsies corresponding to the following (a) to (c): (a) localization-related epilepsies such as temporal lobe epilepsy and cortical epilepsy, (b) generalized epilepsy and myoclonic epilepsy, and (c) undetermined epilepsies and epilepsy syndromes, such as severe myoclonic epilepsy, whether localized or generalized, (3) seizures related to the above-mentioned intractable epilepsies, including tonic seizures, tonic-clonic seizures, atypical absence seizures, atonic seizures, myoclonic seizures, clonic seizures, simple partial seizures, complex partial seizures, and secondarily generalized seizures, and (4) epilepsies such as epilepsy after brain surgery, traumatic epilepsy, and recurrent epilepsy after epilepsy surgery. Characteristics of refractory epilepsy include a high incidence of partial seizures followed by generalized seizures (especially temporal lobe epilepsy), a high incidence of symptomatic epilepsy due to organic brain lesions, and a prolonged lack of treatment from onset to specialist consultation, as well as a high incidence of seizures and a high incidence of status epilepticus in the medical history. The temporal lobe is likely the brain region responsible for refractory epilepsy. Epilepsy has been shown to become more refractory by changing its nature and evolving with repeated acquired seizures. Refractory epilepsy is classified into three clinical types: (a) localization-related epilepsies and syndromes, including temporal lobe epilepsy, frontal lobe epilepsy, and multilobe epilepsy, where temporal lobe epilepsy and frontal lobe epilepsy are typical examples of refractory epilepsy and multilobe epilepsy is thought to be caused by more than one lobe; and (b) generalized epilepsies and syndromes, including myoclonic epilepsy. (c) undetermined epilepsies and syndromes, including severe myoclonic epilepsy, which frequently occur and exhibit various seizure types, including tonic-clonic seizures, whether localized or generalized, and often lead to status epilepticus. Specific treatment by an epileptologist is strongly required (Masako WATANABE, et al., Igakuno Ayumi, 183(1):103-108, 1997). As used herein, the term "isolated" means that the compound described herein is separated from other components of either (a) a natural source, such as a plant or cell, or (b) a synthetic organic chemical reaction mixture, such as by conventional techniques.

[0068] As used herein, the term "mammal" means a rodent (i.e., a mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0069] As used herein, the term "N-alkyl" refers to an alkyl chain substituted with an amine group. Non-limiting examples include: [ka] Examples include, but are not limited to, alkyl groups. The alkyl chain can be linear, branched, cyclic, or any combination thereof. In some embodiments, the alkyl contains 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbons.

[0070] As used herein, the term "nitro" means --NO.sub.2.

[0071] As used herein, the term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiophene is an example of a 5-membered heteroaryl ring.

[0072] As used herein, the phrase "ophthalmically acceptable" means having no lasting adverse effects on the treated eye or its function, or on the general health of the treated subject. However, it is recognized that transient effects, such as mild irritation or a "stinging" sensation, are common with topical ophthalmic administration of drugs, and the presence of such transient effects is not inconsistent with the composition, formulation, or ingredient (e.g., excipient) in question being "ophthalmically acceptable" as defined herein.

[0073] As used herein, the phrase "optionally substituted" means that substitution is optional and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the specified atom or moiety can be replaced with a selection from the specified substituents, as long as the normal valence of the specified atom or moiety is not exceeded and the substitution results in a stable compound. For example, if a methyl group is optionally substituted, three hydrogen atoms on the carbon atom can be replaced with substituents.

[0074] As used herein, the phrase "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals. In some embodiments, "pharmaceutically acceptable" means: By "approved" is meant approved by a federal or state government regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, or more specifically in humans.

[0075] In some embodiments, the salts of the compounds described herein are pharmaceutically acceptable salts thereof. As used herein, the phrase "pharmaceutically acceptable salt(s)" includes, but is not limited to, salts of acidic or basic groups. Basic compounds can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include non-toxic acid addition salts, i.e., sulfate, thiosulfate, citrate, maleate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfite, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, acid tartrate, ascorbate, succinate, maleate, and gentisic acid. Those that form salts containing pharmacologically acceptable anions, including, but not limited to, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsidisylate, tosylate, besylate, orthophosphate, trifluoroacetate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Compounds containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts, and particularly calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. The present embodiments also include quaternary ammonium salts of the compounds described herein, wherein the compounds have one or more tertiary amine moieties.

[0076] As used herein, the term "phenyl" means -C6H5. A phenyl group can be unsubstituted or substituted with one, two, or three suitable substituents.

[0077] As used herein, the term "prodrug" means a derivative of a known direct-acting drug, which has enhanced delivery properties and therapeutic value compared to the drug, and which is converted to the active drug by an enzymatic or chemical process.

[0078] As used herein, the term "purified" means that, when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% by weight of the compound described herein.

[0079] As used herein, the phrase "quaternary ammonium salt" refers to derivatives of the disclosed compounds having one or more tertiary amine moieties, where at least one of the tertiary amine moieties in the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation (the cation can be, for example, Cl). - , CH3COO - , and CF3COO - (This is counterbalanced by anions such as

[0080] As used herein, the term "semicarbazone" means =NNHC(=O)NH2.

[0081] As used herein, the term "solubilizer" refers to a drug that is dissolved in a micellar solution or in a true solubilizer. It means an agent that results in the formation of a solution.

[0082] As used herein, the term "secondary generalized seizure" refers to one of the symptoms associated with intractable epilepsy, a type of partial seizure that exhibits a clinical syndrome and electroencephalographic characteristics observed as neuronal excitation in a limited area of ​​one cerebral hemisphere, indicating the onset of a seizure. Secondary generalized seizures begin as simple partial seizures (without impaired consciousness) or complex partial seizures (with impaired consciousness) and develop into generalized convulsions induced through secondary generalized seizures. Its main symptom is convulsions, such as tonic-clonic, tonic, or clonic seizures.

[0083] As used herein, the term "solution / suspension" means a liquid composition in which a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form in suspension in a liquid matrix.

[0084] As used herein, the term "temporal lobe epilepsy" refers to a type of intractable epilepsy with a seizure focus in the temporal lobe. It is classified under the category of symptomatic and localization-related epilepsies, which also includes frontal lobe epilepsy, parietal lobe epilepsy, and occipital lobe epilepsy, based on the International Classification of Epilepsy. Temporal lobe epilepsy syndromes vary according to the location of the lesion and the type of seizure propagation, given that the temporal lobe has a complex anatomical structure, including the neocortex, anisocortex, and paleocortex. Temporal lobe epilepsy primarily causes clinically observed complex partial seizures, previously defined as psychomotor seizures, as well as simple partial seizures, secondarily generalized seizures, and combinations thereof. Simple partial seizures include autonomic and psychiatric symptoms, as well as sensory symptoms such as olfactory, auditory, or visual disturbances, and are sometimes accompanied by the experience of déjà vu or jamaias. Complex partial seizures often manifest as motor arrest followed by mechanical movements of the feeding function. They are divided into amygdala-hippocampal seizures and lateral temporal lobe seizures according to their localization. In temporal lobe epilepsy, 70–80% of seizures are hippocampal, characterized by aura, motor arrest, lip mechanical movements, and confusion, followed by amnesia. When the lesion is in the amygdala, autonomic symptoms such as epigastric discomfort, phobias, and olfactory hallucinations occur. Lateral temporal lobe seizures include auditory illusions, hallucinations, and dreamlike states, as well as language disorders when the lesion is in the dominant hemisphere. Temporal lobe epilepsy more frequently manifests as a long-term psychotic state in addition to other symptoms and cognitive memory impairments (Medical Dictionary, Nanzando). Treatment for temporal lobe epilepsy is achieved through pharmacotherapy using maximal doses of drug combinations or surgical intervention.

[0085] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

[0086] As used herein, the phrase "suitable substituent" or "substituent" refers to a group that does not abrogate the synthetic or pharmaceutical utility of the compounds described herein or intermediates useful in their preparation. Examples of suitable substituents include, but are not limited to, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C aryl, C-C alkoxy, C-C heteroaryl, C-C cycloalkyl, C-C aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO, -COH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -NH(C aryl), -N(C-C aryl), -CHO, -CO(C-C alkyl), -CO((C-C) aryl), -CO((C-C) alkyl), and -CO((C-C) aryl). One of ordinary skill in the art can readily select suitable substituents based on the stability and pharmacological and synthetic activity of the compounds described herein.

[0087] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or pharmacological response sought in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, the therapeutic effect can be a reduction in the severity of symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or improved treatment, cure, prevention, or elimination of the disorder or side effects. The amount necessary to elicit a therapeutic response can be determined based on the age, health, size, and sex of the subject. The optimal amount can also be determined based on monitoring the subject's response to treatment.

[0088] As used herein, the term "traumatic epilepsy," a type of intractable epilepsy, is broadly divided into two types of epilepsy: "early epilepsy" and "late epilepsy." "Early epilepsy" is caused by brain stimulation induced by convulsions within one week after trauma and is not true epilepsy. In contrast, "late epilepsy" is true epilepsy caused more than one week after trauma. Most traumatic epilepsies are caused by the formation of lesions in the traumatically damaged part of the cortex, and are considered typical examples of partial epilepsy.

[0089] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic and prophylactic measures, the purpose being to slow (alleviate) an undesirable pathophysiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; a decrease in the extent of the condition, disorder, or disease; a stable (i.e., not worsening) state of the condition, disorder, or disease; a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or remission (partial or complete) of the state of the condition, disorder, or disease, whether detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not receiving treatment. Thus, "treatment of epilepsy" or "treating epilepsy" refers to activity that reduces or ameliorates any of the primary or secondary symptoms associated with epilepsy or other conditions described herein.

[0090] As used herein, the term "ureido" means -NHC(=O)-NH2.

[0091] At various places in the present specification, substituents of compounds may be disclosed in groups or in ranges. It is specifically intended that embodiments include each and every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0092] For compounds in which a variable appears multiple times, each variable can be a different moiety selected from the Markush group defining the variable. For example, if a structure is described as having two R groups co-occurring on the same compound, the two R groups can represent different moieties selected from the Markush group defined for R. In another example, multiple optional substituents can be, for example, [ka] It is understood that when specified in the form 1 But, T 1 When is defined to include hydrogen, such as when is CH2, NH, etc., any H can be replaced with a substituent.

[0093] It will be further understood that certain features described herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0094] It is understood that the present embodiments encompass, where applicable, the use of stereoisomers, diastereomers, and optical stereoisomers of the compounds, and mixtures thereof. Furthermore, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds, and mixtures thereof, are within the scope of the embodiments. As non-limiting examples, the mixtures may be racemic, or the mixtures may contain unequal proportions of one particular stereoisomer to another. Furthermore, the compounds may be provided as substantially pure stereoisomers, diastereomers, and optical stereoisomers (e.g., epimers).

[0095] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise specified. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of the compounds are also included within the embodiments and can be isolated as a mixture of isomers or as separated isomeric forms. When a compound capable of stereoisomers or geometric isomers is specified by its structure or name without reference to a specific R / S or cis / trans configuration, all such isomers are intended to be contemplated.

[0096] In some embodiments, the composition comprises a compound, or a pharmaceutically acceptable salt thereof, that is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure, meaning that the ratio of one enantiomer to the other in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or is entirely in the form of one enantiomer relative to the other.

[0097] Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods include optically active acids such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Examples of suitable resolving agents for fractional recrystallization include, but are not limited to, stereoisomerically pure α-methylbenzylamine (e.g., S- and R-isomers, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0098] Compounds may also include tautomeric forms. Tautomeric forms result from the interchange of adjacent double and single bonds with the concomitant migration of a proton. Tautomeric forms include prototopic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototopic tautomers include, but are not limited to, ketone-enol pairs, amide-imidinic acid pairs, lactam-lactin pairs, amide-imidinic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0099] Compounds also include hydrates and solvates, as well as anhydrous and unsolvated forms.

[0100] Compounds may also include isotopes of all atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0101] In some embodiments, the compound or salt thereof is substantially isolated. Partial isolation can include, for example, a composition enriched for the compound. Substantial isolation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0102] While the disclosed compounds are preferred, other functional groups can be incorporated into the compounds with similar results. In particular, thioamides and thioesters are expected to have very similar properties. The distance between aromatic rings can affect the geometric pattern of the compound, and this distance can be varied by incorporating aliphatic chains of various lengths, which can be optionally substituted or contain amino acids, dicarboxylic acids, or diamines. The distance between monomers within a compound and their relative orientation can also be altered by replacing the amide bond with a surrogate containing an additional atom. Thus, replacing a carbonyl group with a dicarbonyl group changes the distance between monomers and the tendency of the dicarbonyl unit to adopt the reverse arrangement of the two carbonyl moieties, changing the periodicity of the compound. Piromellite anhydride represents yet another alternative to the simple amide bond, which can alter the conformation and physical properties of the compound. Modern methods of solid-phase organic chemistry (E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis: A Practical Approach) IRL Press, Oxford 1989) allows the synthesis of homodisperse compounds with molecular weights approaching 5,000 daltons. Other substitution patterns are equally effective.

[0103] The compounds also include derivatives called prodrugs.

[0104] Compounds that contain amine functions can also form N-oxides. In this specification, reference to compounds that contain amine functions also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Examples of N-oxides include the N-oxides of tertiary amines or the nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or peracid (e.g., peroxycarboxylic acid) (see Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience).

[0105]

[0013] Various compounds and salts thereof are provided for methods of treating or preventing seizures, epilepsy, or epilepsy-related syndromes in a subject described herein. If a variable is not specifically listed, the variable may be any of the options described herein unless otherwise stated or dictated by context.

[0106] In some embodiments, the compound is as set forth in the accompanying exemplary, non-limiting claims, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, a compound having Formula I or Formula II, or a pharmaceutically acceptable salt thereof, is provided: [ka] During the ceremony, AA is, [ka] and W is O, S, or NR1; X is O, S, or NR4; V is O, S, or NR 32 and Z is CHR 42 or NR 43 and n is 0, 1, 2, 3, or 4; Y1 and Y2 are independently O, S, NR5, C=O, C=S, or C=NR6; Y3 is O, S, CH2, or NR 34 and m is 0, 1, 2, or 3; A1 is O, S, NR7, C=O, or C=S; A2 and A3 are independently CR 29 or N, B1 is an optionally substituted aryl or heteroaryl group, a carbocycle, or [ka] and B2, B3, and B4 are independently CR 38 or N, D1 is H, OH, NH2, NO2, a ring, an optionally substituted aryl group, a branched or unbranched alkyl alcohol, a halo, a branched or unbranched alkyl, an amido, a cyano, an alkoxy, a haloalkyl, an alkylsulfonyl, a nitrite, or an alkylsulfanyl; R2 and R3 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or R2 and R3 together are optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl; R1, R4, R5, R6, R7, R 29 , R31 , R 32 , R 33 , R 34 , R 38 , and R 43 are independently H, OH, NH, optionally substituted C-C alkyl, optionally substituted C-C hydroxyalkyl, optionally substituted C-C alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; R 30 are independently H, CN, CF3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or optionally substituted haloalkyl; R 42 is independently Br, Cl, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

[0108] In some embodiments of the compound of Formula I or Formula II, D1 and B1 are [ka] and During the ceremony, Z1 and Z2 are independently N or CR 39 and Z3 is O, S, or NR 27 and R 27 and R 39 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aralkyl, koxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; D1 is H, OH, NH2, NO2, a ring, an optionally substituted aryl group, a branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl.

[0109] In some embodiments, one of Z1 and Z2 is N. In some embodiments, both Z1 and Z2 are N. In some embodiments, Z3 is O.

[0110] In some embodiments of the compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, D1 and B1 are [ka] and has the formula During the ceremony, Z4 is O, S, or NR 28 and Z5 is N or CH; R 19 and R 20 are each independently H, OH, NH, NO, ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, alkylthio, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R 19 and R 20 together form an aryl or ring bonded to one or more atoms of B1; R 28 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; D1 is H, OH, NH2, NO2, a ring, an optionally substituted aryl group, a branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl.

[0111] In some embodiments, Z5 is N. In some embodiments, Z4 is O. In some embodiments, Z5 is N and Z4 is O.

[0112] In some embodiments of the compound of Formula I or Formula II, D1 is [ka] and In the formula, R 21 , R 22 , and R 23 are each independently H, OH, NH, NO, ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R 21 , R 22 , and R 23 two of which together form an aryl or ring bonded to one or more of the atoms of D1.

[0113] In some embodiments, R 21 , R 22 , and R 23 One of R is H. In some embodiments, R 21 , R 22 , and R 23 Two of R are H. In some embodiments, R 23 is Me, OH, NH, Cl, NHSOMe, SONH, NH(CO)Me, or (CO)NH. In some embodiments, R 21 and R 22 is H and R 23is Me, OH, NH2, Cl, NHSO2Me, SO2NH2, NH(CO)Me, or (CO)NH2.

[0114] In some embodiments of the compound of Formula I or Formula II, D 1 is optionally substituted aryl or optionally substituted heteroaryl.

[0115] In some embodiments of the compound of Formula I or Formula II, D1 is [ka] and In the formula, R 24 , R 25 , and R 26 are each independently H, OH, NH, NO, a ring (e.g., carbocyclic or heterocyclic), aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R 24 , R 25 , and R 26 two of which together form an aryl or ring bonded to one or more of the atoms of D1.

[0116] In some embodiments, R 24 , R 25 , and R 26 One of R is H. In some embodiments, R 24 , R 25 , and R 26 Two of R are H. In some embodiments, R 26 is H, Me, OH, CF, or OMe. In some embodiments, R 24 and R 25 is H and R 26 is H, Me, OH, CF3, or OMe.

[0117] In some embodiments of the compound of Formula I or Formula II, AA is [ka] where the variables are as defined in the previous embodiment.

[0118] In some embodiments, W is O. In some embodiments, X is O. In some embodiments, R2 and R3 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R2 and R3 are the same. In some embodiments, R2 and R3 are ethyl.

[0119] In some embodiments, D1 is [ka] In some embodiments, R 24 , R 25 , and R 26 One of R is H. In some embodiments, R 24 , R 25 , and R 26 In some embodiments, two of D are H and the other members are as defined herein. [ka] In some embodiments, D1 is [ka] is.

[0120] In some embodiments, R 24 is H. In some embodiments, R 24 In some embodiments, D1 is [ka] In some embodiments, R 24 is OMe.

[0121] In some embodiments, D1 is [ka] In some embodiments, R 24 , R 25 , and R 26 One of R is H. In some embodiments, R 24 , R 25 , and R 26 Two of the are H, and the other members are as defined herein.

[0122] In some embodiments, D1 is [ka] In some embodiments, D1 is [ka] In some embodiments, D1 is [ka] In some embodiments, R 24 is a halide. In some embodiments, R 24 is F.

