Polycyclic compounds

Abstract

Compounds of formula (I), (II) and (III) (including pharmaceutically acceptable salts) are described herein. Such compounds, as well as their pharmaceutically acceptable salts and compositions, are useful for treating diseases or disorders that can be treated with KOR agonists and / or MOR agonists. The compounds described herein, together with their pharmaceutically acceptable salts and compositions, can be used to alleviate at least one symptom of the diseases or disorders described herein.

Description

[Technical field]

[0001] INCORPORATION BY REFERENCE TO PRIORITY APPLICATION This application claims priority to U.S. Provisional Patent Application Nos. 63 / 279,094, filed November 13, 2021, 63 / 282,264, filed November 23, 2021, 63 / 299,749, filed January 14, 2022, 63 / 317,980, filed March 9, 2022, 63 / 321,915, filed March 21, 2022, 63 / 336,476, filed April 29, 2022, and 63 / 375,050, filed September 8, 2022, each of which is incorporated by reference in its entirety herein to the extent not inconsistent with the content of this disclosure. [Background technology]

[0002] Field This application relates generally to pharmaceutical compounds. More specifically, compounds that modulate the KOR and / or MOR receptors are provided.

[0003] explanation Salvinorin A (SalA) is a neoclerodane diterpenoid isolated from the Mexican hallucinogenic plant Salvia divinorum. TIFF2024543479000002.tif88146

[0004] SalA is a potent kappa opioid receptor (KOR) agonist. Several natural substances related to SalA have been identified, including koribolide, which is also a potent KOR agonist. TIFF2024543479000003.tif72136 Summary of the Invention

[0005] Some embodiments provide a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing.

[0006] Some embodiments disclosed herein relate to pharmaceutical compositions that can include an effective amount of one or more compounds of Formula I, Formula II, Formula III, or a pharma- ceutically acceptable salt of any of the foregoing, a pharma- ceutically acceptable carrier, diluent, excipient, or combinations thereof.

[0007] Some embodiments described herein relate to a method for treating a subject having a disease or disorder described herein, which may include administering to the subject an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), to alleviate at least one symptom (such as one, two, or three symptoms) of the disease or disorder. Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), in the manufacture of a medicament for treating a disease or disorder described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), for treating a disease or condition described herein.

[0008] Some embodiments described herein relate to a method for treating a subject having a disease or disorder described herein, which may include contacting a KOR or MOR receptor in the subject with an effective amount of a compound described herein (such as a compound of formula I, formula II, and / or formula III, or a pharma- ceutically acceptable salt of any of the foregoing). Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of formula I, formula II, and / or formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for contacting a KOR or MOR receptor in a subject having a disease or disorder described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of formula I, formula II, and / or formula III, or a pharma- ceutically acceptable salt of any of the foregoing) for contacting a KOR or MOR receptor in a subject having a disease or disorder described herein.

[0009] Some embodiments described herein relate to a method for ameliorating one or more symptoms (such as one, two or three symptoms) of a disease or disorder described herein, which may include administering to a subject suffering from the disease or disorder an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), and which may also include contacting a KOR or MOR receptor with an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing). Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for improving one or more symptoms (such as one, two, or three symptoms) of a disease or disorder described herein; or in the manufacture of a medicament for improving one or more symptoms (such as one, two, or three symptoms) of a disease or disorder described herein, the use comprising contacting the drug with a KOR or MOR receptor. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) for improving one or more symptoms (such as one, two, or three symptoms) of a disease or disorder described herein by contacting the KOR or MOR receptor.

[0010] These and other embodiments are described in further detail below. [Brief description of the drawings]

[0011] [Figure 1] 1A and 1B show a flow chart of compound testing. [Diagram 2] 2A and 2B show the steps in the total synthesis of racemic O6C-20-nor-SalA. [Diagram 3] FIG. 3 shows a method for preparing perdeuterated acetyl-SalA. [Figure 4] FIG. 4 shows a method for synthesizing O6C-20-nor-SalB. [Diagram 5] Figure 5A shows a synthetic route for preparing O-acylated compounds. Figures 5B and 5C show synthetic routes for various embodiments of O-acylated compounds. Figure 5D shows a proposed method for synthesizing C2-epi-O-acylated compounds. [Figure 6] 6A and 6B show methods for O-alkylation or O-arylation of the indicated compounds. [Figure 7] Figure 7A shows a proposed method for N-acylation of the indicated polycyclic compounds, while Figures 7B and 7C show synthetic routes to N-acylated polycyclic compounds of various embodiments. [Figure 8] FIG. 8 shows a second proposed method for the N-acylation of the indicated polycyclic compounds. [Figure 9] 9A and 9B show the synthesis of polycyclic compounds in which the stereochemistry of the furyl group is altered. [Figure 10] FIG. 10 shows a proposed synthesis of the indicated polycyclic compounds. [Figure 11] FIG. 11 shows a proposed synthesis of the indicated polycyclic compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] compound Various embodiments disclosed herein include a compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing, having the structure: For the compound having TIFF2024543479000004.tif60155, R 1 teeth, It could be TIFF2024543479000005.tif53150, R 2 can be O or CH2, R 3 can be H or CH3, R4 teeth, TIFF2024543479000006.tif48154TIFF2024543479000007.tif172154TIFF2024543479000008.tif184154TIFF2024543479000009.tif137157, R 5 can be O or S, R 6 can be F, Cl, or Br, and Each R 10 may be independently H, OMe, NO2, or CF3; R 7 is H or It could be TIFF2024543479000010.tif30117, R 8 is O, OH, or TIFF2024543479000011.tif51161, and TIFF2024543479000012.tif9156 represents a single or double bond, R 8 If is O, then The bond represented by TIFF2024543479000013.tif9156 is a double bond, and R 8 is OH, or If the file is TIFF2024543479000014.tif51161, The bond represented by TIFF2024543479000015.tif9156 is a single bond, R 9 can be CO2Me or CONH2, and NCS is N-chlorosuccinimide; However, the following conditions apply: 2 is CH2, or R 3 is H; and The compound is Not selected from TIFF2024543479000016.tif162149.

[0013] As used herein, TIFF2024543479000017.tif7143 crosses the bond covalently linking Formula I, Formula II, or Formula III at the R group. In some embodiments, to Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing, TIFF2024543479000018.tif118147 or a pharma- ceutically acceptable salt of any of the foregoing.

[0014] As used herein, TIFF2024543479000019.tif9156 represents a bond that can be a single or double bond, R 8 If is O, then TIFF2024543479000020.tif9156 represents a double bond to O, and R 8 but If it is TIFF2024543479000021.tif51161 or OH, TIFF2024543479000022.tif9156 is TIFF2024543479000023.tif51161 or OH represents a single bond to oxygen.

[0015] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has formula Ia: It can be represented as TIFF2024543479000024.tif68148.

[0016] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, It could be TIFF2024543479000025.tif38136.

[0017] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 2 can be O or CH2.

[0018] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 3 can be H or CH. One of ordinary skill in the art will appreciate that CH can be represented as "Me."

[0019] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 4 teeth, TIFF2024543479000026.tif29141 and may contain halogens, and NCS is N-chlorosuccinimide.

[0020] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000027.tif38136, R 2 can be O or CH2, R 3 can be H or CH3, and R 4 teeth, TIFF2024543479000028.tif29141 and NCS is N-chlorosuccinimide. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof can be selected from the following: TIFF2024543479000029.tif172149TIFF2024543479000030.tif203148 (including pharma- ceutically acceptable salts of any of the foregoing).

[0021] In other embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 4 cannot contain a double bond. Exemplary R 4 The part is, The file is TIFF2024543479000031.tif29154.

[0022] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000032.tif38136, R 2 can be O or CH2, R 3 can be H or CH3, and R 4 cannot contain a double bond. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof can be selected from the following: TIFF2024543479000033.tif106154TIFF2024543479000034.tif185155TIFF2024543479000035.tif96145 (including pharma- ceutically acceptable salts of any of the foregoing).

[0023] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 4 teeth, It may contain an aromatic ring, such as TIFF2024543479000036.tif34146.

[0024] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000037.tif38136, R 2 can be O or CH2, R 3 can be H or CH3, and R 4 teeth, TIFF2024543479000038.tif31144. In some embodiments, the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, can be selected from the following: TIFF2024543479000039.tif138149 (including pharma- ceutically acceptable salts of any of the foregoing).

[0025] In other embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 4 can include at least one double bond (such as one or two double bonds), and It does not contain aromatic rings, N (nitrogen), or S (sulfur), such as TIFF2024543479000040.tif45149.

[0026] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000041.tif38136, R 2 can be O or CH2, R 3 can be H or CH3, and R 4 can include at least one double bond (such as one or two double bonds), and TIFF2024543479000042.tif45149 and the like. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof can be selected from the following: TIFF2024543479000043.tif165153TIFF2024543479000044.tif150148 (including pharma- ceutically acceptable salts of any of the foregoing).

[0027] In other embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 4 can contain O (oxygen). Exemplary R 4 The part is, TIFF2024543479000045.tif188148TIFF2024543479000046.tif178152TIFF2024543479000047.tif127158, R 6 can be F, Cl, or Br, and Each R 10 can be independently H, OMe, NO2, or CF.

