Compounds for use in organ preservation and organ transplantation

Abstract

This specification presents, in certain embodiments, methods for preventing, reducing, delaying, or inhibiting organ rejection, damage, or partial or complete death of an organ before, during, or after transplantation to an organ transplant recipient. The methods may include administering one or more compositions or compounds disclosed herein to an organ donor or organ transplant recipient. The methods may also include contacting an organ with one or more compositions or compounds disclosed herein before, during, and / or after transplantation.

Description

[Technical Field]

[0001] The compositions, compounds, and methods disclosed herein relate to the general fields of organ transplantation, organ protection, organ preparation, and organ preservation. [Background technology]

[0002] Organ transplantation, in which a damaged or diseased organ is replaced with a relatively healthy organ from a donor, is the only available treatment for end-stage organ failure. The most commonly transplanted organs are the kidneys, followed by the liver, heart, and lungs. Pancreatic, intestinal, and multi-organ transplants are also performed, but far less frequently. Overall, more than 36,000 organ transplants were performed in the United States alone in 2018. However, due to a shortage of suitable donor organs, the number of people in the United States who need organ transplants now exceeds 113,000 as of April 2019 (data from the United Network for Organ Sharing).

[0003] Aside from a shortage of donor organs, a central challenge in organ transplantation is the rejection of transplanted organs by the recipient's immune system. For some organs, approximately one-quarter to half of transplants fail within five years (data from the U.S. Organ Sharing Network, April 17, 2019). To prevent potential organ rejection, organ recipients often undergo long-term treatment with immunosuppressants, which further endangers their health by increasing their susceptibility to infections and certain types of cancer. These immunosuppressive treatments also carry other potentially serious side effects.

[0004] Graft rejection is classified into three main types, each with a different timescale and underlying mechanism. These three main types are hyperacute rejection, acute rejection, and chronic rejection. Hyperacute rejection occurs when pre-existing antibodies against the transplanted organ are present and can manifest within minutes of transplantation. However, hyperacute rejection is rarely encountered due to the conventional pre-screening of recipients for anti-donor antibodies.

[0005] Acute rejection occurs within the first few months after transplantation. It occurs when the recipient's immune system reacts to antigens on the surface of donor organ cells (primarily antigens of the major histocompatibility complex, MHC). The resulting inflammatory process ultimately leads to necrosis of the graft tissue.

[0006] Chronic rejection occurs months or years after transplantation. It is characterized by multiple vascular conditions, including atherosclerosis and progressive stenosis of the transplanted vessels (transplant vascular disease), often accompanied by fibrosis within the parenchyma of the transplanted organ. The resulting ischemia often leads to necrosis of the transplanted tissue and eventual organ failure. Immunosuppressant treatment of organ recipients appears to have little effect on chronic rejection.

[0007] In addition to the close antigenic compatibility between donor and recipient, the condition of the donor organ at the time of transplantation is considered to have a major influence on both acute and chronic rejection. Organs from living donors generally have a better survival rate (US Organ Sharing Network). However, currently, more than 80% of all organs originate from deceased donors (US Organ Sharing Network). Processes occurring both after donor death and during organ retrieval and handling before transplantation can potentially affect the recipient's immune response.

[0008] Organ donors who are brain dead are generally preferred over those who are cardiac dead because blood continues to be injected into the organs until the moment of retrieval. However, brain death has been shown to produce a significant long-term systemic inflammatory response that can damage potential donor organs. Recent evidence suggests that these inflammatory processes have a negative impact on transplant outcomes, and that targeting inflammatory factors produced after brain death in pre-transplant donors is a potential strategy to improve transplant success rates.

[0009] Organs harvested for transplantation are also susceptible to damage from ischemia-reperfusion injury. After retrieval from a donor, organs are typically maintained under cryogenic storage in preservation solutions. Ischemia-reperfusion injury occurs when the blood supply to an organ is removed, and then restored after the organ is placed in the transplant recipient. Ischemia-reperfusion injury appears to influence both acute and chronic rejection in kidney transplants. [Overview of the Initiative]

[0010] This specification provides a method for preventing, reducing, delaying, or inhibiting transplant rejection in a subject, comprising administering a composition containing a compound disclosed herein to (i) a subject (e.g., an organ transplant recipient), (ii) an organ, and / or (iii) an organ donor. In some embodiments, the compound for use in the method herein is of formula IV;

[0011] [ka]

[0012] This includes the structure of or its pharmaceutically acceptable salts, stereoisomers, or tautomers. [Modes for carrying out the invention]

[0013] This specification presents, in certain embodiments, methods for preventing, reducing, delaying, or inhibiting organ rejection, damage, or partial or complete death of an organ before, during, or after transplantation to a transplant recipient. The methods may include administering one or more compositions or compounds disclosed herein to an organ donor or organ transplant recipient. The methods may also include contacting an organ with one or more compositions or compounds disclosed herein before, during, and / or after transplantation.

[0014] compound In some embodiments, the compounds for use in the methods described herein have the structure of Formula I;

[0015]

Chemical formula

[0016] or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. In some embodiments of Formula I, R 2 is hydrogen (H) or methyl; R 3 is methyl, fluorine-substituted alkyl (e.g., fluoromethyl, difluoromethyl, or trifluoromethyl), or bromine-substituted alkyl (e.g., bromomethyl, dibromomethyl, tribromomethyl); L 3 is carbonyl; each occurrence of R 6 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, hydroxyl, methoxy, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, carboxyl, aryl, substituted aryl, substituted heterocycle, halogen, cyano, cyanoalkyl, amine, methylamine, dimethylamine, nitro, amino, amidino, carbamate, CF3, OCF3, S(O) n R 7 and C(O)R 8 or two adjacent R 6 are joined to form an optionally substituted heteroaryl or heteroalkyl ring fused to the adjacent phenyl moiety; R 7 is H, R 9 NH2, HNR 9 and NR 9 R 10 selected from; R 8 is OH, OR 9 NH2, NHR 9 and NR 9 R 10 selected from; each occurrence of R 9 and R 10n is independently an optionally substituted alkyl group; n is 1 or 2.

[0017] In a particular embodiment of formula I, R at each occurrence 6 These are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyl, alkoxy, methoxy, substituted alkoxy, halogen, carbonyl, carboxyl or C(O)R 8 Selected from; in a particular such manner, R at each occurrence 6 is methyl, methoxy, perfluoromethyl, perfluoromethoxy, hydroxyl, Cl, F, or I. In some embodiments of formula I, L 3 It is a carbonyl group, and R 3 is CF3, and R 2 H is R 6 is either absent or H at each occurrence. In some embodiments of formula I, L 3 It is a carbonyl group, and R 3 is CF3, and R 2 H is R 6 At each occurrence, is independently selected from methyl or methoxy. In some embodiments of formula I, L 3 It is a carbonyl group, and R 3 is CF3, and R 2 It is methyl, and R 6 Each instance, it is independently selected from methyl or methoxy.

