N-substituted C6 cyclylcarboxamide compounds and their uses

Abstract

This specification describes modified monoterpene TRPM8 activating compounds. In particular, the compounds provided herein affect the function of ion channels in cells and are useful as therapeutic agents or in conjunction with therapeutic agents. The compounds provided herein are useful in the treatment of a variety of diseases and conditions, including inflammatory eye diseases such as uveitis, cardiovascular diseases, inflammatory diseases, and diseases characterized by abnormal growth such as cancer. This specification describes Ca 2+ This is an N-substituted C6 cyclylcarboxamide compound that affects intracellular ion transport, such as ions, and is useful as a therapeutic agent or in combination with one or more additional therapeutic agents.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 460,422, filed on 19 April 2023, the entirety of which U.S. Provisional Patent Application is incorporated herein by reference. [Background technology]

[0002] background Transient receptor potential (TRP) channels are a group of ion channels primarily located in the cell membranes of various animal cell species. TRP channels function as non-selective cation-permeable channels; upon activation, they depolarize cells, leading to subsequent voltage-gated ion channel activation and intracellular Ca2+ activity. 2+They cause changes in concentration. Their classification is based on sequence similarity, not on their common functional characteristics. Most of these channels are grouped into two broad groups. Group 1 includes TRPC ("C" meaning standard), TRPV ("V" meaning vanilloid), TRPVL ("VL" meaning vanilloid-like), TRPM ("M" meaning melastatin), TRPS ("S" meaning soromelastatin), TRPN ("N" meaning no mechanoreceptor potential C), and TRPA ("A" meaning ankyrin). Group 2 consists of TRPP ("P" meaning polycystic) and TRPML ("ML" meaning mucolipin). There are other TRP channels that are not as well categorized, such as yeast channels and some Group 1 and Group 2 channels found in non-animals. Many TRP channels mediate a variety of sensations, such as pain, temperature, different types of taste, pressure, and vision. Some TRP channels act as sensors for osmotic pressure, volume, stretch, and vibration. Most channels are activated or inhibited by lipid signaling and belong to the family of lipid-dependent ion channels. TRP channels are found in vertebrates, where they are expressed throughout many cell types and tissues. Most TRP channels consist of a six-transmembrane helix and intracellular N and C-terminuses. Mammalian TRP channels are activated and regulated by a wide range of stimuli and are expressed throughout the body.

[0003] TRP ligands can modulate multiple TRP channels, resulting in activity profiles that include the induction of undesirable sensations. Therefore, selective TRP channel ligands are needed, including the selective TRP channel subfamily M(melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), and the TRP channel polycystin-2 (TRPP2) ligand. [Overview of the project] [Means for solving the problem]

[0004] overview This specification describes Ca 2+ The compounds described herein are N-substituted C6 cyclylcarboxamide compounds that affect intracellular ion transport, such as ions, and are useful as therapeutic agents or in combination with one or more further therapeutic agents. In some embodiments, the compounds described herein are useful for: the treatment of eye diseases, including but not limited to non-infectious uveitis, non-infectious chorioretinitis, iritis, aseptic conjunctivitis, keratitis, episcleritis, dry eye diseases, meibomian gland dysfunction, allergic conjunctivitis, glaucoma, or retinal diseases; as anti-inflammatory agents; for the treatment of skin diseases; for the treatment of cardiovascular diseases; for the treatment of autoimmune disorders, including but not limited to rheumatoid arthritis, Crohn's disease, and ulcerative colitis; or for the treatment of diseases characterized by abnormal growth, including but not limited to cancers, including prostate cancer. [Modes for carrying out the invention]

[0005] Detailed explanation N-substituted C6 cyclylcarboxamide compounds were identified as selective ligands for TRPM8, TRPP2, or both, compared to one or more other TRP channels or one or more groups of TRP channels.

[0006] definition Although this disclosure has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of this disclosure.

[0007] Any grouping of alternative elements or embodiments disclosed herein may be claimed by reference, individually, or in any combination with other members of the group or other elements found herein.

[0008] Unless otherwise defined, all technical and scientific terms used herein shall have the meanings generally known to those skilled in the art.

[0009] Definitions of specific functional groups and chemical terms are described in further detail below. For the purposes of this disclosure, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Identified according to the inside cover of the Ed., specific functional groups are defined as a whole as described therein. In addition, general principles of organic chemistry, methods of chemical transformation, protecting group methodology, and specific functional parts and reactivity are referred to Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989;Carruthers, Some Modern Methods of Organic Synthesis, 3 rdThis information is found in the following publications: Edition, Cambridge University Press, Cambridge, 1987; TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), the entire contents of which are incorporated herein by reference.

[0010] Those skilled in the art will be able to recognize or confirm numerous equivalents of the specific embodiments of the invention described herein using only routine experiments. Such equivalents are intended to be included in the following claims.

[0011] The following definitions apply to specific terms, whether used alone or as part of a phrase or other term.

[0012] The articles "a" and "an" indicate that the grammatical object of the article is one or more than one.

[0013] Numerical values ​​related to measurements are subject to measurement errors, and their accuracy is limited. Therefore, unless otherwise indicated, all numerical values ​​provided herein should be understood to be modified with the term "approximately." Thus, "approximately" refers to an error of ±10%. Otherwise, the last decimal place of the numerical values ​​provided herein indicates the degree of accuracy. Unless another error range is given, and when a given numerical value does not have a decimal point, the maximum range is determined by applying rounding rules to the last decimal place or last significant digit.

[0014] The term "alkyl" refers to a saturated hydrocarbon portion that is branched, cyclic, linear, or a combination thereof.

[0015] As used herein, the term "alkylene" refers to a divalent alkyl group.

[0016] The term "improvement" means a reduction in the severity of at least one indicator of a condition or disease, such as delaying or slowing the progression of one or more indicators of the condition or disease. The severity of an indicator may be determined by subjective or objective measures known to those skilled in the art.

