ABHD12 INHIBITORS AND METHODS FOR MAKING AND USING SAME

Abstract

Provided herein are compounds and compositions useful as modulators of ABHD12. Additionally, the compounds and compositions of the present invention are useful as immunotherapeutics, for example, in the treatment of cancer or infectious diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 847,804, filed May 14, 2019, which is incorporated by reference in its entirety. [Background technology]

[0002] Alpha / beta-hydrolase domain-containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that is involved in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol (2-AG) in the central nervous system. Summary of the Invention

[0003] The disclosure provides, for example, compounds and compositions that are modulators of ABHD12, as well as their use as medicaments, methods for their preparation, and pharmaceutical compositions that include the disclosed compounds as at least one active ingredient. The disclosure also provides the use of the disclosed compounds as medicaments and / or in the manufacture of a medicament for the inhibition of ABHD12 activity in a warm-blooded animal, such as a human.

[0004] In one embodiment, [ka] [ka] or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof.

[0005] In another embodiment is a pharmaceutical composition comprising a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0006] In another embodiment, a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein the disease or disorder is a neuropsychiatric disorder, an autoimmune disease, a neuroinflammatory disease, a neurodegenerative disease, or cancer. In another embodiment, a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein administration of the compound stimulates the patient's immune system. In another embodiment, a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein administration of the compound initiates an immune response. In another embodiment, a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is an immunotherapeutic. In another embodiment, a method of treating an infectious disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein administration of the compound stimulates the patient's immune system. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Detailed Description of the Invention The present disclosure relates, at least in part, to modulators or inhibitors of ABHD12. For example, provided herein are compounds capable of inhibiting ABHD12.

[0008] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, and a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof. When ranges for a physical property, such as a molecular weight, or a chemical property, such as a chemical formula, are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a numerical value or numerical range means that the numerical value or numerical range referred to is approximate within experimental variation (or within statistical experimental error), and thus the numerical value or numerical range may vary from 1% to 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises", or "having" or "including") is not intended to exclude that in other specific embodiments, embodiments such as, for example, any composition, composition, method or process described herein, may "consist of" or "consist essentially of" the described features.

[0009] definition As used in this specification and the appended claims, unless expressly stated to the contrary, the following terms have the meanings indicated below.

[0010] In certain embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomers of the compounds disclosed herein are intended to be contemplated by the present disclosure. When the compounds described herein contain an alkene double bond, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers and their racemic and optically pure forms and all tautomers are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta- and para-isomers around a benzene ring.

[0011] "Tautomer" refers to a molecule capable of proton transfer from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, chemical equilibrium of tautomers may exist. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following: [ka]

[0012] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to include any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0013] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids such as arginate, gluconate and galacturonate are also contemplated (see, for example, Berge SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0014] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. In certain embodiments, pharma-ceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and base ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0015] As used herein, "treatment" or "treat" or "alleviate" or "ameliorate" are used interchangeably herein. These terms refer to an approach to obtain beneficial or desired results, including, but not limited to, therapeutic effect and / or prophylactic effect. A "therapeutic effect" refers to the eradication or amelioration of the underlying disease being treated. A therapeutic effect is also achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, such that an improvement is observed in the patient, even though the patient is still suffering from the underlying disease. For a prophylactic effect, the composition is administered to a patient at risk of developing a particular disease or who reports one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0016] compound The compounds described herein are modulators of ABHD12. The compounds described herein, and compositions comprising these compounds, are useful for treating a disease or disorder selected from neuropsychiatric disorders, autoimmune disorders, neuroinflammatory disorders, neurodegenerative disorders, and cancer. In some embodiments, the compounds described herein, and compositions comprising these compounds, stimulate the immune system of a patient to treat the disease. In some embodiments, the disease is an infectious disease. In some embodiments, the disease is cancer.

[0017] In certain embodiments, the compounds disclosed herein are [ka] [ka] or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof.

[0018] Preparation of compounds The compounds used in the reactions described herein are made according to organic synthesis techniques, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI (including Sigma Chemical and Fluka)), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Matrix Scientific (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc.(Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sandia Meditech (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).

[0019] Suitable references and articles detailing the synthesis or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations", 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Further suitable references and articles detailing the synthesis or referring to articles describing the preparation of reactants useful for the preparation of the compounds described herein are, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai’s 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes are included.

[0020] Specific and similar reactants are also identified by the index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries and online databases (American Chemical Society, Washington, DC). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis vendors, where many of the standard chemical suppliers (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0021] Further forms of the compounds disclosed herein Isomers Further, in certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, syn, anti, opposite (E) and same (Z) isomers and their corresponding mixtures. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic separation of a racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered together with the resolving agent by any practical means that do not result in racemization.

[0022] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering isotopically labeled compounds, such as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as, for example, each of 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compounds described herein and their pharma- ceutically acceptable salts, esters, solvates, hydrates, or derivatives that contain the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Some isotopically labeled compounds, e.g. 3 H and 14 Incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Tritium, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavy isotopes such as H may confer several therapeutic advantages due to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In certain embodiments, isotopically labeled compounds, pharma- ceutically acceptable salts, esters, solvates, hydrates or derivatives thereof are prepared by any suitable method.