[0018] In some embodiments, the compound used in the methods described herein is of formula II;

[0019] [ka]

[0020] The structure of or its pharmaceutically acceptable salts, stereoisomers, or tautomers, in which the formula: (i)R A2 , R A4 , R A5 and RA6 H is R A3 It is methoxy, and R B2 It is methyl, and R B4 It is methyl; (ii)R A2 , R A3 , R A5 and R A6 H is R A4 It is methoxy, and R B2 It is methyl, and R B4 It is methyl; (iii)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 H is R B4 H is; (iv)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 It is methyl, and R B4 It is methyl; (v)R A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 H is R B4 H is; (vi)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 H is R B4 It is methyl; (vii)R A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 H is R B4 It is methyl; (viii)RA2 and R A3 and R A4 and R A5 and R A6 are H, and R B2 is methyl, and R B4 is H; (ix) R A2 and R A4 and R A5 and R A6 are H, and R A3 is methoxy, and R B2 is methyl, and R[[ID=2-8]] B4 is H; (x) R A2 and R A3 and R A5 and R A6 are H, and R A4 is COOH, and R B2 is methyl, and R B4 is methyl; (xi) R A2 and R A4 and R A5 are H, and R A3 and R A6 are hydroxyl, and R B2 is methyl, and R B4 is methyl; (xii) R A2 and R A4 and R A6 are H, and R A3 and R A5 are hydroxyl, and R B2 is methyl, and R B4 is methyl; (xiii) R A2 and R A4 and R A5 are H, and R A3 is methoxy, and R A6 is F, and R B2 is H, and R B4 is Cl; (xiv) R A3 and R A5 are H, and R A2 and R A6F is R A4 is hydroxyl, and R A6 F is R B2 H is R B4 is F; (xv)R A2 , R A4 and R A6 H is R A3 is hydroxyl, and R A5 F is R B2 H is R B4 is F; or (xvi)R A2 , R A5 and R A6 H is R A3 and R A4 Together they form -O-CH2-O-, and R A5 F is R B2 H is R B4 It is F.

[0021] In some embodiments, the compound of formula II, R A2 , R A5 and R A6 H is R A3 It is methoxy, and R B2 and R B4 It is methyl, and R A4 R is selected from H, NO2, OH, methoxy, phenol, methyl, fluorine (F), N(CH3)2, CHC(CN)2, and O-tert-butyldimethylsilyl (OTBDMS). In some embodiments of the compounds of formula II, R A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 It is methyl, and R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A3 , R A5 and R A6 H is R A4 It is methoxy, and RB2 It is methyl, and R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A3 , R A4 , R A5 and R A6 H is R B2 It is methyl, and R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 H is R B4 is H. In some embodiments of the compound of formula II, R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 H is R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A3 , R A4 , R A5 and R A6 H is R B2 H is R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 H is R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 It is methyl, and R B4 is H. In some embodiments of the compound of formula II, R A2, R A3 , R A4 , R A5 and R A6 H is R B2 It is methyl, and R B4 is H. In some embodiments of the compound of formula II, R A2 , R A3 , R A5 and R A6 H is R A4 is a carboxyl, and R B2 It is methyl, and R B4 R is methyl. In some embodiments of the compound of formula II, A2 , R A4 , R A5 and R A6 H is R A3 is a carboxyl, and R B2 It is methyl, and R B4 It is methyl.

[0022] In some embodiments, the compound used in the methods described herein is of formula III;

[0023] [ka]

[0024] The formula comprises the structure of or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, where: R1 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, or tribromomethyl; R2 is methyl, methoxy, hydroxyl, halogen, CF3, OCH3, OCF3, or OCBr3; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen (e.g., Cl, F, or Br), methyl, methoxy, and amine. In some embodiments of formula III, R1 is CF3 (trifluoromethyl), R2 is OCH3, and R3 and R4 are methyl.

[0025] In some embodiments, the compounds used in the methods described herein are those of the following formula IV;

[0026] [ka]

[0027] This includes the structure of or its pharmaceutically acceptable salts, stereoisomers, or tautomers.

[0028] The following terms have the respective definitions set forth below.

[0029] "Alkyl" refers to a linear or branched alkyl group containing approximately 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, etc.). "Substitutive alkyl" refers to an alkyl group having one or more (e.g., 1, 2, 3, 4, or even 5) further substituents as defined herein. "Optionally substituted alkyl" means alkyl or substituted alkyl.

[0030] "Cycloalkyl" refers to a cyclic ring-containing group containing approximately 3 to 12 carbon atoms. "Substitutive cycloalkyl" refers to a cycloalkyl further having one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, and substituents as defined herein. "Optionally substituted cycloalkyl" refers to a cycloalkyl or substituted cycloalkyl.

[0031] Terms such as “heterocycle” and “heterocycle” refer to a cyclic (i.e., ring-containing) group that contains one or more heteroatoms (e.g., N, O, S, etc.) as part of the ring and contains 1 to about 14 carbon atoms. Terms such as “substituted heterocycle” refer to a heterocycle having one or more (e.g., 1, 2, 3, 4, or even 5) further substituents as defined herein. Exemplary heterocyclic moieties include saturated rings, unsaturated rings, and aromatic heteroatom-containing ring systems, such as epoxy, tetrahydrofuran, oxazoline, pyrrole, pyridine, and furan. Terms such as “optionally substituted heterocycle” refer to a heterocycle or a substituted heterocycle.

[0032] References to “arbitrarily substituted bicyclic rings” refer to bicyclic ring structures known in the art that optionally include the substituents defined herein.

[0033] "Alkenyl" refers to a linear, branched, or cyclic hydrocarbyl group containing 2 to about 20 carbon atoms having at least one, 1 to 3, 1 to 2, or 1 carbon-carbon double bond. "Substitutive alkenyl" refers to an alkenyl substituted at one or more positions, e.g., 1, 2, 3, 4, or even 5, by the substituents described herein. "Optionally substituted alkenyl" refers to an alkenyl or a substituted alkenyl. In some embodiments, the alkenyl is ethyleneyl or propyrenyl. In certain embodiments, the substituted alkenyl is substituted ethyleneyl or substituted propyrenyl. In some embodiments, the ethyleneyl or propyrenyl is substituted at one or more CN moieties. For example, in some embodiments, the substituted ethyleneyl contains (CN)2C=CH-.

[0034] "Aryl" refers to an aromatic group containing 6 to approximately 14 carbon atoms. "Substituting aryl" refers to an aryl group having one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from the following: alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, heterocycle, substituted heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanoalkyl, nitro, amino, amide, amidino, carboxyl, carbamate, SO2X (wherein X is H, R, NH2, NHR, or NR2), SO3Y (wherein Y is H, NH2, NHR, or NR2), or C(O)Z (wherein Z is OH, OR, NH2, NHR, or NR2). "Optionally substituted aryl" refers to an aryl or substituted aryl.