[0028] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000048.tif38136, R2 can be O or CH2, R 3 can be H or CH3, and R 4 may include O. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof may be selected from the following: TIFF2024543479000049.tif161150TIFF2024543479000050.tif193145TIFF2024543479000051.tif187154TIFF2024543479000052.tif184150TIFF2024543479000053.tif153144TIFF2024543479000054.tif169152TIFF2024543479000055.tif94118, including pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, may be selected from the following: TIFF2024543479000056.tif103135 (including pharma- ceutically acceptable salts of any of the foregoing).

[0029] In other embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 4 may contain at least one double bond (such as one or two double bonds) and at least one atom selected from N (nitrogen) and S (sulfur) (such as one nitrogen, one sulfur, two nitrogens, two sulfurs, or one nitrogen and one sulfur), for example: The file is TIFF2024543479000057.tif51154.

[0030] In some embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000058.tif38136, R 2 can be O or CH2, R 3 can be H or CH3, and R 4may contain at least one double bond (such as one or two double bonds) and at least one atom selected from N (nitrogen) and S (sulfur) (such as one nitrogen, one sulfur, two nitrogens, two sulfurs, or one nitrogen and one sulfur), for example: TIFF2024543479000059.tif34151. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof can be selected from the following: TIFF2024543479000060.tif97156TIFF2024543479000061.tif186148TIFF2024543479000062.tif184151TIFF2024543479000063.tif96155 (including pharma- ceutically acceptable salts of any of the foregoing).

[0031] In other embodiments of Formula Ia, or a pharma- ceutically acceptable salt thereof, the compound of Formula Ia, or a pharma- ceutically acceptable salt thereof, is TIFF2024543479000064.tif58153 (including any pharma- ceutically acceptable salt thereof) cannot contain

[0032] In some embodiments, the compound of formula II, or a pharma- ceutically acceptable salt thereof, has the formula II.a: It can be represented as TIFF2024543479000065.tif67133.

[0033] In some embodiments of Formula II.a, or a pharma- ceutically acceptable salt thereof, R 2 can be O or CH2.

[0034] In some embodiments of Formula II.a, or a pharma- ceutically acceptable salt thereof, R 3 can be H or CH3.

[0035] In some embodiments of Formula II.a, or a pharma- ceutically acceptable salt thereof, R 2 can be O or CH2, and R3 can be H or CH. In some embodiments, the compound of formula II.a or a pharma- ceutically acceptable salt thereof can be selected from the following: TIFF2024543479000066.tif95160 (including pharma- ceutically acceptable salts of any of the foregoing).

[0036] In some embodiments, the compound of formula III, or a pharma- ceutically acceptable salt thereof, has the formula III.a: It can be represented as TIFF2024543479000067.tif65149.

[0037] In some embodiments of Formula III.a, or a pharma- ceutically acceptable salt thereof, R 1 teeth, It could be TIFF2024543479000068.tif38136.

[0038] In some embodiments of Formula III.a, or a pharma- ceutically acceptable salt thereof, R 2 can be O or CH2.

[0039] In some embodiments of Formula III.a, or a pharma- ceutically acceptable salt thereof, R 3 can be H or CH3.

[0040] In some embodiments of Formula III.a, or a pharma- ceutically acceptable salt thereof, R 1 teeth, TIFF2024543479000069.tif38136, R 2 can be O or CH2, and R 3 can be H or CH. In some embodiments, the compound of formula III.a or a pharma- ceutically acceptable salt thereof can be selected from the following: TIFF2024543479000070.tif147156 (including pharma- ceutically acceptable salts of any of the foregoing).

[0041] In other embodiments of Formula III.a, or a pharma- ceutically acceptable salt thereof, the compound of Formula III.a is TIFF2024543479000071.tif67123 or a pharma- ceutically acceptable salt thereof.

[0042] Those skilled in the art will recognize that compounds of Formula I, II and III (including the pharma- ceutically acceptable salts thereof) may possess one or more stereocenters.

[0043] In some embodiments, the compound of Formula I or Formula III, or a pharma- ceutically acceptable salt thereof, has the structure of Formula Ic or Formula III.c: TIFF2024543479000072.tif82163, R 1 is H or It could be TIFF2024543479000073.tif16146, R 2 can be O or CH2, R 3 can be H or CH3, R 7 is H or TIFF2024543479000074.tif53156, and R 4 teeth, TIFF2024543479000075.tif146159TIFF2024543479000076.tif115153, R 5 can be O or S, R 6 can be F, Cl, or Br, NCS is N-chlorosuccinimide, and OAc is The file is TIFF2024543479000077.tif39163.

[0044] In some embodiments, the compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof, has the structure of Formula Id, Formula II.d, or Formula III.d: TIFF2024543479000078.tif56151, R 1 teeth, It could be TIFF2024543479000079.tif102149, R 2 can be O or CH2, R 3 can be H or CH3, R 4 teeth, TIFF2024543479000080.tif169163TIFF2024543479000081.tif105165, R 5 can be O or S, R 6 can be F, Cl, or Br; R 7 is H or It could be TIFF2024543479000082.tif57169, R 8 teeth, It could be TIFF2024543479000083.tif44169, R 9 can be CO2Me or CONH2, and NCS is N-chlorosuccinimide, and OAc is The file is TIFF2024543479000084.tif28138.

[0045] In some embodiments, the compound of Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing, has the structure of Formula Ie, Formula II.e, or Formula III.e: TIFF2024543479000085.tif58156, R 1 teeth, It could be TIFF2024543479000086.tif106154, R 2 can be O or CH2, R 3 can be H or CH3, R4 teeth, TIFF2024543479000087.tif184148TIFF2024543479000088.tif191153TIFF2024543479000089.tif94145, R 5 can be O or S, R 6 may be F, Cl, or Br, and each R 9 may be independently H, OMe, NO2, or CF3; R 7 is H or It could be TIFF2024543479000090.tif39126, R 8 teeth, It could be TIFF2024543479000091.tif48149, R 9 can be CO2Me or CONH2, and NCS is N-chlorosuccinimide, and OAc is The file is TIFF2024543479000092.tif32154.

[0046] In some embodiments, a compound of formula I, or a pharma- ceutically acceptable salt thereof, can have the structure of formula Ib: TIFF2024543479000093.tif68139

[0047] In some embodiments, the compound of formula II or a pharma- ceutically acceptable salt thereof can have the structure of formula II.b. TIFF2024543479000094.tif71129

[0048] In some embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof can have the structure of formula III.b. TIFF2024543479000095.tif64123

[0049] In some embodiments of Formula Ib, Formula II.b, or Formula III.b, or a pharma- ceutically acceptable salt of any of the foregoing, R 1 The stereochemistry of is: It could be one of the following: TIFF2024543479000096.tif104157.

[0050] In some embodiments of Formula Ib, Formula II.b, or Formula III.b, or a pharma- ceutically acceptable salt of any of the foregoing, R 4 The stereochemistry of is as follows: It can be one of the following: TIFF2024543479000097.tif186155TIFF2024543479000098.tif187155TIFF2024543479000099.tif83155.

[0051] In some embodiments of Formula Ib, Formula II.b, or Formula III.b, or a pharma- ceutically acceptable salt of any of the foregoing, R 7 The stereochemistry of is It could be TIFF2024543479000100.tif31123.

[0052] In some embodiments of Formula Ib, Formula II.b, or Formula III.b, or a pharma- ceutically acceptable salt of any of the foregoing, R 8 The stereochemistry of is as follows: It could be one of the following: TIFF2024543479000101.tif43168.

[0053] In some embodiments, the compound of formula Ib or a pharma- ceutically acceptable salt thereof is TIFF2024543479000102.tif68150 (including any pharma- ceutically acceptable salt thereof) The stereoisomer may be a stereoisomer of O6C-20-nor-SalA selected from:

[0054] In some embodiments, the compound of formula Ib or a pharma- ceutically acceptable salt thereof is enantiomerically enriched. TIFF2024543479000103.tif65133, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula Ib, or a pharma- ceutically acceptable salt thereof, may be enantiomerically pure TIFF2024543479000104.tif65135, or a pharma- ceutically acceptable salt thereof. As used herein, "enantiomerically enriched" means that one enantiomer is obtained in excess over the other. In some embodiments, an enantiomerically enriched mixture has an enantiomeric excess of one enantiomer over the other of greater than 0%, preferably greater than 20%, preferably greater than 40%, preferably greater than 70%, more preferably greater than 80%, more preferably greater than 90%, or more preferably greater than 95%. An "enantiomerically pure" compound 1s is considered a mixture of two enantiomers, which is composed of one enantiomer at 95% or more, preferably greater than 98%, more preferably greater than 99%, and even more preferably greater than 99.5%.

[0055] In some embodiments, the compound of Formula Ib, Formula II.b, or Formula III.b, or a pharma- ceutically acceptable salt of any of the foregoing, is selected from the group consisting of: TIFF2024543479000105.tif91156TIFF2024543479000106.tif178151TIFF2024543479000107.ti f181151TIFF2024543479000108.tif182150TIFF2024543479000109.tif182152TIFF20245434790 00110.tif186155TIFF2024543479000111.tif190149TIFF2024543479000112.tif184144TIFF2024543479000113.tif105144TIFF2024543479000114.tif104146 or a pharma- ceutically acceptable salt of any of the foregoing.