[0123] In some embodiments, R 24 is Me. In some embodiments, R 24 is OMe. In some embodiments, R 24 is OH.

[0124] In some embodiments of the compound of Formula I or Formula II, R2 and R3 together are [ka] In some embodiments, n is 1.

[0125] In some embodiments of the compound of Formula I or Formula II, AA is [ka] where the variables are as defined in the previous embodiment.

[0126] In some embodiments, Y is NR. In some embodiments, R is H.

[0127] In some embodiments, Y2 is C=NR6. In some embodiments, R6 is H.

[0128] In some embodiments, Y2 is C=O. In some embodiments, Y3 is O. In some embodiments, Y3 is CH2. In some embodiments, m is 0. In some embodiments, m is 1.

[0129] In some embodiments of the compound of Formula I or Formula II, AA is [ka] where the variables are as defined in the previous embodiment.

[0130] In some embodiments, A1 is O. In some embodiments, A1 is S. In some embodiments, A2 is N. In some embodiments, A3 is N. In some embodiments, A3 is CR 29 In some embodiments, R 29 is H.

[0131] In some embodiments, A2 is CR 29 In some embodiments, R 29 is H.

[0132] In some embodiments, A1 is NR7. In some embodiments, R7 is [ka] is.

[0133] In some embodiments, D1 is [ka] and R 21 , R 22 , and R 23 One of them is H.

[0134] In some embodiments, D1 is [ka] and R 21 , R 22 , and R 23 and two of are H. In some embodiments, D1 is [ka] In some embodiments, R 21 is an optionally substituted C1-C6 alkyl. In some embodiments, R 21 is ethyl or methyl. In some embodiments, D1 is [ka] is.

[0135] In some embodiments of the compound of Formula I or Formula II, D1 is [ka] and During the ceremony, Z6 is O, S, NR 40 , or CHR 37 and Z7, Z8, Z9, and Z 10 are independently N or CR 41 and R 35 , R 36 , R 37 , R 40 , and R 41 are each independently H, OH, NH, ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R 35 and R 36 together form an aryl or ring bonded to one or more of the atoms of D1.

[0136] In some embodiments, R 35 and R 36 One of them is H.

[0137] In some embodiments, R 35 and R 36 are H. In some embodiments, Z6 is NH. In some embodiments, one of Z7, Z8, and Z9 is N.

[0138] In some embodiments, Z7 is N. In some embodiments, Z8 is CH. In some embodiments, Z9 is CH. In some embodiments, both Z8 and Z9 are CH.

[0139] In some embodiments, AA is [ka] where the variables are as defined in the previous embodiment.

[0140] In some embodiments, W is O. In some embodiments, X is O. In some embodiments, R2 and R3 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, both R2 and R3 are the same. In some embodiments, both R2 and R3 are methyl or ethyl. In some embodiments, n is 1. In some embodiments, D1 is pyrazolyl. In some embodiments, D1 is [ka] is.

[0141] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, and Z3 are as defined herein and above.

[0142] In some embodiments, Z2 is N. In some embodiments, Z1 is N. In some embodiments, Z3 is O. In some embodiments, Z2 and Z1 are N and Z3 is as defined herein. In some embodiments, Z2 and Z1 are N and Z3 is O. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments of the compound of Formula II, D1 and B1 are [ka] where the variables are as defined in the previous embodiment.

[0144] In some embodiments, Z3 is O, and Z1 and Z2 are independently N or CR 39 is.

[0145] In some embodiments, Z1 is N and Z2 is N or CR 39 and Z3 is O, S, or NR 27 In some embodiments, Z1 and Z2 are N and Z3 is O.

[0146] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the previous embodiments. 30 In some embodiments, V is NH. In some embodiments, R 31 is C1-C5 alkyl. In some embodiments, R 31 teeth, [ka] In some embodiments, R 31 is C1-C5 haloalkyl.

[0147] In some embodiments, R 31 teeth, [ka] is.

[0148] In some embodiments of the compound of Formula II, D1, B1, and AA are both: [ka] where the variables are as defined in the previous embodiment.

[0149] In some embodiments, R 30 is CF. In some embodiments, V is O or NH.

[0150] In some embodiments, R 30 is CF3.

[0151] In some embodiments, B1-D1 is [ka] wherein D1 is as defined herein and above. In some embodiments, D1 is [ka] In some embodiments, R 31 teeth, [ka] is.

[0152] In the foregoing embodiments, or as set forth below, or in the appended claims, where a variable (substituent) is not explicitly defined, the variable is as defined above which is readily apparent based on the present embodiment.

[0153] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the present embodiments provide a method of treating or preventing a seizure, epilepsy, or epilepsy-related syndrome, etc., described herein in a subject, the method comprising administering to the subject a compound of the invention described herein, such as any compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof. The method includes administering a pharmaceutical composition comprising one or more compounds provided or described in

[0155] In some embodiments, the present embodiments provide a method of treating or preventing a seizure, epilepsy, or epilepsy-related syndrome, such as those described herein, in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more compounds provided or described herein and a pharmaceutically acceptable carrier.

[0156] In some embodiments, the present embodiments provide methods for treating or preventing seizures, epilepsy, or epilepsy-related syndromes, etc., described herein in a subject, the method comprising administering to the subject one or more compounds described herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds described herein. In some embodiments, the present embodiments provide methods for treating seizures, epilepsy, or epilepsy-related syndromes, etc., described herein in a subject, the method comprising administering to the subject one or more compounds described herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds described herein. In some embodiments, the present embodiments provide methods for preventing seizures, or symptoms associated with epilepsy or epilepsy-related syndromes, etc., described herein in a subject, the method comprising administering to the subject one or more compounds described herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds described herein. He has intractable epilepsy.

[0157] In some embodiments, the epilepsy being treated is refractory epilepsy. In some embodiments, the refractory epilepsy is localization-related epilepsy, generalized epilepsy, or a syndrome thereof. In some embodiments, the localization-related epilepsy is cortical epilepsy or temporal lobe epilepsy. In some embodiments, the cortical epilepsy is frontal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy. In some embodiments, the method is used to treat or prevent epileptic seizures. In some embodiments, the epileptic seizures are refractory localization-related epileptic seizures, refractory secondarily generalized seizures, refractory complex partial seizures, or refractory status epilepticus.

[0158] In some embodiments, the epilepsy is refractory epilepsy. In some embodiments, the refractory epilepsy is localization-related epilepsy, generalized epilepsy, or a syndrome thereof. In some embodiments, the localization-related epilepsy is cortical epilepsy or temporal lobe epilepsy. In some embodiments, the cortical epilepsy is frontal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy. In some embodiments, the epilepsy-related syndrome is epileptic seizures. In some embodiments, the epileptic seizures are refractory localization-related epilepsy, refractory secondarily generalized seizures, refractory complex partial seizures, or refractory status epilepticus.

[0159] In some embodiments, the present embodiments provide a method of treating or preventing epilepsy or an epilepsy-related syndrome in a subject, the method further comprising at least one (i.e., an additional) antiepileptic drug that is not a compound of Formula I or Formula II. In some embodiments, the at least one antiepileptic drug is selected from the group consisting of carbamazepine, clonazepam, eslicarbazepine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, vigabatrin, valproic acid, and zonisamide.

[0160] In some embodiments, the subject is a subject in need thereof. In some embodiments, the epilepsy medication is selected from those described herein.

[0161] In some embodiments, the condition is prevented.

[0162] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, for the methods of treating or preventing seizures, epilepsy, epilepsy-related syndromes, etc. described herein is selected from the compounds shown in the following tables, included in the Examples section of this disclosure, and / or described herein. Any of the compounds provided herein can be prepared as a pharmaceutically acceptable salt and / or as part of a pharmaceutical composition provided herein. Examples of such salts are provided herein. As described herein, the compounds can be prepared according to the schemes and methods described herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-102

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

Table 1-110

[0163] Although the compounds described herein may be depicted with a particular stereochemistry around a particular atom, such as cis or trans, the compounds may be produced in the opposite orientation or in racemic mixtures. Such isomers or racemic mixtures are encompassed by the present disclosure. Additionally, although the compounds are collectively depicted in tables, any compound, or pharmaceutically acceptable salt thereof, may be selected from the tables and used in the embodiments provided herein.

[0164] In some embodiments, there is provided a pharmaceutical composition comprising any compound described herein or a pharmaceutically salt thereof for a method of treating or preventing seizures, epilepsy, or epilepsy-related syndromes in a subject described herein.

[0165] The compounds described herein can be made according to the methods described herein and in the Examples. The methods described herein can be adapted based on the desired compound and the compounds described herein. In some embodiments, the method is made according to the following scheme, where Q and L are substituents shown and described herein, and will be apparent to those skilled in the art based on this disclosure. In some embodiments, the method can be used to make one or more compounds described herein, and it will be apparent to those skilled in the art that compounds can be made according to the methods described herein.

[0166] Conditions and temperatures can be varied as shown in the examples described herein. These schemes are non-limiting synthetic schemes, and the synthetic routes can be modified as would be apparent to one skilled in the art upon reading this specification. Compounds can also be prepared according to the schemes described in the examples.

[0167] The compounds can be used to modulate the S1P1 receptor, and therefore, in some embodiments, the compounds can be referred to as S1P1 receptor modulating compounds.

[0168] The compounds described herein can be administered by any conventional method through any route where they are active.Administration can be systemic, local, or oral.For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ocular, or intravaginal, by inhalation, by depot injection, or by implant.The mode of administration can depend on the condition or disease to be targeted or treated.The selection of a specific administration route can be performed according to methods known to clinicians to obtain the desired clinical response. , can be selected or adjusted by the clinician.

[0169] In some embodiments, it may be desirable to administer one or more compounds, or pharmaceutically acceptable salts thereof, locally to the area requiring treatment. This can be achieved, for example, but not limited to, by local infusion during surgery, topical application, for example, in combination with a wound dressing after surgery, by injection, by catheter, by suppository, or by implant, the implant being a membrane, such as a sialastic membrane, or a porous, non-porous, or gelatinous material, including fibers.

[0170] The compounds described herein can be administered alone or in combination with other pharmaceutical agents (simultaneously or sequentially). For example, the compounds can be administered in combination with other antiepileptic drugs, etc. Examples of other pharmaceutical agents or drugs include, but are not limited to, those known to those skilled in the art and described herein.

[0171] Means and methods for administration are known in the art, and the practitioner can refer to various pharmacological reference works for guidance (see, e.g., Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979), and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980)).

[0172] The amount of the compound administered is a therapeutically effective amount. The administered dose can be easily determined by those skilled in the art (e.g., a clinician) depending on the characteristics of the subject being treated, such as the specific animal being treated, age, weight, health, type of concurrent treatment (if any), and frequency of treatment. Standard protamine dosages can be used and adjusted (i.e., increased or decreased) depending on the above factors. The selection of a specific dosage regimen can be selected, adjusted, or titrated by a clinician according to methods known to clinicians to obtain the desired clinical response.

[0173] The amount of a compound described herein that is effective in the treatment and / or prevention of a particular disease, condition, or disorder will depend on the nature and severity of the disease, condition, or disorder and can be determined by standard clinical techniques. Additionally, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration and the severity of the disorder, and must be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for oral administration are generally about 0.001 milligrams to about 200 milligrams per kilogram of body weight, about 0.01 milligrams to about 100 milligrams per kilogram of body weight, about 0.01 milligrams to about 70 milligrams per kilogram of body weight, about 0.1 milligrams to about 50 milligrams per kilogram of body weight, 0.5 milligrams to about 20 milligrams per kilogram of body weight, or about 1 milligram to about 10 milligrams per kilogram of body weight. In some embodiments, the oral dose is about 5 milligrams per kilogram of body weight.

[0174] In some embodiments, suitable dosage ranges for intravenous (IV) administration are about 0.01 mg to about 500 mg per kg of body weight, about 0.1 mg to about 100 mg per kg of body weight, about 1 mg to about 50 mg per kg of body weight, or about 10 mg to about 35 mg per kg of body weight. Suitable dosage ranges for other modes of administration can be calculated based on the aforementioned dosages known to those skilled in the art. For example, recommended doses for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal, or inhalation administration are about 0.001 mg to about 200 mg per kg of body weight, about 0.01 mg to about 100 mg per kg of body weight, or about 10 mg to about 35 mg per kg of body weight. The range is about 0.00 mg per kg of body weight, about 0.1 mg to about 50 mg per kg of body weight, or about 1 mg to about 20 mg per kg of body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.

[0175] The compounds described herein can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The compounds can be administered by continuous subcutaneous infusion over a period of about 15 minutes to about 24 hours. Injectable formulations can be presented in unit dosage forms, such as ampoules or multi-dose containers, with optional added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents. In some embodiments, the injectable formulations are in the form of short-acting, depot, or implantable and pellet formulations that are injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is in the form of a solution, suspension, emulsion, or dry powder.

[0176] For oral administration, the compounds described herein can be formulated by combining the compounds with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, cachets, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained, for example, by adding a solid excipient, optionally grinding the resulting mixture, adding suitable auxiliary agents as needed, and then processing the mixture of granules to obtain tablet or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including but not limited to lactose, sucrose, mannitol, and sorbitol; cellulose preparations, including but not limited to corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If necessary, disintegrating agents can be added, such as, but not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0177] Orally administered compositions can contain one or more optional agents, such as sweeteners such as fructose, aspartame, or saccharin; flavorings such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives to provide pharmaceutically acceptable preparations.In addition, when in tablet or pill form, the composition can be coated to delay disintegration and absorption in the digestive tract, thereby providing a sustained effect over a long period of time.Selectively permeable membranes surrounding osmotically active driving compounds are also suitable for orally administered compounds.Oral compositions can contain standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.Such vehicles are preferably of pharmaceutical grade.

[0178] The sugar-coated core can be provided with suitable coating.For this purpose, can be used concentrated sugar solution, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.For identification or to characterize different combinations of active compound dosage, dyes or pigments can be added to tablet or sugar-coated coating.

[0179] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules include, but are not limited to, soft, sealed capsules. Push-fit capsules can contain the active ingredients in a mixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers can be added.

[0180] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0181] For administration by inhalation, the compounds described herein can be delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer, using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.For pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges such as gelatin for use in inhalers or insufflators can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0182] The compounds described herein can also be formulated in rectal compositions such as suppositories or retention enemas, such as those containing conventional suppository bases such as cocoa butter or other glycerides. The compounds described herein can also be formulated in vaginal compositions such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine devices.

[0183] For transdermal administration, the compound may be applied to a plaster or may be applied by a transdermal therapeutic system that is then delivered to the organism. In some embodiments, the compound is present in a cream, solution, powder, fluid emulsion, fluid suspension, semisolid, ointment, paste, gel, jelly, and foam, or a patch containing any of these.

[0184] The compounds described herein can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months or longer. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts.

[0185] In some embodiments, the compound can be delivered in a controlled release system, in one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J. Med., 1989, 321, 574). In some embodiments, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol., 1988). 9, 25, 351; see also Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, a controlled-release system can be placed in proximity to the target of the compounds described herein, such as the liver, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533 can be used.

[0186] It is also known in the art that compounds can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, humectants, solubilizers, preservatives, etc. Pharmaceutical compositions can also include suitable solid or gel-phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In some embodiments, the compounds described herein can be used with medications including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or rinses (e.g., Caphosol).

[0187] In some embodiments, the compounds described herein may be delivered in vesicles, particularly liposomes (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327, and the like, all of which are incorporated herein by reference).

[0188] Suitable compositions include, but are not limited to, oral non-absorbable compositions, including, but not limited to, saline, water, cyclodextrin solutions, and buffer solutions of pH 3-9.

[0189] The compounds described herein, or pharmaceutically acceptable salts thereof, can be formulated with a number of excipients, including, but not limited to, purified water, propylene glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid / sodium citrate (pH 3), citric acid / sodium citrate (pH 5), tris(hydroxymethyl)aminomethane HCl (pH 7.0), 0.9% saline, and 1.2% saline, and any combination thereof. In some embodiments, the excipient is selected from propylene glycol, purified water, and glycerin.

[0190] In some embodiments, the formulations can be lyophilized to a solid and reconstituted, for example, with water, prior to use.

[0191] When administered to mammals (eg, animals for veterinary use or humans for clinical use), the compounds may be administered in isolated form.

[0192] When administered to humans, the compound can be sterilized.When the compound of formula I is administered intravenously, water is a suitable carrier.Saline and aqueous dextrose and aqueous glycerol solutions can also be used as liquid carriers, especially for injectable solutions.Suitable pharmaceutical carriers include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, Excipients such as talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0193] The compositions described herein can be in the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, aerosol, spray, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A.R. Gennaro (Editor), Mack Publishing Co.

[0194] In some embodiments, the compound is formulated according to routine procedures as a pharmaceutical composition suitable for administration to humans. Typically, the compound is a solution in a sterile isotonic aqueous buffer solution. If necessary, the composition can also contain a solubilizing agent. Compositions for intravenous administration can optionally contain a local anesthetic such as lidocaine to alleviate pain at the injection site. Generally, the ingredients are supplied in unit dosage form, for example, as a dry lyophilized powder or a water-free concentrate, separately or mixed together, in a sealed container such as an ampoule or sachet indicating the quantity of active agent. When the compound is administered by infusion, it can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical-grade water or saline. When the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0195] Pharmaceutical compositions can be in unit dosage form.In this form, the composition can be divided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, and the package contains discrete amounts of preparations, such as tablets, capsules, and powders packaged in vials or ampoules.The unit dosage form can be a capsule, cachet, or tablet itself, or the appropriate number of any of these packaged forms.

[0196] In some embodiments, the composition is in liquid form and the active agent (i.e., one of the amphiphilic polymers or oligomers disclosed herein) is present in solution, suspension, as an emulsion, or as a solution / suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

[0197] In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, the ophthalmic composition is a solid article that can be inserted into a suitable location in the eye, such as between the eyelids or in the conjunctival sac, and releases an active agent, such as those described in U.S. Patent Nos. 3,863,633, 3,867,519, 3,868,445, 3,960,150, 3,963,025, 4,186,184, 4,303,637, 5,443,505, and 5,869,079. Release from such articles is typically via the cornea, via the tears that bathe the corneal surface, or directly onto the cornea itself, with which the solid article is generally in intimate contact. Solid articles suitable for implantation into the eye in this manner are generally composed primarily of polymers and can be biodegradable or non-biodegradable. Biodegradable polymers that can be used to prepare ocular implants carrying one or more compounds include, but are not limited to, poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polyesters such as polymers and copolymers of aliphatic polycarbonates and polyether lactones. Suitable non-biodegradable polymers include silicone elastomers.

[0198] Compositions described herein can contain antiseptic.Suitable antiseptics include but are not limited to mercury-containing substances such as phenylmercury salts (for example, phenylmercury acetate, phenylmercury borate and phenylmercury nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, and their salts; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; EDTA disodium; and sorbic acid and its salts.