[0035] "Aralkyl" refers to an alkyl group substituted with an aryl group. "Substitutable aralkyl" refers to an aralkyl group further having one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and substituents defined herein. Thus, aralkyl groups include, among others, benzyl, diphenylmethyl, and 1-phenylethyl (-CH(C6H5)(CH3)). "Optionally substituted aralkyl" refers to an aralkyl or substituted aralkyl group.

[0036] A "heteroaryl" refers to an aromatic group that contains one or more heteroatoms (e.g., N, O, S, etc.) as part of an aromatic ring and typically contains 2 to about 14 carbon atoms, while a "substituted heteroaryl" refers to a heteroaryl group that further has one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and the substituents defined above.

[0037] "Heteroaralkyl" and "heteroarylalkyl" refer to alkyl groups substituted with one or more heteroaryl groups. "Substituted heteroaralkyl" refers to a heteroaralkyl further having one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and substituents as defined herein. "Optionally substituted heteroaralkyl" refers to a heteroaralkyl or substituted heteroaralkyl.

[0038] "Halogen" and "halo" refer to fluorine, chlorine, bromine, or iodine.

[0039] "Hydroxyl" and "hydroxy" refer to the functional group -OH.

[0040] "Alkoxy" represents the group -OR, where R is an alkyl group. "Substitutable alkoxy" represents the group -OR, where R is a substituted alkyl group. "Optionally substituted alkoxy" refers to alkoxy or substituted alkoxy.

[0041] "Aryloxy" represents the group -OR, where R is aryl. "Substituting aryloxy" represents the group -OR, where R is substituted aryl. "Optionally substituted aryloxy" refers to aryloxy or substituted aryloxy.

[0042] "Mercapto" and "thiol" refer to the functional group -SH.

[0043] "Alkylthio" and "thioalkoxy" are groups -SR, -S(O) n=1~2 -R refers to alkyl. "Substituted alkylthio" and "substituted thioalkoxy" are groups -SR, -S(O) n=1~2 -R refers to a substituted alkyl group. "Optionally substituted alkylthio" and "optionally substituted thioalkoxy" refer to alkylthio or substituted alkylthio.

[0044] "Arylthio" represents the group -SR, where R is aryl. "Substituting arylthio" represents the group -SR, where R is substituted aryl. "Optionally substituted arylthio" refers to arylthio or substituted arylthio.

[0045] "Amino" refers to unsubstituted, monosubstituted, and disubstituted amino groups containing the substituent -NH2; "monoalkylamino" refers to a substituent having the structure -NHR, where R is alkyl or substituted alkyl; and "dialkylamino" refers to a substituent with the structure -NR2, where each R is independently alkyl or substituted alkyl.

[0046] "Amidino" is a base-C(=NR q )NR r R s This represents, and in the formula, R q , R r and R s These are, independently, hydrogenated or optionally substituted alkyl groups.

[0047] The term "amide group" includes substituents of the structure -C(O)-NR2, where each R is independently H, alkyl, substituted alkyl, aryl, or substituted aryl as defined above. When each R is H, the substituent is also called a "carbamoyl" (i.e., a substituent having the structure -C(O)-NH2). When only one of the R groups is H, the substituent is also called a "monoalkylcarbamoyl" (i.e., a substituent having the structure -C(O)-NHR, where R is an alkyl or substituted alkyl as defined above) or an "arylcarbamoyl" (i.e., a substituent having the structure -C(O)-NH(aryl), where aryl is as defined above, including substituted aryl). When none of the R groups are H, the substituent is also called a "dialkylcarbamoyl" (i.e., a substituent having the structure -C(O)-NR2, where each R is independently an alkyl or substituted alkyl as defined above).

[0048] The term "carbamate" includes the substituents of the structure -OC(O)-NR2, where each R is independently H, alkyl, substituted alkyl, aryl, or substituted aryl.

[0049] The term "ester group" includes substituents in the structure -OC(O)-OR, where each R is independently alkyl, substituted alkyl, aryl, or substituted aryl.

[0050] "Acyl" refers to a group having the structure -C(O)R, where R is hydrogen, alkyl, aryl, etc., as defined herein. "Substitutive acyl" refers to an acyl in which the substituent R is substituted as defined herein. "Optionally substituted acyl" refers to acyls and substituted acyls.

[0051] "Cyanoalkyl" refers to the group -R≡N, where R is an optionally substituted alkylenyl group.

[0052] As used herein, “substitution” means that one atom or group of atoms is replaced by another atom or group of atoms (i.e., a substituent), and includes all levels of substitution, e.g., monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even hexasubstituted, where chemically permitted. Substitutions can occur at any chemically available position and at any atom, for example, one or more substitutions are possible on carbon and any heteroatoms, e.g., oxygen, nitrogen, or sulfur. For example, a substituted portion may include one or more hydrogen atoms or one or more bonds to carbon atoms contained therein being replaced by one or more bonds to non-hydrogen atoms and / or non-carbon atoms. Substitutions include, but are not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and heteroatoms in other groups, as is well known in the art.

[0053] Non-limiting examples of substituents include halogens, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR, -SR, -OC(O)R, and -OC(S)R. , -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -S(O)R, -S(O)2R, -C(O)NHR, -C(S)NHR, -C(O)NRR, - C(S)NRR, -S(O)2NHR, -S(O)2NRR, -C(NR)NHR, -C(NH)NRR, -NHC(O)R, -NHC(S)R, -NRC(O)R, -NRC(S)R, -NHS(O)2R, -NRS(O)2R, -NHC(O)NHR, -NHC(S)NHR, -NRC(O)NH2, -NRC(S)NH2, -NRC(O)NHR, -NRC(S)NHR, -NHC(O)NRR, -NHC(S)NRR, -NRC(O)NRR, -NRC(S)NRR, -NHS(O)2NHR, -NRS(O)2NH2, -NRS(O)2NHR, -NHS(O)2NRR, -NRS(O)2NRR, -NHR, -NRR are examples, but are not limited to these. In each of the formulas, R is independently H, an arbitrarily substituted alkyl, an arbitrarily substituted aryl, or an arbitrarily substituted heteroaryl.Additionally, the following chemical functional groups: -O-, -S-, -NR-, -OC(O)-, -OC(O)-O-, -OC(O)-NR-, -NR-C(O)-, -NR-C(O)-O-, -NR-C(O)-NR-, -S C(O)-, -SC(O)-O-, -SC(O)-NR-, -S(O)-, -S(O)2-, -OS(O)2-, -OS(O)2-O, -OS(O)2-NR-, -OS(O)-, -OS(O)-O-, - OS(O)-NR-, -O-NR-C(O)-, -O-NR-C(O)-O-, -O-NR-C(O)-NR-, -NR-OC(O)-, -NR-OC(O)-O-, -NR-OC(O)-NR-, -O -NR-C(S)-, -O-NR-C(S)-O-, -O-NR-C(S)-NR-, -NR-OC(S)-, -NR-OC(S)-O-, -NR-OC(S)-NR-, -OC(S)-, -OC(S)- O-, -OC(S)-NR-, -NR-C(S)-, -NR-C(S)-O-, -NR-C(S)-NR-, -SS(O)2-, -SS(O)2-O-, -SS(O)2-NR-, -NR-OS(O)- , -NR-OS(O)-O-, -NR-OS(O)-NR-, -NR-OS(O)2-, -NR-OS(O)2-NR-, -O-NR-S(O)-, -O-NR-S(O)-O-, -O-NR-S(O)- Substitutions with optionally substituted hydrocarbyl moieties, including one or more of NR-, -O-NR-S(O)2-O-, -O-NR-S(O)2-NR-, -O-NR-S(O)2-, -OP(O)R2-, -SP(O)R2-, or -NRP(O)R2-, are also intended, where R in each instance is independently H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

[0054] In some embodiments, the compounds for use in the methods described herein include isomers, including stereoisomers (e.g., enantiomers and diastereomers), structural isomers, tautomers, conformational isomers, and geometric isomers of the compounds disclosed herein.