[0056] In other embodiments of Formula Ib, Formula II.b, or Formula III.b, or a pharma- ceutically acceptable salt of any of the foregoing, the compound is: TIFF2024543479000115.tif159153TIFF2024543479000116.tif158152TIFF2024543479000117.tif160154 or a pharma- ceutically acceptable salt of any of the foregoing.

[0057] Salvinorin A has several drawbacks. Exemplary drawbacks of Salvinorin A include low stability (e.g., possible epimerization), short half-life, short brain resonance time, and hallucinations.Therefore, there is a need for a compound as described herein that addresses one or more drawbacks associated with Salvinorin A.

[0058] Some advantages of the compounds described herein may include increased half-life (e.g., by adding one or more halogen atoms or lipophilic moieties), higher solubility (e.g., by adding one or more carbonyl and / or hydroxyl groups), higher affinity to KOR and / or MOR receptors, higher potency to KOR and / or MOR receptors, higher stability, and lower cytotoxicity.For example, these advantages are relative to naturally occurring Salvinorin A.

[0059] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions that can include an effective amount of one or more compounds described herein (such as one, two or three compounds of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), and a pharma- ceutically acceptable carrier, diluent, excipient, and / or combination thereof. In some embodiments, the pharmaceutical composition can include at least one compound described herein, or a pharma- ceutically acceptable salt thereof (such as one, two or three compounds of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing). In some embodiments, the pharmaceutical composition includes at least two compounds of Formula I, or a pharma- ceutically acceptable salt thereof (such as two or three compounds of Formula I, or a pharma- ceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition includes at least two compounds of Formula II, or a pharma- ceutically acceptable salt thereof (such as two or three compounds of Formula II, or a pharma- ceutically acceptable salt thereof). In other embodiments, the pharmaceutical composition comprises at least two compounds of formula III, or a pharma- ceutically acceptable salt thereof, such as two or three compounds of formula III, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may comprise at least two compounds of formula I, formula II, or formula III, or a pharma- ceutically acceptable salt of any of the foregoing, such as two compounds of formula I, two compounds of formula II, or one compound of formula II and one compound of formula II, or a pharma- ceutically acceptable salt of any of the foregoing.

[0060] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutical compositions are generally tailored to the particular intended route of administration.

[0061] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (e.g., 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting the compound with organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedicarboxylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form salts such as alkali metal salts, such as ammonium salts, sodium salts, potassium salts, lithium salts, alkaline earth metal salts, such as calcium salts, magnesium salts, carbonate salts, bicarbonate salts, salts of organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids, such as arginine and lysine. For compounds of formula I, one skilled in the art will recognize that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 is protonated to NH3 + ), the positive charge is due to a negatively charged counterion (e.g., Cl - ) to understand that this can be balanced.

[0062] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues.For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of a subject.

[0063] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity, but may be pharma- ceutical necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. Common forms of diluents in the art are, but are not limited to, buffered aqueous solutions such as phosphate buffered saline that mimic the pH and isotonicity of human blood.

[0064] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide, but not limited to, bulk, consistency, stability, binding ability, lubricity, disintegration ability, etc. to the composition. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0065] In some embodiments, the pharmaceutical compositions described herein can be administered to a subject by themselves or in pharmaceutical compositions mixed with other active ingredients, such as in combination therapy, or in carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.The techniques for formulating and administering the compounds described herein are known to those skilled in the art.

[0066] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, extruding, emulsifying, encapsulating, encapsulating or tabletting processes.Furthermore, the active ingredient is contained in an amount effective to achieve its intended purpose.Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts with pharma-ceutically compatible counterions.

[0067] There are multiple techniques in the art for administering compounds, salts and / or compositions, including, but not limited to, oral (enteral), mucosal (nasal, vaginal, rectal or sublingual), pulmonary, topical, transdermal (via patch), aerosol, injection, infusion, and parenteral delivery, including intramuscular injection, subcutaneous injection, intravenous injection (IV), intramedullary injection, intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection, and intraocular injection. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered orally.

[0068] The compounds, salts and / or compositions can also be administered locally rather than systemically, for example by injecting or implanting the compounds directly into the affected area, often as a depot or sustained release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example liposomes coated with tissue-specific antibodies. The liposomes are targeted to and taken up selectively by organs. For example, intranasal or pulmonary delivery may be desirable to target respiratory diseases or conditions.

[0069] The compositions may be presented in a pack or dispenser device, optionally containing one or more unit dosage forms containing the active ingredient. The pack may be, for example, constructed of metal or plastic foil, such as a blister pack. The pack or dispenser may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the government agency of the form of drug for human or veterinary administration. Such notice may be, for example, the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Compositions that may include the compounds and / or salts described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0070] synthesis Figure 1A and Figure 1B show an example of a flow chart for synthesizing and testing various compounds provided herein. In short, compounds are first synthesized, then their physical and biochemical properties are tested. They are then tested in cell culture, and then their efficacy is tested in animal models.

[0071] In some embodiments, the compounds described herein, together with their pharma- ceutically acceptable salts, are synthesized by chemical methods. Such methods are known in the art. See, for example, Crowley RS et al., ACS Chem. Neurosci DOI: 10.1021 / acschemneuro.0c00191 (2020); Beguin C et al., Bioorganic & Medicinal Chemistry Letters 16:4679-4685 (2006); Riley AP et al., J. Med. Chem. 57:10464-10475 (2014); Hill SJ et al., Nat. Prod. Rep. DOI: 10.1039 / d0np00028k (2020). In other embodiments, the compounds are biosynthetically synthesized by methods known in the art, for example, in transgenic plants, yeast or bacteria. See Jamieson CS et al., Chem. Soc. Rev. DOI: 10.1039 / d1cs00065a (2021); Kutrzeba L. et al., Phytochemistry 68:1872-1881 (2007); and Pelot KA. et al., The Plant Journal 89:885-897 (2017).

[0072] Non-limiting examples of chemical synthesis methods are shown in Figures 2-11. Compounds of formula I, II and III (including pharma- ceutically acceptable salts thereof), as well as those described herein, can be prepared in a variety of ways. General synthetic routes for preparing compounds of formula I, II and III (including pharma- ceutically acceptable salts thereof), as well as some examples of starting materials used to synthesize compounds described herein, are shown and described herein. Non-limiting examples of chemical synthesis are depicted in Figures 2-11. Furthermore, for purposes of the general synthetic routes, the depicted structures are appropriately protected as known to those of skill in the art, and the general structures are meant to include these protecting groups. The routes shown and described herein are exemplary and are not intended, nor should they be construed, to limit the scope of the claims in any manner. Those of skill in the art will be able to recognize modifications of the disclosed syntheses and devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0073] FIG. 2A shows the synthetic route to racemic O6C-20-nor-SalA from the starting compound Hagemann ester. In the following description of FIG. 2A and FIG. 2B, compounds 1-12 refer to the compounds labeled as such in FIG. 2A and FIG. 2B. Hagemann ester 1 can be subjected to a multicomponent conjugate addition / alkylation reaction with a cuprate formed from (4-((tert-butyldimethylsilyl)oxy)butyl)magnesium chloride, followed by the addition of acrolein to produce allylic alcohol 2. Removal of the allylic alcohol of 2 can be accomplished by treatment with methanesulfonyl chloride and an organic base to form (R)-dienecyclohexane 3. Compound 3 can undergo deprotection of the silyl ether under acidic hydrolysis conditions to produce an intermediate primary alcohol, which can be subjected to oxidation conditions to produce primary aldehyde 4. 4 can be cyclized under Knoevenagel conditions to produce bicyclic aldehyde 5, which can undergo a thermal equilibration process to set the stereochemistry of the ring junction. Pinnic oxidation of 5 gives the bicyclic carboxylic acid 6, which on oxidation conditions gives the α-keto alcohol 7, whose stereochemistry can be defined as the C2 alcohol carbon (R). Acetoxylation of this alcohol under thermal conditions in the presence of an organic base gives the α-acetoxyketone 8, with inversion of the stereochemistry at the C2 position. Heck reaction of the terminal alkene of 8 with 3-bromofuran gives the furanyl adduct 9, which can be converted with monomethyl malonate to the β-ketoester 10. Compound 10 undergoes a Lewis acid catalyzed hydroalkylation cyclization reaction to give the tricyclic adduct 11, which on decarboxylation conditions gives compound 12.

[0074] Figure 2B shows a method for preparing the allylic alcohol 2 mentioned in the legend to Figure 2A via a Grignard reaction. Experimental data for the synthesis depicted in Figure 2B is included in Table 1. In Table 1, compounds H-1 through H-5 refer to the compounds so labeled in Figure 2B.

[0075] Figure 3 shows a method for preparing perdeuterated acetylsalvinorin A. The method depicted in Figure 3 can be adapted to any of the compounds described herein without undue experimentation.