[0199] Optionally, one or more stabilizers can be included in the composition to enhance chemical stability. Suitable stabilizers include, but are not limited to, chelating or complexing agents, such as the calcium complexing agent ethylenediaminetetraacetic acid (EDTA). For example, an appropriate amount of EDTA or a salt thereof, such as the disodium salt, can be included in the composition to complex excess calcium ions and prevent gel formation during storage. EDTA or a salt thereof may be included in an amount of preferably about 0.01% to about 0.5%. In those embodiments containing a preservative other than EDTA, EDTA or a salt thereof, more specifically, disodium EDTA, may be present in an amount of about 0.025% to about 0.1% by weight.

[0200] One or more antioxidants can also be included in the composition.Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, or other agents known to those skilled in the art.Such preservatives are typically used at a level of about 0.001% to about 1.0% by weight.

[0201] In some embodiments, the compound is at least partially solubilized by an acceptable solubilizing agent. Certain acceptable non-ionic surfactants, such as polysorbate 80, can be useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400 (PEG-400), and glycol ethers.

[0202] A suitable solubilizer for solution and solution / suspension compositions is cyclodextrin. Suitable cyclodextrins can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, alkyl cyclodextrins (e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin), hydroxyalkyl cyclodextrins (e.g., hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), carboxy-alkyl cyclodextrins (e.g., carboxymethyl-β-cyclodextrin), sulfoalkyl ether cyclodextrins (e.g., sulfobutyl ether-β-cyclodextrin), etc. The ophthalmic use of cyclodextrins is reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.

[0203] In some embodiments, composition optionally contains suspending agent.For example, in those embodiments where composition is aqueous suspension or solution / suspension, composition can contain one or more polymers as suspending agent.Useful polymers include but are not limited to water-soluble polymers, such as cellulose-based polymers, for example, hydroxypropylmethylcellulose, and water-insoluble polymers, such as cross-linked carboxyl-containing polymers.

[0204] One or more acceptable pH adjusting and / or buffering agents may be included in the composition, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffering agents are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0205] One or more acceptable salts may be included in the composition in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include, but are not limited to, those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions. In some embodiments, the salt includes sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate. In some embodiments, the salt is sodium chloride.

[0206] Optionally, one or more acceptable surfactants, preferably nonionic surfactants, or cosolvents may be included in the composition to enhance the solubility of the components of the composition, to provide physical stability, or for other purposes.Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10, octoxynol 40; polysorbate 20, 60, and 80; polyoxyethylene / polyoxypropylene surfactants (e.g., Pluronic® F-68, F84, and P-103); cyclodextrin; or other agents known to those skilled in the art.Typically, such cosolvents or surfactants are used in the composition at a level of about 0.01% to about 2% by weight.

[0207] In some embodiments, a pharmaceutical pack or kit is provided that includes one or more containers filled with one or more compounds described herein. Optionally, associated with such container(s) may be a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, reflecting approval by the agency of the manufacture, use, or sale for human administration to treat a condition, disease, or disorder described herein. In some embodiments, the kit includes two or more compounds described herein. In some embodiments, the kit includes a compound described herein in a single injectable form, such as a single dose in an injectable device, such as a syringe with a needle.

[0208] Modulation of the S1P1 receptor has been found to be a target for the treatment of certain disorders.

[0209] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered to a subject for any condition or indication provided herein without causing significant lymphopenia or immunosuppression, hi some embodiments, the method is performed without causing lymphopenia or immunosuppression.

[0210] In some embodiments, the methods described herein comprise administering to a subject one or more compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof. In some embodiments, the subject is a subject in need of such treatment. As described herein, in some embodiments, the subject is a mammal, such as, but not limited to, a human.

[0211] In some embodiments, also provided are one or more compounds as described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more compounds as described above, for use in the manufacture of a medicament for the treatment and / or prevention of seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, the conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0212] In some embodiments, also provided is one or more compounds as described above, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds as described above, for use in the manufacture of a medicament for the treatment of seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, the conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0213] In some embodiments, also provided is one or more compounds as described above, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds as described above, for use in the manufacture of a medicament for the prevention of seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, the conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0214] In some embodiments, also provided are one or more compounds as described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more compounds as described above, for use in the treatment and / or prevention of seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0215] In some embodiments, also provided are one or more compounds as described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more compounds as described above, for use in treating seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0216] In some embodiments, also provided are one or more compounds as described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more compounds as described above, for use in preventing seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, the conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0217] In some embodiments, also provided are one or more compounds as described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more compounds as described above, for use in the treatment and / or prevention of seizures, epilepsy, and / or epilepsy-related syndromes, such as those described herein, in a subject, including but not limited to, conditions described herein. In some embodiments, the subject is a subject in need thereof.

[0218] The present embodiments also provide use of one or more of the compounds described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more of the compounds described above, in modulating S1P1 receptor activity, such as its presence on the surface of a cell. In some embodiments, the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof modulate the internalization, transport, and / or degradation of the S1P1 receptor. In some embodiments, the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof modulate the G protein regulatory pathway of the S1P1 receptor.

[0219] The present embodiments also provide use of one or more of the compounds described above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more of the compounds described above, in modulating S1P1 receptor activity, such as its presence on the surface of a cell. In some embodiments, the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof modulate the internalization, transport, and / or degradation of the S1P1 receptor. In some embodiments, the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof modulate the G protein regulatory pathway of the S1P1 receptor.

[0220] As used herein, "modulation" can refer to either inhibition or enhancement of a particular activity. For example, modulation of the S1P1 receptor can refer to inhibition and / or activation of the G protein-mediated pathway of the S1P1 receptor. In some embodiments, modulation refers to inhibition or activation of the β-arrestin-mediated pathway of the S1P1 receptor. In some embodiments, modulation refers to inhibition or activation of the internalization of the S1P1 receptor. In some embodiments, modulation refers to inhibition or activation of any cell signaling pathway or intracellular and / or extracellular entity that is directly or indirectly regulated by the S1P1 receptor. The activity of the S1P1 receptor can be measured by any method, including, but not limited to, the methods described herein.

[0221] The compounds described herein can be agonists, or agonist-like, or antagonists, or antagonist-like of S1P1 receptor.The ability of a compound to stimulate or inhibit S1P1 receptor signal transduction can be measured using any assay known in the art that is used to detect S1P1 receptor-mediated signal transduction or S1P1 receptor activity, or the absence of such signal transduction / activity." S1P1 receptor activity " refers to the ability of S1P1 receptor to transduce signals.This activity can be measured, for example, by connecting S1P1 receptor (or chimeric S1P1 receptor) to downstream effectors such as adenylate cyclase in heterologous cells.

[0222] As used herein, "natural ligand-induced activity" refers to the activation of the S1P1 receptor by its endogenous ligand. Activity can be assessed using any number of endpoints to measure S1P1 receptor activity.

[0223] Generally, assays for testing compounds that modulate S1P1 receptor-mediated signal transduction include determining any parameter that is indirectly or directly under the influence of the S1P1 receptor, e.g., functional, physical, or chemical effect.

[0224] Samples or assays containing the S1P1 receptor treated with a potential activator, inhibitor, or modulator are compared to control samples containing no inhibitor, activator, or modulator to determine the degree of inhibition. The control sample (untreated with an inhibitor) is assigned a relative S1P1 receptor activity value of 100%. Inhibition of the S1P1 receptor is achieved when the S1P1 receptor activity value relative to the control is approximately 80%, 50%, or 25%. Activation of the S1P1 receptor is achieved when the S1P1 receptor activity value relative to the control (untreated with an activator) is 110%, 150%, 200-500% (i.e., 2-5 times higher than the control), or 1000-3000% or higher. For example, in some embodiments, assays containing the S1P1 receptor treated with a potential activator, inhibitor, or modulator are used to measure the functional ability of test compounds to either inhibit the activity of known S1P1 receptor agonists or activate the cell signaling pathway measured in the assay. Inhibition of the S1P1 receptor is achieved when the measured activity induced by S1P (endogenous ligand) or a known S1P1 receptor agonist, such as fingolimod, is blocked by the compound being tested. Activation of the S1P1 receptor by the test compound is measured relative to the full efficacy of the known agonist (S1P, fingolimod). This is achieved when the temperature is 50% or higher.

[0225] The effect of compound on the function of S1P1 receptor can be measured by examining any of the above parameters.Any suitable physiological change that affects S1P1 receptor activity can be used to evaluate the effect of compound on S1P1 receptor and natural ligand-mediated S1P1 receptor activity.When functional results are determined using intact cells or animals, various effects can also be measured, such as the change of intracellular second messengers such as cAMP.

[0226] Modulators of S1P1 receptor activity can be tested using either recombinant or naturally occurring S1P1 receptor polypeptides described herein. Proteins can be isolated, expressed intracellularly, expressed in membranes derived from cells, expressed in tissues, or expressed in animals. For example, neuronal cells, cells of the immune system, transformed cells, or membranes can be used to test the S1P1 receptor polypeptides described herein. Modulation can be tested using one of the in vitro or in vivo assays described herein. Chimeric molecules, such as the extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and / or cytoplasmic domain of a receptor, can also be used to examine signal transduction and cellular trafficking in vitro with soluble or solid-state reactants. Additionally, the ligand-binding domain of a protein of interest can be used to assay ligand binding in vitro, with soluble or solid-state reactions.

[0227] Ligand binding to the S1P1 receptor, domain, or chimeric protein can be tested in several formats. Binding can be performed in solution, in a bilayer membrane, bound to a solid phase, in a lipid monolayer, or in a vesicle. For example, in an assay, the binding of a natural ligand to its receptor is measured in the presence of a candidate modulator, such as a compound described herein. Alternatively, the binding of a candidate modulator can be measured in the presence of the natural ligand. Often, a competitive assay is used to measure the ability of a compound to compete with the binding of a natural ligand to the receptor. Binding can be tested, for example, by measuring changes in spectroscopic properties (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape), or chromatographic or solubility properties.

[0228] Another technique that can be used to assess S1P1 receptor-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion of BRET can be found in Kroeger et al., J. Biol. Chem., 276(16):12736 43(2001).

[0229] After the receptor is expressed in the cells, the cells can be grown in an appropriate medium in an appropriate cell plate. For example, cells can be seeded at 5,000 to 10,000 cells per well in a 384-well plate. In some embodiments, cells are seeded at approximately 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 cells per well. Plates can have any number of wells, and the number of cells can be modified accordingly.

[0230] Any agent having utility in the applications described herein may be used in combination therapy, co-administration, or co-formulation with the above compositions. Thus, the compounds described herein may be administered either before, simultaneously with, or after such therapeutic agent is administered to the subject.

[0231] The additional agents may be administered in combination therapy (including combination formulations) with one or more of the compounds described herein.

[0232] In some embodiments, response to treatment of the disease or disorder is monitored, and the treatment regimen is adjusted as needed in light of such monitoring.

[0233] Dosing frequency is typically such that the dosing interval, e.g., the period between one dose and the next during waking hours, is about 2 to about 12 hours, about 3 to about 8 hours, or about 4 to about 6 hours. An appropriate dosing interval is determined by the amount of time that the selected composition will maintain the concentration (e.g., EC 50 It will be understood by those skilled in the art that the administration of a given compound will depend in part on the length of time that the compound can be maintained above the EC (the minimum concentration of compound that modulates the activity of the receptor by 90%). Ideally, the concentration will be above the EC for at least 100% of the administration interval. 50 If this cannot be achieved, concentrations should remain above the EC 50 or for at least about 40% of the dosing interval. 50 It is desirable that the temperature should be maintained above 100°C.

[0234] The present disclosure also provides the following non-limiting embodiments.

[0235] In order to more effectively understand the embodiments disclosed herein, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the embodiments in any way. Throughout these examples, molecular cloning reactions and other standard recombinant DNA techniques may be described, which were performed according to the methods described in Maniatis et al., Molecular Cloning - A Laboratory Manual, 2nd ed., Cold Spring Harbor Press (1989), using commercially available reagents unless otherwise noted.

[0236] The following examples are illustrative, but not limiting, of the methods and compositions described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in the treatments, compositions, and other embodiments disclosed herein are within the spirit and scope of the embodiments. [Example]

[0237] Example 1: Synthesis of compounds Certain synthetic schemes (both general and specific) are provided herein. The compounds disclosed herein can be made according to the methods described herein, or intermediates leading to the compounds disclosed herein can be made according to the methods described herein. Substitutions can be varied according to the compounds or intermediates made based on the following examples and other modifications known to those skilled in the art.

[0238] The following compounds were prepared according to the following examples or by varying the examples according to one skilled in the art to prepare the compounds. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

Table 2-74

Table 2-75

Table 2-76

Table 2-77

Table 2-78

Table 2-79

Table 2-80

Table 2-81

Table 2-82

Table 2-83

Table 2-84

Table 2-85

Table 2-86

Table 2-87

Table 2-88

Table 2-89

Table 2-90

Table 2-91

Table 2-92

Table 2-93

Table 2-94

Table 2-95

Table 2-96

Table 2-97

Table 2-98

Table 2-99

Table 2-100

Table 2-101

Table 2-102

Table 2-103

Table 2-104

Table 2-105

Table 2-106

Table 2-107

Table 2-108

Table 2-109

Table 2-110

[0239] General Procedure A: [ka]

[0240] Example 2 Intermediate 2-2: Synthesis of N,2-dihydroxypyridine-3-carboximidamide [ka] To a mixture of 2-1 (2-hydroxypyridine-3-carbonitrile) (200 mg, 1.67 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (174 mg, 2.50 mmol) and diisopropylethylamine (430 mg, 3.33 mmol) at 20° C. The mixture was then heated to 90° C. and stirred for 16 hours. was concentrated in vacuo to remove some of the ethanol, the resulting mixture was filtered, and the solid was dried in vacuo and used as the product in the next step without further purification (185 mg, 69% yield). 1 H NMR (400MHz, DMSO-d6)δ=12.06(br,s,1H), 9.50(br,s,1H),7.95(dd,J=7.2,2.4Hz,1H),7.51(dd,J=6.0,2.0Hz,1H),6.3-6.30(m,3H).

[0241] General Procedure B Intermediate 3-2: Synthesis of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid [ka]

[0242] Alternative synthesis of intermediate 4-4: 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid [ka]

[0243] 4-2: Synthesis of 6-bromo-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-4-one [ka] To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (20 g, 93.0 mmol, 1 equiv.) in methanol (400 mL) was added pyrrolidine (7.94 g, 112 mmol, 1.2 equiv.) and pentan-3-one (9.61 g, 112 mmol, 1.2 equiv.). The mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography to give the desired product 4-2 (12 g, 46% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3)δ=7.93(d,J=2.5Hz,1H ),7.52(dd,J=8.8,2.6Hz,1H),6.84(d,J=8.8Hz,1H),2.70(s,2H),1.86-1.62(m,4H),0.92(t,J=7.5Hz,6H).

[0244] Intermediate 4-3: Synthesis of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carbonitrile [ka] To a solution of 6-bromo-2,2-diethyl-chroman-4-one (10 g, 35.3 mmol, 1 equiv.) in DMF (100 mL) was added zinc cyanide (6.22 g, 53.0 mmol, 1.5 equiv.) and tetratriphenylphosphine palladium (4.08 g, 3.53 mmol, 0.1 equiv.). The mixture was stirred at 130 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the desired product 4-3 (8 g, 99% yield). 1 H NMR (400MHz, DMSO-d6)δ=8.08(d,J=1.9Hz, 1H),7.96(dd,J=8.7,2.0Hz,1H),7.20(d,J=8.7Hz,1H),2.88(s,2H),1.86-1.59(m,4H),0.86(br,t,J=7.4Hz,6H).

[0245] Intermediate 4-4: Synthesis of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid [ka] A suspension of 2,2-diethyl-4-oxochroman-6-carbonitrile (6.05 g, 26.4 mmol, 1 equiv.) in acetic acid (60 mL) and concentrated hydrochloride solution (60 mL) was stirred at 120° C. for 16 h, and the residue was triturated with water (500 mL), filtered, and dried under vacuum to give the title product 4-4 (5.8 g, 89% yield). 1 H NMR (400MHz, DMSO-d6)δ=8.27(d,J=1.9Hz, 1H),8.06(dd,J=8.7,2.0Hz,1H),7.11(d,J=8.7Hz,1H),2.85(s,2H),1.77-1.68(m,4H),0.87(t,J=7.4Hz,6H).

[0246] General Procedure C: [ka]

[0247] Synthesis of Compound 9a-1: 2,2-diethyl-6-(3-(2-hydroxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)chroman-4-one [ka] A mixture of 4-4 (268 mg, 1.08 mmol) in N,N-dimethylformamide (6 mL) was treated with HOBt (159 mg, 1.18 mmol, 1. 2 equiv.) and EDCI (225 mg, 1.18 mmol, 1.2 equiv.) were added. The mixture was stirred for 30 min, then 2-2 (150 mg, 980 umol, 1 equiv.) was added, and the resulting mixture was heated to 120 °C and stirred for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 35% to 65%, 12 min) to give product 9-1 as a white solid (20 mg, yield 6%). 1 H NMR (400MHz, DMSO-d6)δ=12.23(br,s,1H), 8.44(d,J=2.0Hz,1H),8.33(dd,J=7.2,2.0Hz,1H),8.28(dd,J=8.8,2.4Hz,1H),7.68(dd,J=6.0,2.0Hz, 1H),7.29(d,J=8.8Hz,1H),6.42(t,J=6.8Hz,1H),2.93(s,2H),1.81-1.70(m,4H),0.90(t,J=7.2Hz,6H).

[0248] Synthesis of the compound 2,2-diethyl-6-[3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]-3H-1-benzopyran-4-one [ka] To a solution of compound 4-4 (16.41 g, 66.08 mmol, 1 equiv) in DMF (50 mL) was added EDCI (15.20 g, 79.29 mmol, 1.2 equiv) and HOBt (8.93 g, 66.08 mmol, 1.0 equiv) and stirred at 20 °C for 0.5 h. Compound 9b-1 (10 g, 79.29 mmol, 1.2 equiv) was then added. The mixture was stirred at 20 °C for 0.5 h, then heated to 120 °C and stirred for 2 h. The mixture was diluted with water (100 mL), extracted with EtOAc (150 mL*3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give 9b-2 (7.2 g, 30% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=13.49(br.s,1H), 8.47(s,1H),8.42(d,J=2.3Hz,1H),8.26(dd,J=2.3,8.8Hz,1H),8.06(s,1H), 7.26(d,J=8.7Hz,1H),2.91(s,2H),1.79-1.69(m,4H),0.89(t,J=7.4Hz,6H).