[0055] Examples of structural isomers include, but are not limited to, isomers arising from differences in the bonding properties of functional groups that form compounds for use in the methods described herein, such as 1-propyl substitution versus 2-propyl substitution. Combinations of structural isomerism with tautomerism further include bond rearrangements involving the movement of double bonds and substituents. For example, structural isomerism can arise from a combination of tautomerism and 1-3 polyhedral hydrogen shifts.

[0056] Exemplary conformational isomers, as is well known in the art, include, but are not limited to, isomers that arise from rotation around a certain bond, provided that the rotation is hindered to the extent that separable isomers are produced.

[0057] Exemplary geometric isomers, as are well known in the art, include, for example, double bonds in the "E" or "Z" configuration.

[0058] Compounds for use in the methods described herein can be readily prepared using appropriate synthetic methods. For example, curcumin can be condensed with phenylhydrazine by heating under reflux overnight in toluene. Optionally, a catalytic amount of acid (HCl) can be used. In some embodiments, pure curcumin (relative to industrial grade) and freshly distilled phenylhydrazine can be used.

[0059] As another example, 3-methoxybenzaldehyde can be condensed with 2,4-dimethylphenylhydrazine in methanol using standard hydrazone preparation conditions (e.g., heating in a microwave to accelerate the reaction time). The free NH is then acylated with TFAA (trifluoroacetic anhydride) + catalytic (0.1%) DMAP (dimethylaminopyridine), THF (tetrahydrofuran), or DCM (dichloromethane).

[0060] In some embodiments, CF3-substituted triazoles can be prepared by 1,3-dipolar cycloaddition between a suitable aryltrifluoromethylacetylene and an aryl azide. Regioselectivity can be obtained by utilizing appropriate click chemistry (see, for example, Huisgen R. (1984) 1,3-Dipolar Cycloaddition Chemistry, pp.1-176, Lodon: Wiley; Padwa (1991) Comprehensive Organic Synthesis, Vol.4: pp.1069-1109, Oxford: Pergamon; and Fan & Katritzky (1996) Comprehensive Heterocyclic Chemistry II, Vol.4: pp.101-126, Oxford: Pergamon). Further methods for generating the compounds disclosed herein can be found in Lima et al., (2015) Chem. Commun. 51:10784-10796 and Kim et al., (2015) Org. Biomol. Chem. 13:9564-9569.

[0061] In some embodiments, the compounds for use in the methods described herein are provided in the form of pharmaceutically acceptable salts. The compounds for use in the methods described herein can form complexes with any suitable inorganic or organic salt. In some embodiments, salts of the compounds for use in the methods described herein are prepared by reacting the compounds for use in the methods described herein with a suitable organic or inorganic acid or base. Non-limiting examples of organic salts intended for use in the methods described herein, along with compounds for use in the methods described herein, include methanesulfonates, acetates, oxalates, adipates, alginates, aspartates, valerates, oleates, laurates, borates, benzoates, lactates, phosphates, toluenesulfonates (tosylates), citrates, malates, maleates, fumarates, succinates, tartrates, napsylates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, benzenesulfonates, butyrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, glucoheptanoates, glycerophosphates, heptanoates, hexanoates, undecanoates, 2-hydroxyethanesulfonates, and ethanesulfonates. In some embodiments, inorganic salts can be formed from inorganic acids such as sulfates, bisulfates, hemisulfates, hydrochlorides, chlorates, perchlorates, hydrobromids, and hydroiodides. Non-limiting examples of base salts include ammonium salts; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and phenylethylamine; and salts with amino acids such as arginine and lysine. Salt forms of compounds for use in the methods described herein can be prepared using appropriate methods.

[0062] In some embodiments, methods are provided herein for inhibiting, reducing, delaying, or preventing organ transplant rejection in a subject, comprising administering a composition comprising one or more compounds disclosed herein in a therapeutically effective amount to the subject. In some embodiments, one or more compounds are selected from formulas I, II, III, and IV or their pharmaceutically acceptable salts, stereoisomers, or tautomers. In some embodiments, the subject is an organ transplant recipient. In some embodiments, the subject is in need of or about to undergo an organ transplant. In certain embodiments, the composition is administered to the subject before, during, and / or after the organ transplant procedure. For example, the compositions disclosed herein may be administered to the subject within seconds to weeks prior to the organ transplant procedure. In some embodiments, the composition is administered to the subject 1 to 10 weeks, 1 to 30 days, 1 to 14 days, or 1 to 3 days prior to the organ transplant procedure. In some embodiments, the composition is administered to the subject 1 to 48 hours prior to the organ transplant procedure. In some embodiments, the composition is administered to the subject at least 48 hours, at least 24 hours, at least 12 hours, at least 1 hour, or at least 1 minute before the organ transplantation procedure. In some embodiments, the composition is administered to the subject during the transplantation procedure. In some embodiments, the composition is administered to the subject at least 1 to 48 hours, at least 1 to 30 days, at least 1 to 10 weeks, or for several months or years after the organ transplantation procedure.

[0063] In some embodiments, methods for inhibiting, reducing, delaying, or preventing organ rejection in a subject include inhibiting, reducing, delaying, or preventing acute organ rejection. In some embodiments, methods for inhibiting, reducing, delaying, or preventing organ rejection in a subject include inhibiting, reducing, delaying, or preventing chronic organ rejection.

[0064] In some embodiments, methods for preparing organs for transplantation into a subject, either ex vivo or in vitro, are presented herein, comprising contacting the organ with a composition containing an effective amount of a compound selected from one of formulas I to IV or its pharmaceutically acceptable salts, stereoisomers, or tautomers. In some or all embodiments of the ex vivo methods described herein, the organ is contacted with the composition or compound after extraction from a subject (e.g., from an organ donor) and / or before transplantation into an organ transplant recipient. In some or all embodiments of the ex vivo methods described herein, the organ contacted with the composition is an organ that is not connected to or attached to a subject (e.g., a human body). In some or all embodiments of the ex vivo methods described herein, the organ contacted with the composition is an organ that is not operably connected to a subject (e.g., a human body).