[0076] FIG. 4 shows a synthetic route from O6C-20-nor-SalA to O6C-20-nor-SalB. In the following description, compounds 13 and 14 refer to the compounds so labeled in FIG. 4. In one step, O6C-20-nor-SalA (compound 13) can be deacetylated at room temperature to form the secondary alcohol O6C-20-nor-SalB (compound 14). Experimental data for the described synthesis are shown in Table 1. One of skill in the art will appreciate that compound 14 can be used as an intermediate to form various embodiments described herein.

[0077] FIG. 5A shows a synthetic route from O6C-20-nor-SalA to O-acylated derivatives at C2. O6C-20-nor-SalA can be deacetylated at room temperature to form O6C-20-nor-SalB. Ester formation can be achieved using activated ester reagents, such as acid chlorides, succinates, and acyl anhydrides. Those skilled in the art will appreciate that a variety of chemical methods can be used to form the various embodiments described herein. See also Bioorg.Med.Chem.Lett. 2004, 14, 5099; J. Med.Chem.2005, 48, 4765; Bioorg.Med.Chem.Lett. 2015, 25, 4689; Tetrahedron Lett. 2010, 51, 5207.

[0078] FIG. 5B shows an exemplary synthesis from O6C-20-nor-SalB to an O-acylated compound, referred to herein as target 1. The hydroxyl group of O6C-20-nor-SalB (compound 14) can be acylated with cinnamoyl chloride in the presence of an organic base to form the O-acylated compound shown. Those skilled in the art will appreciate that a variety of chemical methods can be used to form the various embodiments described herein. Experimental data for the described synthesis is shown in Table 1.

[0079] 5C shows an exemplary synthesis from O6C-20-nor-SalB to an O-acylated compound, referred to herein as target X. The hydroxyl group of O6C-20-nor-SalB (compound 14) can be acylated with 2-thiocyanatoacetic acid in the presence of an acid activator and an organic base to form the O-acylated compound shown.

[0080] Figure 5D shows a proposed synthesis from O6C-20-nor-SalB to a C2-epi-O-acylated compound, referred to herein as target Y. The hydroxyl group of O6C-20-nor-SalB can be epimerized and acylated to form a C2-epi-O-acylated compound.

[0081] FIG. 6A shows the proposed synthesis from O6C-20-nor-SalB to various embodiments described herein. The hydroxyl group of O6C-20-nor-SalB (compound 14) can be alkylated to form O-alkylated compounds. Alkyl ether formation can be achieved using activated alkane reagents, such as alkyl halides and alkyl sulfonates, or using O-alkylation chemistry methods that would be understood by one of skill in the art to form the various embodiments described herein. Alkyl ether formation can be achieved using activated aryl reagents to form the various embodiments described herein using O-arylation chemistry methods known to one of skill in the art.

[0082] FIG. 6B shows an exemplary synthesis from O6C-20-nor-SalB to an O-alkylated compound, referred to herein as target 3. The hydroxyl group of O6C-20-nor-SalB (compound 14) can be alkylated with methoxymethyl chloride to form the O-alkylated compound shown. Those skilled in the art will appreciate that a variety of chemical methods can be used to form the various embodiments described herein. Experimental data for the described synthesis is included in Table 1. See also Bioorg. Med. Chem. Lett. 2005, 15, 3744; Bioorg. Med. Chem. Lett. 2012, 23, 1023; Bioorg. Med. Chem. 2008, 16, 1279.

[0083] FIG. 7A shows a proposed method for N-acylation of OC-20-nor-SalB for various embodiments described herein. This method utilizes a double inversion of stereochemistry at C2. The hydroxyl group of OC-20-nor-SalB can be replaced with a halide with inversion of stereochemistry. The activated leaving group of the compound produced in the previous reaction can be replaced with a primary amine surrogate, also with inversion of stereochemistry. One method can replace the activated leaving group with an azide reagent and then reduce to produce the primary amine shown. The amino group of the compound can be acylated to form an N-acylated compound, which can be understood to be a reaction intermediate, as with the various embodiments described herein. Amide compounds can be N-alkylated to form N-acyl-N-alkyl compounds. Those skilled in the art will appreciate that various chemical methods can be used at each step to form the various embodiments described herein, and that various modifications can be made to the above methods and compositions without departing from the scope of this application. See also Sharma et al., Bioorg. Med. Chem. 18:6886 (2010); Majer et al., Bioorg. Med. Chem. 22:256 (2014).

[0084] FIG. 7B shows an exemplary synthesis from OC-20-nor-SalB to an N-acylated compound, referred to herein as target Z. The hydroxyl group of OC-20-nor-SalB can be replaced with a halide with inversion of stereochemistry. The activated leaving group of the compound produced by the previous reaction can be replaced with a primary amine surrogate, also with inversion of stereochemistry, to produce a nitrogen-linked adduct that retains the overall configuration from OC-20-nor-SalB. The activated leaving group can be reacted with an azide reagent and then reduced to produce the primary amine shown in FIG. 7B. The primary amine group can be acylated to form an N-acylated compound, which can be understood to be a reaction intermediate as in the various embodiments described herein. Those skilled in the art will appreciate that various chemical methods can be used at each stage to form the various embodiments described herein, and that various modifications can be made in the methods and compositions described above without departing from the scope of this application. See also J. Med. Chem. 2008, 51, 2421.

[0085] FIG. 7C shows an exemplary synthesis from OC-20-nor-SalB to a compound referred to herein as target 6. The secondary alcohol group of OC-20-nor-SalB can undergo displacement with a carboxylic acid in the presence of a disubstituted azodicarboxylate or similar reagent and a trisubstituted phosphine, or a combination of similar reagents. This displacement can produce an ester with inversion of the stereochemistry, and the adduct can then be hydrolyzed to give a secondary alcohol with inversion of the stereochemistry of the alcohol. This alcohol can be activated by adding a functional group to be a leaving group, such as an alkyl or aryl sulfonate, followed by addition of a nitrogen nucleophile to produce a secondary amine product with inversion of the stereochemistry again, while retaining the configuration of the process that started with OC-20-nor-SalB. In the two-step process, the intermediate sulfonate can be isolated or used in situ for the second step amination. The amino group of the compound produced in this step can be understood to be a reaction intermediate as in the various embodiments described herein, and can be an alkyl amine as well as an aryl amine. The amine moiety can be acylated to form N-acyl-N-substituted compounds. Those skilled in the art will understand that various chemical methods can be used in each step to form the various embodiments described herein, and that various modifications can be made in the above methods and compositions without departing from the scope of the present invention. See also Bioorg.Med.Chem.Lett. 2006, 16, 4679.

[0086] Figure 8 shows additional proposed methods for N-acylation of O6C-20-nor-salvinorin B for various embodiments described herein. The original Mitsunobu inversion / hydrolysis procedure using 4-nitrobenzoic acid can generate the Salvinorin B epimer, which can undergo a second inversion by Mitsunobu amination using a DPPA / Staudinger azide reduction two-step protocol to prepare C2-amino-salvinorin A. These methods can be adapted to any of the compounds described herein without undue experimentation.

[0087] FIG. 9A shows the synthesis of a compound referred to herein as target 21. The first line of FIG. 9A shows the final steps in the synthesis of racemic O6C-20-nor-SalA. The epimer identified above can be isolated and then subjected to decarboxylation conditions to produce target 21. The experimental data for the final steps in the synthesis of target 21 shown in the second line of FIG. 9A are included in Table 1.

[0088] Figure 9B shows an alternative synthesis of a compound referred to herein as target 21. In this reaction, O6C-20-nor-SalA is subjected to thermal conditions to epimerize the C12 carbon to form target 21. See also Bioorg.Med.Chem. 2012, 20, 31004.

[0089] FIG. 10 shows the proposed synthesis of O6C-20-nor-SalA to various embodiments described herein. O6C-20-nor-SalA can be deacetylated to form O6C-20-nor-SalB. O6C-20-nor-SalB can be oxidized to the corresponding ketone, which exists primarily in the enol tautomer. In the example shown, copper(II) acetate can be used for the oxidation step. The hydroxide group of the compound generated by the previous reaction can be selectively acylated to form various embodiments of the polycyclic compounds described herein. See also J. Med.Chem.Lett. 2016, 59, 11027; ACS Chem.Neurosci.2020, 11, 1781.

[0090] FIG. 11 shows the proposed synthesis from the starting compound (S)-glyceraldehyde acetonide to the indicated polycyclic compounds. In the following description, compounds 1-11 refer to the compounds labeled as such in FIG. 11. Dialkyl(1-diazo-2-oxopropyl)phosphonate reagents can be reacted with aldehydes (compound 1) under basic Bestmann-Ohira conditions to produce homologated alkyne compound 2. Homologated alkyne compound 2 can be acylated at the terminal alkyne carbon with an acyl halide or anhydride and a strong base to produce propargyl ketone compound 3. Propargyl ketone compound 3 can be subjected to thermal Diels-Alder conditions with methyl (E)-4-(trisubstituted silyl)oxypenta-2,4-dienoate to produce cyclohexadiene silyl ether compound 4, which can undergo hydrolysis of the silyl ether to produce cyclohexene adduct compound 5. The cyclohexene adduct 5 can undergo selective alkylation with a cuprate reagent, in this case lithium dimethylcuprate, to give the cyclohexane compound 6, which has a tetrasubstituted carbon at C3. Similar to aluminum hydride reagents, selective reduction of the ketone functionality produces an intermediate secondary alcohol alkoxide, which undergoes intramolecular acylation to give the bridged bicyclic product compound 7. Hydrolysis of the acetonide moiety followed by selective reduction of the primary can give the α-hydroxyaldehyde compound 8. The aldehyde moiety of the α-hydroxyaldehyde compound 8 can be reacted with a Grignard reagent formed from a 3-halofuran, preferably in the presence of a Lewis acid, to give the diol compound 9. The diol compound 9 can be converted to the cyclohexanone of compound 10 by a two-step process in which the secondary benzyl-like alcohol is selectively activated by treatment with a sulfonyl halide reagent, followed by intramolecular ring closure of the corresponding sulfonate under basic conditions to replace it with the enolate of a methyl ketone to give the ketone of compound 10. The ketone of compound 10 can be acylated with an activated benzoic acid equivalent under basic conditions to form one embodiment of the polycyclic compounds described herein.Those skilled in the art will appreciate that various modifications can be made to the methods and compositions described above without departing from the scope of the invention.