[0249] General Procedure D: [ka]

[0250] 11-1: Synthesis of 3-bromo-5-(3-methoxyphenyl)-1,2,4-thiadiazole [ka] To a solution of (3-methoxyphenyl)boronic acid (247.25 mg, 1.63 mmol, 1 equiv) in DME (5 mL) was added Pd(dppf)Cl (119.06 mg, 162.71 μmol, 0.1 equiv), KPO (1.04 g, 4.88 mmol, 3 equiv), and 10-1,3-bromo-5-chloro-1,2,4-thiadiazole (649.07 mg, 3.25 mmol, 2 equiv). The mixture was stirred at 80 °C for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EA=10 / 1) to give 11-1 (3-bromo-5-(3-methoxyphenyl)-1,2,4-thiadiazole) (200 mg, 737.64 μmol, 45% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=8.23(dd,J=1.6,7 .8Hz,1H),7.78-7.57(m,1H),7.38(d,J=8.4Hz,1H),7.21(t,J=7.6Hz,1H),4.13(s,3H).

[0251] 12-1 Synthesis of 2,2-diethyl-6-[5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl]-3,4-dihydro-2H-1-benzopyran-4-one [ka] To a solution of 3-bromo-5-(2-methoxyphenyl)-1,2,4-thiadiazole (100 mg, 368.82 μmol, 1 equiv) and 2,2-diethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one (146.15 mg, 442.59 μmol, 1.2 equiv) in DMF (1 mL) and HO (0.5 mL) was added KPO (234.87 mg, 1.11 mmol, 3 equiv) and Pd(PPh) (42.62 mg, 36.88 μmol, 0.1 equiv) and stirred at 120 °C for 0.25 h. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 x 10 μm, mobile phase: [water (0.225% FA)-ACN], B%: 70% to 100%, 10 min) to obtain 2,2-diethyl-6-[5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl]chroman-4-one (34.5 mg, 87.46 μmol, yield 23.71%, purity 100%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ=8.66(d,J=2.1Hz, 1H),8.52-8.41(m,2H),7.71-7.62(m,1H),7.39(d,J=8.3Hz,1H),7.26(t,J=7.5Hz,1H),7.19(d, J=8.7Hz,1H),4.14(s,3H),2.88(s,2H),1.76(quint,J=7.2,14.4Hz,4H),0.90(t,J=7.4Hz,6H).

[0252] 10-8 Synthesis of 2,2-diethyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran-4-one [ka] To a solution of 6-bromo-2,2-diethyl-chroman-4-one (1 g, 3.53 mmol, 1 equiv.) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- Dioxaborolane (986.48 mg, 3.88 mmol, 1.1 equiv), DPPF (195.78 mg, 353.16 µmol, 0.1 equiv), Pd(dppf)Cl (258.41 mg, 353.16 µmol, 0.1 equiv), and KOAc (415.92 mg, 4.24 mmol, 1.2 equiv) were added and the mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EA=1 / 1) to give 2,2-diethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one (1 g, 3.03 mmol, 85.75% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.26 (d, J = 1.6 Hz, 1H), 7.86-7.75 (m, 1H), 6.85 (d, J = 8.3 Hz, 1H), 2.64 (s, 2H), 1.82-1.58 (m, 4H), 1.32-1.21 (m, 12H), 0.85 (t, J = 7.5 Hz, 6H).

[0253] 14-5: Synthesis of 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-benzotriazole [ka]

[0254] 14-2 Synthesis of 4-bromo-2-nitro-N-(propan-2-yl)aniline [ka] To a solution of 4-bromo-1-fluoro-2-nitro-benzene (5 g, 22.73 mmol, 2.79 mL, 1.00 equiv) and propan-2-amine (2.02 g, 34.09 mmol, 2.92 mL, 1.50 equiv) in THF (250.00 mL) was added DIEA (7.34 g, 56.82 mmol, 9.90 mL, 2.50 equiv) at 10 °C and stirred for 1 h. The reaction mixture was diluted with water (500 mL) and extracted with EA (500 mL × 2). The combined organic layers were washed with NaHCO (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 4-bromo-N-isopropyl-2-nitro-aniline (3.2 g, 12.35 mmol, 54.34% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6)δ=8.14(d,J=2.4Hz, 1H),7.88(brd,J=7.5Hz,1H),7.63(dd,J=2.3,9.3Hz,1H),7.07(d,J=9.4Hz,1H),3.92(sxtd,J=6.5,13.2Hz,1H),1.25(d,J=6.4Hz,6H).

[0255] 14-3 Synthesis of 4-bromo-1-N-(propan-2-yl)benzene-1,2-diamine [ka] To a solution of 4-bromo-N-isopropyl-2-nitroaniline (2 g, 7.72 mmol, 1 equiv.) in EtOH (20 mL), SnCl2.2HO (5.23 g, 23.16 mmol, 1.93 mL, 3 equiv.) was added and stirred at 80 °C for 16 h. The reaction mixture was quenched with aqueous NaOH (4 M, 50 mL), then diluted with water (50 mL), and extracted with EA (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EA = 100 / 1 to 1 / 1) to give 4-bromo-N-isopropyl-benzene-1,2-diamine (850 mg, 3.71 mmol, 48.06% yield) as a dark brown solid. 1 H NMR (400 MHz, chloroform-d) δ = 6.82 (dd, J = 2.1, 8.4 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 8.3 Hz, 1H), 3.56-3.40 (m, 1H), 1.14 (d, J = 6.4 Hz, 6H).

[0256] 14-4 Synthesis of 5-bromo-1-(propan-2-yl)-1H-1,2,3-benzotriazole [ka] To a solution of 4-bromo-N-isopropyl-benzene-1,2-diamine (750 mg, 3.27 mmol, 1.00 equiv) in HCl (5 mL, 6 M), NaNO (271.04 mg, 3.93 mmol, 213.42 uL, 1.20 equiv) in HO (2 mL) was added dropwise at 5 °C and stirred for 0.5 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (1 / 1) to give 5-bromo-1-isopropyl-benzotriazole (700 mg, 2.92 mmol, 89.06% yield) as a dark brown solid. 1H NMR (400MHz, DMSO-d6)δ=8.32(d,J=1.7Hz, 1H),7.94(d,J=8.8Hz,1H),7.60-7.60(m,1H),7.67(dd,J=1.8,8.9Hz,1H),5.32-5.16(m,1H),1 .62(d,J=6.7Hz,6H).

[0257] 14-5 Synthesis of 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-benzotriazole [ka] To a solution of 5-bromo-1-isopropyl-benzotriazole (700 mg, 2.92 mmol, 1 equiv) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (814.38 mg, 3.21 mmol, 1.1 equiv), DPPF (161.63 mg, 291.55 µmol, 0.1 equiv), Pd(dppf)Cl (213.33 mg, 291.5 µmol, 0.1 equiv) and KOAc (343.35 mg, 3.50 mmol, 1.2 equiv), and the mixture was stirred at 100 °C for 1 h. The mixture was diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (PE / EA = 100 / 1 to 1 / 1) to give 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazole (300 mg, 1.04 mmol, 35.83% yield) as a yellow solid. 1 H-NMR (400MHz,chloroform-d)δ=8.57(s,1H),7.89(dd,J=0.7,8.3Hz,1H),7.55(dd,J=0.8 ,8.4Hz,1H),5.11(spt,J=6.8Hz,1H),1.75(d,J=6.8Hz,6H),1.47-1.34(m,12H).

[0258] General Procedure E: [ka]

[0259] 19-6 and 19-7 Synthesis of 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-thiadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one and 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-oxadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one [ka]

[0260] 19-2: Synthesis of methyl 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carboxylate [ka] A mixture of 1-isopropylbenzotriazole-5-carbonitrile (1 g, 5.37 mmol, 1 equiv.) in HCl / MeOH (20 mL, 4 M) was stirred at 80° C. for 2 h. The mixture was concentrated, diluted with water (20 mL), extracted with EA (20 mL × 2), dried over NaSO, and concentrated to dryness. The crude product, methyl 1-isopropylbenzotriazole-5-carboxylate (0.9 g, 4.11 mmol, 76.44% yield), was used in the next step without further purification.

[0261] 19-3 Synthesis of 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carbohydrazide [ka] A mixture of methyl 1-isopropylbenzotriazole-5-carboxylate (0.5 g, 2.28 mmol, 1 equiv.) and NH2NH2·HO (1.14 g, 22.81 mmol, 1.11 mL, 10 equiv.) in EtOH (10 mL) was stirred at 80 °C for 2 h. The mixture was concentrated to dryness. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:1) to give 1-isopropylbenzotriazole-5-carbohydrazide (0.38 g, 1.73 mmol, 76.00% yield) as a white solid.

[0262] 19-5 Synthesis of 2,2-diethyl-4-oxo-N'-[1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carbonyl]-3,4-dihydro-2H-1-benzopyran-6-carbohydrazide [ka] To a mixture of 2,2-diethyl-4-oxo-chroman-6-carboxylic acid (274.04 mg, 1.10 mmol, 1.1 equiv) and 1-isopropylbenzotriazole-5-carbohydrazide (220 mg, 1.00 mmol, 1 equiv) in THF (10 mL) was added HATU (419.70 mg, 1.10 mmol, 1.1 equiv) and DIEA (142.66 mg, 1.10 mmol, 192.26 uL, 1.1 equiv) and stirred for 2 h at 15° C. The mixture was diluted with water (50 mL), extracted with EA (50 mL × 2), dried over NaSO, and concentrated in vacuo. N'-(2,2-Diethyl-4-oxo-chroman-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (420 mg, 934.37 umol, 93.12% yield) was obtained as a yellow solid without further purification.

[0263] 19-7: Synthesis of 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-thiadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one [ka] A mixture of N'-(2,2-diethyl-4-oxo-chroman-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (200 mg, 444.94 μmol, 1 equiv) and Lawesson's reagent (359.93 mg, 889.88 μmol, 2 equiv) in THF (2 mL) was stirred for 2 h at 80° C. The mixture was diluted with water (20 mL), extracted with EA (20 mL × 2), dried over NaSO, and concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 x 10 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 62%-92%, 13 min) to obtain 2,2-diethyl-6-[5-(1-isopropylbenzotriazol-5-yl)-1,3,4-thiadiazol-2-yl]chroman-4-one (61 mg, 29.99 μmol, yield 6.74%, purity 22%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.62 (d, J = 0.6 Hz, 1H), 8.38-8.36 (m, 1H), 8.36-8.33 (m, 1H), 8.33-8.30 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 5.22-5.11 (m, 1H), 2.82 (s, 2H), 1.95-1.83 (m, 4H), 1.82-1.80 (m, 6H), 0.99 (t, J = 7.5 Hz, 6H).

[0264] 19-7: Synthesis of 2,2-diethyl-6-{5-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,3,4-oxadiazol-2-yl}-3,4-dihydro-2H-1-benzopyran-4-one [ka] A mixture of N'-(2,2-diethyl-4-oxo-chroman-6-carbonyl)-1-isopropyl-benzotriazole-5-carbohydrazide (200 mg, 444.94 μmol, 1 equiv.) and Burgess reagent (530.17 mg, 2.22 mmol, 5 equiv.) in DCM (2 mL) was stirred at 15°C for 2 hours. The mixture was diluted with water (20 mL), extracted with EA (20 mL x 2), dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 x 10 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 55%-85%, 12 min) to obtain 2,2-diethyl-6-[5-(1-isopropylbenzotriazol-5-yl)-1,3,4-oxadiazol-2-yl]chroman-4-one (56 mg, 129.78 μmol, yield 29.17%, purity 100%) as a white solid. 1 H-NMR (400MHz,chloroform-d)δ=8.85(s,1H),8.61(d,J=2.3Hz,1H),8.35(t,J=2.1Hz,1H),8.33(t,J=2.1Hz,1H),7.75(d,J=8.7Hz,1H),7.16 (d,J=8.8Hz,1H),5.24-5.11(m,1H),2.84(s,2H),1.94-1.85(m,2H),1.82(d,J=6.8Hz,5H),1.80-1.75(m,2H),1.00(t,J=7.5Hz,6H)

[0265] 25-2: Synthesis of 5-[5-(1H-1,3-benzodiazol-5-yl)-1,3,4-oxadiazol-2-yl]-2-fluorobenzonitrile [ka] A suspension of 1 (N'-(1H-1,3-benzodiazole-5-carbonyl)-3-cyano-4-fluorobenzohydrazide, 541 mg, 1.67 mmol) in phosphorus oxychloride (10 mL, excess) was heated at 105 °C for 3 h. The mixture was concentrated, and the residue was suspended in water with sonication / stirring. The resulting solid was collected, washed with saturated NaHCO and water, and then dried under N / vacuum in a filter funnel. The tan solid was suspended in MeCN, concentrated twice to remove residual water, and dried under high vacuum to give 25-2 (0.55 g, 107%). MH+ = 306.1.

[0266] 26-2 Synthesis of 6-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-methyl-2,3-dihydro-1,3-benzoxazol-2-one [ka] To a suspension of 3-(6-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,3-benzoxazol-2-one trifluoroacetate, 13 mg, 0.031 mmol) in DMF (1 mL) was added potassium carbonate (8.6 mg, 0.062 mmol), followed by methyl iodide (5.2 mg, 0.037 mmol), and the resulting white suspension was heated to 100 °C for 45 min. The reaction was cooled to room temperature, filtered, and purified by reverse-phase chromatography, 25%-75% MeCN / water / 0.1% TFA. The product fractions were lyophilized to give 26-2 (1.6 mg, 12%). MH+ = 324.1. 1 HNMR (400MHz, DMSO) 7.93-7.9 1(3H,m),7.59-7.54(1H,m),7.44-7.41(1H,m),7.25-7.22(1H,m),7.11-7.07(1H,m),3.88(3H,s);3.45(3H,s)

[0267] 27-3 Synthesis of methyl N-({6-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl}sulfonyl)carbamate [ka] To a dry mixture of 27-1 (2-methoxyphenylhydrazide, 139 mg, 0.837 mmol), 27-2 (benzoxazol-2-one-6-carboxylic acid, 150 mg, 0.837 mmol), and HATU (318 mg, 0.837 mmol), THF (10 mL) was added to give a cloudy, reddish solution. DIPEA (0.29 mL, 1.67 mmol) was added, and the reaction was stirred at room temperature for 2 h. Burgess reagent (499 mg, 2.09 mmol) was added in one portion, and the reaction was heated to 60 °C overnight. An additional 499 mg of Burgess reagent was added, and heating was continued. After 4 h, 2 N KHSO (10 mL) was added, and the resulting oily mixture was extracted 3x with EtOAc. The combined organics were washed once with water and once with brine, filtered through cotton, concentrated to an orange solid, and purified by reverse phase chromatography, 20%-60% MeCN / water / 0.1% TFA to give 67 mg of 27-3 (18%) MH+=447.0. 1 HNMR(400MHz,DMSO)8.02-7.97(3H,m),7.74(1H,d,J=8.4Hz),7.64(1H,t,J=8 .2Hz),7.30(1H,d,J=8.4Hz),7.18(1H,t,J=7.4Hz),3.95(3H,s),3.39(3H,s).

[0268] 28-2: Synthesis of 2-[(2-fluoropropyl)amino]-5-[5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,3,4-oxadiazol-2-yl]benzonitrile [ka] In a small nitrogen-purged Parr hydrogenation bottle, 10% Pd / C (14 mg) was added. The mixture was added to a 500 ml column and moistened with a small amount of EtOH. 28-1 (2-[(2-fluoroprop-2-en-1-yl)amino]-5-[5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,3,4-oxadiazol-2-yl]benzonitrile trifluoroacetate, 70 mg, 0.139 mmol) was added with EtOH (10 mL) and EtOAc (90 mL) to give a milky white mixture, which was added to a hydrogenation bottle. The mixture was hydrogenated under 50 psi H for 24 hours. MeCN was added until the milky white mixture became clear, then filtered through Celite and concentrated. The residue was heated in a small amount of DMF, cooled, filtered, and purified by reverse-phase chromatography using 30%-75% MeCN / water / 0.1% TFA. The product fractions were lyophilized to give 28-2 (12.8 mg, 18%) as a fluffy white solid. MH+ = 392.1. 1 HNMR(400MHz,DMSO)10.40(1H,s),8.25(1H,d,J=2.1Hz),8.11(1H,dd,J=2.0 ,9.2Hz),7.92-7.81(2H,m),7.22(1H,t,J=6.3Hz),7.11(1H,d,J=9.2Hz),7. 11(1H,d,J=9.4Hz),7.02(1H,d,J=8.7Hz),7.04-7.00(1H,m),5.00-4.80(1H ,m),3.60-3.51(2H,m),3.01(2H,t,J=7.4Hz),1.35(3H,dd,J=6.2,24.0Hz).

[0269] 29-3: Synthesis of 5-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,3-dihydro-2,1-benzoxazol-3-one [ka] A nitrogen-purged hydrogenation bottle was charged with 10% Pd / C (12 mg), which was wetted with EtOH. A suspension of 29-1 (methyl 5-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-2-nitrobenzoate, 112 mg, 0.281, prepared according to Wuxi's 1,3,4-oxadiazole experiment) in EtOH (25 mL) and EtOAc (20 mL) was hydrogenated at 48 psi H. After 30 min, the reaction was filtered and concentrated to solid 29-2 (113 mg, 105%), which was used without further purification. MH+ = 342.1.

[0270] To a solution of 29-2 (47 mg, 0.132 mmol) in DMF (2 mL), triethylamine (0.1 mL) and then water (0.2 mL) were added, and the resulting solution was stirred at room temperature for 60 h. The reaction mixture was directly purified by reverse-phase chromatography, 20%-65% MeCN / water / 0.1% TFA, to give 8 mg of 29-3 (14%). MH+ = 310.1. 1 HNMR(400MHz,DMSO)12.52(1H,s),8.42-8.38(2H,m),8.03(1H,d,J=6.9Hz),7.65(1H,t,J =8.3Hz),7.57(1H,d,J=7.6Hz),7.32(1H,d,J=8.3Hz),7.17(1H,t,J=6.9Hz),3.96(3H,s).

[0271] 30-1: Synthesis of 5-[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1-methyl-1,3-dihydro-2,1-benzoxazol-3-one [ka] To a solution of 29-2 (8 mg, 0.019 mmol) in DMF (0.5 mL) was added potassium carbonate (2.6 mg, 0.019 mmol), followed by methyl iodide (4.0 mg, 0.028 mmol), and the resulting solution was heated at 100 °C for 15 min. The reaction was cooled to room temperature, filtered, and directly purified by reverse-phase chromatography, 25%-75% MeCN / water / 0.1% TFA, to afford 5.3 mg of 30-1 (64%) as a white solid. MH+=324.1. 1 HNMR(400MHz,DMSO)8.40(1H,d,J=8.7Hz),8.32(1H,s),7.97(1H,d,J=8.0Hz),7.73(1H,d,J=8.7H z),7.58(1H,t,J=8.3Hz),7.25(1H,d,J=8.0Hz),7.10(1H,t,J=7.7Hz),3.89(3H,s),3.49(3H,s).