[0065] In some embodiments, the process of bringing an organ into contact with the composition described herein includes perfusion of the composition into the organ. In some embodiments, the process of bringing an organ into contact with the composition described herein includes partial or complete immersion of the organ in the composition. In some embodiments, the process of bringing an organ into contact with the composition described herein includes perfusion of the composition into the organ and partial or complete immersion of the organ in the composition.

[0066] In some embodiments, methods for preparing organs for transplantation are presented herein, comprising contacting the organs with a composition comprising an effective amount of a compound selected from any one of formulas I to IV or its pharmaceutically acceptable salts, stereoisomers, or tautomers.

[0067] In some embodiments of the in situ methods described herein, the subject is an organ donor. The organ donor may be alive, brain dead, or deceased. In some embodiments of the in situ methods described herein, the organ is brought into contact with the composition described herein before the organ is removed from the subject (e.g., from the donor). In some embodiments of the in situ methods described herein, the organ is brought into contact with the composition described herein while the organ is operably connected to the subject. In some embodiments of the in situ methods described herein, the organ is brought into contact with the composition described herein while it is operably connected to the subject in its naturally occurring anatomical configuration. In some embodiments of the in situ methods described herein, the subject (e.g., the donor) is alive. In some embodiments of the in situ methods described herein, the subject (e.g., the donor) is brain dead. In some embodiments of the in situ methods described herein, the subject is deceased or has recently died (e.g., within minutes or hours).

[0068] In some embodiments, the process of contacting an organ with the composition described herein includes perfusion of the composition into the organ. In some embodiments, the process of contacting an organ with the composition described herein includes partial or complete immersion of the organ in the composition. In some embodiments, the process of contacting an organ with the composition described herein includes perfusion of the composition into the organ and partial or complete immersion of the organ in the composition. Organs located inside or outside the subject can be perfused with the composition described herein by appropriate means.

[0069] In some embodiments, methods are presented herein for inhibiting, reducing, delaying, or preventing reperfusion injury of a transplanted organ in a subject (e.g., an organ transplant recipient), comprising administering a composition to the subject containing a therapeutically effective amount of a compound comprising a structure selected from any one of Formulas I to IV, and / or contacting the organ with a composition containing a therapeutically effective amount of a compound comprising a structure selected from any one of Formulas I to IV. In some embodiments, methods are presented herein for inhibiting, reducing, delaying, or preventing cell death of organ cells in a subject, comprising administering a composition to the subject containing a therapeutically effective amount of a compound comprising a structure selected from any one of Formulas I to IV, and / or contacting the organ with a composition containing a therapeutically effective amount of a compound comprising a structure selected from any one of Formulas I to IV. The compositions may be administered to the subject during, before, and / or after organ transplantation. In some embodiments, the organ is contacted with the compositions disclosed herein by ex vivo or in vitro methods described herein. The organ may be contacted with the compositions before, during, or, in certain embodiments, after transplantation.

[0070] The term “cell death” includes cell death characterized by apoptosis, cell death characterized by necrosis, cell death characterized by necroptosis, and / or cell death characterized by autophagy. In some embodiments, administration of the compositions disclosed herein inhibits, reduces, delays, or prevents apoptosis of cells in an organ (e.g., a transplanted organ or an organ intended for transplantation). In some embodiments, administration of the compositions disclosed herein inhibits, reduces, delays, or prevents necrosis of cells in an organ (e.g., a transplanted organ or an organ intended for transplantation). In some embodiments, administration of the compositions disclosed herein inhibits, reduces, delays, or prevents necroptosis of cells in an organ (e.g., a transplanted organ or an organ intended for transplantation). In some embodiments, administration of the compositions disclosed herein inhibits, reduces, delays, or prevents autophagy of cells in an organ (e.g., a transplanted organ or an organ intended for transplantation).

[0071] In some embodiments, methods are presented herein for ex vivo or in vitro for inhibiting, reducing, delaying, or preventing cell death in organs, comprising contacting the organ with a composition comprising an effective amount of a compound comprising a structure selected from any one of Formulas I to IV. In some embodiments, methods are presented herein for in situ for inhibiting, reducing, delaying, or preventing cell death in organs, comprising contacting the organ (e.g., organs of a donor, e.g., subject or cadaver) with a composition comprising an effective amount of a compound comprising a structure selected from any one of Formulas I to IV. In some embodiments, contacting an organ with the compositions disclosed herein inhibits, reduces, delays, or prevents apoptosis of cells in an organ (e.g., a transplanted organ or organ intended for transplantation). In some embodiments, contacting an organ with the compositions disclosed herein inhibits, reduces, delays, or prevents necrosis of cells in an organ (e.g., a transplanted organ or organ intended for transplantation). In some embodiments, contact with an organ with the compositions disclosed herein inhibits, reduces, delays, or prevents cellular necroptosis in the organ (e.g., a transplanted organ or an organ intended for transplantation). In some embodiments, contact with an organ with the compositions disclosed herein inhibits, reduces, delays, or prevents cellular autophagy in the organ (e.g., a transplanted organ or an organ intended for transplantation).

[0072] organs An “organ” is any organ or part of an object suitable for transplantation to the same or a different object, and non-limiting examples include solid organs, tissues, body parts, cells, and platelets. Non-limiting examples of solid organs include kidneys, livers, hearts, lungs, pancreas, intestines, thymus, eyes, parts of them, and combinations thereof. Non-limiting examples of tissues include skin, bones, tendons, middle ears, corneas, heart valves, veins, cartilage, ligaments, parts of them, and combinations thereof. Non-limiting examples of body parts include hands, thumbs, fingers, toes, feet, faces, noses, ears, eyes, arms, legs, parts of them, and combinations thereof. Non-limiting examples of cells include red blood cells, stem cells (e.g., umbilical cord blood stem cells, peripheral blood stem cells), bone marrow, parts of them, and combinations thereof.

[0073] subject The term "subject" refers to a mammal. Any suitable mammal can be treated with the methods or compositions described herein. Non-limiting examples of mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, etc.), pets (e.g., dogs and cats), livestock (e.g., horses, cattle, goats, sheep, pigs), and laboratory animals (e.g., mice, rats, rabbits, guinea pigs). In some embodiments, the subject is a non-human primate or a human. In some embodiments, the subject is a human. The subject may be of any age or any developmental stage (e.g., adult, adolescent, child, infant, or intrauterine mammal). The subject may be male or female.

[0074] In some embodiments, the subject is an organ donor. In some embodiments, the organ donor is alive. In some embodiments, the organ donor is brain dead. In some embodiments, the organ donor is alive and brain dead. In some embodiments, the organ donor is recently deceased. For example, in some embodiments, a recently deceased organ donor is determined to be clinically dead for a period of time ranging from a few seconds to several hours (e.g., up to 1 hour, up to 4 hours, up to 12 hours, or up to 24 hours). In some embodiments, the organ donor is a corpse.