[0017] The term "aryl," as used herein, refers to a phenyl group or a bicyclic fused ring system. Bicyclic fused ring systems are exemplified by cycloalkyl groups, phenyl groups, heteroaryl groups, or phenyl groups fused to a heterocycle, as defined herein, attached to a parent molecule. Representative examples of aryls include, but are not limited to, indolyl, naphthyl, phenyl, quinolinyl, and tetrahydroquinolinyl.

[0018] The term “C e~k " refers to a region containing e~k carbon atoms, where e and k are integers.

[0019] The terms “composition” and “pharmaceutical composition” each refer to a mixture of at least one compound described herein and a carrier or pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to a patient or subject. Multiple administration techniques for compositions exist, including, but are not limited to, intravenous, oral, nasal, rectal, vaginal, aerosol, parenteral, buccal, sublingual, ocular, pulmonary, transdermal, and topical administration.

[0020] As used herein, the term "cycloalkyl" refers to a carbocyclic ring system containing 3 to 10 carbon atoms and lacking heteroatoms and double bonds. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyl groups may be substituted or unsubstituted.

[0021] The terms “effective dose” and “therapeutic dose” refer to the amount of a therapeutic compound, such as those described herein, that is effective in administering to a subject as a single dose or as part of a series of doses to produce the desired therapeutic effect. Generally, the therapeutic dose can be initially estimated using either a cell culture assay or a mammalian model (e.g., non-human primates, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine doses and routes of administration that are useful for administration in non-human and human subjects.

[0022] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0023] The term "haloalkyl," as used herein, refers to at least one halogen atom attached to the parent molecule through an alkyl group as defined herein.

[0024] The term "heteroalkyl," as used herein, means an alkyl group as defined herein, in which one or more carbon atoms are replaced by heteroatoms selected from S, O, P, and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkylamines, amides, and alkyl sulfides. Heteroalkyl groups may be substituted or unsubstituted.

[0025] The term “heteroaryl” as used herein refers to an aromatic monocyclic ring or an aromatic bicyclic ring system. An aromatic monocyclic ring is a five- or six-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., one, two, three, or four heteroatoms independently selected from O, S, and N). A five-membered aromatic monocyclic ring has two double bonds, and a six-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryl groups are exemplified by monocyclic heteroaryl rings fused to a parent molecule and monocyclic cycloalkyl groups, monocyclic aryl groups, monocyclic heteroaryl groups, or monocyclic heterocycles as defined herein. Representative examples of heteroaryls include, but are not limited to, indolyl, pyridinyl (including pyridine-2-yl, pyridine-3-yl, and pyridine-4-yl), pyrimidinyl, thiazolyl, and quinolinyl. The heteroaryl group may be substituted or not.

[0026] The terms “heterocyclic” or “heterocyclic formula” as used herein mean monocyclic, bicyclic, or tricyclic heterocyclic rings. A monocyclic heterocyclic ring is a 3, 4, 5, 6, 7, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3 or 4-membered ring contains no double bond or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains no double bond or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains no double bond or one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings either contain no double bonds or contain one, two, or three double bonds and contain one, two, or three heteroatoms selected from the group consisting of O, N, and S. The heterocyclic group may be substituted or unsubstituted.

[0027] The term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, additive, thickener, solvent, or encapsulating material, that is involved in the delivery or transport of at least one pharmaceutically active ingredient described herein into or to a patient, so that the pharmaceutically active ingredient may exert its intended function. A given carrier must be “acceptable” in the sense that it is compatible with other components of a particular cream formulation containing the pharmaceutically active ingredient described herein and is not harmful to the patient. Other components that may be included in the pharmaceutical cream described herein are known in the art and are described, for example, in “Remington's Pharmaceutical Sciences” (Genaro (Ed.), Mack Publishing Co., 1985) (the entire contents of which are incorporated herein by reference).

[0028] The term “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound has been modified by converting the present acidic or base moiety to its salt form. pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of these two solvents. A list of suitable salts can be found in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (P. Heinrich Stahl & Camille G. Wermuth (Eds.), VHCA & Wiley-VCH, 2002), the entire contents of which are incorporated herein by reference. In this specification, references to a type or class of compound should be understood to include pharmaceutically acceptable salts of that compound.

[0029] The term "refractory disease" refers to a disease that continues to progress during treatment with medicinal components other than the active pharmaceutical ingredients provided herein, responds partially to other treatments, or responds transiently to other treatments. The aforementioned terms may be applied to each of the diseases referred to herein.

[0030] The term "substituted" or "substituted" refers to replacing a hydrogen atom bonded to another group with an atom or group of atoms acting as a substitution substituent, each substituent being independently selected.

[0031] The term “treatment” or “treating” refers to the application of one or more specific procedures used to improve a disease. “Preventive” treatment refers to slowing the progression of the disease or condition being treated, delaying the onset of the aforementioned disease or condition, or reducing the severity of its onset.

[0032] The enumeration of value ranges in this specification is intended solely as a convenient way to refer individually to each distinct value that falls within the aforementioned range. Unless otherwise stated herein, each distinct value is incorporated herein as if it were individually enumerated herein. Unless otherwise indicated herein, or unless it is clearly inconsistent with the context, all methods described herein may be performed in any appropriate order. The use of any examples or illustrative language provided herein (e.g., "etc.") is intended merely to clarify the subject matter described herein and does not otherwise limit the scope of the subject matter described in the claims. Nothing in this specification should be construed as indicating that any element not described in any claim is essential to the practice of the subject matter described herein.

[0033] The grouping of alternative elements or embodiments of the present disclosure should not be construed as a limitation. Members of each group may be referred to individually or in any combination with other members of the group or other elements found herein and may be recited in the claims. Further, for convenience or reasons of patentability, the recited members of a group may be included in or excluded from another recited group.