[0023] In certain embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0024] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharma- ceutically acceptable salts as pharmaceutical compositions.

[0025] In certain embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharma- ceutically acceptable salts, in certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0026] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, methods of treating diseases by administering such solvates. Methods of treating diseases by administering solvates, such as pharmaceutical compositions, are further described herein.

[0027] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0028] Pharmaceutical Compositions In certain embodiments, the compounds described herein are administered as pure chemicals. In certain embodiments, the compounds described herein are administered as pure chemicals according to the selected route of administration and the principles of, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 2013). st The pharmaceutical compositions are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected on the basis of standard pharmaceutical practice as described in U.S. Pat. No. 6,313,315, Ed. Mack Pub. Co., Easton, PA (2005)).

[0029] Thus, provided herein are pharmaceutical compositions comprising at least one compound described herein or its stereoisomer, pharma- ceutically acceptable salt, hydrate, solvate or N-oxide together with one or more pharma- ceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0030] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0031] Another embodiment provides a pharmaceutical composition consisting essentially of a pharma- ceutically acceptable excipient and a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0032] In certain embodiments, the compounds described herein are substantially pure, in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as contaminating intermediates or by-products produced, for example, during one or more of the steps of a synthetic method.

[0033] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), vaginal, ocular or aerosol administration, although the most suitable form of administration in any given case will depend on the level and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions are formulated as a unit dose and / or formulated for oral or subcutaneous administration.

[0034] Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, for example in solid, semi-solid or liquid form, containing one or more of the disclosed compounds as active ingredients in a mixture with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. In some embodiments, the active ingredient is compounded with a conventional non-toxic pharma- ceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0035] In some embodiments for preparing solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical carrier, such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogenous mixture of the disclosed compounds or their non-toxic pharma-ceutically acceptable salts. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0036] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the compositions of the invention may be combined with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as crospovidone, The composition is mixed with croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the composition includes a buffering agent. In some embodiments, solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0037] In some embodiments, tablets are prepared by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. In some embodiments, molded tablets are prepared by molding a mixture of the composition of the present invention moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms such as dragees, capsules, pills and granules are segmented or prepared with coatings and shells, such as enteric coatings and other coatings.

[0038] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders.Liquid dosage forms for oral administration include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the compositions of the present invention, in some embodiments, the liquid dosage forms contain inert diluents, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (optionally cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0039] In certain embodiments, suspensions contain, in addition to the compositions of this invention, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof.

[0040] In certain embodiments, formulations for rectal or vaginal administration are presented as suppositories, which are prepared by mixing the compositions of the present invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent(s).

[0041] Dosage forms for transdermal administration of the compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In certain embodiments, the active ingredient is admixed under sterile conditions with a pharma- ceutical acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0042] In certain embodiments, the ointments, pastes, creams and gels contain, in addition to the compositions of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0043] In some embodiments, powders and sprays contain, in addition to the composition of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. In some embodiments, sprays further contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0044] In certain embodiments, the compounds described herein are formulated as eye drops for intraocular administration.

[0045] Alternatively, the compositions and compounds disclosed herein are administered by aerosol. This is accomplished by preparing aqueous aerosols, liposomal formulations or solid particles containing the compounds. In some embodiments, non-aqueous (e.g., fluorocarbon propellant) suspensions are used. In some embodiments, ultrasonic nebulizers are used to minimize exposure of the drug to shear that can cause degradation of the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the compositions of the present invention together with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular compositions of the present invention, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0046] Pharmaceutical compositions suitable for parenteral administration comprise, in certain embodiments, a composition of the invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions containing antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders to be reconstituted into sterile injectable solutions or dispersions immediately prior to use.

[0047] Examples of suitable aqueous and non-aqueous carriers used in pharmaceutical compositions include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate and cyclodextrin. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0048] Enteral pharmaceutical formulations comprising the disclosed compounds, enteric materials and their pharma- ceutically acceptable carriers or excipients are also contemplated. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and mostly soluble in intestinal fluids at a particular pH. The small intestine is the portion of the digestive tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5. Thus, the enteric material does not dissolve until the pH is, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8 or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal collophorium, and several commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit Examples of suitable materials include FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric. The solubility of each of the above materials is known or can be readily determined in vitro.

[0049] Dosages of compositions containing at least one compound described herein will vary depending on the condition of the patient (eg, human), i.e., the stage of the disease, general health, age, and other factors.

[0050] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the suitable duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. In general, an appropriate dose and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or prophylactic effect (e.g., improved clinical outcome, e.g., a higher frequency of complete or partial remission, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms). Optimal dosages are generally determined using experimental models and / or clinical trials. In certain embodiments, optimal dosages depend on the patient's size, weight, or blood volume.

[0051] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0052] method Disclosed herein is a method of modulating the activity of ABHD12. Possible methods include, for example, exposing the enzyme to a compound described herein. In some embodiments, the compound used by one or more of the above methods is one of the general, subclass, or specific compounds described herein, such as the compounds described herein. In some embodiments, provided herein is a compound described herein, where the compound is an ABHD12 inhibitor. In some embodiments, provided herein is a compound described herein, where the compound is a selective ABHD12 inhibitor. The ability of the compounds described herein to modulate or inhibit ABHD12 is evaluated by procedures known in the art and / or described herein. Another aspect of the disclosure provides a method of treating a disease associated with ABHD12 expression or activity in a patient. In some embodiments, provided herein is a compound described herein, where the compound is selective for inhibiting ABHD12 when compared to inhibition of other serine hydrolases. In certain embodiments, provided herein are compounds described herein, wherein the compounds are 10, 100, or 1000-fold more selective for inhibiting ABHD12 compared to inhibition of other serine hydrolases.