[0272] General Procedure F: [ka]

[0273] 32-2 Synthesis of N-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carboximidamide [ka] To a mixture of 2-oxoindoline-5-carbonitrile (200 mg, 1.26 mmol, 1 equiv.) in ethanol (5 mL), hydroxylamine hydrochloride (176 mg, 2.53 mmol, 2.0 equiv.) and diisopropylethylamine (327 mg, 2.53 mmol, 2.0 equiv.) were added under a nitrogen atmosphere at 20° C. The mixture was then heated to 90° C. and stirred for 16 hours. The mixture was concentrated in vacuo to precipitate a white solid. The suspension was filtered, and the white solid was dried in vacuo to give product 32-2 (210 mg, 83% yield). 1 H NMR (400MHz, DMSO-d6)δ=10.46(br,s,1H), 9.45(br,s,1H),7.51(s,1H),7.50(d,J=10.8Hz,1H),6.79(d,J=8.0Hz,1H),5.70(br,s,2H),3.49(s,2H).

[0274] 33-1: Synthesis of 2-[(cyclopropylmethyl)amino]-5-[3-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl]benzonitrile [ka] To a mixture of 3-cyano-4-(cyclopropylmethylamino)benzoic acid (107 mg, 496 μmol, 1.2 equiv.) in N,N-dimethylformamide (1 mL) was added HOBt (67.0 mg, 496 μmol, 1.2 equiv.) and EDCI (95.1 mg, 496 μmol, 1.2 equiv.) at 20° C. The mixture was stirred for 30 minutes, then N-hydroxy-2-oxo-indoline-5-carboxamidine (79 mg, 413 μmol, 1 equiv.) was added, and the resulting mixture was heated to 150° C. and stirred for 1 hour. The cooled reaction mixture was analyzed by preparative HPLC (column: Boston Green ODS 150×30 Direct purification by 5u, mobile phase: [water (0.225% FA)-ACN], B%: 47%-77%, 10 min) gave product 33-1 (20 mg, 12% yield). 1 H NMR (400MHz, DMSO-d6)δ=10.73(br,s,1H), 8.23(d,J=2.4Hz,1H),8.11(dd,J=9.2,2.0Hz,1H),7.93(d,J=8.0Hz,1H),7.89(s,1H),7.17(t,J=6.4Hz,1H),7.07(d,J=9.2 Hz,1H),7.00(d,J=8.0Hz,1H),3.61(s,2H),3.20(t,J=6.4Hz,2H),1.16-1.13(m,1H),0.52-0.47(m,2H),0.33-0.29(m,2H).

[0275] General Procedure G: [ka]

[0276] 35-2 Synthesis of 3-cyano-4-[(cyclopropylmethyl)amino]benzoic acid [ka] To a mixture of 3-cyano-4-fluorobenzoic acid (5 g, 30.3 mmol, 1 equiv.) and cyclopropylmethanamine (5.38 g, 75.7 mmol, 2.5 equiv.) in dimethyl sulfoxide (30 mL) was added potassium carbonate (12.6 g, 90.8 mmol, 3 equiv.) at 20 °C. The mixture was then heated to 100 °C and stirred for 16 h. The mixture was filtered, and the filtrate was diluted with water (50 mL) and acidified to pH = 4-5 with hydrochloride solution (2 N). A yellow solid precipitated, and the suspension was filtered, and the solid was washed with water (50 mL × 3). The solid was dried in vacuo to give the desired product 35-2 (5 g, 73% yield). 1HNMR(400MHz,DMSO-d6)δ=7.95(d,J=1.2Hz,1H),7.90(d,J=9.2Hz,1H),6.88(d,J=9.2Hz,1H), 6.85-6.82(m,1H),3.13(t,J=6.0,2H),1.16-1.06(m,1H),0.49-0.44(m,2H),0.29-0.25(m,2H).

[0277] 36-2 Synthesis of 5-[3-(1H-indol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(prop-2-en-1-yl)amino]benzonitrile [ka] To a mixture of tert-butyl 5-[5-[4-(allylamino)-3-cyano-phenyl]-1,2,4-oxadiazol-3-yl]indole-1-carboxylate (60.0 mg, 136 μmol, 1.00 equiv) in dichloromethane (10.0 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 50 equiv) at 20 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Gemini 150 × 25 5 μl, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 47% to 77%, 12 min) to give product 36-2 (15 mg, 30% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=8.33(s,1H),8.27 (d,J=2.0Hz,1H),8.14(dd,J=8.8,2.0Hz,1H),7.80(dd,J=8.4,1.2Hz,1H),7.56(d,J=8.8Hz,1H),7.48(t,J=2.4Hz ,1H),7.39(t,J=5.6Hz,1H),6.91(d,J=8.8Hz,1H),6.61(s,1H),5.94-5.85(m,1H),5.24-5.16(m,2H),3.97(s,1H).

[0278] General Procedure H: [ka]

[0279] 38-4 Synthesis of 1-cyclopentyl-N-hydroxy-1H-1,2,3-benzotriazole-5-carboximidamide [ka]

[0280] 38-1 Synthesis of 4-(cyclopentylamino)-3-nitrobenzonitrile [ka] Preparation of 1: To a solution of 4-fluoro-3-nitro-benzonitrile (1.00 g, 6.02 mmol, 1.00 equiv.) and cyclopentanamine (767 mg, 9.03 mmol, 1.50 equiv.) in THF (20.00 mL), DIEA (1.95 g, 15.05 mmol, 2.63 mL, 2.50 equiv.) was added, and the mixture was stirred at 10 °C for 16 h. The mixture was evaporated to dryness, diluted with HO (50 mL), extracted with DCM (50 mL × 2), dried over NaSO, filtered, and concentrated to dryness. Compound 4-(cyclopentylamino)-3-nitrobenzonitrile (1.36 g, 5.91 mmol, 98.10% yield) was obtained as a yellow solid, which was used directly in the next step.

[0281] 38-2 Synthesis of 3-amino-4-(cyclopentylamino)benzonitrile [ka] Preparation of 2: A solution of 4-(cyclopentylamino)-3-nitro-benzonitrile (5.00 g, 21.62 mmol, 1.00 equiv) in MeOH (150.00 mL) was added to Pd / C (1.00 g, 4.32 mmol, 10% purity, 0.20 equiv) was added. The mixture was then stirred under H (50 psi) at 20 °C for 12 h. The mixture was filtered, and the filtrate was concentrated to dryness to give 3-amino-4-(cyclopentylamino)benzonitrile (4.20 g, 20.87 mmol, 96.52% yield) as a black solid, which was used directly in the next step. 1 HNMR(400MHz,DMSO-d6)δ=8.77(s,1H),8.12(d,J=8.7Hz,1H),7.91(d,J=8.7Hz,1H),5. 43(m,1H),2.37-2.21(m,2H),2.18-2.06(m,2H),1.99-1.85(m,2H),1.81-1.67(m,2H).

[0282] 38-4: Synthesis of 1-cyclopentyl-N-hydroxy-1H-1,2,3-benzotriazole-5-carboximidamide [ka] Preparation of 3: To a solution of 1-cyclopentylbenzotriazole-5-carbonitrile (1.50 g, 7.07 mmol) in ethanol (15.00 mL), hydroxylamine hydrochloride (736.64 mg, 10.60 mmol) and DIPEA (2.01 g, 15.55 mmol, 2.72 mL) were added. The mixture was then stirred at 70° C. for 4 hours. The mixture was filtered to give 1-cyclopentyl-N-hydroxy-benzotriazole-5-carboxamidine (1.20 g, 4.89 mmol, 69.20% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.77 (s, 1H), 8 .31 (s, 1H), 7.97 - 7.89 (m, 1H), 7.87 - 7.79 (m, 1H), 5.98 (s, 2H), 5.34 (q, J=7.0 Hz, 1H), 2.36 - 2.21 (m, 2H), 2.19 - 2.07 (m, 2H), 1.99 - 1.84 (m, 2H), 1.81 - 1.67 (m, 2H).

[0283] General Procedure I: [ka]

[0284] 42-2 Synthesis of 5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]-1-cyclopentyl-1H-1,2,3-benzotriazole [ka] To a solution of 3-methylbenzoic acid (66.61 mg, 489.24 μmol) in DMF (4.00 mL) were added EDCI (93.79 mg, 489.24 μmol) and HOBt (66.11 mg, 489.24 μmol). The mixture was stirred at 20° C. for 1 hour, and 1-cyclopentyl-N-hydroxy-benzotriazole-5-carboxamidine (100.00 mg, 407.70 μmol) was added to the mixture. The mixture was then stirred at 120° C. for 12 hours under N2. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC (TFA) to give t3-(1-cyclopentylbenzotriazol-5-yl)-5-(m-tolyl)-1,2,4-oxadiazole (96.00 mg, 277.94 μmol, 68.17% yield) as a white solid. 1 HNMR(400MHz,CDCl3)δ=8.93(s,1H),8.30(dd,J=1.3,8.7Hz,1H),8.08(s,1H),8.06(br d,J=6.8Hz,1H),7.68(d,J=8.8Hz,1H),7.51-7.42(m,2H),5.22(quin,J=7.0H z,1H),2.50(s,3H),2.43-2.32(m,4H),2.15-2.01(m,2H),1.92-1.81(m,2H).

[0285] 44-2 Synthesis of 2-{5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]-1H-1,2,3-benzotriazol-1-yl}acetic acid [ka] To a solution of methyl 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl]acetate (40.00 mg, 96.57 μmol, 1.00 equiv) in dioxane (2.00 mL) and HO (2.00 mL), NaOH (15.45 mg, 386.28 μmol, 4.00 equiv) was added. The mixture was then stirred at 20 °C for 12 h. The mixture was adjusted to pH 2-3 with HCl (1 N) and extracted with ethyl acetate (15 mL × 2). The organic layer was dried over Na2SO4 and concentrated to give 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl]acetic acid (17.30 mg, 43.23 umol, 44.76% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=8.70(s,1H),8.26 (m,3H),7.93(m,2H),7.66(m,2H),5.24(brs,2H)

[0286] 45-1 Synthesis of 2-{5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]-1H-1,2,3-benzotriazol-1-yl}ethan-1-ol [ka] To a solution of methyl 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl]acetate (50.00 mg, 120.71 umol, 1.00 equiv) in THF (1.00 mL) was added LiBH (5.26 mg, 241.42 umol, 2.00 equiv) and stirred at 10 °C for 16 h. The mixture was diluted with HO (20 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (TFA condition) to give 2-[5-[5-(2-bromophenyl)-1,2,4-oxadiazol-3-yl]benzotriazol-1-yl]ethanol (10.00 mg, 25.89 μmol, 21.45% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=8.74(s,1H),8.43 (brs,1H),8.25(dd,J=1.1,8.8Hz,1H),8.17(dd,J=1.9,7.4Hz,1H),8.12(d,J=8.7Hz,1 H),8.01-7.92(m,1H),7.74-7.60(m,2H),4.84(t,J=5.1Hz,2H),3.93(t,J=5.1Hz,2H).

[0287] General Procedure J: [ka]

[0288] 46-1 Synthesis of 3-(2-isopropoxyphenyl)-5-(1-isopropylindol-5-yl)-1,2,4-oxadiazole [ka] To a solution of N-hydroxy-2-isopropoxy-benzamidine (90.00 mg, 393.86 umol, 1.00 equiv) in DMF (2.00 mL) was added 1-isopropylindole-5-carboxylic acid (80.05 mg, 393.86 umol, 1.00 equiv), HOBt (63.86 mg, 472.63 umol, 1.20 equiv), and EDCI (90.60 mg, 472.63 umol, 1.20 equiv), and the reaction was stirred at 120° C. for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give 3-(2-isopropoxyphenyl)-5-(1-isopropylindol-5-yl)-1,2,4-oxadiazole (26.00 mg, 71.93 μmol, 18.26% yield, 98.9% purity) as a yellow oil. 1 H NMR (400MHz,chloroform-d)δ=8.56(d,J=1.1Hz,1H),8.10(dt,J=1.7,8.6Hz,2H),7.53-7.43(m,2H),7.35(d,J=3.3Hz, 1H),7.14-7.07(m,2H),6.69(d,J=3.3Hz,1H),4.81-4.65(m,2H),1.60(d,J=6.7Hz,7H),1.46(d,J=6.1Hz,6H).

[0289] 48-2 Synthesis of 5-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-(propan-2-yl)-1H-1,2,3-benzotriazole [ka] To a solution of 1-isopropylbenzotriazole-5-carboxylic acid (100.00 mg, 487.31 μmol, 1.00 equiv) in DMF (1.00 mL) was added HOBt (79.01 mg, 584.77 μmol, 1.20 equiv) and EDCI (112.10 mg, 584.77 μmol, 1.20 equiv). The mixture was stirred at 10° C. for 0.5 h, and then N-hydroxy-2-methoxy-benzamidine (80.98 mg, 487.31 μmol, 1.00 equiv) was added and stirred at 120° C. for 12 h. The mixture was diluted with HO (20 mL) and extracted with EA (30 mL × 2). The combined organic layer was dried over NaSO, filtered, concentrated, and dried. The residue was purified by preparative HPLC (column: Welch Ultimate AQ-C18 150 x 30 mm x 5 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 50% to 80%, 13 min) to obtain 5-(1-isopropylbenzotriazol-5-yl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (110.00 mg, 328.01 μmol, yield 67.31%) as a white solid. 1 H-NMR (400MHz,chloroform-d)δ=8.99(s,1H),8.36(dd,J=1.2,8.7Hz,1H),8.17(dd,J=1.6,7.7Hz,1H),7.74(d,J=8.7 Hz,1H),7.59-7.48(m,1H),7.20-7.05(m,2H),5.16(spt,J=6.8Hz,1H),4.03(s,3H),1.81(d,J=6.8Hz,6H).

[0290] General Procedure K: [ka]

[0291] 49-1: Synthesis of 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carbothioamide [ka] To a solution of 1-isopropylbenzotriazole-5-carbonitrile (2 g, 10.74 mmol, 1 equiv.) in HCl / dioxane (100 mL, 4 M), thioacetamide (1.61 g, 21.48 mmol, 2 equiv.) was added and stirred for 2 h at 110° C. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (PE / EA=2 / 1 to 1 / 1) to give 1-isopropylbenzotriazole-5-carbothioamide (2.1 g, 9.53 mmol, 88.76% yield) as a yellow solid.

[0292] 51-25-{5-[2-(methyl-λ 3 Synthesis of {1-(2-hydroxyphenyl)-1,3-thiazol-2-yl}-1-(propan-2-yl)-1H-1,2,3-benzotriazole [ka] To a solution of 1-isopropylbenzotriazole-5-carbothioamide (300 mg, 1.36 mmol, 1 equiv.) in DMF (3 mL) was added CsCO (443.71 mg, 1.36 mmol, 1.00 equiv.) and 2-bromo-1-(2-methoxyphenyl)ethanone (311.95 mg, 1.36 mmol, 1 equiv.). The mixture was stirred at 100° C. for 12 h. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 60%-90%, 10 min) to give 2-(1-isopropylbenzotriazol-5-yl)-5-(2-methoxyphenyl)thiazole (190 mg, 509.65 μmol, yield 37.42%, purity 94%) as a yellow solid. 1H NMR (400MHz,chloroform-d)δ=8.60(s,1H),8.37(dd,J=1.7,7.8Hz,1H),8.22(dd,J=1.1,8.8Hz,1H),7.91(s,1H),7.55(d,J=8.8Hz,1H) ),7.31-7.23(m,1H),7.05(t,J=7.5Hz,1H),6.96(d,J=8.3Hz,1H),5.04(spt,J=6.8Hz,1H),3.92(s,3H),1.70(d,J=6.7Hz,6H).

[0293] General Procedure L: [ka]

[0294] 52-1: Synthesis of 1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carboxamide: To a solution of 46-1 (1.0 g, 5.4 mmol) in HOAc (10 mL) was added HSO (0.5 mL) and the reaction was heated at 120 °C for 90 min in a MW oven. It was cooled overnight. The reaction mixture was poured onto ice, neutralized, and extracted with EtOAc. The solvent was evaporated to give a dark solid. Silica gel chromatography (10-50% acetone in hexanes) afforded the residue, which was triturated with a small amount of acetone, and the off-white solid was collected by filtration to give the title compound (52-1) (0.5 g, 45%).

[0295] 52-3: Synthesis of 5-(4-phenyl-1,3-oxazol-2-yl)-1-(propan-2-yl)-1H-1,2,3-benzotriazole: To a mixture of 52-1 (50 mg, 0.25 mmol) and 52-2 (51 mg, 0.25 mmol), AgSbF6 (86 0.25 mmol) was added, and the mixture was heated to 90 °C for approximately 3 h and then cooled to room temperature. The reaction was worked up with NaHCO3 and CHCl2. The organic layer was separated and evaporated to give a dark oil. The residue was chromatographed (0-5% MeOH in CHCl2) to give a residue that was further purified by reverse-phase HPLC. The appropriate fractions were combined and lyophilized to give the title compound as an off-white solid. (7 mg, 10%).

[0296] General Procedure M [ka]

[0297] Synthesis of 5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-amine 53-2: To a solution of 53-1 (1.9 g, 10.0 mmol) in CHCl (50 mL) was added DMF (0.2 mL), followed by oxalyl chloride (1.7 mL, 20.0 mmol) in small portions, and the solution was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo. To the residue was added thiosemicarbazide (1.1 g, 15 mmol), followed by POCl (2.8 mL, 30 mmol), and the reaction mixture was heated to 90 °C. After approximately 45 min to 1 h, the heat was turned off and allowed to cool overnight. The mixture was quenched with ice and treated with KCO and EtOAc. The organic layer was washed with saturated NaHCO and dried over NaSO. Filtration and evaporation gave a yellow residue which was triturated with CH2Cl2 to recover the title compound as a beige solid (0.9 g, 43%). This material was used directly in the next step.

[0298] Synthesis of 2-bromo-5-(2-methoxyphenyl)-1,3,4-thiadiazole 53-3: A mixture of t-Bu-nitrite (0.9 mL, 9.6 mmol) and CuBr (2.2 g, 9.6 mmol) in MeCN (30 mL) was stirred for 10 min, and then 53-2 (0.9 g, 1.76 mmol) was added in two portions. Stirring was continued for approximately 1 h, and then the solvent was removed in vacuo. The residue was suspended in EtOAc and washed twice with 1 N HCl, followed by brine and drying over Na SO . Filtration and evaporation afforded the title compound as a yellow-orange solid (1 g, 86%).