[0075] In some embodiments, the subject requires organ transplantation. In some embodiments, the subject is an organ transplant recipient (e.g., an organ transplant recipient). In some embodiments, an organ transplant recipient is a subject who is seeking or scheduled to receive an organ transplant. In some embodiments, an organ transplant recipient is a subject who has received and / or has received an organ transplant. In some embodiments, an organ transplant recipient is alive. An organ transplant recipient is not a deceased subject, is not a dead subject, and / or is not a corpse.

[0076] composition In some embodiments, a composition or pharmaceutical composition comprises one or more compounds described herein. In some embodiments, a composition or pharmaceutical composition is essentially composed of one or more compounds described herein. For example, a composition essentially composed of compounds described herein does not contain any other active pharmaceutical ingredient (API), but may contain adjuvants, diluents, additives, or carriers. In some embodiments, a composition or pharmaceutical composition comprises an effective amount or a therapeutically effective amount of a compound described herein. In some embodiments, provided herein are pharmaceutical compositions comprising compounds described herein for use in inhibiting, reducing, delaying, or preventing transplanted organ rejection; for use in inhibiting, reducing, delaying, or preventing transplanted organ reperfusion injury; and / or inhibiting, reducing, delaying, or preventing cell death in transplanted organs. In some embodiments, a pharmaceutical composition comprises compounds described herein and pharmaceutically acceptable adjuvants, diluents, additives, or carriers.

[0077] In some embodiments, the pharmaceutical composition is formulated for a suitable route of administration. In some embodiments, the pharmaceutical composition is formulated for contact with an organ. In some embodiments, the pharmaceutical composition is formulated for oral, subcutaneous (sc), intradermal, intramuscular, intraperitoneal and / or intravenous (iv) administration. In certain embodiments, the pharmaceutical composition includes, for example, formulation materials for modifying, maintaining, or preserving the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or permeability of the composition. In certain embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borates, bicarbonates, tris-HCl, citrates, phosphates (e.g., phosphate-buffered saline), or suitable organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); proteins (such as serum albumin, gelatin, or immunoglobulin); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); solvents (such as glycerin, propylene glycol, or polyethylene glycol); diluents; and adjuvants and / or auxiliary agents. In particular, the pharmaceutical composition is described in “Remington: The Science And Practice Of Pharmacy” Mack Publishing Co., Easton, PA, 19 th Edition, (1995) (hereinafter referred to as Remington '95) or “Remington: The Science And Practice Of Pharmacy”, Pharmaceutical Press, Easton, PA, 22 ndThis may include any suitable carrier, formulation, or component, or combination thereof, as listed in Edition, (2013) (hereinafter referred to as Remington 2013), the entire contents of the aforementioned document are incorporated herein by reference.

[0078] In certain embodiments, the pharmaceutical composition comprises suitable adjuvants, non-limiting examples of which include anti-adhesion agents (e.g., magnesium stearate), binders, fillers, monosaccharides, disaccharides, other carbohydrates (e.g., glucose, mannose, or dextrin), sugar alcohols (e.g., mannitol or sorbitol), coatings (e.g., cellulose, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, synthetic polymers, shellac, gelatin, corn protein zein, enteric-coated or other polysaccharides), and starches (e.g., potato, corn). Examples include rocco or wheat starch), silica, colorants, disintegrants, fragrances, lubricants, preservatives, absorbents, sweeteners, excipients, suspending agents, surfactants and / or wetting agents (Pluronic®, PEG, sorbitan esters, polysorbates, e.g., polysorbate 20, polysorbate 80, Triton, tromethamine, lecithin, cholesterol, tyroxapal, etc.), stability enhancers (e.g., sucrose or sorbitol), and tensile strength enhancers (e.g., alkali metal halides, sodium chloride or potassium chloride, mannitol, sorbitol, etc.) and / or any excipients disclosed in Remington '95 or Remington 2013. As used herein, the term “binding agent” refers to a compound or component that helps to keep a pharmaceutical mixture bound together. Binding agents suitable for the manufacture of pharmaceutical formulations and often used in the preparation of pharmaceutical tablets, capsules and granules are known to those skilled in the art.

[0079] In some embodiments, the pharmaceutical composition includes suitable pharmaceutically acceptable additives and / or carriers. Non-limiting examples of suitable additives include suitable pH adjusters, analgesics, buffers, sulfur-containing reducing agents, and antioxidants. Non-limiting examples of sulfur-containing reducing agents include those having a sulfhydryl group (e.g., thiols), such as N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and C1-C7 thioalkanoates. Non-limiting examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, triamyl gallate and propyl gallate, as well as chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate and sodium metaphosphate. Furthermore, diluents, additives and adjuvants may include other commonly used components, such as inorganic salts like sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate and sodium bicarbonate, as well as organic salts like sodium citrate, potassium citrate and sodium acetate.

[0080] The pharmaceutical compositions used herein can be stable for long periods, for example, on the order of months or years. In some embodiments, the pharmaceutical composition comprises one or more suitable preservatives. Non-limiting examples of preservatives include benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, hydrogen peroxide, and / or combinations thereof. The preservative may include quaternary ammonium compounds, such as benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, or domiphene bromide (BRADOSOL®). The preservative may include alkyl mercury salts of thiosalicylic acids such as thimerosal, phenylmercury nitrate, phenylmercury acetate, or phenylmercury borate. The preservative may include parabens such as methylparaben or propylparaben. The preservative may include alcohols such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol. The preservative may include chlorohexidine or a biguanide derivative such as polyhexamethylene biguanide. The preservative may include sodium perborate, imidazolidinyl urea, and / or sorbic acid. The preservative may include a stabilized oxychloro complex, such as one commercially available under the trade name PURITE®. The preservative may include a polyglycol-polyamine condensation resin, such as one commercially available from Henkel KGaA under the trade name POLYQUART®. The preservative may include stabilized hydrogen peroxide. The preservative may be benzalkonium chloride. In some embodiments, the pharmaceutical composition is preservative-free.

[0081] In some embodiments, the compositions, pharmaceutical compositions, or compounds for use in the methods described herein are substantially free of impurities (e.g., blood cells, platelets, polypeptides, minerals, blood-derived compounds or chemicals, viruses, bacteria, other pathogens, toxins, etc.). In some embodiments, the compositions, pharmaceutical compositions, or compounds for use in the methods described herein are substantially free of serum and serum impurities (e.g., serum proteins, serum lipids, serum carbohydrates, serum antigens, etc.). In some embodiments, the compositions, pharmaceutical compositions, or compounds for use in the methods described herein are substantially free of pathogens (e.g., viruses, parasites, or bacteria). In some embodiments, the compositions, pharmaceutical compositions, or compounds for use in the methods described herein are substantially free of endotoxins. In some embodiments, the compositions, pharmaceutical compositions, or compounds for use in the methods described herein are substantially sterile. In some embodiments, the compositions, pharmaceutical compositions, or compounds for use in the methods described herein are sterile. In certain embodiments, the compositions or pharmaceutical compositions disclosed herein contain compounds of formula I, II, III, or IV.