[0053] In another embodiment, a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein the disease or disorder is a neuropsychiatric disorder, an autoimmune disease, a neuroinflammatory disease, a neurodegenerative disease, or cancer. In another embodiment, a method of treating a neuropsychiatric disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. In another embodiment, a method of treating an autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. In another embodiment, a method of treating a neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. In another embodiment, a method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. In another embodiment, a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0054] In another embodiment, a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein the compound is an immunotherapeutic agent.

[0055] In some embodiments, the compounds described herein stimulate the immune system of a patient to treat the disease. In some embodiments, the method of treating a disease in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, where the administration of the compound stimulates the immune system of the patient. In another embodiment, the method of treating cancer in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, where the administration of the compound stimulates the immune system of the patient. In another embodiment, the method of treating cancer in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, where the administration of the compound initiates an immune response.

[0056] In another embodiment, a method of treating an infectious disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein the compound is an immunotherapeutic agent.

[0057] In another embodiment, a method of treating an infectious disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, where administration of the compound stimulates the patient's immune system. In another embodiment, a method of treating an infectious disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, where administration of the compound stimulates the patient's immune system. In another embodiment, a method of treating an infectious disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, where administration of the compound initiates an immune response.

[0058] In certain embodiments, the disclosed compound used by one or more of the above methods is one of the specific compounds described herein.

[0059] The disclosed compounds are administered to patients (animals and humans) in need of such treatment in dosages that provide optimal pharmaceutical efficacy. It is understood that the dosage required for any particular use will vary from patient to patient, depending not only on the particular compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, any concurrent medications or special diets the patient may follow, and other factors, and the appropriate dosage is ultimately at the discretion of the attending physician. To treat the above conditions and diseases, contemplated compounds disclosed herein are administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmacologic carriers, adjuvants, and vehicles. Parenteral administration includes subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.

[0060] Combination therapy, such as the co-administration of the disclosed compounds and additional active agents as part of a specific treatment plan intended to obtain beneficial effects from the interaction of these therapeutic agents, is also contemplated herein. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of therapeutic agents. The administration of these combinations of therapeutic agents is typically carried out over a period of time (usually weeks, months or years, depending on the combination selected). Combination therapy is intended to include sequential administration of multiple therapeutic agents (i.e., each therapeutic agent is administered at a different time) as well as near-simultaneous administration of these therapeutic agents or at least two of the therapeutic agents.

[0061] Near-simultaneous administration can be accomplished, for example, by administering to the subject multiple times a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or a single formulation (e.g., capsule) for each of the therapeutic agents). Sequential or near-simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination can be administered by intravenous injection while the other therapeutic agent of the combination is administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection.

[0062] Combination therapy also includes administration of the above-mentioned therapeutic agent further combined with other biologically active ingredients and non-drug therapy.When combination therapy further includes non-drug therapy, the non-drug therapy is administered at any suitable time, as long as the beneficial effect of the interaction of the combination of therapeutic agent and non-drug therapy can be obtained.For example, in appropriate cases, the beneficial effect can still be obtained when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, perhaps for a few days or even weeks.

[0063] The components of the combination are administered to a patient simultaneously or sequentially. It will be understood that the components are present in the same pharma- ceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially. The present invention may include the following aspects. [1] Below formula: [ka] [ka] or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof. [2] 13. A pharmaceutical composition comprising the compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient. [3] 11. A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein the disease or disorder is a neuropsychiatric disorder, an autoimmune disease, a neuroinflammatory disease, a neurodegenerative disease, or cancer. [4] 11. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein administration of the compound stimulates the patient's immune system. [5] 11. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein administration of the compound initiates an immune response. [6] 11. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein the compound is an immunotherapeutic agent. [7] 11. A method for treating an infectious disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein administration of the compound stimulates the immune system of the patient.

[0064] The following examples are offered merely as illustrations of various embodiments and should not be construed as limiting the invention in any way. EXAMPLES

[0065] List of abbreviations As used above, and throughout the description of the present invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN: Acetonitrile Bn: Benzyl BOC or Boc: tert-butyl carbamate CDI: 1,1'-carbonyldiimidazole Cy: Cyclohexyl DCE: Dichloroethane (ClCH 2 CH 2 Cl) DCM: dichloromethane (CH 2 Cl 2 ) DIPEA or DIEA: Diisopropylethylamine DMAP: 4-(N,N-dimethylamino)pyridine DMF: Dimethylformamide DMA: N,N-Dimethylacetamide DMSO: Dimethyl sulfoxide equiv: equivalent amount Et: Ethyl EtOH: Ethanol EtOAc: ethyl acetate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography LAH: Lithium aluminum hydride Me: Methyl MeOH: Methanol MS: Mass spectrometry NMM: N-methylmorpholine NMR: nuclear magnetic resonance PMB: para-methoxybenzyl TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography

[0066] I. Chemical synthesis Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized. Column and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. For proton spectra, the solvent peak was used as the reference peak.