[0034] With regard to the compounds described herein, the groups and substituents thereof can be selected according to the possible valences of the atoms and substituents such that the selection and substitution result in stable compounds that do not spontaneously undergo transformation at ambient temperature, for example, by rearrangement, cyclization, elimination, etc.

[0035] The citation of patent documents or other publications herein, if any, serves as a function of incorporation herein by reference to the entire content of such documents or publications.

[0036] Embodiments of the present disclosure are illustrative. Accordingly, the present disclosure is not strictly limited to what is illustrated and described.

[0037] Compound N-Substituted C6 cycloalkyl (e.g., cyclohexyl or phenyl) carboxamide compounds are described.

[0038] In some embodiments, provided herein is a compound having the formula:

Chemical formula

[0039] In some embodiments, J 1 C 1~6 Alkyl-NH2, (CH2) 0~2 -CN, (CH2) 0~2 -CCH, (CH2)0~2 -Ph, (CH2) 0~2 -Ph-O-(C 1~6 Alkyl), (CH2) 0~2 -Ph-((C 2~5 (Heterocycloalkyl)-(C 1~3 Alkyl)), (CH2) 0~2 -Ph-O-(C 1~6 (heteroalkyl), (CH2) 0~2 -Ph-(C 1~6 Alkyl), (CH2) 0~2 -Ph-(C 1~6 Alkyl-NH2), (CH2) 0~2 -Ph-OH, (CH2) 0~2 -Ph-(C 1~6 Alkyl-OH), (CH2) 0~2 -Ph-(C 3~6 Cycloalkyl), (CH2) 0~2 -Ph-(C 2~8 (heterocycloalkyl), or (CH2) 0~2 -Ph-O-(C 1~6 Alkyl)-(C 2~8 It is a heterocycloalkyl (heterocycloalkyl) compound.

[0040] In some embodiments, J 1 It contains 0 to 3 rings and a molecular weight of approximately 80 to 200, C 1~13 H 2~19 N 0~2 O 0~3 S 0~1 B 0~1 F 0~3 Cl 0~1 In some embodiments, J 1 It includes one, two, or three rings. In some embodiments, J 1 It contains a molecular weight of approximately 80 to approximately 200. In some embodiments, J 1 It comprises at least one atom independently selected from N, O, S, B, F, or Cl. In some embodiments, J 1 It comprises at least two atoms independently selected from N, O, S, B, F, or Cl. In some embodiments, J 1 It is not p-anisolyl.

[0041] In some embodiments, [Chemical formula] is [Chemical formula] or a pharmaceutically acceptable salt thereof, where J 8 is CH2 or O; J 9 is CH3, NH2, or OH; J 10 is CH3, NH2, or OH; J 11 is NH2, CN, C 1~3 alkyl, F, C 1~3 haloalkyl, O(C 1~3 alkyl), (C 1~3 alkenylenyl)CN, (C 1~3 alkenylenyl)OH, (C 1~3 alkenylenyl)O(C 1~3 alkyl), C(O)OH, (C 1~3 alkenylenyl)C(O)OH, C(O)O(C 1~3 alkyl), (C 1~3 alkenylenyl)C(O)O(C 1~3 alkyl), C(O)O(C 1~6 alkyl), tetramethyldioxaborolanyl, CO2NH2, C(O)N(C 1~3 alkyl)O(C 1~3 alkyl), N(H)C(O)(C 1~3 alkenylenyl)OH, or N(H)C(O)O(C 1~3 alkyl); J 12 is CH3, NH2, or OH; J 13 is O(C 1~3 alkyl) or C(O)O(C 1~3 alkyl); J 14 is H; J 15is CH3, NH2, or OH; J 16 H, O(C) 1~3 Alkyl), or O(C 1~3 Alkyrenyl)O(C 1~3 Alkyl) is; J 17 is either H, or NH2 or NHC(O)(C 1~3 C substituted with alkylenyl)NH2 8~10 It forms a spirocycloalkyl group.

[0042] In some embodiments, J 11 However, these are NH2, CN, CH2CH3, F, CH2CF3, OCH3, OCH2CH3, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, C(O)OH, CH2C(O)OH, C(O)OCH3, CH2C(O)OCH3, C(O)OC(CH3)3, tetramethyldioxavoranyl, CO2NH2, C(O)N(CH3)OCH3, N(H)C(O)CH2OH, or N(H)C(O)OCH3.

[0043] In some embodiments, J 13 However, it is either OCH3 or C(O)OCH3.

[0044] In some embodiments, J 16 However, it is H, OCH3, or OCH2CH2OCH3.

[0045] In some embodiments, J 17 However, it forms a spirononanyl which is either H or substituted with NH2 or NHC(O)CH2NH2.

[0046] In some embodiments, J 9 , J 10 , J 12 , and J 15 This is CH3.

[0047] In some embodiments, J 1 teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0048] In some embodiments, J 2 teeth, [ka] That is the case.

[0049] In some embodiments, J 4 H, [ka] That is the case.

[0050] In some embodiments, J 1 and J 4 However, along with the nitrogen to which they bind, [ka] It forms.