[0299] Synthesis of 5-[5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl]-1-(propan-2-yl)-1H-1,2,3-benzotriazole 53-4: 52-3 (95 mg, 0.25 mmol), 14-5 (45 mg, 0.3 mmol), KPO (132 mg, 0.625 mmol), and Pd(PhP) (58 mg, 0.05 mmol) were combined in a mixture of DMF (4 mL) and water (1 mL). The mixture was heated at 120 °C for 30 min in a microwave oven. The residue was evaporated and chromatographed on silica (0-30% EtOAc in hex). The appropriate fractions were combined and the solvent was evaporated. The residue was further purified by reverse-phase HPLC to give the title compound (30 mg, 20%) as an off-white solid.

[0300] Synthesis of 2-{3-[1-(propan-2-yl)-1H-1,2,3-benzotriazol-5-yl]-1,2,4-thiadiazol-5-yl}phenol 53-5:5 3-4 (40 mg, 0.11 mmol) was dissolved in HR and heated to 120 °C. After about 48 h, the starting material disappeared. It was neutralized with NaHCO3. The residue was purified by reverse phase HPLC to give the title compound (10 mg, 22%). [M+H] + :338.0

[0301] General Procedure N [ka]

[0302] 54-3: Synthesis of 4-amino-3-(3-ethyl-3-hydroxypent-1-yn-1-yl)benzonitrile To a solution of compound 54-1 (1 g, 5.08 mmol, 1 equiv.) in DMF (7 mL) and TEA (2.18 g, 21.55 mmol, 3 mL, 4.25 equiv.), compound 54-2 (683.15 mg, 6.09 mmol, 783.43 μL, 1.2 equiv.), CuI (48.33 mg, 253.77 μmol, 0.05 equiv.), and Pd(PPh3)2Cl2 (178.12 mg, 253.77 μmol, 0.05 equiv.) were added. The mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. TLC showed the formation of one new spot. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL × 2), washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (PE:EA=5:1) to give compound 3 (1 g, 86% yield) as a yellow oil. 1 HNMR(400MHz,CDCl3)δ=7.52(d,J=1.6Hz,1H),7.34(dd,J=8.6,1.8Hz,1H),6.68(d,J=8.4Hz,1H ),4.76(s,2H),2.95(s,1H),2.88(s,1H),2.32(s,1H),1.85-1.70(m,4H),1.10(t,J=7.4Hz,6H).

[0303] 54-4: Synthesis of 2,2-diethyl-4-oxo-1,3-dihydroquinoline-6-carboxylic acid A mixture of compound 54-3 (300 mg, 1.31 mmol) in concentrated hydrochloric acid solution (1 mL) and acetic acid (1 mL) was stirred at 115° C. for 3 h. The mixture was basified with 1N sodium hydroxide solution to pH=10, washed with EtOAc (20 mL×3), and the aqueous phase was acidified with 1N hydrochloric acid solution to pH=3, filtered, and the filtrate cake was washed with water (10 mL) and dried under vacuum to give compound 54-4 (35 mg, 11% yield) as a white solid. 1H NMR (400MHz, DMSO-d6)δ=12.08(br.s,1H), 7.90(d,J=2.0Hz,1H),7.52(dd,J=2.0,8.7Hz,1 H),7.14(s,1H),6.58(d,J=8.7Hz,1H),1.73(s,1H),1.36-1.19(m,4H),0.58(t,J=7.4Hz,6H).

[0304] 55-1: Synthesis of 2,2-diethyl-6-[3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl]-1,3-dihydroquinolin-4-one [ka] To a solution of compound 54-4 (100 mg, 404.39 μmol, 1 equiv.) in DMF (1 mL) was added HOBt (65.57 mg, 485.26 μmol, 1.2 equiv.) and EDCI (93.02 mg, 485.26 μmol, 1.2 equiv.). After stirring at 20° C. for 30 min, compound 55-2 (63.24 mg, 444.82 μmol, 1.1 equiv.) was added and stirred for an additional 30 min. The mixture was then heated to 120° C. and stirred for 2 h. The mixture was triturated with EA (20 mL), filtered, washed with EA (10 mL), and the residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 50%-80%, 13 min) to give 55-1 (45 mg, 29% yield) as an orange solid. 1 HNMR(400MHz,DMSO-d6)δ=8.36-8.27(m,2H),7.96(dd,J=2.0,8.8Hz,1H),7.79(dd,J=3.0,5.0Hz,1H),7.71 (s,1H),7.62(d,J=5.0Hz,1H),6.99(d,J=8.9Hz,1H),2.59(s,2H),1.67-1.48(m,4H),0.86(t,J=7.3Hz,6H).

[0305] General Procedure O [ka]

[0306] 57-3: Synthesis of 5-(4-methoxy-1,3-benzoxazol-2-yl)-1-(2-methylpropyl)-1,2,3-benzotriazole [ka]

[0307] 57-2: Synthesis of N-(2-hydroxy-6-methoxyphenyl)-1-(2-methylpropyl)-1,2,3-benzotriazole-5-carboxamide To a solution of compound 57-1 (100 mg, 487.30 μmol, 1 equiv.) in DMF (3 mL) was added HOBt (65.85 mg, 487.30 μmol, 1 equiv.) and EDCI (112.10 mg, 584.76 μmol, 1.2 equiv.). After the addition, the mixture was stirred at 20° C. for 0.5 h, and then compound 57-4 (81.37 mg, 584.76 μmol, 1.2 equiv.) was obtained. mol, 1.2 equiv) was added and the mixture was stirred at 20°C for another 12 hours. LCMS showed consumed compound 57-1, and a major peak with the desired MS was detected. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL*2), washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give compound 57-2 (159 mg, crude) as a brown oil, which was used directly in the next step without further purification. LCMS: 327.2 [M+1]

[0308] 57-3: Synthesis of 5-(4-methoxy-1,3-benzoxazol-2-yl)-1-(2-methylpropyl)-1,2,3-benzotriazole To a solution of compound 57-2 (159 mg, crude) in xylene (10 mL) was added TsOH ·HO (370.70 mg, 1.95 mmol, 4 equiv.) was added. After the addition, the mixture was stirred at 120 °C for 2 h. LCMS showed consumed compound 57-2, and a major peak with the desired MS was detected. The mixture was concentrated, diluted with saturated sodium bicarbonate solution (20 mL), extracted with EtOAc (20 mL * 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergistic Purification by C18 150*25*10um, mobile phase: [water (0.1% TFA)-ACN], B%: 42%-72%, 10 min) gave 57-3 (53 mg, 35% yield) as a gray solid. 1 H NMR (400MHz, CDCl3)δ=8.95(s,1H),8.51(d d,J=1.1,8.8Hz,1H),7.69(d,J=8.8Hz,1H),7.37-7.31(m,1H),7.28-7.27(m,1H) ,6.85(d,J=7.9Hz,1H),5.18-5.08(m,1H),4.10(s,3H),1.80(s,3H),1.78(s,3H)

[0309] 58-3: Synthesis of 1-isopropyl-5-(7-methoxy-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole [ka]

[0310] 58-2: Synthesis of N-(2-bromo-3-methoxyphenyl)-1-isopropyl-1,2,3-benzotriazole-5-carboxamide A mixture of compound 58-1 (200 mg, 989.86 μmol, 1 equiv.), compound 58-1 (243.76 mg, 1.19 mmol, 1.2 equiv.), and EDCI (284.64 mg, 1.48 mmol, 1.5 equiv.) in pyridine (3 mL) was stirred at 20° C. for 12 hours. The mixture was diluted with EtOAc (30 mL), washed with 1N hydrochloric acid solution (20 mL*3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (PE:EA=3:1) to give compound 58-2 (150 mg, 38% yield) as a brown oil. LCMS: 391.1 [M+1]

[0311] 58-3: Synthesis of 1-isopropyl-5-(7-methoxy-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole Compound 58-2 (50 mg, 128.45 umol, 1 equiv) in DME (2 mL), A mixture of 1,10-phenanthroline (2.31 mg, 12.85 μmol, 0.1 equiv.), CsCO (62.78 mg, 192.68 μmol, 1.5 equiv.), and CuI (1.22 mg, 6.42 μmol, 0.05 equiv.) was heated to 85°C and stirred under a nitrogen atmosphere for 12 h. The mixture was diluted with EtOAc (20 mL), washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 45%-75%, 12 min) to give 58-3 (8 mg, 19% yield) as a gray solid. 1 H NMR (400MHz, DMSO-d6)δ=8.76(s,1H),8.32 (dd,J=1.3,8.8Hz,1H),8.13(d,J=8.7Hz,1H),7.44-7.28(m,2H),7.07(d,J=7.8Hz,1H),5.29(spt,J=6.7Hz,1H),4.02(s,3H),1.66(d,J=6.6Hz,6H).

[0312] 59-3: Synthesis of 1-isopropyl-5-(6-methoxy-4-methyl-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole [ka]

[0313] 59-3: Synthesis of 1-isopropyl-5-(6-methoxy-4-methyl-1,3-benzoxazol-2-yl)-1,2,3-benzotriazole To a solution of compound 59-2 (1-isopropyl-N-(4-methoxy-2-methylphenyl)-1,2,3-benzotriazole-5-carboxamide), prepared according to the procedure for preparing 58-2 (50 mg, 154.14 μmol, 1 equiv.), in o-xylene (2 mL) was added Cu(OTf) (11.12 mg, 30.83 μmol, 0.2 equiv.). The reaction was stirred at 130° C. for 16 h under an oxygen atmosphere. The mixture was diluted with water (20 mL), extracted with EtOAc (30 mL*3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (PE:EA=4:1) to give 59-3 (1.1 mg, 2% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ=8.80(s,1H),8.33(d d,J=1.4,8.7Hz,1H),7.59(d,J=8.8Hz,1H),6.91(d,J=2.2Hz,1H),6.72(d,J= 1.5Hz,1H),5.16-4.93(m,1H),3.81(s,3H),2.58(s,3H),1.72(d,J=6.8Hz,6H)

[0314] Example 2: In vitro activity of compounds DiscoverX has developed stable cloned Chinese hamster ovary K1 (CHO-K1) cells co-expressing EA-β-arrestin2 and human sphingosine-1-phosphate receptor 1 (NM_001400, S1P1) with a C-terminal Prolink™ tag. Corporation (catalog number: 93-0207C2).

[0315] Cell culture and assay seeding Cell lines were cultured in AssayComplete™ Media 6 (DiscoverX Corporation, Catalog No. 920018GF2) in a humidified CO - and temperature-controlled incubator at 37° C. and 5% CO To initiate assay seeding, cells were washed with Dulbecco's Phosphate Buffered Saline (CellGro, Catalog No. 21-031-CV) and lifted from the culture flask by incubation in a CellStripper (Cellgro, Catalog No. 25-056-CI) (37° C., 5 min). The lifted cells were resuspended at 250,000 cells per milliliter in AssayComplete™ Cell Plating 11 Reagent (DiscoverX Corporation, Catalog Number: 93-0563R11B) and plated at 5,000 cells per well into white, opaque 384-well plates (GreinerBio-One Item Number: 20-784080). The plated cells were incubated overnight at 37°C and 5% CO in a humidified, CO and temperature-controlled incubator.

[0316] Detection of inhibition of cAMP production Agonist-stimulated G protein responses were measured by measuring changes in intracellular cAMP using the HTRF® cAMP HiRange Kit (CisBio, catalog number: 62AM6PEJ), which is based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology. The AssayComplete™ Cell Plating 11 reagent was removed and replaced with Ham's F-12 (CellGro, catalog number: 10-080-CM) containing isobutyl-methyl-xanthine (IBMX, 500 μM, Tocris Bioscience, catalog number: 2845) and NKH-477 (1.5 μM, Tocris Bioscience, catalog number: 1603) along with the desired concentrations of test or reference compounds. After 30 minutes of incubation at 37°C and 5% CO in a humidified CO2- and temperature-controlled incubator, the components of the cAMP HiRange Kit were added according to the manufacturer's instructions. After 1 hour of incubation at room temperature, the plates were analyzed by a BMG PheraStar microplate reader. The response was measured as the ratio of fluorescence emission at 665 nm to fluorescence emission at 620 nm.

[0317] β-arrestin 2 recruitment assay Agonist-stimulated β-arrestin2 recruitment to sphingosine-1-phosphate 1 receptors was determined using the β-arrestin PathHunter® Detection Kit (DiscoverX Corporation, catalog number 93-0001). In this system, β-arrestin2 is fused to an N-terminal deletion mutant of β-galactosidase (termed the enzyme acceptor or EA), and the C-terminus of a GPCR of interest is fused to a smaller (42 amino acid) weakly complementary fragment called ProLink™. In cells stably expressing these fusion proteins, stimulation with a cognate agonist results in the interaction of β-arrestin2 and the ProLink™-tagged GPCR. This allows complementation of the two β-galactosidase fragments, resulting in the formation of a functional enzyme with β-galactosidase activity. The AssayComplete™ Cell Plating 11 reagent was removed and replaced with Ham's F-12 containing IBMX (500 μM) and NKH-477 (1.5 μM) along with the desired concentrations of test or reference compounds. After 60 minutes of incubation at 37°C and 5% CO in a humidified CO and temperature-controlled incubator, the components of the β-arrestin PathHunter® Detection Kit were added according to the manufacturer's instructions. After 1 hour of incubation at room temperature, the plates were analyzed using a BMG PheraStar microplate reader.

[0318] activity table The compounds described herein were able to modulate the activity of sphingosine-1-phosphate 1 receptors (inhibition of cAMP production and β-arrestin2 recruitment) as described herein. The following tables contain the potencies of the compounds normalized to the maximal potency of a reference compound, referred to as "SPAN." These values ​​are normalized to fingolimod, a known agonist of sphingosine-1-phosphate 1 receptors. The tables also contain potency values ​​(pEC50) for modulating individual receptor-mediated activities (inhibition of cAMP production and β-arrestin2 recruitment). This value represents the estimated concentration to promote half of the maximal potency (or SPAN) observed for each compound. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17]

[0319] Example 3: Compounds are expected to be effective in protecting animals from induced seizures in the mouse 6 Hz 44 mA psychomotor seizure model. Compounds are tested for efficacy in a 6 Hz, 44 mA psychomotor seizure model in mice. The 6 Hz, 44 mA model assesses the ability of compounds to prevent seizures induced by 6 Hz corneal stimulation at a current intensity of 44 mA. These seizures are considered to model partial seizures observed in humans. The 6 Hz test employs the same technique as described for the MES test. Mice are challenged for 3 seconds with a 44 mA current (twice that of CC97) delivered through corneal electrodes to induce psychomotor seizures (1). Typically, seizures are characterized by an initial, transient stun, followed immediately by jaw clonus, forelimb clonus, vibrissa twitching, and tail lift lasting at least 1 second. Animals that do not exhibit this behavior are considered "protected."

[0320] Initial qualitative screening for anticonvulsant activity in the 6 Hz seizure model is performed on N = 4 male CF-1 mice per dose per time point. The default doses and time points are 0.1, 1, and 10 mg / kg sc at 0.5 and 2 hours post-dose. The dose and / or time point may be adjusted if supported by other study data. ED50 quantification is performed at the time of peak effect (TPE). To determine TPE, mice are treated with the investigational compound at 0.25, 0.5, 1.0, 2.0, and 4.0 hours, or based on time points from previous studies. Groups of N = 8 mice are tested with various doses of the investigational compound until at least two points between 100% protection or the limit of toxicity and 0% protection can be clearly established (i.e., at least four test doses). Data for each condition are presented as N / F, where N = number of animals protected and F = number of animals tested. The ED50, 95% confidence interval, slope of the regression line, and SEM of the slope are calculated by Probit analysis.

[0321] Example 4: Compounds are expected to be effective in protecting animals from induced seizures in the mouse subcutaneous metrazol seizure model and the intravenous metrazol seizure threshold model. Compounds are tested for efficacy in the subcutaneous metrazol seizure model and the intravenous metrazol seizure threshold model in mice.

[0322] Subcutaneous metrazol seizure threshold test (scMET) The scMET test detects the ability of test compounds to elevate the chemical seizure threshold of animals, thus protecting them from exhibiting clonic forebrain seizures. A dose of 85 mg / kg of metrazol in mice and 56.4 mg / kg in rats was injected into a loose fold of skin at the midline of the neck. Animals were placed in isolation cages to minimize stress and observed for the next 30 minutes for the presence or absence of seizures. The endpoint was the approximately 3-5 second onset of clonic convulsions of the forelimbs and / or hindlimbs, jaw, or vibrissae. Forelimb and / or hindlimbs clonus, jaw biting, or sensory hair clonus were not observed. Animals that do not exhibit hair twitching are considered protected.

[0323] Initial qualitative screening for anticonvulsant activity in the scMET test is performed on N = 4 male CF-1 mice per dose per time point. Baseline doses and time points are 1, 2.5, 5, 7.5, and 10 mg / kg sc at 0.5 and 2 hours post-dose. Dose and / or time points may be adjusted if supported by other study data. ED50 quantification is performed at the time of peak effect (TPE). To determine TPE, mice are treated with the investigational compound at 0.25, 0.5, 1.0, 2.0, and 4.0 hours, or based on time points from previous studies. Groups of N = 8 mice are tested with various doses of the investigational compound until at least two points can be clearly established between 100% protection or the limit of toxicity and 0% protection (i.e., at least four test doses). Data for each condition are presented as N / F, where N = number of animals protected and F = number of animals tested. The ED50, 95% confidence interval, slope of the regression line, and SEM of the slope are calculated by Probit analysis.

[0324] Intravenous Metrazol Seizure Threshold Test (ivMET) Although this test is not routinely performed, it is useful for assessing the effects of investigational compounds on MET. That is, whether the compound increases or decreases the threshold at which seizures can be induced by MET. Timed intravenous infusion of MET into mice is used as a chemoconvulsant test to distinguish between compounds that lower the seizure threshold and thus may be proconvulsants, and compounds that increase the seizure threshold and therefore are anticonvulsants. Male CF1 mice (n = 10 per dose level) are injected 2 minutes apart with vehicle or one of two doses (ED50 and TD50, i.p.) of a test compound previously determined to be effective in seizure testing and motor impairment assessment screening. During dosing, animals maintain the same dosing order until all mice have been injected according to the described method. At the previously determined TPE, 0.5% MET solution is then infused into the lateral tail vein of the mice at a constant rate of 0.34 mL / min through a cannulated length of No. 20 PE tubing. At the start of the MET infusion, the hemostat clamped on the guide tube to prevent backflow was removed, the infusion was initiated, and two stopwatches were started. The time (seconds) from the start of the infusion to the appearance of the "first twitch" and the time to the onset of sustained clonus were recorded, or 90 seconds if a seizure-free interval had elapsed. The mean and SEM for each of the three groups (vehicle, ED50, and TD50) were calculated, as well as significant differences between the test group and the control. An increase in mg / kg to the first twitch or clonus indicates that the test substance increases the seizure threshold, while a decrease indicates that the test substance decreases the seizure threshold or may promote seizures.