[0067] Example 1: 1-(pyridin-3-yl)-3-(1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)urea [ka] Step 1: Preparation of t-butyl (1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate [ka] 2-Fluoro-6-(trifluoromethyl)pyridine (82 mg, 0.50 mmol, 1.00 equiv.) and t-butyl N-(piperidin-4-yl)carbamate (100 mg, 0.50 mmol, 1.00 equiv.) in DMF (3 mL) and K 2 CO 3 A mixture of (138 mg, 1.00 mmol, 2.00 equiv) was stirred at 100° C. for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give t-butyl (1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate (155 mg, 90%) as a yellow solid. LCMS (ESI, m / z): 346 [M+H] + .

[0068] Step 2: Preparation of 1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine [ka] A solution of t-butyl (1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate (155 mg, 0.50 mmol, 1.00 equiv) in TFA (1 mL) and DCM (5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by NH 3 H 2 The mixture was neutralized to pH 9 with O. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give 1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine (100 mg, 91%) as a white solid. LCMS (ESI, m / z): 246 [M+H] + .

[0069] Step 3: Preparation of 1-(pyridin-3-yl)-3-(1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)urea [ka] 1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine (74 mg, 0.30 mmol, 1.00 equiv) and Cs in ACN (5 mL) 2 CO 3To a stirred mixture of (98 mg, 0.30 mmol, 1.00 equiv) was added 3-isocyanatopyridine (36 mg, 0.30 mmol, 1.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC to give 1-(pyridin-3-yl)-3-(1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)urea (19.9 mg, 18%) as a yellow solid. 1 H NMR (400 MHz, methanol-d 4 )9.32(s,1H), 8.33(d,J=4.8Hz, 1H), 8.26(d,J=8.4Hz, 1H), 7.89(dd,J 1 =8.0Hz, J 2 =5.6Hz, 1H), 7.69(t,J=8.0Hz, 1H), 7.05(d,J=8.8Hz, 1H), 6.96(d,J=7.2Hz, 1H), 4.37(d ,J=13.2Hz, 2H), 3.95-3.89(m,1H), 3.16-3.08(m,2H), 2.04(d,J=11.6Hz, 2H), 1.54(dd,J 1 = 20.0Hz, J 2 =11.2Hz, 2H).LCMS(ESI, m / z):366[M+H] + .

[0070] Example 2: 1-(1-(3-chloro-4-(4-chloro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] Step 1: Preparation of t-butyl (1-(3-chloro-4-iodopyridin-2-yl)piperidin-4-yl)carbamate [ka] A flask was charged with 3-chloro-2-fluoro-4-iodopyridine (2.57 g, 0.01 mol, 1.00 equiv.), t-butyl piperidin-4-ylcarbamate (2.00 g, 0.01 mol, 1.00 equiv.), DMF (15 mL), and K 2 CO 3 (2.76 g, 0.02 mmol, 2.00 equiv). The resulting solution was stirred at 100° C. for 1 h, cooled to room temperature, and poured into 100 mL of ice water. The solid was isolated by filtration and dried to give 3.50 g (80% yield) of t-butyl (1-(3-chloro-4-iodopyridin-2-yl)piperidin-4-yl)carbamate as an off-white solid. LCMS (ESI, m / z): 438 [M+H] + .

[0071] Step 2: Preparation of 1-(3-chloro-4-(4-chloro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-amine [ka] A flask was charged with t-butyl(1-(3-chloro-4-iodopyridin-2-yl)piperidin-4-yl)carbamate (400 mg, 0.91 mmol, 1.00 equiv.), 4-chloro-3-(trifluoromethoxy)phenol (387 mg, 1.83 mmol, 2.00 equiv.), CuI (86.8 mg, 0.46 mmol, 0.50 equiv.), Cu (29.2 mg, 0.46 mmol, 0.50 equiv.), Cs 2 CO 3 (890 mg, 2.73 mmol, 3.00 equiv) and DMA (5 mL). The resulting solution was stirred at 150° C. for 1 h and then cooled to room temperature. The resulting solution was filtered and purified by preparative HPLC to give 200 mg (52% yield) of 1-(3-chloro-4-(4-chloro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-amine as a white solid. LCMS (ESI, m / z): 422 [M+H] + .

[0072] Step 3: Preparation of 1-(1-(3-chloro-4-(4-chloro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] A flask was charged with pyridin-3-amine (49.0 mg, 0.52 mmol, 2.00 equiv), DIEA (67.2 mg, 0.52 mmol, 2.00 equiv), CDI (100 mg, 0.62 mmol, 2.40 equiv) and DCM (5 mL). The resulting solution was stirred at room temperature for 3 h before adding 1-(3-chloro-4-(4-chloro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-amine (109 mg, 0.26 mmol, 1.00 equiv) and DIPEA (100.6 mg, 0.78 mmol, 3.00 equiv). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with DCM (25 mL) and saturated NaHCO 3 The organic layer was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to give 17.3 mg (14% yield) of 1-(1-(3-chloro-4-(4-chloro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea as a white solid. 1 H NMR (400 MHz, methanol-d 4 )8.57(s,1H), 8.16(d,J=6.0Hz, 1H), 8.10(d,J=6.4Hz, 1H), 7.98-7.95(m,1H), 7.54(d,J=10.4Hz, 1H), 7.38-7.34(m,2H), 7.16-7.13(m ,1H), 6.59(d,J=6.0Hz, 1H), 3.85-3.79(m,3H), 3.15-3.04(m,2H), 2.10(d,J=8.8Hz, 2H), 1.73-1.70(m,2H).LCMS(ESI, m / z):542[M+H] + .