[0091] Uses and Treatments Opioid receptors, including KOR and MOR, are G protein-coupled receptors that are widely expressed throughout the central nervous system and brain and regulate a variety of physiological processes, including pain, inflammation, remyelination, stress response, and mood. See Dalefield et al., "The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies" Frontiers in Pharm (2022) 13:Article 837671. Ligands of the endogenous opioid system, such as β-endorphin, enkephalin, and dynorphin, bind to KOR and MOR and regulate multiple biological responses in humans. Activation of KOR by agonists activates the G protein G i KOR binds to / G0 and increases phosphodiesterase activity. Phosphodiesterase breaks down cAMP, exerting an inhibitory effect on neurons. KOR can bind to inward direct current potassium ion channels and N-type calcium ion channels. Some KOR agonists have been shown to be MOR agonists.

[0092] Both KOR and MOR are involved in the progression and prevention of diseases, including but not limited to peripheral inflammation, neuroinflammation, blood coagulation disorders, hypoperfusion, and substance use disorders. Classical opioid analgesics such as morphine act as MOR agonists and are commonly used to treat moderate to severe acute pain associated with inflammation and various cancers. KOR agonists have attracted attention for their non-addictive and antinociceptive properties, while KOR / MOR dual agonists such as eluxadoline have been approved for the treatment of abdominal pain due to irritable bowel syndrome. See Cichon et al., "Therapeutic Potential of Salvinorin A and Its Analogues in Various Neurological Disorders" Transl Perioper Pain Med (2022) 9(2):452-457. Inflammation is a common factor in many human diseases, including arthritis, asthma, atherosclerosis, cancer, neurodegenerative diseases, stroke, and traumatic brain injury involving the infiltration of peripheral immune cells. Targeting KORs and MORs with non-toxic, anti-nociceptive small molecules is a viable approach that can alleviate disease-associated pain and inflammation and improve the quality of life of people suffering from these conditions.

[0093] KOR agonists have been shown to treat pain, myocardial infarction, pruritus, inflammation, edema, neuroinflammation (including HIV-induced), emesis, stroke and other brain injuries, hypoxic pulmonary hypertension, multiple sclerosis, substance use disorders (addiction), and osteoarthritis. See Beck et al., "Therapeutic Potential of Kappa Opioid Agonists" Pharmaceuticals (Basel) (2019)12(2):95. Additional indications may include mood conditions (e.g., stress, anxiety, depression), Alzheimer's disease, cognitive impairment, Parkinson's disease, Tourette's syndrome, immune-mediated diseases (e.g., arthritis, inflammation, diseases associated with overproduction of cytokines such as IL-6, IL-1, and TNF-a), atopic dermatitis, gastrointestinal diseases (e.g., inflammatory bowel disease (Crohn's disease, ulcerative colitis), and irritable bowel syndrome (IBS)), cancer (e.g., those involving vascular EGFR-2 expression), hypoxia, ischemia, and cardiac dysfunction. See Dalefield et al., "The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies" Frontiers in Pharm (2022) 13:Article 837671. KOR agonists have been shown to treat acute kidney injury, such as renal ischemia-reperfusion injury. See Liu et al., "Kappa-opiod receptor agonist U50448H protects against renal ischemia-reperfusion injury in rats via activating the PI3K / Akt signaling pathway" Act Pharmacologica Sinica (2018) 39:97-106. KOR agonists have been shown to treat cerebral arterial dysfunction and constriction (e.g., pulmonary hypertension and cerebral vasospasm) via activation of nitric oxide synthase adenosine triphosphate-sensitive potassium channels.See Su et al., "Salvinorin A Produces Cerebrovasodilation through Activation of Nitric Oxide Synthase, k Receptor, and Adenosine Triphosphate-sensitive Potassium Channel" Anesthesiology (2011) 114(2):374-479 and Su et al., "Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic / ischemic injury via extracellular signal-regulated kinase / mitogen-activated protein kinase in piglets" (2012) 114(1):200-204.

[0094] As used herein, the term "stronger" in relation to salvinorin A means having a higher affinity for a target receptor than salvinorin A and / or having a higher potency in producing a biological response upon binding to a target receptor than salvinorin A. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may be stronger KOR agonists than salvinorin A. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may be stronger MOR agonists than salvinorin A. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may have substantial MOR agonist activity compared to salvinorin A, and in some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may have substantial KOR agonist activity compared to salvinorin A. As used herein, "substantial" agonist activity refers to when the compounds described herein or pharma- ceutically acceptable salts thereof have 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or greater than 75% agonist activity compared to a comparable compound, such as salvinorin A. In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may have similar or greater affinity to MOR and / or KOR than salvinorin A, and may be less potent than salvinorin A. Those skilled in the art will appreciate that the affinity and / or potency of a compound to MOR or KOR agonists can be determined using methods known in the art, such as the assays described herein.

[0095] The compound may be altered in bias towards G protein-coupled receptor (GPCR)-initiated pathway or β-arrestin pathway. In some embodiments, the MOR signaling of the compound described herein or its pharmaceutically acceptable salt may be biased towards GPCR-initiated pathway. In other embodiments, the MOR signaling of the compound described herein or its pharmaceutically acceptable salt may be biased towards β-arrestin pathway. In further embodiments, the MOR signaling of the compound described herein or its pharmaceutically acceptable salt may be balanced between β-arrestin pathway and GPCR-initiated pathway. In other embodiments, the KOR signaling of the compound described herein or its pharmaceutically acceptable salt may be balanced between β-arrestin pathway and GPCR-initiated pathway. In yet other embodiments, the KOR signaling of the compound described herein or its pharmaceutically acceptable salt may be biased towards GPCR-initiated pathway. In yet other embodiments, the KOR signaling of the compound described herein or its pharmaceutically acceptable salt may be biased towards β-arrestin pathway.

[0096] Compounds were evaluated by measuring their affinity for KOR or MOR (K i ) and efficacy (EC 50 ) may differ. In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may have both high affinity and high efficacy for KOR and / or MOR. In other embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may have high affinity for KOR and / or MOR but low efficacy. In still other embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may have low affinity but high efficacy for KOR and / or MOR. Methods for determining affinity and efficacy are known to those skilled in the art. In some embodiments of this section, the affinity and efficacy of the compounds described herein or pharma- ceutically acceptable salts thereof are compared to salvinorin A using methods known to those skilled in the art.

[0097] Some embodiments described herein may include administering to a subject an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) to alleviate at least one symptom (such as one, two, or three symptoms) of a disease or disorder. Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for treating a disease or disorder described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), for treating a disease or condition described herein.

[0098] Some embodiments described herein relate to a method for treating a subject having a disease or disorder described herein, which may include contacting the KOR and / or MOR receptor in the subject with an effective amount of a compound described herein (such as a compound of formula I, formula II, and / or formula III, or a pharma- ceutically acceptable salt of any of the foregoing). Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of formula I, formula II, and / or formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for contacting the KOR and / or MOR receptor in a subject having a disease or disorder described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of formula I, formula II, and / or formula III, or a pharma- ceutically acceptable salt of any of the foregoing) for contacting the KOR and / or MOR receptor in a subject having a disease or disorder described herein.

[0099] Some embodiments described herein include a method for ameliorating one or more symptoms (such as one, two or three symptoms) of a disease or disorder described herein, which may include administering to a subject suffering from the disease or disorder an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing), and may also include contacting a KOR receptor and / or a MOR receptor with an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing). Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for improving one or more symptoms (such as one, two, or three symptoms) of a disease or disorder described herein; or in the manufacture of a medicament for improving one or more symptoms (such as one, two, or three symptoms) of a disease or disorder described herein, the use comprising contacting a KOR and / or MOR receptor with the drug. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) for improving one or more symptoms (such as one, two, or three symptoms) of a disease or disorder described herein by contacting a KOR and / or MOR receptor.