[0325] Example 5: Compounds are expected to be effective in protecting animals from induced seizures in the mouse corneal ablation seizure model. Compounds are tested for efficacy in the mouse corneal ablation seizure model (CKM). The pharmacological profile of corneal ablation mice is consistent with human partial epilepsy, effectively identifying the anticonvulsant potential of compounds such as levetiracetam for this condition. Male C57BL / 6 mice are electrically ablated with corneal electrodes at 3 s, 3 mA, 60 Hz, and a criterion of five consecutive stage 5 seizures (facial clonus and head nodding progressing to forelimb clonus, and finally rearing and falling with generalized clonic seizures). After receiving corneal stimulation twice daily, mice typically reach their first stage 5 seizure within approximately 10–14 days. Stimulation continues twice daily for each mouse until the mouse achieves the criterion of five consecutive stage 5 seizures and is considered "fully ablated." The fully ablated mouse is then stimulated every other day until all other mice in the group reach the criterion of five consecutive stage 5 seizures. Mice that do not achieve a fully ablated state are not included in any evaluation of investigational compounds.

[0326] Testing of investigational compounds begins at least 5-7 days after the last stimulation. Mice are stimulated on day 1 to ensure that all mice used in drug studies exhibit stage 5 seizures. For identification studies, test compounds are administered at 3 and 5 mg / kg sc to groups of eight fully cauterized mice per group, with testing at 0.5 and 1 hour post-administration. Based on the experimental results, the compound is then retested to determine its ED50 value. After testing, the corneal-cauterized animals are returned to their home cages. Unlike the acute seizure studies performed by the ETSP, each corneal-cauterized mouse is allowed at least 3-4 days between tests to "wash out" any investigational compound after testing.

[0327] Example 6: Compound 469 can inhibit seizures. Compound 469 was tested as described in Example 5. Data for Compound 469 are shown in Tables 1-4. Compound 469 had an ED of 6.2 mg / kg at 2 hours in the corneal ablation stroke model. 50 It was found to have the following structure: [Table 4] [Table 5] [Table 6] [Table 7]

[0328] These data demonstrate that compounds provided herein, such as compound 469, can reduce seizures and therefore can be used to treat seizure disorders, such as those provided herein.

[0329] Example 7: Compounds are expected to be effective in protecting animals from induced seizures in the lamotrigine (LTG)-resistant amygdala ablation seizure model in rats. Compounds are tested for efficacy in a lamotrigine (LTG)-resistant amygdala ablation seizure model in rats. The LTG-resistant amygdala ablation rat model is useful not only for identifying compounds effective against secondarily generalized partial seizures, but also allows for the differentiation of compounds that may be effective in therapy-resistant patients. Daily administration of lamotrigine (LTG; 5 mg / kg) during the ablation acquisition phase does not prevent the development of ablation in test animals, but results in an LTG-resistant state in fully ablated rats. Other sodium channel blockers, such as phenytoin and carbamazepine, also do not block ablation acquisition, despite being highly effective against fully ablated seizures in drug-naive rats. Conversely, valproate can prevent the development and progression of ablation and block the development of fully ablated seizures. Addition of conventional ASDs, carbamazepine or lamotrigine, during the onset of ablation seizures in this model ultimately impairs the efficacy of lamotrigine against fully ablated seizures. These findings suggest that the presence of lamotrigine during the epileptogenic process leads to subsequent resistance to other Na+ channel blockers, making this a useful model of drug resistance. This model can serve as a means to identify compounds that may be effective against treatment-resistant seizures. Anesthetized male Sprague-Dawley rats (250-300 g) were surgically implanted with electrodes into the left amygdala. The animals were then allowed to recover for one week before initiating ablation. The ablation procedure consisted of delivering 200 μA of stimulation (suprathreshold) daily until all animals in both treatment groups exhibited consistent stage 4 or 5 seizures. One week after ablation of all animals, the animals received a challenge dose of LTG (30 mg / kg, i.p.) before being stimulated to confirm LTG sensitivity in vehicle-treated control animals and LTG resistance in the LTG-treated group. The animals were then allowed a three-day washout period. On the third washout day, the animals were pre-stimulated to ensure complete recovery of ablated seizures. On day 4, the cauterized rats are challenged with a dose of the study drug (the dose that produced minimal motor impairment) and then challenged with a cauterizing stimulus at a predetermined TPE of the study drug.If drug treatment is observed to significantly reduce seizure scores and afterdischarges, a dose-response study can be performed. For this study, the ability of the candidate substance to reduce afterdischarge duration (ADD) and behavioral seizure score (BSS) is quantified by varying doses between 0 and 100% effective. Unlike other acute seizure studies performed by the ETSP, each ablated rat is allowed to "wash out" any investigational compound after testing, with at least 3-4 days between tests. The mean seizure score ± SEM and afterdischarge duration (ADD) are recorded, as are the number of animals protected from seizures (defined as a Racine score <3) relative to the number of animals tested.

[0330] The following procedure is used for surgical implantation of electrodes. Male Sprague-Dawey rats are anesthetized using 1-3% isoflurane or a ketamine / xylazine cocktail. Ketamine is provided as a 100 mg / ml solution and dosed at 50 mg / kg i.p. Xylazine is provided as a 100 mg / ml solution and dosed at 20 mg / kg i.p. The two solutions are combined in one syringe and administered i.p. as a single injection. The rats are monitored throughout the surgery. If the rat responds to tail pinch, administer half the dose of ketamine / xylazine or increase the isoflurane rate. Administer 0.02 mg / kg sc buprenorphine for pain management. Shave the surface of the head using an electric razor. The rat is positioned over an external heat source on a stereotaxic apparatus to ensure the height of the incisor bar and the positioning of the ear bars are consistent with the reference guide. The entire scalp is scrubbed with Betadine (three times) and wiped with alcohol. Ophthalmic ointment is applied to each eye. All instruments are sterilized via autoclave before starting surgery. During surgery, instruments are placed on sterile drapes. For subsequent surgeries on the same day, instruments can be placed in a hot bead sterilizer between surgeries. Stainless steel screws and electrodes are sterilized with 70% alcohol and placed on sterile drapes. Using a sterile scalpel blade, begin the scalp incision from the midline at the eyes and return to an imaginary line connecting the ears. The fascia should be gently separated and pulled away from the scalp. The incision can be held open using a retractor / forceps. A dermal drill is used to drill screw holes without penetrating the dura, and four anchor screws are installed into the skull. The bipolar stimulating electrode was implanted through the fourth hole drilled in the left amygdala (anteroposterior, AP, +5.7 mm; mediolateral, ML, +4.5 mm; dorsoventral, DV, +2.0 mm from intraaural zero). The electrode assembly was fixed to the skull via stainless steel screws using dental acrylic cement. After the incision was closed with sutures, antibiotic ointment was applied around the incision. The rats were administered penicillin 60,000 units sc and Rimidyl injection 0.03 mg / kg. The rats were kept in a heat source until they were ambulatory.

[0331] Example 8: Compounds are expected to be effective in protecting animals from induced seizures in a pilot study of status epilepticus-induced spontaneous recurrent seizures as measured by video-EEG monitoring in rats. Compounds are tested for efficacy in a pilot study of status epilepticus-induced spontaneous recurrent seizures measured by video-EEG monitoring in rats.

[0332] Induction of chronic epilepsy: Forty-eight Sprague-Dawley rats are induced with status epilepticus using a repeated low-dose kainic acid (KA) paradigm. Rats are injected intraperitoneally (ip) with 7.5 mg / kg KA at time 0, 1 hour, and every half hour thereafter (up to 4 hours), or until the animals exhibit two Racine stage 5 seizures. The dose may be reduced by half or one-third as needed for animals exhibiting lower stage seizures. At the end of the injection period, rats are given 3 ml of Ringer's solution to prevent dehydration. Approximately 36 rats are expected to survive this procedure.

[0333] After 10 weeks, the rats are implanted with a Millar wireless telemeter. The telemeter is implanted in the peritoneal cavity. An EEG cable is routed from the stomach to the head under the skin. Three holes are drilled in the skull and three fixation screws are placed. Two additional holes are drilled and an EEG wire is placed in each. The wires are secured with super glue. The skull is sutured closed, the excess wire is wrapped around the peritoneal space, and the stomach is sutured closed. The rats are placed in the EEG suite and initial seizure rates are obtained over a 1-week period. The 24 rats with the highest seizure rates are selected. Rats with a seizure burden score (seizure burden is calculated as the sum of all seizure scores divided by the number of test days) of less than 10 per day are excluded from further studies.

[0334] Stage 1 Chronic Monitoring: In this paradigm, rats receive subcutaneous (sc) or oral (po) injections of vehicle or drug twice or three times daily based on the known pharmacokinetic profile of the drug being tested (if available) or the drug's time-to-peak effect (TPE) in a previously evaluated seizure model. (It is anticipated that the lamotrigine-resistant amygdala ablation model will be used as the primary guide for determining treatment strategy in the Stage 1 chronic monitoring study.) During the first week (Week 1), baseline seizure rates are determined. During the following week (Week 2), injections are administered over five days, Monday through Friday. Rats are divided into 8-12 groups (vehicle and drug-treated groups). After treatment is completed in Week 2, rats are monitored during Week 3 (a washout period). This process (Weeks 1-3) is repeated for up to five separate test runs.

[0335] Possible design variations include: (1) a crossover paradigm: one group receives the drug for the first 5 days (week 2) and the vehicle for the next 5 days (week 3). Similarly, the second group receives the vehicle first, followed by the drug. The rats then enter a 1-week washout period (week 4). (2) Group sizes can vary and will be updated once an initial power analysis is completed to verify the number of rats required to achieve statistical significance. For example, the initial group of 24 rats enrolled in chronic monitoring in Stage 1 can be divided into two (N = 12 / group) or three (N = 8 / group) treatment groups.

[0336] Data review and analysis EEG data are reviewed daily in a blinded manner. The order of data channels is randomly scrambled and unlabeled. A list of potentially detectable events is automatically generated overnight by an automated seizure detection algorithm. Reviewers review these detection lists in sequential order and score detected positive events. Data are accumulated at the end of the paradigm and analyzed via a MATLAB GUI. Factors analyzed include seizure burden, frequency, and Racine score distribution.

[0337] Example 9: Compounds are expected to be effective in protecting animals from induced seizures in an oral dosing study of status epilepticus-induced spontaneous recurrent seizures as measured by video-EEG monitoring in rats. Compounds are tested for efficacy in an oral dosing study of status epilepticus-induced spontaneous recurrent seizures, as measured by video-EEG monitoring in rats. This paradigm utilizes an automated feeder system to provide drug in the food on a fixed schedule. Induction of chronic epilepsy and implantation of telemeters in rats are performed identically to those described for the pilot study. Animals are divided into two groups and fed 45 g / kg of either drug or control food per day for two weeks. The amount of drug per gram in the food is fixed to ensure appropriate dosing. The number of "meals," i.e., automated pellet distribution, is based on the known pharmacokinetic profile of the drug being tested (if available) or the drug's time-to-peak effect (TPE) in previously evaluated seizure models. During the first week (week 1), baseline seizure rates are determined. During the following two weeks (weeks 2–3), rats are fed food based on their group. After treatment is completed in week 3, rats are monitored during week 4 (a washout period). This process (weeks 1–4) is repeated for up to four separate test runs.

[0338] Data review and analysis EEG data are reviewed daily in a blinded manner. The order of data channels is randomly scrambled and unlabeled. A list of potentially detectable events is automatically generated overnight by an automated seizure detection algorithm. Reviewers review these detection lists in sequential order and score detected positive events. Data are accumulated at the end of the paradigm and analyzed via a MATLAB GUI. Factors analyzed included seizure burden, frequency, and distribution of Racine scores.

[0339] Example 10: Compounds are expected to be effective in protecting animals from induced seizures in the PTZ (pentylenetetrazol) test Compounds were tested for efficacy in the PTZ (pentylenetetrazole) test. In the experiment, test animals (mice, ICR, and rats, SD) were administered intraperitoneally (ip) or orally. Male SD rats were purchased from OrientBio or Nara Biotech, Korea, and housed 4–5 mice per cage for 4–5 days. Mice weighed 19–26 g, and rats weighed 100–130 g. After peak times (0.5, 1, 2, and 4 h) from administration, PTZ (pentylenetetrazole) was administered subcutaneously at a concentration sufficient to induce 97% intermittent convulsions (mice and rats: 90–110 mg / kg body weight, 2 μl / g). If clonic seizures were not observed for at least 3 seconds in PTZ-administered animals, the test compound was considered to have nonconvulsive seizure activity. The median effective dose (ED50) is determined using 6 animals per concentration (a total of 3 different concentrations) and calculated by the Litchfield and Wicoxon log-probit method of dose-response relationships.

[0340] Example 11: Compounds are expected to be effective in protecting animals from induced seizures in the minimally clonic seizure (6 Hz) test. Compounds are tested for efficacy in the minimal clonic seizure (6 Hz) test. Some clinically useful AEDs are ineffective in standard MES and scPTZ tests, but still possess anticonvulsant activity in vivo. To identify potential AEDs with this profile, compounds can be tested in the minimal clonic seizure (6 Hz or "neuromotor") test (Barton et al. 2001). Similar to the maximal electroshock (EMS) test, the minimal clonic seizure (6 Hz) test is used to evaluate the efficacy of compounds against electrically induced seizures, but at a lower frequency (6 Hz) and with a longer stimulation duration (3 seconds).

[0341] Mice were pre-administered with test compounds via intraperitoneal injection. At various times, individual mice (four per time point) were challenged with sufficient current (32 or 44 mA, 3 seconds) delivered via corneal electrodes to induce psychomotor seizures in 97% of animals (Toman et al. 1952). Untreated mice exhibited seizures characterized by a minimal clonic phase followed by stereotyped voluntary movements, originally described as similar to the auras of human patients with partial seizures. Animals that did not exhibit this behavior were considered protected. The test could be quantitatively assessed by measuring responses at various doses at a determined time of peak effect (TPE). (See Barton ME, Klein BD, Wolf HH and White HS (2001) Pharmacological characterization of the 6Hz psychomotor seizure model of partial epilepsy,Epilepsy Res.47:217-227. / Toman JE, Everett GMand Richards RK(1952),The search for new drugs against epilepsy.Tex.Rep.Biol.Med.10:96-104.).

[0342] Example 12: Compounds are expected to be effective in protecting animals from induced seizures in the lithium-pilocarpine-induced status epilepticus model. Compounds are tested for efficacy in the lithium-pilocarpine-induced status epilepticus model.

[0343] Prevention Research Male Sprague-Dawley rats (purchased from Orient Bio Inc. Korea) weighing 200–230 g were used in these studies. They were housed four to five rats per cage for four to five days. The day before status epilepticus (SE), rats received 127 mg / kg lithium chloride (Sigma, St. Louis, MO, USA) intraperitoneally (i.p.). Approximately 18–20 h after this treatment, rats received 43 mg / kg pilocarpine (Sigma) intraperitoneally. Thirty minutes before pilocarpine, 2 mg / kg methylscopolamine (Sigma) was administered i.p. to block the effects of muscarinic agonists on peripheral cholinergic receptors. Test drugs were administered intraperitoneally (i.p.) at a volume of 2 μl / g body weight. The pharmacological effects of all test materials were evaluated and compared between the test group (n = 6) and the control group (n = 6). The control group received vehicle only. The peak time was determined by random dosing of the test material at 0.5, 1, 2, and 4 h. The time with the highest protection was defined as the peak time, and the ED50 was determined by administering other doses at the peak time. The animals were then transferred to observation cages and continuously observed for 90 min. Seizure activity was induced in approximately 95% of the control group. Protection was defined as the complete absence of seizure grades 4–5 based on the Racine scale (Racine, 1972) over the 90-min observation period. The effective dose of compound required to protect against seizures to 50% of controls (i.e., ED50) was determined by log-probit analysis using the SPSS software program (SPSS Inc.).

[0344] Intervention trials Male Sprague-Dawley rats (purchased from Orient Bio Inc. Korea) weighing 200–230 g were used in these studies. They were housed four to five rats per cage for four to five days. The day before SE, rats received 127 mg / kg lithium chloride (Sigma, St. Louis, MO, USA) intraperitoneally (i.p.). Approximately 18–20 h after this treatment, rats received 43 mg / kg pilocarpine (Sigma) intraperitoneally. Thirty minutes before pilocarpine, 2 mg / kg methylscopolamine (Sigma) was administered i.p. to block the effects of muscarinic agonists on peripheral cholinergic receptors. The effects of test compounds dissolved in 30% polyethylene glycol 400 (Acros Organics, Geel, Belgium) or 20% Tween 80 were studied at various times or 30 minutes after the first motor seizure or SE onset. Drugs were administered intraperitoneally at a volume of 2 μl / g body weight. Pharmacological effects were evaluated by comparing the test and control groups (n=8). The control group received vehicle only. (See Racine RJ (1972). Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroenceph. Clin. Neurophysiol. 32:281-294.)

[0345] Example 13: Compounds are expected to be potential pharmacological treatments for benzodiazepine-resistant status epilepticus. The compounds were tested for efficacy in a study of potential pharmacological treatments for benzodiazepine-resistant status epilepticus.

[0346] The lithium-pilocarpine model is used to study the effects of test compounds on the electrographic characteristics of benzodiazepine-resistant SE. Adult rats are implanted for electroencephalography (EEG) recording and then pretreated with lithium chloride (127 mg / kg, 24 hours) and scopolamine bromide (1 mg / kg; 30 minutes) before administration of pilocarpine (50 mg / kg). Thirty or 60 minutes after the onset of the first motor seizure, animals receive diazepam (10 mg / kg). Ten minutes after diazepam, experimental groups receive the test compound and control groups receive vehicle. Typically, eight animals constitute a "study," with two animals serving as controls (i.e., vehicle only) and six receiving the test compound; this is dependent on the number of animals that actually experience SE. The number of trials varies depending on the animal. To have a sufficient number of replicates, two (or more) trials are performed. If necessary, additional control animals are derived from other temporally adjacent trials using the same protocol.

[0347] Example 14: Compounds selective for the S1P1 receptor In vitro selectivity assay Stable cloned Chinese hamster ovary K1 (CHO-K1) cells co-expressing EA-β-arrestin2 and human sphingosine-1-phosphate receptor 2 (NM_004230.3, S1P2), human sphingosine-1-phosphate receptor 3 (NM_005226, S1P3), and sphingosine-1-phosphate receptor 5 (NM_001166215.1, S1P5) with a C-terminal Prolink™ tag were purchased from DiscoverX Corporation (S1P2: Catalog No. 93-0256C2, S1P3: Catalog No. 93-0217C2, S1P5: Catalog No. 93-0583C2).