[0073] Example 3: 1-(1-(5-acetylpyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] Step 1: Preparation of t-butyl 4-(3-(pyridin-3-yl)ureido)piperidine-1-carboxylate [ka] A flask was charged with pyridin-3-amine (2.35 g, 25.0 mmol, 1.00 equiv), DIPEA (6.46 g, 49.9 mmol, 2.00 equiv) and DCM (100 mL). A solution of triphosgene (2.96 g, 9.98 mmol, 0.400 equiv) was added to the reaction mixture at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and a solution of DIPEA (6.46 g, 49.9 mmol, 2.00 equiv) and t-butyl 4-aminopiperidine-1-carboxylate (5.00 g, 25.0 mmol, 1.00 equiv) was added to the reaction at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then quenched with water (100 mL). The resulting solution was extracted with DCM (3×100 mL), and the organic layers were combined and washed with brine (1×100 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 4.27 g (53% yield) of t-butyl 4-(3-(pyridin-3-yl)ureido)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m / z): 321 [M+H] + .

[0074] Step 2: Preparation of 1-(piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] A flask was charged with t-butyl 4-(3-(pyridin-3-yl)ureido)piperidine-1-carboxylate (4.27 g, 13.3 mmol, 1.00 equiv), HCl (20 mL, 4 M in dioxane) and DCM (100 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction was concentrated under reduced pressure to give 3.33 g (crude) of 1-(piperidin-4-yl)-3-(pyridin-3-yl)urea as a yellow oil. LCMS (ESI, m / z): 221 [M+H] + .

[0075] Step 3: Preparation of 1-(1-(5-acetylpyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] A flask was charged with 1-(piperidin-4-yl)-3-(pyridin-3-yl)urea (150 mg, 0.681 mmol, 1.00 equiv.), 1-(6-chloropyridin-3-yl)ethan-1-one (96.0 mg, 0.681 mmol, 1.00 equiv.), K 2 CO 3 (138 mg, 1.361 mmol, 2.00 equiv) and DMF (10 mL). The reaction mixture was stirred at 70° C. for 12 h and then quenched with water (20 mL). The resulting solution was extracted with EtOAc (3×20 mL) and the organic layers were combined, washed with brine (1×20 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 52.1 mg (17% yield) of 1-(1-(5-acetylpyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea as a yellow solid. 1 H NMR (400 MHz, methanol-d 4)δ 8.76(d,J=2.4Hz, 1H), 8.56(d,J=2.6Hz, 1H), 8.16(dd,J=4.8Hz, 1.5Hz, 1H), 8.0 6(dd,J=9.2Hz, 2.4Hz, 1H), 7.98-7.91(m,1H), 7.39-7.31(m,1H), 6.88(d,J=9.1 Hz, 1H), 4.46(d,J=13.5Hz, 2H), 4.14-3.94(m,1H), 3.29-3.18(m,2H), 2.52(s,3) H), 2.07(dd,J=13.1Hz, 3.7Hz, 2H), 1.57-1.43(m,2H).LCMS(ESI, m / z):340[M+H] + .

[0076] Example 4: 1-(pyridin-3-yl)-3-(1-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)urea [ka] Step 1: Preparation of 1-(1-(4-bromopyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] A flask was charged with 1-(piperidin-4-yl)-3-(pyridin-3-yl)urea (943 mg, 4.5 mmol, 1.5 equiv.) (as prepared in Example 10, steps 1-2), 4-bromo-2-fluoropyridine (500 mg, 3.0 mmol, 1 equiv.), K 2 CO 3 (789.00 mg, 6.00 mmol, 2.00 equiv) and DMF (5 mL). The reaction mixture was stirred at 70° C. for 2 h and then quenched with water (20 mL). The resulting solution was extracted with EtOAc (3×20 mL) and the organic layers were combined, washed with brine (1×20 mL) and washed with anhydrous Na 2 SO 4The mixture was dried over 100 ml of hexane and concentrated under reduced pressure. The crude product was purified by C-18 column chromatography to give 1-(1-(4-bromopyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea (900 mg, 84%) as a white solid. LCMS (ESI, m / z): 376 [M+H] + .