[0082] The pharmaceutical compositions described herein may be configured to be administered to a subject in any appropriate form and / or amount according to the therapy in which they are employed. For example, a pharmaceutical composition configured for parenteral administration (e.g., by injection or infusion) may take the form of a suspension, solution or emulsion in an oily or aqueous excipient, which may include a formulating agent, a supplement, an additive and / or diluent, e.g., an aqueous or non-aqueous solvent, an auxiliary solvent, a suspension, a preservative, a stabilizer and / or a dispersant. In some embodiments, a pharmaceutical composition suitable for parenteral administration may include one or more supplements. In some embodiments, the pharmaceutical composition is lyophilized in the form of a dry powder. In some embodiments, the pharmaceutical composition is lyophilized in the form of a dry powder suitable for reconstitution with a suitable pharmaceutical solvent (e.g., water, saline, isotonic buffer (e.g., PBS), DMSO, or a combination thereof). In certain embodiments, the reconstituted form of the lyophilized pharmaceutical composition is suitable for parenteral administration to mammals (e.g., intravenous administration).

[0083] In certain embodiments, the pharmaceutical composition is configured for oral administration and can be formulated as tablets, microtablets, minitablets, micropellets, powders, granules, capsules (e.g., capsules filled with microtablets, micropellets, powders, or granules), emulsions, solutions, etc., or combinations thereof. The pharmaceutical composition configured for oral administration may include a coating suitable for delaying or prolonging the release of the active ingredient, and non-limiting examples thereof include enteric coatings, e.g., fatty acids, waxes, shellac, synthetic resins, methyl acrylate-methacrylate copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylate copolymer, cellulose acetate trimellitate, sodium alginate, zein, plant fibers, etc., and combinations thereof.

[0084] In some embodiments, the pharmaceutical compositions described herein may be configured for topical administration and may contain one or more binders and / or lubricants, polyglycols, gelatin, cocoa butter, or other suitable waxes or fats. In some embodiments, the pharmaceutical compositions described herein may be incorporated into a topical formulation comprising a topical carrier suitable for topical drug administration and any suitable material known to those skilled in the art. In certain embodiments, the topical formulation of the pharmaceutical composition is formulated to administer the compound for use in the method herein from a topical patch.

[0085] In some embodiments, the pharmaceutical compositions described herein may be configured for contact with and / or perfusion of organs. For example, in some embodiments, a pharmaceutical composition configured for contact with an organ may be substantially sterile and comprise a solution of a salt which is isotonic with the body fluid of the subject and comprises one or more compounds disclosed herein.

[0086] In a particular embodiment, the optimal pharmaceutical composition is determined by those skilled in the art, for example, depending on the intended route of administration, the form of delivery, and the desired dose (see, for example, Remington '95 or Remington 2013 above). The pharmaceutical composition can be manufactured by any suitable method, including, for example, conventional mixing, dissolution, granulation, dragéing, excipient formation, emulsification, encapsulation, encapsulation, or tableting steps (see, for example, the methods described in Remington '95 or Remington 2013).

[0087] In some embodiments, the composition further comprises immunosuppressants, non-limiting examples of which include calcineurin inhibitors, cyclosporine (e.g., cyclosporine A), antiproliferative agents, steroids (e.g., corticosteroids), cyclophyllin D, RIPK1 kinase inhibitors (e.g., necrostatin-1 (Nec-1)), immunoglobulin G-degrading enzymes (e.g., imifidase (IdeS)), heme alginate, anti-inflammatory agents, and combinations thereof.

[0088] Route of administration Any suitable method of administering the compositions, pharmaceutical compositions, or compounds for use in the methods described herein may be used. Any suitable formulation and / or route of administration may be used for administering the compounds for use in the methods described herein or the compositions disclosed herein (see, for example, Fingl et al. 1975, “The Pharmacological Basis of Therapeutics,” the entire content of which is incorporated herein by reference). Suitable formulations and / or routes of administration may be selected by a healthcare professional (e.g., a physician) taking into consideration, for example, the risks, age, and / or medical condition of the subject. Non-limiting examples of routes of administration include local or local (e.g., percutaneous or cutaneous (e.g., on the skin or epidermis), intraocular or supraocular, transnasal, transmucosal, intraaural, intraaural (e.g., behind the eardrum)), enteral (e.g., delivery through the gastrointestinal tract, e.g., orally (e.g., as tablets, capsules, granules, liquids, emulsions, lozenges or combinations thereof), sublingual, via a gastrointestinal feeding tube, rectally, etc.), parenteral administration (e.g., parenteral, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, subcutaneous, intracavitary, intracranial, intra-articular, intra-articular cavity, intracardiac (intracardiac), intracavernosal injection, intrafocal (intracutaneous wound), intraosseous injection (intrabone marrow), intrasacral (intraspinal canal), intrauterine, intravaginal, intravesical injection, intravitreal) or combinations thereof.

[0089] In some embodiments, the compounds for use in the methods described herein or the pharmaceutical compositions described herein are administered to the lungs, bronchial passages, trachea, esophagus, venous sinuses or nasal cavity by appropriate means, non-limiting examples thereof include intranasal administration, intratracheal infusion and oral inhalation (e.g., by the use of inhalers, e.g., single / multiple dose dry powder inhalers, nebulizers, etc.).

[0090] In some embodiments, a compound or pharmaceutical composition disclosed herein for use in the method herein is provided to a subject. For example, a composition provided to a subject may be provided for self-administration or for administration to the subject by another person (e.g., a non-medical professional). In another example, a composition may be provided as instructions written by a healthcare professional (e.g., a prescription) authorizing the provision of the composition or treatment described herein to a patient. In yet another example, a composition may be provided to a subject for self-administration, for example, orally, intravenously, or using an inhaler.

[0091] Alternatively, the compounds or compositions used in the methods described herein may be administered topically rather than systemically, for example, by direct application to the skin, mucous membranes, or treatment site, including the use of depot formulations or sustained-release formulations.

[0092] In certain embodiments, a pharmaceutical composition containing the compound for use in the method herein is administered alone (for example, as a single active ingredient (AI) or, for example, as a single pharmacokinetic ingredient (API)). In other embodiments, a pharmaceutical composition containing the compound for use in the method herein is administered in combination with one or more additional AI / APIs, for example, as two separate compositions, or as a single composition in which one or more additional AI / APIs are mixed or formulated together with the compound for use in the method herein in the pharmaceutical composition.

[0093] Dosage and effective amount In some embodiments, the amount of a compound (e.g., in a pharmaceutical composition) for use in the method herein is a therapeutically effective amount. In certain embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound disclosed herein. In some embodiments, a therapeutically effective amount of a compound for use in the method herein is administered to a subject. In some embodiments, a therapeutically effective amount of a compound for use in the method herein is the amount necessary to obtain an effective therapeutic outcome. In certain embodiments, a therapeutically effective amount of a compound for use in the method herein is sufficient to inhibit, delay, reduce, or prevent rejection of a transplanted organ. In certain embodiments, an effective amount of a compound for use in the method herein is sufficient to inhibit, delay, reduce, or prevent organ injury (e.g., reperfusion injury), necrosis, or cell death intended herein. Determining an effective or therapeutically effective amount is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosures provided herein.

