Claims for Patent: 11,931,350

Summary for Patent: 11,931,350

Title:	Opioid receptor ligands and methods of using and making same
Abstract:	This application describes compounds that can act as opioid receptor ligands, which compounds can be used in the treatment of, for example, pain and pain related disorders.
Inventor(s):	Dennis Yamashita, Dimitar Gotchev, Philip Pitis, Xiao-Tao Chen, Guodong Liu, Catherine C. K. Yuan
Assignee:	Trevena Inc
Application Number:	US17/367,021
Patent Claims:	1. A compound, or a pharmaceutically acceptable salt thereof, having a formula of: or a stereoisomer thereof, wherein: A2 is selected from the group consisting of CH2, CHR5, and CR5R6; A4 is elected from the group consisting of CH2, CHR9, CR9R10, and a cycle of the formula C(CH2)n, where n=2-5, and when A4 is CH2, CR5R6 is not C(CH3)2, C(CH3)CH2CH3, or CHCH2(CH3)2 and when A2 is CH2, CR9R10 is not C(CH3)2, C(CH3)CH2CH3, or CHCH2(CH3)2; R5, R6, R9 and R10 are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, and phenyl; B3 is selected from the group consisting of H, alkyl, branched alkyl, optionally substituted aryl, optionally substituted arylalkyl, alkoxycarbonyl, and alkylsulfonyl; B4 is selected from the group consisting of null, CH2, CHR19, CR19R20, and CO; B5 is selected from the group consisting of alkyl, branched alkyl, optionally substituted carbocycle, carbocycle-substituted alkyl, optionally substituted aryl, and optionally substituted arylalkyl; and D1 is an optionally substituted heteroaryl. 2. The compound of claim 1, wherein each heteroaryl group or each cycle group is independently substituted with one or more substitution groups selected from the group consisting of F, Cl, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF3, methoxycarbonyl, methanesulfonyl, Ph, benzyl, formyl, and acetyl. 3. The compound of claim 1, wherein the each aryl group is independently selected from the group consisting of: 4. The compound of claim 1, wherein the cycle is selected from the group consisting of: wherein X1 and X2 in the cycle are independently selected from the group consisting of O, S, N, NH, and NR18, wherein R18 is selected from the group consisting of cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl and alkoxycarbonyl. 5. The compound of claim 1, wherein A2 and A4 are connected by a carbon bridge. 6. The compound of claim 5, wherein the bridge comprises —CH2— or —CH2CH2—. 7. The compound claim 1, wherein the ring containing A2, A4, and the carbon connected to D1 is fused with another ring selected from the group consisting of benzene, pyridine, pyrimidine, furan, thiophene and pyridazine. 8. The compound of claim 1, wherein each aryl is independently multiply substituted with groups selected from cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, cycle and cycle-alkyl. 9. The compound of claim 1, wherein each cycle is independently multiply substituted with groups selected from cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, cycle and cycle-alkyl. 10. The compound of claim 1, wherein the compound has a formula of: wherein: A2 is selected from the group consisting of CH2, CHR5 and CR5R6; A4 is elected from the group consisting of CH2, CHR9, CR9R10 and a cycle of the formula C(CH2)n, where n=2-5; R5, R6, R9 and R10 are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu and phenyl; B3 is selected from the group consisting of H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl and alkylsulfonyl; B4 is selected from the group consisting of null, CH2, CHR19, CR19R20 and CO; B5 is selected from the group consisting of alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl and arylalkyl; and D1 is an optionally substituted heteroaryl. 11. The compound of claim 1, wherein the compound has a formula of: wherein: A2 is selected from the group consisting of CH2, CHR5 and CR5R6; A4 is selected from the group consisting of CH2, CHR9, CR9R10 and a cycle of the formula C(CH2)n, where n=2-5; R5, R6, R9 and R10 are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu and phenyl; B3 is selected from the group consisting of H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl and alkylsulfonyl; B4 is selected from the group consisting of null, CH2, CHR19, CR19R20 and CO; B5 is selected from the group consisting of alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl and arylalkyl; and D1 is an optionally substituted heteroaryl. 12. A method of treating pain comprising administering to a subject or a subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof. 13. A method of treating pain comprising administering to a subject a compound of claim 11, or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1, wherein the pharmaceutically acceptable salt is formed from an acid selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, or toluene sulfonic acid. 15. The compound of claim 1, wherein the pharmaceutically acceptable salt is a fumaric acid salt. 16. The compound of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, has a formula of or a stereoisomer thereof, wherein: A2 is selected from the group consisting of CH2, CHR5, and CR5R6; R5 and R6 are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, and phenyl; B3 is selected from the group consisting of H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl; B4 is selected from the group consisting of null, CH2, CHR19, CR19R20, and CO; B5 is selected from the group consisting of alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl, and arylalkyl; and D1 is an optionally substituted heteroaryl. 17. A method of treating pain comprising administering to a subject a compound of claim 14, or a pharmaceutically acceptable salt thereof. 18. A method of treating pain comprising administering to a subject a compound of claim 15, or a pharmaceutically acceptable salt thereof. 19. A method of treating pain comprising administering to a subject a compound of claim 16, or a pharmaceutically acceptable salt thereof. 20. A method of treating drug abuse comprising administering to a subject a compound of claim 1, or a pharmaceutically acceptable salt thereof.