[0077] Step 2: Preparation of 1-(pyridin-3-yl)-3-(1-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)urea [ka] H 2 1-(1-(4-bromopyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea (200.00 mg, 0.53 mmol, 1.00 equiv), 4-(trifluoromethoxy)phenylboronic acid (131.35 mg, 0.63 mmol, 1.20 equiv), Pd(dppf)Cl in O (1.00 mL) and dioxane (4.00 mL). 2 (77.79 mg, 0.10 mmol, 0.20 equiv.) and K 2 CO 3 A mixture of (146.93 mg, 1.06 mmol, 2.00 equiv) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was quenched with water (10 mL), extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed with brine (2 x 10 mL) and anhydrous Na 2 SO 4 The residue was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by C-18 column chromatography and preparative HPLC to give 1-(pyridin-3-yl)-3-(1-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)urea (12.20 mg, 5%) as a white solid. 1 H NMR (400 MHz, methanol-d 4)δ 8.59-8.53(m,1H), 8.20-8.12(m,2H), 7.99-7.92(m,1H), 7.85-7.77(m,2H), 7.44-7.37(m,2H), 7.41-7.31(m,1H), 7.09-7.04(m,1H), 6.9 7-6.91(m,1H), 4.34-4.26(m,2H), 3.95-3.83(m,1H), 3.22-3.10(m,2H), 2.11-2.02(m,2H), 1.64-1.50(m,2H).LCMS(ESI, m / z):458[M+H] + .

[0078] Example 5: 1-(1-(3-chloro-4-(4-fluoro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] Step 1: Preparation of 1-(1-(4-bromo-3-chloropyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] A flask was charged with 4-bromo-3-chloro-2-fluoropyridine (1.00 g, 4.76 mmol, 1.00 equiv.), 1-(piperidin-4-yl)-3-(pyridin-3-yl)urea (1.15 g, 5.24 mmol, 1.10 equiv.) (as prepared in Example 3, steps 1-2), K 2 CO 3 (1.98 g, 14.3 mmol, 3.00 equiv) and DMF (15 mL). The reaction mixture was stirred at 80° C. for 12 h and then quenched with water (30 mL). The resulting solution was extracted with EtOAc (3×30 mL) and the organic layers were combined, washed with brine (1×30 mL) and washed with anhydrous Na 2 SO 4The mixture was dried over 100 ml of 1-(1-(4-bromo-3-chloropyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 750 mg (38% yield) of 1-(1-(4-bromo-3-chloropyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea as a white solid. LCMS (ESI, m / z): 410 [M+H] + .

[0079] Step 2: Preparation of 1-(1-(3-chloro-4-(4-fluoro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] A flask was charged with 1-(1-(4-bromo-3-chloropyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea (65.0 mg, 0.158 mmol, 1.00 equiv.), 4-fluoro-3-(trifluoromethoxy)phenol (34.0 mg, 0.174 mmol, 1.10 equiv.), Cs 2 CO 3 (155 mg, 0.474 mmol, 3.00 equiv), dimethylglycine (5.00 mg, 0.0474 mmol, 0.300 equiv), CuI (3.00 mg, 0.0158 mmol, 0.100 equiv) and DMF (3 mL). The reaction mixture was stirred for 2 hours at 4°C for 10 min at 20°C for 30 min at 20°C. The reaction mixture was then charged with N 2 The mixture was stirred at 100° C. for 12 h under reduced pressure, diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (3×20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 7.4 mg (9% yield) of 1-(1-(3-chloro-4-(4-fluoro-3-(trifluoromethoxy)phenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6)δ 8.54(d,J=2.5Hz, 2H), 8.11(t,J=5.3Hz, 2H),7.93-7.85(m,1H), 7.68-7 .55(m,2H), 7.33-7.28(m,1H), 7.26(dd,J=8.3, 4.7Hz, 1H), 6.51(d,J=5. 6Hz, 1H), 6.43(d,J=7.7Hz, 1H), 3.75-3.64(m,3H), 3.00(t,J=11.5Hz, 2H), 1.96(d,J=12.6Hz, 2H), 1.66-1.51(m,2H).LCMS(ESI, m / z):526[M+H] + .

[0080] Example 6: 1-(1-(3-chloro-4-(2-chloro-4-ethynylphenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] Step 1: Preparation of 4-(4-bromo-2-chlorophenoxy)-2,3-dichloropyridine [ka] A mixture of 4-bromo-2-chlorophenol (632 mg, 3.0 mmol, 1.0 equiv) and NaH (123 mg, 3.0 mmol, 1.0 equiv) in DMF (5 mL) was stirred at room temperature for 30 min, then 2,3,4-trichloropyridine (500 mg, 2.70 mmol, 0.90 equiv) was added. The reaction mixture was stirred at 100° C. for 2 h, quenched with water (10 mL), extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine (2×10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by C-18 column chromatography to give 4-(4-bromo-2-chlorophenoxy)-2,3-dichloropyridine (500 mg, 46%) as a yellow solid. LCMS (ESI, m / z): 352 [M+H] + .

[0081] Step 2: Preparation of t-butyl (1-(4-(4-bromo-2-chlorophenoxy)-3-chloropyridin-2-yl)piperidin-4-yl)carbamate [ka] 4-(4-bromo-2-chlorophenoxy)-2,3-dichloropyridine (300 mg, 0.84 mmol, 1.0 equiv.) t-butyl N-(piperidin-4-yl)carbamate (510 mg, 2.54 mmol, 3.0 equiv.) and Cs in DMSO (5.00 mL). 2 CO 3 The mixture of (443 mg, 1.35 mmol, 1.60 equiv) was stirred at 100 °C overnight and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine (2 × 10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by C-18 column chromatography to give t-butyl (1-(4-(4-bromo-2-chlorophenoxy)-3-chloropyridin-2-yl)piperidin-4-yl)carbamate (120.00 mg, 27%) as a yellow oil. LCMS (ESI, m / z): 516 [M+H] + .