[0100] In some embodiments, the compounds described herein can be used to treat or inhibit any disease or disorder treatable with a KOR agonist and / or MOR agonist, or side effects of a drug. In some embodiments, the disease or disorder or side effect is stroke, ischemia, hypoxia, hypoxic-ischemic encephalopathy, Raynaud's disease, Alzheimer's disease, migraine, headache, pain, myocardial infarction, cardiac arrest, acute respiratory distress syndrome, acute lung injury, conditions associated with pruritus, conditions at risk for or experiencing excessive or inappropriate clot formation, inflammation, conditions associated with inflammation, edema, conditions associated with edema, HIV-induced neuroinflammation, vomiting, conditions associated with vomiting, hemorrhage, interstitial lung disease, hemorrhagic stroke, ischemic stroke. middle, diseases related to anesthesia induction including spinal cord injury and nerve injury, spinal cord injury, nerve injury, hypoxic pulmonary hypertension, multiple sclerosis, addiction or substance use disorder, post-traumatic cartilage regeneration, psychiatric disorders, mood disorders, mania, bipolar disorder, autism spectrum disorder, irritable bowel disease, circulatory disease or disorder, heart disease, brain disease or injury, traumatic brain injury, chronic traumatic encephalopathy, aneurysm, lung disease or disorder, spinal cord disease or disorder, dopamine-related diseases, intestinal motility including diarrhea, rheumatism, obesity, stress, cognition reduction in side effects associated with apoptosis or another type of programmed cell death (e.g., PANoptosis, pyroptosis, etc.) promoted or induced by a drug or disease or disorder, epilepsy, seizures, diuresis, cerebral edema, intracerebral hemorrhage, subarachnoid hemorrhage, intraventricular hemorrhage, dementia, allergic disease, asthma, respiratory viral infection, or one or more complications of a respiratory viral infection, including, but not limited to, a coronavirus (e.g., COVID-19) (e.g., endothelial cell damage to organs or vasculature due to injury), chronic pruritus including but not limited to cancer-related pruritus, brachioradial pruritus, postherpetic pruritus, aquatic pruritus, uremic pruritus, prurigo nodularis, idiopathic pruritus, neuropathic pruritus, multiple sclerosis-induced pruritus, HIV protease inhibitors, hepatitis C chemotherapy, burns, chronic liver cirrhosis, atopic dermatitis, lichen simplex chronicus, psoriasis, pruritus due to primary sclerosing cholangitis, Hodgkin's lymphoma, psychiatric disorders, primary biliary cholangitis or polycythemia vera,The condition may be selected from chronic cough, including refractory chronic cough and chronic cough due to COPD, emphysema, chronic bronchitis, GERD, heart failure, idiopathic nonspecific interstitial pneumonia, bronchiectasis, hypersensitivity pneumonitis, asthma, lung cancer, idiopathic pulmonary fibrosis, unclassifiable idiopathic interstitial pneumonia, autoimmune interstitial lung disease, other interstitial lung disease (e.g., sarcoidosis), post nasal drip, or tobacco smoke / use. In certain embodiments, the disease or disorder includes endothelial damage, dysfunction, apoptosis or another type of programmed cell death (PANoptosis, pyroptosis, etc.), including allergic rhinitis (see Shou et al., FEBS Open Bio 11:2166-2173 (2021)), diseases caused by disruption of endothelial mitochondrial function (Dong et al., Exp. Neurology 322:113045 (2019)), vascular damage, vasoplegia or conditions associated with vasoplegia, inflammation, pneumonia, myocardial damage or injury (including but not limited to myocardial ischemia, myocardial infarction, myocarditis), vascular constriction, macrophage and / or neutrophil infiltration, and vascular diseases caused by respiratory viruses such as COVID-19. In some embodiments, the disease is a disease caused by disruption of endothelial mitochondrial function, including allergic rhinitis, vascular diseases caused by respiratory viruses such as COVID-19, or asthma or other allergic diseases (see Siddiqi et al., Trends in Cardiovascular Medicine 31:1-5 (2021)), or asthma and other allergic diseases (Rossi et al., Front. Pharmacol. 7:525 (2017)).

[0101] If the disease or disorder is COVID-19, particularly if the subject is at high risk (see, e.g., cdc.gov / coronavirus / 2019-ncov / need-extra-precautions / people-with-medical-conditions.html), has O2 saturation <95%, or is short of breath, a compound described herein or a pharmacokinetic or pharmacokinetic salt thereof may be administered in combination with paxlovir (nilmatovir), molnupiravir, dexamethasone, remdesivir, or other antiviral drugs. It may be used in combination with other COVID-19 therapeutics including, but not limited to, Syvir, convalescent plasma, monoclonal antibodies treating COVID or another respiratory virus (e.g., sotrovimab, vanlanivimab, etesevimab, casirivimab, imdevimab), fluvoxamine, and medications for subjects who are hospitalized, on oxygen, or intubated on a ventilator (e.g., benzodiazepines, propofol, dexmedetomidine, other sedatives, fentanyl, or other pain medications).

[0102] Some embodiments described herein relate to methods for activating KOR and / or MOR receptors, which may include contacting a cell with an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing). Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for activating KOR and / or MOR receptors in a cell. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) for activating KOR and / or MOR receptors in a cell.

[0103] Some embodiments described herein relate to methods for modulating the activity of KOR and / or MOR receptors, which may include contacting a cell with an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing). Other embodiments described herein relate to the use of an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) in the manufacture of a medicament for modulating the activity of KOR and / or MOR receptors in a cell. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of Formula I, Formula II, and / or Formula III, or a pharma- ceutically acceptable salt of any of the foregoing) for modulating the activity of KOR and / or MOR receptors in a cell.

[0104] In some embodiments, two or more of the compounds described herein (including pharma- ceutically acceptable salts thereof) may be administered to a subject, for example, at least two compounds from Formula I, or a pharma- ceutically acceptable salt thereof, at least two compounds from Formula II, or a pharma- ceutically acceptable salt thereof, at least two compounds from Formula III, or a pharma- ceutically acceptable salt thereof, or at least two compounds from Formula I, Formula II, or Formula III, or a pharma- ceutically acceptable salt thereof.

[0105] As used herein, a "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, shellfish, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, especially humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult.

[0106] As used herein, the terms "treat," "treating," "treatment," and "therapy" do not necessarily mean a complete cure or abolition of a disease or condition. Any alleviation of undesirable signs or symptoms of a disease or condition can be considered treatment and / or therapy. Furthermore, treatment may include actions that may worsen the overall health or appearance of a subject.

[0107] The term "effective amount" is used to indicate the amount of an active compound or pharmaceutical agent that induces a biological or pharmaceutical response indicated. For example, an effective amount of a compound, salt or composition is the amount necessary to prevent, alleviate or ameliorate the symptoms of a disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human, and includes alleviating the signs or symptoms of the disease or condition being treated. Determination of an effective amount is within the capabilities of one of ordinary skill in the art in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dosage depends on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal being considered. Dosage can be adjusted to achieve the desired effect, but depends on factors such as body weight, diet, concurrent medication, and other factors that one of ordinary skill in the art would recognize.

[0108] For example, an effective amount of a compound is an amount that results in (a) the reduction, alleviation, or elimination of one or more symptoms caused by a disease or disorder, (b) elimination of the disease or disorder, and / or (c) long-term stabilization of the disease or disorder.

[0109] The amount of the compound of formula I, formula II, or formula III, or its pharmaceutically acceptable salt, required for therapeutic use varies not only with the particular compound or salt selected, but also with the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the subject, and is ultimately at the discretion of the attending physician or clinician. When administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or far exceed the dosage ranges described herein in order to effectively and aggressively treat, particularly malignant diseases or conditions.

[0110] As is readily apparent to those skilled in the art, the useful in vivo dose and the specific mode of administration to be administered vary according to age, weight, severity of the affliction, mammalian species to be treated, the specific compound employed, and the specific application for which these compounds are employed.Determination of effective dose level, i.e., the dose level required to obtain desired results, can be performed by those skilled in the art using routine methods, such as human clinical trials, in vivo tests, and in vitro tests.For example, the useful dose of the compound of formula I, formula II, or formula III, or their pharma-ceutically acceptable salts, can be determined by comparing their in vitro activity and in vivo activity in animal models.Such comparison can be performed by comparison with established compounds such as salvinorin A.

[0111] Dosage and dosing intervals can be tailored to provide plasma levels of the active ingredient sufficient to maintain the modulating effect, i.e., the minimum effective concentration (MEC). The MEC varies from compound to compound but can be estimated from in vivo and / or in vitro data. The dose required to achieve the MEC varies with individual characteristics and route of administration. However, HPLC assays or bioassays can be used to measure plasma concentrations. Dosing intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma concentrations above the MEC for 10-90%, preferably 30-90%, and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0112] It should be noted that the attending physician would know how and when to discontinue, interrupt or adjust dosing due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (excluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and with the route of administration. The severity of the disease or condition can be assessed, for example, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps frequency of administration will also vary according to the age, weight and response of the individual subject. Programs comparable to those described above may be used in veterinary medicine.

[0113] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety unless otherwise stated.In this specification, if there are multiple definitions for a term, the definition in this section shall prevail unless otherwise stated.

[0114] As used herein, "C" is a formula in which "a" and "b" are integers. a From Cb " refers to the number of carbon atoms in the group. The designated group can contain from "a" to "b" carbon atoms. Thus, for example, a "C1 to C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified, the broadest ranges described in these definitions are intended.