[0051] In some embodiments, the compounds provided herein are selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2]

[0052] In some embodiments, the compounds provided herein are selected from the compounds in Table 2 or pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2]

[0053] In some embodiments, the compounds provided herein are selected from the compounds in Table 3 or pharmaceutically acceptable salts thereof. [Table 3-1] [Table 3-2]

[0054] In some embodiments, the compounds provided herein are selected from the compounds in Table 4 or pharmaceutically acceptable salts thereof. [Table 4-1] [Table 4-2]

[0055] In some embodiments, the compounds provided herein are selected from the compounds in Table 5 or pharmaceutically acceptable salts thereof. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0056] In some embodiments, the compounds provided herein are selected from the compounds in Table 6 or pharmaceutically acceptable salts thereof. [Table 6]

[0057] This disclosure also includes isotope-labeled compounds that are identical to those described in the formulas herein, except that one or more atoms are replaced by atoms having atomic masses or mass number abundances different from those normally found in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, each but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 It is Cl. Deuterium, that is 2 Substitution with heavier isotopes such as H may be preferable in some situations because it can yield certain therapeutic benefits, such as improved metabolic stability, an extended half-life in vivo, or a reduction in the required dose. Compounds can incorporate positron emission isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron emission isotopes that can be incorporated into the compounds herein are: 11 C, 13 N, 15 O, and 18F is used herein. In this specification, isotope-labeled compounds can generally be prepared by prior art known to those skilled in the art, or by processes similar to those described herein, using appropriate isotope-labeled reagents or starting materials instead of unlabeled reagents or starting materials. Therefore, in some embodiments, what is provided herein are compounds of the formula herein in which at least one atom is replaced by its corresponding atom having an atomic mass or mass number abundance different from that normally found in nature. For example, the compound may be independently, 2 H or 3 One or more H's that are replaced by H (for example, 1 It has H). In some embodiments, one or more Cs independently, 13 C or 14 It is replaced by C. 15 It is replaced by N. In some embodiments, one or more Os are independently 18 O or 17 It is substituted with O. In some embodiments, one or more Ps are independently 32 It is replaced by P. In some embodiments, one or more S are independently 35 It is replaced by S. In some embodiments, one or more Fs are independently, 18 It is substituted with F. In some embodiments, one or more Cls are independently, 35 Cl, 36 Cl, or 37 It is replaced with Cl.

[0058] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” means a salt or amphoteric ion of a compound that is suitable for therapeutic use without excessive toxicity, irritation, or allergic reactions, is effective for its intended use, and is commensurate with a reasonable benefit / risk ratio. Salts can be prepared during the final isolation and purification of the compound, or, for example, by separately reacting the amino group of the compound with a suitable acid. For example, a compound may be dissolved in a suitable solvent such as methanol or water, but is not limited, and treated with at least one equivalent of an acid. Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by the reaction of a suitable base (e.g., a cation hydroxide, carbonate, or bicarbonate) with an acidic group (e.g., a carboxyl group). The resulting salt can then be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and any excess acid can be removed under reduced pressure to provide the salt.

[0059] In some embodiments, the compounds provided herein are substantially purified. In some embodiments, the compounds are prepared by a process that includes precipitating the compound from a solution containing the compound, or a salt thereof, and a solvent. In some embodiments, the process includes drying the precipitated compound. In some embodiments, the precipitated compound is converted into particles (e.g., by grinding, impacting, or rolling).

[0060] In some embodiments, a composition comprising one or more compounds described herein is provided. In some embodiments, the composition is a pharmaceutical composition. The composition may further comprise a pharmaceutically acceptable carrier.

[0061] In some embodiments, the compound is present in the composition in an amount of at least about 90% by weight.

[0062] In some embodiments, the composition is a pharmaceutical composition consisting essentially of compounds.

[0063] Pharmaceutical compositions for use as disclosed herein may be formulated using one or more physiologically acceptable carriers or additives suitable for a particular route of administration. Thus, compounds and their physiologically acceptable salts and solvates may be formulated, for example, in solid form, eye drops, topical oily formulations, for administration by injection (systemically or into specific tissues of the eye, including injection of a drug-eluting device), inhalation (oral or nasally), implantation, or oral, buccal, parenteral, or rectal administration. Intranasal drug administration may allow bypassing the blood-brain barrier and enable delivery to the central nervous system via the olfactory pathway (olfactory bulb) or respiratory pathway (brainstem, pons). Techniques and formulations can be commonly found in "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, PA).

[0064] synthesis In some embodiments, the N-substituted C6 cyclylcarboxamide compounds provided herein are synthesized by condensation of a carboxylic acid or acid chloride with an amine to form the desired compound.

[0065] In some embodiments, the compounds described herein can be prepared according to the following scheme. [ka]

[0066] In some embodiments, the compounds described herein can be prepared according to the following scheme. [ka]

[0067] In some embodiments, the compounds described herein can be prepared according to the following scheme. [ka]

[0068] In some embodiments, the compounds described herein can be prepared according to the following scheme. [ka]

[0069] In some embodiments, the compounds described herein can be prepared according to the following scheme. [ka]

[0070] In some embodiments, the compounds described herein can be prepared according to the following scheme. [ka]

[0071] J 1 -NH2 is shown in the scheme above, but under similar reaction conditions, secondary amines, such as compounds containing secondary amines, can be used instead. In some embodiments, the secondary amines include azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azokanyl, azonanyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazepanyl, or a diazepanyl ring.

[0072] Therefore, in some embodiments, the compounds described herein are compounds [ka] or so that a salt thereof is formed, [ka] of [ka] To bring into contact with (Here, J 1 This is defined herein; J 2 This is defined herein; J 3 is either OH or Cl; J 4 (as defined herein), It can be prepared by a process that includes a condensation reaction.

[0073] In some embodiments, the compound is synthesized by condensation of a carboxylic acid (e.g., (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid or (1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxylic acid) or an acid chloride (e.g., (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl chloride or (1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-carbonyl chloride) with an amine R-NH2.

[0074] In some embodiments of these synthesis methods, R is selected from the corresponding part shown in any one of the compounds listed in Table 1, Table 2, Table 3, Table 4, Table 5, or Table 6, or the corresponding part of the general formula provided herein. In some embodiments, the condensation reaction proceeds without a coupling agent, but the reaction mixture can proceed by heating, for example, above about 100°C. In some embodiments, the condensation reaction is facilitated by one or more coupling agents. In some embodiments, the coupling agent is independently a metal chloride, including but not limited to TiCl4, or a carbodiimide or salt thereof, including but not limited to dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). In some embodiments, the condensation further includes one or more racemization inhibitors. In some embodiments, the racemization inhibitor is a triazole, ethyl cyanohydroxyiminoethyl acetate, or N-hydroxysuccinimide, but is not limited to 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt).