[0082] Step 3: Preparation of t-butyl (1-(3-chloro-4-(2-chloro-4-((trimethylsilyl)ethynyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate [ka] t-Butyl (1-(4-(4-bromo-2-chlorophenoxy)-3-chloropyridin-2-yl)piperidin-4-yl)carbamate (100 mg, 0.19 mmol, 1.00 equiv.), trimethylsilylacetylene (190 mg, 1.93 mmol, 10.00 equiv.), Pd(PPh 3 ) 4(45 mg, 0.039 mmol, 0.2 equiv.), CuI (7 mg, 0.039 mmol, 0.2 equiv.) and Et 3 A mixture of N (59 mg, 0.58 mmol, 3 equiv.) and N 2 The mixture was stirred under reduced pressure at 100° C. overnight. The mixture was diluted with water (20 mL), extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine (2×10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give t-butyl (1-(3-chloro-4-(2-chloro-4-((trimethylsilyl)ethynyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate (100 mg, 97%) as a yellow solid. LCMS (ESI, m / z): 534 [M+H] + .

[0083] Step 4: Preparation of 1-(3-chloro-4-(2-chloro-4-ethynylphenoxy)pyridin-2-yl)piperidin-4-amine [ka] A mixture of t-butyl (1-(3-chloro-4-(2-chloro-4-((trimethylsilyl)ethynyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate (100 mg, 0.18 mmol, 1.00 equiv) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give 1-(3-chloro-4-(2-chloro-4-ethynylphenoxy)pyridin-2-yl)piperidin-4-amine (60 mg, crude) as a yellow oil. LCMS (ESI, m / z): 362 [M+H] + .

[0084] Step 5: Preparation of 1-(1-(3-chloro-4-(2-chloro-4-ethynylphenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea [ka] To a mixture of 3-aminopyridine (16 mg, 0.20 mmol, 1.0 equiv) and triphosgene (29 mg, 0.10 mmol, 0.60 equiv) in DCM (5 mL) was added DIPEA (64 mg, 0.60 mmol, 3.0 equiv) dropwise under nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 1 h before adding a mixture of 1-(3-chloro-4-(2-chloro-4-ethynylphenoxy)pyridin-2-yl)piperidin-4-amine (60.00 mg, 0.20 mmol, 1.00 equiv) in DCM (3 mL). The reaction mixture was stirred at 0° C. for an additional 1 h and quenched with water (10 mL). The resulting mixture was extracted with DCM (3×10 mL) and the combined organic layers were washed with brine (2×10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by C-18 column chromatography and preparative HPLC to give 1-(1-(3-chloro-4-(2-chloro-4-ethynylphenoxy)pyridin-2-yl)piperidin-4-yl)-3-(pyridin-3-yl)urea (8.20 mg, 10%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ 8.59-8.54(m,1H), 8.19-8.13(m,1H), 8.06-8.00(m,1H), 8.00-7.93(m,1 H), 7.72-7.67(m,1H), 7.55-7.48(m,1H), 7.40-7.32(m,1H), 7.22-7.15(m ,1H), 6.37-6.31(m,1H), 3.87-3.77(m,3H), 3.69-3.65(m,1H), 3.13-3.0 2(m,2H), 2.14-2.03(m,2H), 1.80-1.60(m,2H).LCMS(ESI, m / z):482[M+H] + .

[0085] Example 7: 1-(pyridin-3-yl)-3-(1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)urea [ka] Step 1: Preparation of 2,3-dichloro-4-(4-(trifluoromethyl)phenoxy)pyridine [ka] A flask was charged with 4-(trifluoromethyl)phenol (402 mg, 2.48 mmol, 1.00 equiv), NaH (60 mg, 2.48 mmol, 1.00 equiv) and DMF (10 mL). The reaction mixture was stirred at room temperature for 0.5 h. A solution of 2,3,4-trichloropyridine (406 mg, 2.23 mmol, 0.900 equiv) was added to the reaction mixture. The reaction mixture was stirred at 100° C. for 2 h and then quenched with water (30 mL). The resulting solution was extracted with DCM (3×30 mL) and the organic layers were combined, washed with brine (1×30 mL) and purified with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 500 mg (65% yield) of 2,3-dichloro-4-(4-(trifluoromethyl)phenoxy)pyridine as a white solid. LCMS (ESI, m / z): 308 [M+H] + .

[0086] Step 2: Preparation of t-butyl (1-(3-chloro-4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate [ka] A flask was charged with 2,3-dichloro-4-(4-(trifluoromethyl)phenoxy)pyridine (480 mg, 1.56 mmol, 1.00 equiv.), t-butyl piperidin-4-ylcarbamate (342 mg, 1.71 mmol, 1.10 equiv.), Cs 2 CO 3(1.53 g, 4.68 mmol, 3.00 equiv), CuI (29 mg, 0.156 mmol, 0.100 equiv) and 1,4-dioxane (10 mL). The reaction mixture was stirred at 130 °C for 48 h and then quenched with water (30 mL). The resulting solution was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give 400 mg (54% yield) of t-butyl (1-(3-chloro-4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate as a white solid. LCMS (ESI, m / z): 472 [M+H] + .