[0115] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl portion may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1 to 30 carbon atoms (wherever it appears herein, a numerical range such as "1 to 30" refers to each integer within the given range; for example, "1 to 30 carbon atoms" means that the alkyl group may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and the like, up to and including 30 carbon atoms, although this definition also covers occurrences of the term "alkyl" where no numerical range is specified. The alkyl group may also be a medium sized alkyl having 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0116] As used herein, the term "methyl" refers to a -CH group. Those of skill in the art will understand that methyl may be abbreviated as Me.

[0117] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (having no double or triple bonds). When composed of more than one ring, the rings may be joined in a fused, bridged or spiro fashion. As used herein, the term "fused" refers to two rings that have two atoms and one bond in common. As used herein, the term "bridged cycloalkyl" refers to a compound in which a cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that have one atom in common and the two rings are not connected by a bridge. Cycloalkyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. Cycloalkyl groups can be unsubstituted or substituted. Exemplary mono-cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0118] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) that has a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of the C6-C 14 Aryl groups, C6-C 10 It may be an aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. The aryl group may be substituted or unsubstituted.

[0119] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen (N), oxygen (O), and sulfur (S). The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Additionally, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0120] As used herein, "heterocyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems, in which carbon atoms, together with one to five heteroatoms, make up said ring system. Heterocycles can contain one or more unsaturated bonds, optionally positioned such that a fully delocalized pi-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl functional groups, such that the definition includes oxo systems. When composed of two or more rings, the rings can be joined in the form of fused, bridged, or spiro bonds. As used herein, the term "fused" refers to two rings that share one bond with two atoms. As used herein, the term "bridged heterocyclyl" refers to compounds in which the heterocyclyl contains one or more atom linkages connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share one atom and the two rings are not connected by a bridge. Heterocyclyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. Additionally, any nitrogen in a heterocyclyl may be quaternized. Heterocyclyl groups may be unsubstituted or substituted.Examples of such "heterocyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazolidine, tetrahydro-1,4-thiazine, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, tetrahydro-1,4-thi ... Examples of suitable amines include, but are not limited to, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogues thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

[0121] As used herein, the term "hydroxy" refers to an --OH group.

[0122] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. Alkoxy can be substituted or unsubstituted.

[0123] As used herein, the term "acetoxy" refers to the group -OCOCH. One of ordinary skill in the art will appreciate that acetoxy can be abbreviated as AcO or OAc.

[0124] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) as substituents linked through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. Acyl may be substituted or unsubstituted.

[0125] The term "halogen" as used herein means any one of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0126] The term "ester" refers to the group "-C(=O)OR", where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. Esters can be substituted or unsubstituted.

[0127] A "nitro" group refers to a "-NO2" group.

[0128] A "sulfonyl" group refers to a "SO2R" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfonyl can be substituted or unsubstituted.

[0129] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced with halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0130] As used herein, the term "amino" refers to the group --NH.

[0131] A "monosubstituted amino" group refers to an "-NHR" group, where R can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. The monosubstituted amino can be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0132] A "disubstituted amino" group is defined as "-NR A R B " group, where R A and R Bmay be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. Di-substituted amino may be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0133] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more halogens, which may be the same or different.

[0134] In compounds described herein having one or more chiral centers, when absolute stereochemistry is not specified, it is understood that each center may be independently R-configuration or S-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, in compounds described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomers are also intended to be included.

[0135] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0136] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, it may be explicitly disclosed or understood that a hydrogen atom is present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, in this specification, reference to a compound encompasses all possible isotopic forms, unless the context clearly dictates otherwise.

[0137] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, including different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates include stoichiometric or non-stoichiometric amounts of solvent, and can be formed during crystallization with pharma-ceutically acceptable solvents, such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Furthermore, the compounds provided herein can exist in unsolvated forms 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.

[0138] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of the range, are encompassed within an embodiment.

[0139] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, unless expressly recited otherwise, should be construed as open ended, as opposed to limiting. As an example of the foregoing, the term "including" should be construed to mean "including, without limitation," "including but not limited to," and the like; the term "comprising," as used herein, is synonymous with "including," "containing," or "characterized by," and is inclusive or open ended, not excluding additional, non-recurring elements or method steps; the term "having" should be construed as "having at least;" the term "includes" should be construed to mean "includes but not limited to," and the like. The term "example" is used to provide illustrative examples of the items under discussion and is not an exhaustive or limiting list thereof; the use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but instead should be understood as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps.When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may include additional features or components.

[0140] With respect to the use of virtually any plural and / or singular term in this specification, a person skilled in the art can translate from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly provided herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope. References Akins, NS, Mishra, N., Harris, HM, Dudhipala, N., Kim, SJ, Keasling, AW, Majumdar, S., Zjawiony, JK, Paris, JJ, Ashpole, NM, & Le, HV (2022). 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects. ChemMedChem, 17(7), e202100684. https: / / doi.org / 10.1002 / cmdc.202100684 Beck, T. C., Hapstack, M. A., Beck, K. R., & Dix, T. A. (2019). Therapeutic Potential of Kappa Opioid Agonists. Pharmaceuticals (Basel, Switzerland), 12(2), 95. https: / / doi.org / 10.3390 / ph12020095 Beguin C et al., Bioorganic & Medicinal Chemistry Letters 16:4679-4685 (2006). Beguin C et al., J. Pharmacol. Exp. Ther. 324:188-195 (2008). Berman YE et al., J. Org. Chem. 74:2589-2591 (2009). Bhowmik S et al., Nature Communications doi.org / 10.1038 / s41467-021-23736-2 (2021). Bonaventura J. et al., Mol. Psychiatry doi.org / 10.1038 / s41380-021-01093-2 (2021). Bonaventura A. et al., Nat. Reviews / Immunology 21:319-329 (2021). Brito-da-Costa AM et al., Pharmaceuticals 14:116 (2021). Brust, T. F., Morgenweck, J., Kim, S. A., Rose, J. H., Locke, J. L., Schmid, C. L., Zhou, L., Stahl, E. L., Cameron, M. D., Scarry, S. M., Aube, J., Jones, S. R., Martin, T. J., & Bohn, L. M. (2016). Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Science signaling, 9(456), ra117. https: / / doi.org / 10.1126 / scisignal.aai8441 Butelman ER and Kreek MJ, Front. Pharmacol. 6:190 (2015). Chakraborty S and Majumdar S, Biochemistry DOI: 10.1021 / acs.biochem.0c00629 (2020). Chunhua C et al., Transl Perioper Pain Med. 1:27-34 (2014). Cichon, J., Liu, R., & Le, H. V. (2022). Therapeutic Potential of Salvinorin A and Its Analogues in Various Neurological Disorders. Translational perioperative and pain medicine, 9(2), 452-457. Crowley RS et al., ACS Chem. Neurosci DOI: 10.1021 / acschemneuro.0c00191 (2020). Dalefield, M. L., Scouller, B., Bibi, R., & Kivell, B. M. (2022). The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies. Frontiers in pharmacology, 13, 837671. https: / / doi.org / 10.3389 / fphar.2022.837671 Dong et al., Exp. Neurology 322:113045 (2019). Grothusen J, Transl Perioper & Pain Med 8:337-341 (2021). Gupta A et al., Proc. Natl. Acad. Sci. USA 113:6041-6046 (2016). Hernandez-Alvarado RB et al., ACS Chemical Neuroscience doi.org / 10.1021 / acschemneuro.0c00608 (2020). Hill SJ et al., Nat. Prod. Rep. DOI: 10.1039 / d0np00028k (2020). Hirasawa S et al., Bioorg Med Chem Lett. 28:2770-2772 (2018). Ibarra, YE, Doctoral Dissertation, Harvard University (2013). Jamieson CS et al., Chem. Soc. Rev. DOI: 10.1039 / d1cs00065a (2021). Ji F et al., Brain Res. 1490: 95-100 (2013). Kutrzeba L. et al., Phytochemistry 68:1872-1881 (2007). Liu, L. J., Yu, J. J., & Xu, X. L. (2018). Kappa-opioid receptor agonist U50448H protects against renal ischemia-reperfusion injury in rats via activating the PI3K / Akt signaling pathway. Acta pharmacologica Sinica, 39(1), 97-106. https: / / doi.org / 10.1038 / aps.2017.51 Majer et al., Bioorg. Med. Chem. 22:256 (2014). Mores KL et al., Front. Pharmacol. 10:407 (2019). Paton KF et al., Front. Neurosci. 14:765 (2020). Paton, K. F., Atigari, D. V., Kaska, S., Prisinzano, T., & Kivell, B. M. (2020). Strategies for Developing κ Opioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects. The Journal of pharmacology and experimental therapeutics, 375(2), 332-348. https: / / doi.org / 10.1124 / jpet.120.000134 Pelot KA. et al., The Plant Journal 89:885-897 (2017). Polepally PR et al., Eur. J. Med. Chem. 85:818-829 (2014). Prisinzano T and Rothman RB., Chem. Rev. 108:1732-1743 (2008). Remington: The Science and Practice of Pharmacy, Lippincot Williams & Wilkins, 2006. 2393 pages. Riley AP et al., J. Med. Chem. 57:10464-10475 (2014). Roach JJ and Shenvi RA, Bioorg Med Chem Lett. 28:1436-1445 (2018). Rossi et al., Front. Pharmacol. 7:525 (2017). Roth, B. L., Baner, K., Westkaemper, R., Siebert, D., Rice, K. C., Steinberg, S., Ernsberger, P., & Rothman, R. B. (2002). Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. 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[0141] Working Example Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way. [Table 1]