[0075] The compounds provided herein are prepared using substantially the same procedures as those described above and in the following examples, with appropriate modifications.

[0076] method The compounds described herein are useful for modulating the action of ion channels. Therefore, in some embodiments, the compounds described herein are useful in methods for treating diseases or conditions affected by ion channels. For example, it is possible to prepare the action of ion channels using the above compounds and compositions in vitro (e.g., in cells) or in vivo.

[0077] Generally, the compounds provided herein are useful in methods involving the administration of the compounds to subjects requiring them. In some embodiments, the compounds may be selected from any of the formulas described herein or from any of the compounds listed in the tables provided herein, and may be provided in a neutral form or as salts of the compounds.

[0078] In some embodiments, a method is provided to activate an ion channel, comprising the steps of applying an effective amount of the compound disclosed herein to a culture medium such as an assay medium, or contacting it with cells, either in vitro or in vivo. In one embodiment, the ion channel to be activated or inhibited is TRPM8. TRPM8 modulators or activators are useful for treating a variety of TRPM8-related diseases or disorders. Examples of TRPM8-related diseases include diseases or conditions involving the sensation of cold or dryness. Further examples of TRPM8-related diseases include dry eye, eye pain, eye discomfort, eye irritation, and non-infectious uveitis. In some embodiments, the disease is dry eye.

[0079] In some embodiments, provided herein are methods for activating ion channels in cells, tissues, or subjects such as humans, comprising the step of contacting cells with one or more compounds of the Disclosure in an amount effective to activate ion channels. In some embodiments, the compounds are administered, for example, in or with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

[0080] In some embodiments, the compounds of the Disclosure are used in a method for modulating the action of ion channels in cells, the method comprising the step of contacting cells with one or more of the compounds of the Disclosure in an amount effective to modulate the action of ion channels in cells. In some embodiments, the compounds of the Disclosure are administered, for example, in or with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

[0081] The treatment of diseases or conditions for which the compounds of this disclosure may be useful includes diseases or conditions related to ion channel activity, or diseases or conditions affected by ion channels. In some embodiments, these types of diseases include inflammatory diseases, inflammatory conditions of the eye, such as non-infectious uveitis, chorioretinitis, iritis, aseptic conjunctivitis, keratitis, episcleritis, dry eye diseases, meibomian gland dysfunction (MGD), allergic conjunctivitis, inflammation of the eye related to injury, dry eye syndromes, primary and secondary Sjögren's syndrome, redness, blepharitis, keratoconjunctivitis sicca, conjunctival hyperemia, inflammatory eye diseases, dermatological disorders, respiratory signs, or cancer (e.g., prostate cancer).

[0082] In some embodiments, the compounds of this disclosure may be administered in combination with one or more further therapeutic agents. A preferred class of further therapeutic agents includes, but is not limited to, ROCK inhibitors, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotics, cholinergics, epinephrine compounds, neuroprotective agents, or anti-inflammatory agents. Non-limited examples include corticosteroids, immunosuppressants, or JAK inhibitors.

[0083] Accordingly, in some embodiments, what is provided herein is a method for treating an eye disorder in a subject requiring such treatment, the method comprising the step of administering a compound, composition, or pharmaceutical composition provided herein to the subject.

[0084] In some embodiments, methods for reducing ocular inflammation in subjects requiring reduction of ocular inflammation are provided herein, comprising the step of administering a compound, composition, or pharmaceutical composition provided herein to the subject.

[0085] In some embodiments of the methods described herein, the ocular disorder is dry eye. In some embodiments, the ocular disorder is meibomian gland dysfunction (MGD). In some embodiments, the ocular disorder is uveitis. In some embodiments, the ocular disorder is blepharitis.

[0086] In some embodiments, what is provided herein is a method for reducing inflammation in a subject in need thereof, the method comprising the step of administering a compound, composition, or pharmaceutical composition provided herein to the subject.

[0087] In some embodiments of these aspects, the compound, composition, or pharmaceutical composition is administered topically to the eye of the subject.

[0088] kit In some embodiments, the compounds described herein may be formulated for ophthalmic use. In some embodiments, the compounds described herein may be formulated as a cream, ointment, or gel for topical administration to the area around the eyes of a subject, or as an eye drop for topical application to the eyes. In some embodiments, provided herein is a packaged formulation comprising a container for holding a therapeutically effective amount of at least one formulation described herein, and instructions for using at least one formulation according to one or more of the methods provided herein.

[0089] The formulations and related materials can be manufactured into commercially viable products by conventional processes practiced in this art (e.g., appropriate sterilization and packaging processes). For example, the materials can be treated by UV / vis irradiation (200-500 nm) using, for example, a photoinitiator having different absorption wavelengths (e.g., Irgacure 184, 2959), preferably a water-soluble initiator (e.g., Irgacure 2959, e.g., 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one). Such irradiation is typically carried out for an irradiation time of 1-60 minutes, but longer irradiation times may be applied depending on the specific method. The materials according to this disclosure can finally be sterile-packaged to maintain sterility until use and packaged in a suitable container (e.g., a box) (e.g., with the addition of a specific product information leaflet).

[0090] In further embodiments, the formulation may also be provided in kit form, combined with other components necessary for administering the formulation to a patient. For example, a disclosed kit, such as one for use in the treatment of an eye disease, may further include administration materials, such as a spatula or ruler.

[0091] The kits are designed in various forms based on the specific deficiency being treated.