[0087] Step 3: Preparation of t-butyl (1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate [ka] A flask was charged with t-butyl (1-(3-chloro-4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate (380 mg, 0.805 mmol, 1.00 equiv), Pd / C (19.0 mg, 0.161 mmol, 0.200 equiv) and MeOH (10 mL). The reaction mixture was diluted with H 2 The mixture was stirred at room temperature under atmospheric pressure for 8 hours. The resulting solution was filtered, the filter cake was washed with EtOAc (3×10 mL), and the filtrate was concentrated under reduced pressure to give t-butyl (1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate (300 mg crude) as a yellow oil. LCMS (ESI, m / z): 438 [M+1] + .

[0088] Step 4: Preparation of -(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-amine [ka] A flask was charged with t-butyl (1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)carbamate (300 mg, 0.686 mmol, 1.00 equiv), TFA (3 mL) and DCM (10 mL). The reaction mixture was stirred at room temperature overnight. The pH value of the solution was adjusted using NaHCO 3 The resulting mixture was extracted with DCM (3×30 mL), and the organic layers were combined, washed with brine (1×30 mL), and concentrated in anhydrous Na 2 SO 4 The mixture was dried over 100 ml of 1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-amine and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 100 mg (43% yield) of 1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-amine as a yellow oil. LCMS (ESI, m / z): 338 [M+H] + .

[0089] Step 5: Preparation of 1-(pyridin-3-yl)-3-(1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)urea [ka] A flask was charged with pyridin-3-amine (31 mg, 0.326 mmol, 1.10 equiv) and DIPEA (77.0 mg, 0.594 mmol, 2.00 equiv) in DCM (2 mL). A solution of triphosgene (44.0 mg, 0.148 mmol, 0.500 equiv) in DCM (4 mL) was added dropwise at 0° C. The mixture was then stirred at room temperature for 2 h and concentrated under reduced pressure. To a solution of 1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-amine (100 mg, 0.297 mmol, 1.00 equiv) in ACN (3 mL) was added the above residue followed by DBU (181 mg, 1.19 mmol, 4.00 equiv) and DMAP (7.00 mg, 0.0594 mmol, 0.200 equiv). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The resulting mixture was extracted with DCM (3×20 mL), and the combined organic layers were washed with brine (1×20 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 44 mg (33% yield) of 1-(pyridin-3-yl)-3-(1-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)piperidin-4-yl)urea as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.57-8.46(m,2H), 8.15-8.03(m,2H), 7.92-7.84(m,1H), 7.80(d,J=8.4Hz, 2H) , 7.35-7.20(m,3H), 6.54(d,J=2.0Hz, 1H), 6.36(d,J=7.6Hz, 1H), 6.27(dd,J=5 .7, 1.9Hz, 1H), 4.12(dd,J=11.5, 7.0Hz, 2H), 3.84-3.65(m,1H), 3.12-2.95(m, 2H), 1.87(dd,J=13.0, 3.8Hz, 2H), 1.45-1.30(m,2H).LCMS(ESI, m / z):458[M+H] + .

[0090] Examples 8-29: Examples 8-29 were prepared in a similar manner to Examples 1-7.

[0091] [Table 1]

[0092] [Table 2]

[0093] [Table 3]

[0094] [Table 4]

[0095] [Table 5]

[0096] II. Biological Evaluation Compounds were tested to assess their ABHD12 activity using the following assays.

[0097] In vitro competitive activity-based protein profiling Mouse brain membrane proteome (50 μL, 1.0 mg / mL total protein concentration) was preincubated with various concentrations of inhibitors at 37°C. After 30 min, FP-rhodamine probe (1.0 μL, 50 μM in DMSO) was added and the mixture was incubated at room temperature for 30 min. The reaction was quenched with SDS loading buffer (15 μL-4 times) and proteins were separated by SDS-PAGE gel (10% acrylamide). After in-gel fluorescence imaging, enzyme activity was determined by measuring the intensity of the gel band corresponding to ABHD12 using ImageJ software. Percent enzyme inhibition at 1 μM and IC from these assays 50 The data are shown in Table 1.

[0098] [Table 6]

Claims

1. Below formula: 【Chemistry 1】 【change】 or a pharma- ceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

3. 13. A pharmaceutical composition for treating a disease or disorder in a patient, comprising the compound of claim 1, or a pharma- ceutical acceptable salt thereof, wherein the disease or disorder is a neuropsychiatric disorder, an autoimmune disease, a neuroinflammatory disease, a neurodegenerative disease, or cancer.

4. 13. A pharmaceutical composition for treating cancer in a patient, comprising a compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein said compound or said pharma- ceutically acceptable salt thereof stimulates the immune system of said patient.

5. 13. A pharmaceutical composition for treating cancer in a patient, comprising a compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein an immune response is initiated by said compound or said pharma- ceutically acceptable salt thereof.

6. 13. A pharmaceutical composition for treating cancer in a patient, comprising the compound of claim 1, or a pharma- ceutical acceptable salt thereof, wherein the compound or a pharma- ceutical acceptable salt thereof is an immunotherapeutic agent.

7. 13. A pharmaceutical composition for treating an infectious disease in a patient, comprising a compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound or the pharma- ceutically acceptable salt thereof stimulates the immune system of the patient.

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