# US 11,998,538 B2 · Piperidine urea derivatives as soluble epoxide hydrolase inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,998,538 B2 - Document ID: US11998538B2 - Status: Granted - Kind: B2 - Application number: 17/720,450 - Filed: 2022-04-14 - Published: 2022-11-10 - Granted: 2024-06-04 - Earliest claimed: 2021-04-14 - Assignees: NeuroPn Therapeutics, Inc. - Applicants: NeuroPn Therapeutics, LLC - Inventors: Ish Khanna; Sivaram Pillarisetti - Web page: https://patentgrep.com/patent/US11998538B2 ## CPC - A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine - C07D 211/68: having one double bond between ring members or between a ring member and a non-ring member - A61K 31/445: Non condensed piperidines, e.g. piperocaine - A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone - A61K 31/497: containing further heterocyclic rings - A61K 31/506: not condensed and containing further heterocyclic rings - A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/02: for peripheral neuropathies - A61P 25/16: Anti-Parkinson drugs - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - C07D 401/10: linked by a carbon chain containing aromatic rings - C07D 401/12: linked by a chain containing hetero atoms as chain links - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Described herein are novel piperidine urea derived compounds and their pharmaceutical compositions for the treatment of conditions and diseases mediated by soluble epoxide hydrolase. ## Claims ### Claim 1 A composition comprising at least one compound of Formula I: its stereoisomers or pharmaceutically acceptable salts thereof; wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH and p is from 0-2, however when p=0, Y1-Y2 is not CH—CH2 or CH—O, and R1 is not aryl; Y1-Y2 are selected from CH—CH2, CH—O, or C═CH, however when Y1-Y2 is CH—O, X is selected from O or NH, and R1 is not hydrogen, or alkyl; and Y3 is selected from H or Me. ### Claim 2 (depends on 1) A composition according to claim 1, according to Formula II: its stereoisomers or pharmaceutically acceptable salts thereof; wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH and p is from 0-2, however when p=0, Yi-Y2 is not CH—CH2 or CH—O, and R1 is not aryl; and Y1-Y2 are selected from CH—CH2, CH—O, or C═CH, however when Y1-Y2 is CH—O, X is selected from O or NH, and R1 is not hydrogen, or alkyl. ### Claim 3 (depends on 1) A composition according to claim 1, according to Formula III: its stereoisomers or pharmaceutically acceptable salts thereof; wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl; and X is selected from O, (CH2)p, NH and p is from 0-2. ### Claim 4 (depends on 1) A composition according to claim 1, wherein the composition is according to Formula IV: its stereoisomers or pharmaceutically acceptable salts thereof; wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl, aryl or heteroaryl may optionally be substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; and X is selected from O, (CH2)p, NH; wherein p is selected from 0-2, however when p=0, R1 is not aryl. ### Claim 5 (depends on 1) A composition according to claim 1, comprising one or more of the following compounds, its stereoisomers or pharmaceutically acceptable salts thereof; ### Claim 6 (depends on 1) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of claim 1. ### Claim 7 (depends on 2) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of claim 2. ### Claim 8 (depends on 3) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of claim 3. ### Claim 9 (depends on 4) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of claim 4. ### Claim 10 (depends on 5) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of claim 5. ### Claim 11 A method for treatment of pain, neuro degenerative disease, or inflammatory disease in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of Formula I: its stereoisomers or pharmaceutically acceptable salts thereof wherein; R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R6, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl, aryl or heteroaryl may optionally be substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; X is selected from O, (CH2)p, NH and p is from 0-2, however when p=0, Y1-Y2 is not CH—CH2 or CH—O, and R1 is not aryl; Y1-Y2 are selected from CH—CH2, CH—O, or C═CH, however when Y1-Y2 is CH—O, X is selected from O or NH, and R1 is not hydrogen, or alkyl; and Y3 is selected from H or Me. ### Claim 12 (depends on 11) The method according to claim 11, further comprising administrating to the subject a compound according to Formula II its stereoisomers or pharmaceutically acceptable salts thereof, wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH and p is from 0-2, however when p=0, Y1-Y2 is not CH—CH2 or CH—O, and R1 is not aryl; and Y1-Y2 are selected from CH—CH2, CH—O, or C═CH, however when Y1-Y2 is CH—O, X is selected from O or NH, and R1 is not hydrogen or alkyl. ### Claim 13 (depends on 11) The method according to claim 11, further comprising administrating to the subject a compound according to Formula III: its stereoisomers or pharmaceutically acceptable salts thereof wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl; and X is selected from O, (CH2)p, NH and p is from 0-2. ### Claim 14 (depends on 11) The method according to claim 11, further comprising administrating to the subject a compound according to Formula IV: its stereoisomers or pharmaceutically acceptable salts thereof, wherein R1 is selected from a group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl and wherein when R1 is aryl, heteroaryl or 5 52366371 v1 heterocycloalkyl, R1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5, SO2NHR2, or COR3; R2 is selected from a group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 is selected from a group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R4 is selected from a group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5, SO2NHR2, or COR3; R5 is selected from a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R6 is selected from a group consisting of alkyl, cycloalkyl, aryl or heteroaryl, aryl or heteroaryl may optionally be substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; and X is selected from O, (CH2)p, NH; wherein p is selected from 0-2, however when p=0, R1 is not aryl. ### Claim 15 (depends on 11) The method according to claim 11, further comprising administering to the subject a compound selected from one or more of: ### Claim 16 (depends on 1) A method for treatment of neuropathic or inflammatory pain in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1. ### Claim 17 (depends on 2) A method for the treatment of neuropathic or inflammatory pain in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 2. ### Claim 18 (depends on 1) A method for treatment of Parkinson's disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1. ### Claim 19 (depends on 2) A method for treatment of Parkinson's disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 2. ### Claim 20 (depends on 1) A method for treatment of diabetic peripheral neuropathy in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1. ### Claim 21 (depends on 2) A method for treatment of diabetic peripheral neuropathy in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 2. ### Claim 22 (depends on 16) A method of claim 16, wherein the neuropathic pain is peripheral neuropathic pain. ### Claim 23 (depends on 17) A method of claim 17, wherein the neuropathic pain is peripheral neuropathic pain. ### Claim 24 (depends on 16) A method of claim 16, wherein the neuropathic pain is selected from a group consisting of post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa central pain, spinal cord injury, multiple sclerosis, peripheral neuropathy, HIV, or chemotherapy-induced pain. ### Claim 25 (depends on 17) A method of claim 17, wherein the neuropathic pain is selected from a group consisting of post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa central pain, spinal cord injury, multiple sclerosis, peripheral neuropathy, HIV, or chemotherapy-induced pain.