[0142] Experiment 3.1 The ability of test compounds to act as kappa opioid receptor (KOR) agonists was assessed using the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit. A summary of the compounds tested is shown in Table 2. The DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit is designed to detect inhibition of intracellular cyclic AMP (cAMP) production in response to agonist stimulation of the kappa opioid receptor. cAMP production was stimulated by treatment with a constant concentration of forskolin in parallel with a concentration response of salvinorin A or test compound. Agonist binding to the KOR is predicted to inhibit the production of cAMP in a concentration-dependent manner. cAMP production was measured in the presence of varying concentrations of salvinorin A or test compound and was measured at the half-maximal effective concentration (EC 50 ) was used to determine [Table 2] TIFF2024543479000120.tif176155

[0143] Agonist concentration responses were performed in a 96-well plate format using the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit. In this assay, 15 μM forskolin was sufficient to induce cAMP production to levels that fell within the dynamic range of the standard curve provided in the kit. Salvinorin A and ALB-230937 inhibited cAMP production 100% at the lowest concentration tested, 0.1 nM. Due to the high potency of both Salvinorin A and ALB-230937, complete dose-response curves could not be obtained and definitive EC 50 Although the EC 50 The EC value of ALB-231360 is estimated to be <0.1 nM. 50The CAMP-dependent KOR agonist activity was 4.6 μM. These results confirmed that the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit worked as designed and that ALB-230937 acted as a potent KOR agonist.

[0144] Experiment 3.2 The ability of Salvinorin A and the tested compounds to act as kappa opioid receptor (KOR) agonists was assessed using the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit. The DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit is designed to detect inhibition of intracellular cyclic AMP (cAMP) production in response to agonist stimulation of the kappa opioid receptor. cAMP production was stimulated by treatment with a fixed concentration of forskolin in parallel with a concentration response of Salvinorin A or test compound. Agonist binding to the KOR is predicted to inhibit the production of cAMP in a concentration-dependent manner. cAMP production was measured in the presence of varying concentrations of Salvinorin A or test compound and was measured at the half-maximal effective concentration (EC 50) ) was used to determine

[0145] Agonist concentration responses were performed in a 384-well plate format using the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit. The introduction of automated liquid handling devices such as Echo555, Mantis, MultiDrop, and BlueWasher has significantly increased the throughput of assay kits in a 384-well plate format. In this assay, 15 μM forskolin was sufficient to induce cAMP production to a level that was within the dynamic range of the standard curve provided with the kit. Salvinorin A and test compounds were tested for concentration response in this assay. EC 50Values ​​were estimated due to issues with plate handling and cross-contamination of negative controls. Despite plate handling and contamination of controls, the potencies of Salvinorin A and ALB-230937 determined in experiment 3.2 were consistent with the observations in experiment 3.1, and agonist concentration ranges were confirmed for all eight analogs. All compounds exhibited EC50 values ​​as outlined in Table 3. 50 There were enough data points to generate a value.

[0146] As shown by the data in Table 3, the compounds described herein are active in this assay. In Table 3, "A" = EC 50 ≦1nM; "B"=EC 50 >1nM and ≤100nM; "C" = EC 50 >100 nM and ≤1,000 nM; and "D" = EC 50 >1,000 nM and ≤10,000 nM. These results confirmed that the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit worked as designed and that ALB-230937 acted as a potent KOR agonist. The assay also demonstrated that ALB-231273 and ALB-230936 had estimated EC 50 values ​​<0.1 nM, indicating it is a potent KOR agonist. [Table 3]

[0147] Experiment 3.3 The DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit was used to assess the ability of Salvinorin A and the tested compounds as kappa opioid receptor (KOR) agonists. The DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit is designed to detect inhibition of intracellular cyclic AMP (cAMP) production in response to agonist stimulation of the kappa opioid receptor. cAMP production was stimulated by treatment with a constant concentration of forskolin in parallel with a concentration response of Salvinorin A or test compound. Binding of the agonist to the KOR is predicted to inhibit the production of cAMP in a concentration-dependent manner. cAMP production was measured in the presence of varying concentrations of Salvinorin A or test compound and was determined using the half-maximal effective concentration (EC 50 ) was used to determine

[0148] Agonist concentration responses were performed in 384-well plate format using the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit. The use of automated liquid handling devices such as Echo555, Mantis, MultiDrop, and BlueWasher further increased the throughput of the assay kit in 384-well plate format. In this assay, 15 μM forskolin was sufficient to induce cAMP production to levels that fell within the dynamic range of the standard curve provided by the kit. Salvinorin A and test compounds were tested for concentration response in this assay. EC 50 Values ​​were calculated using the positive and negative controls included in the assay. The potency of Salvinorin A and ALB-230937 in experiment 3.3 was calculated using the EC 50 All compounds had EC 50 There were sufficient data points to generate values, which are summarized in Table 4.

[0149] As shown by the data in Table 4, the compounds described herein are active in this assay. In Table 3, "A" = EC 50 ≦1nM; "B"=EC 50 >1nM and ≤100nM; "C" = EC 50 >100 nM and ≤1,000 nM; and "D" = EC 50 >1,000 nM and ≤10,000 nM. These results confirmed that the DiscoverX cAMP Hunter eXpress KOR GPCR Assay Kit was functioning as designed and confirmed that ALB-230937 acts as a potent KOR agonist. In addition, the data in Table 4 show that ALB-231273 and ALB-230936 are also potent KOR agonists with estimated EC 50 It is found that the value is <0.1 nM. [Table 4]

[0150] Moreover, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the disclosure, but rather are intended to cover all changes and alterations which fall within the true scope and spirit of the invention.

Claims

1. Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt of any of the foregoing: R １ teeth, and R ２ is O or CH ２ and R ３ is H or CH ３ and R ４ teeth, is selected from R ５ is O or S, R ６ is F, Cl, or Br, and Each R １０ are independently H, OMe, NO ２ , or CF ３ and R ７ is H or and R ８ is O, OH, or and represents a single or double bond, R ８ If is O, then is a double bond, and R ８ is OH, or If The bond represented by is a single bond, R ９ is CO ２ Me or CONH ２ and and NCS is N-chlorosuccinimide; However, the following conditions are met: ２ is CH ２ or R ３ is H, and The compound is or a pharmaceutically acceptable salt thereof, A compound or a pharmaceutically acceptable salt thereof.

2. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula I.a: or a pharmaceutically acceptable salt thereof.

3. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R １ teeth, or a pharmaceutically acceptable salt thereof.

4. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ２ is O or CH ２ or a pharmaceutically acceptable salt thereof.

5. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ３ is H or CH ３ or a pharmaceutically acceptable salt thereof.

6. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ４ contains a halogen, or is, or or a pharmaceutically acceptable salt thereof.

7. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

8. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ４ does not contain a double bond, or a pharmaceutically acceptable salt thereof.

9. 9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R ４ teeth, or a pharmaceutically acceptable salt thereof, wherein:

10. 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

11. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ４ teeth, or a pharmaceutically acceptable salt thereof.

12. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

13. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ４ contains at least one double bond and does not contain aromatic rings, N or S, or or a pharmaceutically acceptable salt thereof.

14. 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

15. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ４ contains at least one double bond and at least one atom selected from N and S, or a pharmaceutically acceptable salt thereof.

16. 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R ４ teeth, or a pharmaceutically acceptable salt thereof.

17. 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

18. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula II.a: or a pharmaceutically acceptable salt thereof.

19. 19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R ２ is O or CH ２ or a pharmaceutically acceptable salt thereof.

20. 19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R ３ is H or CH ３ or a pharmaceutically acceptable salt thereof.

21. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

22. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula III.a: or a pharmaceutically acceptable salt thereof.

23. 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R １ teeth, or a pharmaceutically acceptable salt thereof.

24. 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R ２ is O or CH ２ or a pharmaceutically acceptable salt thereof.

25. 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R ３ is H or CH ３ or a pharmaceutically acceptable salt thereof.

26. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

27. Formula I.b, Formula II.b or Formula III.b 10. The compound of claim 1, having the formula: R １ teeth, and R ２ is O or CH ２ and R ３ is H or CH ３ and R ４ teeth, is selected from R ５ is O or S, R ６ is F, Cl, or Br, and Each R １０ are independently H, OMe, NO ２ , or CF ３ and R ７ is H or and R ８ Is, O, or and represents a single or double bond, R ８ If is O, then is a double bond, and R ８ but or If The bond represented by is a single bond, R ９ is CO ２ Me or CONH ２ and and NCS is N-chlorosuccinimide, and OAc is and However, the following conditions are met: ２ is CH ２ or R ３ is H, and The compound is or a pharmaceutically acceptable salt thereof, A compound or a pharmaceutically acceptable salt thereof.

28. 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof, selected from any of these.

29. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

30. Use of an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29, in the manufacture of a medicament for treating a disease or disorder treatable with a KOR agonist or MOR agonist.

31. Use of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, in the manufacture of a medicament for activating a KOR receptor or an MOR receptor.

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