[0348] Cell culture and assay seeding Cell lines were cultured in AssayComplete™ Media 6 (DiscoverX Corporation, Catalog No. 920018GF2) in a humidified CO - and temperature-controlled incubator at 37° C. and 5% CO To initiate assay seeding, cells were washed with Dulbecco's Phosphate Buffered Saline (CellGro, Catalog No. 21-031-CV) and lifted from the culture flask by incubation in a CellStripper (Cellgro, Catalog No. 25-056-CI) (37° C., 5 min). The lifted cells were resuspended at 250,000 cells per milliliter in either AssayComplete™ Cell Plating 11 Reagent (S1P5 cell line) (DiscoverX Corporation, Catalog Number: 93-0563R11B) or AssayComplete™ Cell Plating 2 Reagent (S1P2 and S1P3 cell lines) (DiscoverX Corporation, Catalog Number: 93-0563R2B) and plated at 5,000 cells per well (S1P3 cell line) or 7,500 cells per well (S1P2 and S1P5 cell lines) into white, opaque 384-well plates (Greiner Bio-One Item Number: 20-784080). The plated cells were incubated overnight at 37°C and 5% CO in a humidified, CO2- and temperature-controlled incubator.

[0349] Detection of inhibition of cAMP production Based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology, S1P3 and S1P5 agonist-stimulated G protein responses were determined by measuring changes in intracellular cAMP using the HTRF® cAMP HiRange Kit (CisBio, catalog number: 62AM6PEJ). The AssayComplete™ Cell Plating 11 reagent was removed and replaced with Ham's F-12 (CellGro, catalog number: 10-080-CM) containing isobutyl-methyl-xanthine (IBMX, 500 μM, Tocris Bioscience, catalog number: 2845) and NKH-477 (1.5 μM, Tocris Bioscience, catalog number: 1603) along with the desired concentrations of test or control compounds. After a 30-minute room temperature incubation, the components of the cAMP HiRange Kit were added according to the manufacturer's instructions. After a 1-hour incubation at room temperature, the plate was analyzed using a BMG PheraStar microplate reader. The response was measured as the ratio of the signal at 665 nm to the signal at 620 nm over the background.

[0350] Detection of inositol monophosphate production Based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology, S1P2 agonist-stimulated G protein responses were determined by measuring changes in intracellular inositol monophosphate using the IP-one TB kit (CisBio, Cat. No. 62IPAPEJ). The AssayComplete™ Cell Plating 2 reagent was removed and replaced with 1× IP-one stimulation buffer (according to the manufacturer's instructions) along with the desired concentration of test or control compound. After 60 minutes of incubation at 37°C and 5% CO2 in a humidified CO2- and temperature-controlled incubator, the IP-one The components of the TB kit were added according to the manufacturer's instructions. After 1 hour of incubation at room temperature, the plate was analyzed using a BMG PheraStar microplate reader. The response was measured as the ratio of the fluorescence signal at 665 nm to the fluorescence signal at 620 nm relative to the background.

[0351] Activity table As shown herein, the compounds were able to modulate the activity (inhibition of cAMP production or inositol monophosphate accumulation) of sphingosine-1-phosphate 2, sphingosine-1-phosphate 3, and sphingosine-1-phosphate 5 receptors. The following tables contain the potencies of the compounds normalized to the maximum potency of the reference compound, referred to as "SPAN." These values ​​are normalized to fingolimod, a known agonist of sphingosine-1-phosphate 3 and 5 receptors, or CYM5520, a known agonist of sphingosine-1-phosphate 2 receptors. The tables also contain potency values ​​(pEC50) for modulating the respective receptor-mediated activity (inhibition of cAMP production or inositol monophosphate accumulation). This value represents the estimated concentration required to promote half of the maximum potency (or SPAN) observed for each compound. Exemplary compounds found to be selective are listed below. [Table 8]

[0352] Thus, the compounds were found to be fully selective for S1P1.

[0353] Example 15: Compounds do not inhibit hERG channel activity. A standard automated Qpatch patch clamp assay is used, with the selective hERG inhibitor E4031 serving as a positive control. [Table 9]

[0354] Example 16: Compound does not cause lymphopenia. Compounds were tested for changes in peripheral blood lymphocytes in C57bl / 6 mice. In acute studies, animals (n=5 / group) were administered test compound subcutaneously at a dose of 3 mg / kg. At specific time points, animals were sacrificed and 500 μL of whole blood was collected in EDTA(K2) Eppendorf tubes. Blood was stored on ice and shipped via express overnight delivery to Charles River Laboratories for analysis. CRL ran samples through a WBC / differential panel on an Advia120 instrument. Peripheral lymphocyte counts (10 3 Cells / μl) were counted. Mean values ​​of treatment groups were compared with the vehicle-treated group for statistical significance. In chronic studies, animals (n=6-8 / group) were administered test compounds subcutaneously for 3-7 days at doses at least 5-fold higher than the effective dose in the pharmacological / behavioral assays. On the final day, animals were sacrificed 45 minutes to 6 hours after the final dose. Whole blood was collected and analyzed as described for acute studies. No compounds demonstrated a statistically significant reduction in peripheral blood lymphocytes in either the acute or chronic studies. Non-limiting exemplary data are provided below. [Table 10]

Claims

1. 1. A method of treating or preventing seizures, or epilepsy or epilepsy-related syndromes in a subject, comprising administering to the subject a compound having Formula I or Formula II, or a pharmaceutically acceptable salt thereof; 【Chemical 1】 During the ceremony, A.A. is, 【Chemistry 2】 and W is O, S, or NR １ and X is O, S, or NR ４ and V is O, S, or NR ３２ and Z is CHR ４２ or NR ４３ and n is 0, 1, 2, 3, or 4; Y １ and Y ２ are independently O, S, NR ５ , C═O, C═S, or C═NR ６ and Y ３ is O, S, CH ２ , or NR ３４ and m is 0, 1, 2, or 3; A １ is O, S, NR ７ , C═O, or C═S; A ２ and A ３ is independently, CR ２９ or N, B １ is an optionally substituted aryl or heteroaryl group, a carbocycle, or 【Chemistry 3】 and B ２ , B ３ , and B ４ is independently, CR ３８ or N, D １ is H, OH, NH ２ , NO ２ , a ring, an optionally substituted aryl group, a branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl; R ２ and R ３ are independently H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or R ２ and R ３ are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl; R １ , R ４ , R ５ , R ６ , R ７ , R ２９ , R ３１ , R ３２ , R ３３ , R ３４ , R ３８ , and R ４３ are independently H, OH, NH ２ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; R ３０ are independently H, CN, CF ３ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or optionally substituted haloalkyl; R ４２ are independently selected from Br, Cl, F, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ The foregoing method, wherein the aryl group is alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

2. D １ and B １ but, 【Chemistry 4】 and has the formula During the ceremony, Z １ and Z ２ are independently N or CR ３９ and Z ３ is O, S, or NR ２７ and R ２７ and R ３９ are independently H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; D １ But H, OH, NH ２ , NO ２ , a ring, an optionally substituted aryl group, a branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl.

3. Z １ and Z ２ The method of claim 2 , wherein one of

4. Z １ and Z ２ and (b) are N.

5. Z ３ The method of claim 2 , wherein is O.

6. D １ and B １ but, 【Chemistry 5】 and has the formula During the ceremony, Z ４ is O, S, or NR ２８ and Z ５ is N or CH, R １９ and R ２０ are each independently H, OH, or NH ２ , NO ２ , ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, alkylthio, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R １９ and R ２０ Both of these are B １ forming an aryl or ring bonded to one or more of the atoms of R ２８ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; D １ But H, OH, NH ２ , NO ２ , a ring, an optionally substituted aryl group, a branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl.

7. Z ５ The method of claim 6 , wherein is N.

8. Z ４ The method of claim 6 , wherein is O.

9. D １ but, 【Chemistry 6】 and R ２１ , R ２２ , and R ２３ are each independently H, OH, or NH ２ , NO ２ , ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R ２１ , R ２２ , and R ２３ Two of them are D １ 10. The method of claim 1, wherein the aryl or ring bonded to one or more of the atoms of

10. R ２１ , R ２２ , and R ２３ 10. The method of claim 9, wherein one of

11. R ２１ , R ２２ , and R ２３ 10. The method of claim 9, wherein two of

12. R ２３ Me, OH, NH2, Cl, NHSO ２ Me, SO ２ NH ２ , NH(CO)Me, or (CO)NH ２ The method of claim 11, wherein

13. D １ 10. The method of claim 1, wherein is optionally substituted aryl or optionally substituted heteroaryl.

14. D １ but, 【Chemistry 7】 and R ２４ , R ２５ , and R ２６ are each independently H, OH, or NH ２ , NO ２ , ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R ２４ , R ２５ , and R ２６ Two of them are D １ 10. The method of claim 1, wherein the aryl or ring bonded to one or more of the atoms of

15. R ２４ , R ２５ , and R ２６ 15. The method of claim 14, wherein one of

16. R ２４ , R ２５ , and R ２６ 15. The method of claim 14, wherein two of

17. R ２６ But, H, Me, OH, CF ３ 17. The method of claim 16, wherein the hydroxyl group is OMe, or OMe.

18. A.A. 【Chemistry 8】 2. The method of claim 1, wherein the variables are as defined in claim 1.

19. 19. The method of claim 18, wherein W is O.

20. 20. The method of claim 19, wherein X is O.

21. R ２ and R ３ are independently H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ 21. The method of claim 20, wherein the aryl group is alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

22. R ２ and R ３ 22. The method of claim 21, wherein both of are the same.

23. R ２ and R ３ 23. The method of claim 22, wherein both of are Et.

24. D １ but, 【Chemistry 9】 20. The method of claim 19, wherein:

25. R ２４ , R ２５ , and R ２６ 25. The method of claim 24, wherein one of

26. R ２４ , R ２５ , and R ２６ 25. The method of claim 24, wherein two of are H.

27. D １ but, 【Chemistry 10】 27. The method of claim 26, wherein:

28. D １ but, 【Chemistry 11】 28. The method of claim 27, wherein:

29. R ２４ 28. The method of claim 27, wherein is H.

30. R ２４ 28. The method of claim 27, wherein is OH.

31. D １ but, 【Chemistry 12】 28. The method of claim 27, wherein:

32. R ２４ 32. The method of claim 31 , wherein is OMe.

33. D １ but, 【Chemistry 13】 20. The method of claim 19, wherein:

34. R ２４ , R ２５ , and R ２６ 34. The method of claim 33, wherein one of

35. R ２４ , R ２５ , and R ２６ 34. The method of claim 33, wherein two of are H.

36. D １ but, 【Chemistry 14】 36. The method of claim 35, wherein:

37. D １ but, 【Chemistry 15】 37. The method of claim 36, wherein:

38. D １ but, 【Chemistry 16】 37. The method of claim 36, wherein:

39. R ２４ 37. The method of claim 36, wherein is a halide.

40. R ２４ The method of claim 39, wherein is F.

41. R ２４ The method of claim 36, wherein is Me.

42. R ２４ 37. The method of claim 36, wherein is OMe.

43. R ２４ The method of claim 36, wherein is OH.

44. R ２ and R ３ Both, 【Chemistry 17】 The method of claim 1, wherein

45. 45. The method of claim 44, wherein n is 1.

46. A.A. 【Chemistry 18】 2. The method of claim 1, wherein the variables are as defined in claim 1.

47. Y １ But NR ５ 47. The method of claim 46, wherein:

48. R ５ The method of claim 47, wherein is H.

49. Y ２ But C=NR ６ 47. The method of claim 46, wherein:

50. R ６ 50. The method of claim 49, wherein is H.

51. Y ２ 47. The method of claim 46, wherein is C=O.

52. Y ３ The method of claim 46, wherein is O.

53. Y ３ But CH ２ 47. The method of claim 46, wherein:

54. 47. The method of claim 46, wherein m is 0.

55. 47. The method of claim 46, wherein m is 1.

56. A.A. 【Chemistry 19】 2. The method of claim 1, wherein the variables are as defined in claim 1.

57. A １ The method of claim 56, wherein is O.

58. A １ The method of claim 56, wherein is S.

59. A ２ is N.

60. A ３ is N.

61. A ３ But, CR ２９ 57. The method of claim 56, wherein:

62. R ２９ 62. The method of claim 61 , wherein is H.

63. A ２ But, CR ２９ 57. The method of claim 56, wherein:

64. R ２９ The method of claim 63, wherein is H.

65. A １ But NR ７ 57. The method of claim 56, wherein:

66. R ７ but, 【Chemistry 20】 66. The method of claim 65, wherein:

67. D １ but, 【Chemical 21】 and R ２１ , R ２２ , and R ２３ 57. The method of claim 56, wherein one of

68. D １ but, 【Chemical 22】 and R ２１ , R ２２ , and R ２３ 57. The method of claim 56, wherein two of are H.

69. D １ but, 【Chemical 23】 69. The method of claim 68, wherein:

70. R ２１ is optionally substituted C １ -C ６ 70. The method of claim 69, wherein the alkyl is alkyl.

71. R ２１ The method of claim 70, wherein is Me.

72. D １ but, 【Chemistry 24】 72. The method of claim 71, wherein:

73. D １ but, 【Chemistry 25】 and During the ceremony, Z ６ is O, S, NR ４０ , or CHR ３７ and Z ７ , Z ８ , Z ９ , and Z １０ are independently N or CR ４１ and R ３５ , R ３６ , R ３７ , R ４０ , and R ４１ are each independently H, OH, or NH ２ , ring, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amido, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, or alkylsulfanyl, or R ３５ and R ３６ Both, D １ 10. The method of claim 1, wherein the aryl or ring is bonded to one or more of the atoms of

74. R ３５ and R ３６ 74. The method of claim 73, wherein one of is H.

75. R ３５ and R ３６ and R are H.

76. Z ６ 76. The method of claim 75, wherein is NH.

77. Z ７ , Z ８ and Z ９ 77. The method of claim 76, wherein one of is N.

78. Z ７ is N.

79. Z ８ 79. The method of claim 78, wherein is CH.

80. Z ９ 79. The method of claim 78, wherein is CH.

81. Z ８ and Z ９ and R are CH.

82. A.A. 【Chemical 26】 74. The method of claim 73, wherein the variables are as defined in claim 1.

83. 83. The method of claim 82, wherein W is O.

84. 84. The method of claim 83, wherein X is O.

85. R ２ and R ３ are independently H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ 85. The method of claim 84, wherein the cycloalkyl group is alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

86. R ２ and R ３ 86. The method of claim 85, wherein both of are the same.

87. R ２ and R ３ 87. The method of claim 86, wherein both of are Et.

88. 88. The method of claim 87, wherein n is 1.

89. D １ 89. The method of claim 88, wherein is pyrazolyl.

90. D １ but, 【Chemical 27】 90. The method of claim 89, wherein:

91. Formula I is 【Chemical 28】 91. The method of claim 90, having the formula:

92. Z ２ is N.

93. Z １ is N.

94. Z ３ The method of claim 91, wherein is O.

95. wherein said formula I is 【Chemical 29】 92. The method of claim 91, having the formula:

96. having formula II, D １ and B １ Both, 【Chemistry 30】 2. The method of claim 1, wherein the variables are as defined in claim 2.

97. Z ３ The method of claim 96, wherein is O.

98. Z １ is N.

99. Z ２ is N.

100. Formula II: 【Chemical 31】 100. The method of claim 99, wherein the variables are as defined in claim 1.

101. R ３０ The method of claim 100, wherein is CN.

102. 101. The method of claim 100, wherein V is NH.

103. R ３０ The method of claim 102, wherein is CN.

104. R ３１ But C １ -C ５ The method of claim 103, wherein the alkyl is alkyl.

105. R ３１ but, 【Chemical 32】 The method of claim 104, wherein

106. R ３１ But C １ -C ５ 104. The method of claim 103, wherein the alkyl is haloalkyl.

107. R ３１ but, 【Chemical 33】 The method of claim 106, wherein

108. having formula II, D １ , B １ , and AA are both 【Chemical 34】 2. The method of claim 1, wherein the variables are as defined in claim 1.

109. R ３０ But CF ３ The method of claim 108, wherein

110. 109. The method of claim 108, wherein V is O or NH.

111. R ３０ But CF ３ The method of claim 110, wherein

112. B １ and D １ Both, 【Chemistry 35】 The method of claim 108, wherein

113. D １ but, 【Chemical 36】 The method of claim 112, wherein

114. R ３１ but, 【Chemical Formula 37】 The method of claim 113, wherein

115. 1. A method for treating or preventing seizures, epilepsy, or epilepsy-related syndromes in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound described herein.

116. 1. A method of treating or preventing seizures, epilepsy, or epilepsy-related syndromes in a subject, comprising administering to the subject: 【Chemical 38】 or a pharmaceutically acceptable salt thereof.

117. 117. A method of treating or preventing seizures, or epilepsy or epilepsy-related syndromes in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of any one of claims 1 to 116, or a pharmaceutically acceptable salt thereof.

118. 118. The method of claim 117, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

119. 119. A method of treating or preventing seizures, or epilepsy or epilepsy-related syndromes in a subject, comprising administering to the subject a compound according to any one of claims 1 to 116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 117 or 118.

120. 120. The method of any one of claims 1 to 119, wherein the epilepsy is intractable epilepsy.

121. 121. The method of claim 120, wherein the intractable epilepsy is localization-related epilepsy, generalized epilepsy, or a syndrome thereof.

122. 122. The method of claim 121, wherein the localization-related epilepsy is cortical epilepsy or temporal lobe epilepsy.

123. 123. The method of claim 122, wherein the cortical epilepsy is frontal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy.

124. 120. The method of any one of claims 1 to 119, wherein the epilepsy-related syndrome is epileptic seizures.

125. 125. The method of claim 124, wherein the epileptic seizures are refractory localization-related epileptic seizures, refractory secondarily generalized seizures, refractory complex partial seizures, or refractory status epilepticus.

126. 126. The method of any one of claims 1 to 125, wherein the method further comprises administering at least one antiepileptic drug other than a compound of Formula I or Formula II.

127. 127. The method of any one of claims 126, wherein the at least one antiepileptic drug is selected from the group consisting of carbamazepine, clonazepam, eslicarbazepine, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, vigabatrin, valproate (valproic acid), and zonisamide.

128. The method of any one of claims 1 to 127, wherein the subject is in need thereof.

129. 128. The method of any one of claims 1 to 127, wherein the seizures or epilepsy-related conditions or symptoms are prevented.

130. The compound is 【Chemical 39】 130. The method of any one of claims 1 to 129, having the formula:

131. The compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered in a therapeutically effective amount. The method of any one of claims 1 to 130, wherein the

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