[0092] The formulations provided herein may be prepared and placed in containers for storage at ambient temperature or high temperatures. When formulations are stored in polyolefin plastic containers, discoloration of the formulations may be reduced compared to polyvinyl chloride plastic containers. While not wishing to be bound by theory, containers may reduce the exposure of the contents to electromagnetic radiation, whether visible light (e.g., having wavelengths of about 380–780 nm) or ultraviolet (UV) light (e.g., having wavelengths of about 190–320 nm (UV B) or about 320–380 nm (UV A)). Some containers also include the ability to reduce adhesion or adsorption of active agents to the surface of the container. Some containers also include the ability to reduce the exposure of the contents to infrared radiation, or include a second component having such an ability. Containers that can be used include polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly containers made from polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container, and the user removes the contents from the container using a measuring spatula, scoop, etc. In some embodiments, the container is flexible, allowing the user to squeeze the contents out of the container. The container may further be placed in a second container (e.g., in a container of paper, cardboard, board, metal film, or foil, or a combination thereof) to further reduce the exposure of the contents of the container to UV, visible light, or infrared light. The formulations provided herein benefit from reduced discoloration, decomposition, or both during storage in such a container. The formulations provided herein may require storage for a period of up to three months or more than three months; in some cases, up to one year or more than one year. The container may be any form suitable for holding the contents; for example, a bag, bottle, tube, or box. In some embodiments, the container is a single-use blow-fill seal tube. In some embodiments, the container is a multi-dose bottle.

[0093] The following embodiments further illustrate aspects of the present disclosure. However, the embodiments are not in any way limited to the teachings and disclosures set forth herein. [Examples]

[0094] Example 1: Compound Synthesis (1R,2S,5R)-2-isopropyl-5-methyl-N-(3-(methylsulfonyl)cyclopentyl)cyclohexane-1-carboxamide is prepared according to the following scheme. [ka]

[0095] (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (38 mg, 0.21 mmol) in DMF (0.8 mL) was mixed with 3-(methylsulfonyl)cyclopentan-1-amine (50 mg, 0.25 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC·HCl, 48 mg, 0.25 mmol), and DMAP (31 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The compounds were poured into ethyl acetate, extracted with HCl (1N), dried, filtered, and evaporated. Pure (1R,2S,5R)-2-isopropyl-5-methyl-N-(3-(methylsulfonyl)cyclopentyl)cyclohexane-1-carboxamide (42 mg, 60%) was obtained using an automated column (4 g Teledyne cartridge) with 0-100% siRNA. Example 2 compound synthesis

[0096] (1R,2S,5R)-2-isopropyl-N-(6-methoxy-5-methylpyridine-3-yl)-5-methylcyclohexane-1-carboxamide is prepared according to the following scheme. [ka]

[0097] (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg, 1.6 mmol) was mixed with thionyl chloride (1.5 mL), and the solution was stirred under reflux at 85-87°C. After 1.5 hours, the solution was cooled, and the residual thionyl chloride was evaporated to obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl chloride (319 mg, >95%).

[0098] 6-methoxy-5-methylpyridine-3-amine (72 mg, 0.52 mmol) was added to CH2Cl2 (0.5 mL), to which pyridine (104 μL, 1.3 mmol) was added, and the solution was cooled to 0°C. Then, (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl chloride (115 mg, 0.57 mmol) was added, and the solution was warmed to room temperature and stirred. After 1.3 hours, the compound was poured into ethyl acetate and extracted with HCl (1N), then with saturated NaHCO3. The organic layer was dried over (Na2SO4), filtered, and evaporated. Pure (1R,2S,5R)-2-isopropyl-N-(6-methoxy-5-methylpyridine-3-yl)-5-methylcyclohexane-1-carboxamide (86 mg, 54%) was obtained by automated column chromatography (4 g Teledyne cartridge, 0-15-20% siRNA). Example 3 compound synthesis

[0099] (1S,2S,4R)-N-(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxamide is prepared according to the following scheme. [ka]

[0100] (1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxylic acid in CH2Cl2 (2 mL) was mixed with EDC·HCl (131 mg, 0.7 mmol), DMAP (83 mg, 0.7 mmol), and 4-methoxyaniline (84 mg, 0.7 mmol), and the solution was stirred overnight at room temperature. The mixture was diluted with CH2Cl2, extracted with HCl (1N), dried, evaporated, and filtered. Pure (1S,2S,4R)-N-(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxamide (119 mg, 73%) was obtained by automated column chromatography (Teledyne 4 g cartridge, 0-30% SiO-hexane). Example 4 compound synthesis

[0101] Isopregylcarboxylic acid is prepared according to the following scheme. [ka]

[0102] To a solution of 6.95 g (52 mmol) of NCS in 75 mL of dry THF cooled in an ice bath under N2, a 20 mL solution of 312.8 g (48.8 mmol) of PPh was slowly added over 1 hour via an addition funnel. The solution was warmed to room temperature and stirred for 1 hour. Then, a solution of 5.016 g (32.5 mmol) of (-)-isoplegol (4-1) in dry THF (75 mL) was added dropwise. The reaction mixture was stirred under N2 at room temperature for 4 days, during which time it changed to a very dark chestnut color. When TLC showed that the starting material was absent, the reaction mixture was concentrated and then 200 mL of pentane was added. The solid was filtered off through a Celite pad, and the crude material was purified by distillation to obtain 5.1 g of 4-2 in 91% yield. TLC: 100% pentane.

[0103] In a round-bottom flask dried in an oven, 82.7 mg (34.0 mmol) of freshly crushed magnesium shavings were activated with I2 and DBE at 50°C, and then cooled. 4.2 g (24.3 mmol) of 4-2 chloride in dry THF was gradually added to the activated magnesium at 50-60°C. Foaming and darkening of the magnesium occurred. The reaction mixture was stirred overnight under N2 at 50°C. The reaction mixture was cooled and used immediately.

[0104] At room temperature, CO2 (g) was aerated through the reaction mixture for 3 hours. The reaction mixture was quenched with 1 M KHSO4 and extracted three times with ethyl acetate. The combined organic layer was extracted with 1 M NaOH and then acidified with 1 M HCl. This aqueous layer was extracted three times with ethyl acetate. Subsequently, it was extracted twice with DCM. The combined organic layer was then washed with brine and dried. After column chromatography, 1.189 g of isopregylcarboxylic acid 4-4 was obtained in 27% yield. Pentane was used instead of heptane. TLC: (9:1:1) pentane:ethyl acetate:acetic acid. Example 5 compound synthesis

[0105] (1R,2R,5R)-2-acetyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide is prepared according to the following scheme. [ka]

[0106] To a DCM solution of (1R,2R,5R)-5-methyl-2-(propa-1-en-2-yl)cyclohexane-1-carboxylic acid (4-4) (50 mg, 0.27 mmol, 1.0 eq), p-anisidine (41 mg, 0.29 mmol, 1.1 eq., 4-5), EDC HCl (83 mg, 0.43 mmol, 1.6 eq.), and 4-DMAP (6.6 mg, 0.05 mmol, 0.20 eq.) were added. The solution was stirred at room temperature. After 6 hours, the reaction mixture was poured into aqueous sodium bicarbonate and ethyl acetate. The layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic matter was dried over magnesium sulfate, filtered, and evaporated. The crude residue was purified by column chromatography (hexane:ethyl acetate) to obtain (1R,2R,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propa-1-en-2-yl)cyclohexane-1-carboxamide in 92% yield.

[0107] Sodium periodate (61 mg, 0.29 mmol, 2.5 eq.) was dissolved in acetic acid (0.5 mL), water (0.5 mL), and THF (0.5 mL). (1R,2R,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propa-1-en-2-yl)cyclohexane-1-carboxamide (33 mg, 0.11 mmol, 1 eq.) was dissolved in 1 mL of THF and added to the sodium periodate solution. Osmium tetroxide (4% aqueous solution, 0.08 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic matter was dried over magnesium sulfate, filtered, and then evaporated. The crude residue was purified by column chromatography (hexane:ethyl acetate) to obtain (1R,2R,5R)-2-acetyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide in 62% yield. Example 6 TRPM8 and TRPV1 assays

[0108] The compound can be tested using Eurofins' commercially available kit "TRPM8 Human Transient Potential Ion Channel Cell Based Agonist Calcium Flux Assay, Cerep" item number 3316, or using the assay described by Behrendt et al. "Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay," Br J Pharmacol. 2004 Feb;141(4):737-45, which are incorporated herein by reference, respectively. For reference, the TRPM8 EC assay for specific TRPM8 agonists is also available. 50 Behrendt et al. have reported that the following values ​​have relative potency: Icillin (0.2±0.1 μM) > Frescolat® ML (3.3±1.5 μM) > WS-3 (3.7±1.7 μM) > (-) Menthol (4.1±1.3 μM) > Frescolat® MAG (4.8±1.1 μM) > cooling agent 10 (6±2.2μM) > (+) Menthol (14.4±1.3μM) > PMD38 (31±1.1μM) > WS-23 (44±7.3μM) > Coolact(registered trademark) P (66±20μM) > Geraniol (5.9±1.6mM) > Linalool (6.7±2.0mM) > Eucalyptol (7.7±2.0mM) > Hydroxycitronellal (19.6±2.2mM). 4. For reference, IC of specific TRPV1 antagonists that block the TRPM8 response to menthol. 50 The values ​​are described by Behrendt et al. as follows: BCTC (4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazine carboxamide; 0.8±1.0 μM), thio-BCTC (3.5±1.1 μM), and capsazepine (18±1.1 μM).

[0109] In short, the compounds provided herein are diluted to appropriate concentration levels, typically logarithmic or semi-logarithmic dilutions with a central concentration of 1 μM, using the control activator ligand, ishirin. The assay is performed at room temperature, and calcium flow is measured. The website uses dl-menthol at 6000 nM TRPM8 EC 50 It contains ishirin at 28 nM TRPM8 EC 50 It has been reported that it possesses [the characteristic]. The activity of the specific compounds described herein is shown in Tables 7, 8, 9, and 10. [Table 7] [Table 8] [Table 9] [Table 10-1] [Table 10-2] Example 7 Topical pharmaceutical compositions

[0110] Topical ophthalmic drug compositions for treating inflammation are prepared by conventional methods and formulated as shown in Table 11. [Table 11]

[0111] When the composition is administered topically to one or both eyes once daily, it reduces ocular inflammation in subjects suffering from MGD or DED. Example 8 Topical pharmaceutical compositions

[0112] Topical ophthalmic drug compositions for treating inflammation are prepared by conventional methods and formulated as shown in Table 12. [Table 12]

[0113] When the composition is administered topically to the eye once a day (for example, by topical eye drops), the composition reduces ocular inflammation in subjects suffering from meibomian gland dysfunction (MGD) or dry eye disease (DED).

Claims

1. formula: 【Chemistry 28】 A compound having or a pharmaceutically acceptable salt thereof, During the ceremony, J １ is C １～１３ H ２～１９ N ０～２ O ０～３ S ０～１ B ０～１ F ０～３ Cl ０～１ and contains from 0 to 3 rings and a molecular weight of from about 39.0 to about 220.3; J ２ teeth, 【Chemistry 29】 And, Here, J ５ Hello, C １～３ Alkyl, C １～３ Haloalkyl, OH, NH ２ , N(H)Ac, N(H)Boc, N(H)Fmoc, or N(H)Cbz; J ６ H is; J ７ H, propyl, ethyl-NH ２ These are ethyl-OH, acetyl, propenyl, propenolyl, methyloxyranyl, or methylenecyclopropanyl; Or, J ６ and J ７ Together C １～６ Forms alkylenyl crosslinks; J ４ H, C １～６ Heteroalkyl, C ６～１２ Aryl, or C(O)-(C １～３ Alkylene) - (C ２～８ (Heterocycloalkyl) Or, J １ and J ４ Along with the nitrogen to which they bind, unsubstituted C ２～８ Heterocycloalkyl, or C １～６ Alkyl or C １～６ C is substituted with one or two groups independently selected from the haloalkyl group. ２～８ Heterocycloalkyl is formed, where hetero refers independently to one, two, or three N, O, or S atoms. A compound or a pharmaceutically acceptable salt thereof. 【Request Item 2】 【Chemistry 30】 but, 【Chemistry 31】 And, Here, J ８ CH ２ or O; J ９ CH ３ NH ２ , or OH; J １０ CH ３ NH ２ , or OH; J １１ NH ２ , CN, C １～３ Alkyl, F, C １～３ Haloalkyl, O(C) １～３ (Alkyl), (C １～３ Alkyrenyl)CN, (C １～３ (Alkyrenyl)OH, (C １～３ Alkyrenyl)O(C) １～３ Alkyl), C(O)OH, (C １～３ Alkyrenyl)C(O)OH, C(O)O(C １～３ (Alkyl), (C １～３ Alkyrenyl)C(O)O(C １～３ Alkyl), C(O)O(C １～６ Alkyl), tetramethyldioxavoloranil, CO ２ NH ２ , C(O)N(C １～３ Alkyl)O(C １～３ Alkyl), N(H)C(O)(C １～３ Alkyrenyl)OH, or N(H)C(O)O(C) １～３ It is alkyl; J １２ CH ３ NH ２ , or OH; J １３ O(C) １～３ Alkyl) or C(O)O(C １～３ It is alkyl; J １４ H is; J １５ CH ３ NH ２ , or OH; J １６ is H, O(C) １～３ Alkyl), or O(C) １～３ Alkyrenyl)O(C) １～３ It is alkyl; J １７ is either H or NH ２ Or NHC(O)(C １～３ Alkirenyl NH ２ C is replaced by ８～１０ Forms a spirocycloalkyl group. The compound according to claim 1.

3. J １１ is NH ２ , CN, CH ２ CH ３ F, CH ２ CF ３ OCH ３ OCH ２ CH ３ CH ２ CN, CH ２ OH, CH ２ CH ２ OH, CH ２ OCH ３ C(O)OH, CH ２ C(O)OH, C(O)OCH ３ CH ２ C(O)OCH ３ C(O)OC(CH ３ ( ３ tetramethyldioxaborolanyl, CO ２ NH ２ C(O)N(CH ３ )OCH ３ N(H)C(O)CH ２ OH, or N(H)C(O)OCH ３ ; J １３ However, OCH ３ or C(O)OCH ３ And; J １６ However, H, OCH ３ , or OCH ２ CH ２ OCH ３ is; or J １７ However, is it H or NH? ２ Or NHC(O)CH ２ NH ２ Forms spirononanyl which is substituted with The compound according to claim 2.

4. J １ but, 【Chemistry 32-1】 【Chemistry 32-2】 【Chemistry 32-3】 【Chemistry 32-4】 And; J ２ but, 【Transformation 33】 And; J ４ However, H, 【Transformation 34】 And; Or J １ and J ４ However, along with the nitrogen to which they bind, 【Chemistry 35】 to form The compound according to claim 1.

5. J １ The compound according to claim 1, wherein it comprises one, two, or three rings, a molecular weight of about 80 to about 200, and at least two atoms independently selected from N, O, S, B, F, or Cl.

6. A process for preparing a compound according to one of claims 1 to 5, wherein the compound 【Transformation 36】 or so that a salt thereof is formed, 【Chemistry 37】 of 【Transformation 38】 To bring into contact with (Here, J ３ (is OH or Cl) A process that includes condensation reactions.

7. A composition comprising a compound according to one of claims 1 to 5.

8. The composition according to claim 7, further comprising a pharmaceutically acceptable carrier.

9. A method comprising administering to a subject a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8.

10. The method according to claim 9, which is a method for activating ion channels in the eye tissue of the subject.

11. A method for adjusting the activity of transient receptor potential cation channel subfamily M member 8 (TRPM8), comprising the step of contacting a TRPM8 channel with a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8.

12. A method for adjusting ion channel activity, comprising the step of contacting an ion channel with a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8.

13. The method according to claim 12, wherein the ion channel is a transient receptor potential (TRP) channel.

14. A method of treatment comprising administering a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8 to a subject in need thereof, wherein the treatment is for the treatment of an inflammatory eye disease.

15. The method according to claim 14, wherein the inflammatory eye disease is uveitis.

16. A method of treatment comprising administering a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8 to a subject in need thereof, wherein the treatment is a treatment for a cardiovascular disease.

17. A method of treatment comprising administering a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8 to a subject in need thereof, wherein the treatment is for the treatment of an inflammatory disease.

18. A method of treatment comprising administering a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8 to a subject in need thereof, wherein the treatment is a treatment for cancer.

19. A method of treatment comprising administering a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8 to a subject requiring the same, wherein the treatment is selected from treatment of eye diseases, e.g., non-infectious uveitis, non-infectious chorioretinitis, iritis, aseptic conjunctivitis, keratitis, episcleritis, dry eye disease, meibomian gland dysfunction, allergic conjunctivitis, glaucoma, or retinal diseases; anti-inflammatory treatment; treatment of skin diseases; treatment of cardiovascular diseases; treatment of autoimmune disorders, e.g., rheumatoid arthritis, Crohn's disease, or ulcerative colitis; or treatment of diseases characterized by abnormal growth, e.g., cancer, e.g., prostate cancer.

20. The method according to one of claims 9 to 19, wherein the administration is by topical eye drop administration.

21. A manufactured product comprising a compound according to one of claims 1 to 5 or a composition according to one of claims 7 to 8, and instructions for use.

Images