[0094] In certain embodiments, a therapeutically effective amount is a sufficiently high amount to provide an effective therapeutic effect (e.g., a beneficial therapeutic effect) and a sufficiently low amount to minimize undesirable side effects. Therefore, in certain embodiments, the therapeutically effective amount of a compound for use in the method herein may often vary from subject to subject, depending on the subject's age, weight, overall health, the amount of fluid loss due to trauma or surgery, and / or the specific combination of drugs administered to the subject. Thus, in some embodiments, the therapeutically effective amount is determined empirically. Therefore, the therapeutically effective amount of a compound for use in the method herein, administered to a subject, may be determined by a person skilled in the art, for example, based on amounts found effective in animal or clinical studies, the physician's experience, and recommended dose ranges or administration guidelines.

[0095] In certain embodiments, the therapeutically effective amount of the compound for use in the method herein is administered in an appropriate dose (e.g., an appropriate volume, frequency, and / or concentration, often depending on the subject's body weight, age, and / or condition) aimed at obtaining an acceptable therapeutic outcome. In certain embodiments, the therapeutically effective amount of the compound for use in the method herein includes one or more doses selected from at least 0.01 mg / kg (e.g., mg of the compound for use in the method herein per kg of the subject's body weight), at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1 mg / kg, at least 10 mg / kg, or at least 100 mg / kg. In certain embodiments, the therapeutically effective amount of the compound for use in the method herein is approximately 0.001 mg / kg (e.g., mg of the compound for use in the method herein per kg of body weight of the subject) to approximately 5000 mg / kg, 0.01 mg / kg to 1000 mg / kg, 0.01 mg / kg to 500 mg / kg, 0.1 mg / kg to 1000 mg / kg, 1 mg / kg to 1000 mg / kg, 10 mg / kg to 1000 mg / kg, and 100 mg / kg to 1000 mg The dosage is selected from one or more doses of 0.1 mg / kg, 0.1 mg / kg to 500 mg / kg, 0.1 mg / kg to 250 mg / kg, 0.1 mg / kg to 150 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 75 mg / kg, 0.1 mg / kg to 50 mg / kg, 0.1 mg / kg to 25 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.1 mg / kg to 5 mg / kg, 0.5 mg / kg to 5 mg / kg, amounts in between, and combinations thereof.In some embodiments, the therapeutically effective doses of the compound for use in the method herein administered to a subject include one or more doses of about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, 500 mg / kg, and amounts in between and combinations thereof. In some embodiments, the therapeutically effective doses of the compound for use in the method herein are about 0.1 mg / kg to about 50 mg / kg.

[0096] In some embodiments, administering a therapeutically effective amount of a compound for use in the method herein, or a pharmaceutical composition containing a compound for use in the method herein, involves administering an appropriate dose at the frequency or intervals necessary to obtain an effective therapeutic outcome. In some embodiments, administering a therapeutically effective amount of a compound for use in the method herein, or a pharmaceutical composition disclosed herein, involves administering an appropriate dose every hour, every two hours, every four hours, every six hours, three times a day, twice a day, once a day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, in combination thereof, and / or at regular or irregular intervals thereof, and / or simply at the frequency or intervals required or recommended by a healthcare professional. In some embodiments, a therapeutically effective amount of a compound for use in the method herein, or a pharmaceutical composition containing a therapeutically effective amount of a compound for use in the method herein, is administered continuously, for example, by intravenous administration.

[0097] In some embodiments, a therapeutically effective amount of the compound for use in the method herein is administered to the subject before, during, and / or after the organ transplantation procedure. In some embodiments, a therapeutically effective amount of the compound for use in the method herein is administered to the subject up to 3 days, 2 days, 1 day, 20 hours, 15 hours, 10 hours, 5 hours, 2 hours, or 1 hour before the organ transplantation procedure. In some embodiments, a therapeutically effective amount of the compound for use in the method herein is administered to the subject 0 to 72 hours, 0 to 48 hours, 0 to 24 hours, 0 to 12 hours, 0 to 6 hours, 0 to 4 hours, or 0 to 2 hours before the organ transplantation procedure. In some embodiments, a therapeutically effective amount of the compound for use in the method herein is administered during the perioperative period. In some embodiments, a therapeutically effective amount of the compound for use in the method herein is administered during the organ transplantation procedure. In some embodiments, therapeutically effective amounts of the compound for use in the method herein are administered intermittently or continuously up to 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 1 week, 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or up to 36 months after the organ transplantation procedure. In some embodiments, therapeutically effective amounts of the compound for use in the method herein are administered for several years after the organ transplantation procedure and / or until the death of the subject.

[0098] In certain embodiments, the effective amount of the compound for use in the method described herein is selected from concentrations in the range of 0.001 μg / ml to 2 g / ml, 0.001 μg / ml to 1000 mg / ml, 0.001 μg / ml to 500 mg / ml, 0.001 μg / ml to 100 mg / ml, 0.001 μg / ml to 50 mg / ml, 0.01 μg / ml to 50 mg / ml, 0.1 μg / ml to 50 mg / ml, 1 μg / ml to 50 mg / ml, 50 μg / ml to 50 mg / ml, and intermediate concentrations therebetween.

[0099] kit In some embodiments, what is provided herein is a kit comprising a compound for use in the method herein or a pharmaceutical composition comprising a compound for use in the method herein. In some embodiments, the kit comprises one or more containers comprising the composition disclosed herein, each container comprising an amount or dose of the compound for use in the method herein. In some embodiments, the kit comprises one or more packs and / or one or more dispenser devices that can contain one or more doses or amounts of the compound or composition for use in the method herein. Non-limiting examples of packs include metal, glass, or plastic containers, syringes, or blister packs containing the compound for use in the method herein or the composition described herein. In certain embodiments, the kit comprises a dispenser device, such as a syringe or inhaler, which may or may not contain the compound for use in the method herein or the composition described herein.

[0100] In some embodiments, the kit includes a flexible container or intravenous bag containing a sterile isotonic pharmaceutical composition suitable for intravenous administration, comprising the compound described herein at a concentration ranging from 0.001 μg / ml to 100 mg / ml.

[0101] In some embodiments, the kit, container, or pack contains an amount of the compound for single use, or for example, for a single perfusion. In some embodiments, the kit, container, or pack contains an amount of the compound for use in the method herein sufficient to administer to a subject over a period of time from 1 day to 1 year, 1 day to 180 days, 1 day to 120 days, 1 day to 90 days, 1 day to 60 days, 1 day to 30 days, 1 to 24 hours, 1 to 12 hours, 1 to 4 hours, or an intermediate period.

[0102] The kit may include, as necessary, a product label and / or one or more product inserts, which provide a description of its components or instructions for the in vitro, in vivo, ex vivo, or in situ use of those components. Exemplary instructions may include instructions for administration protocols or treatment regimens. In certain embodiments, the kit includes packaging materials, which means a physical structure that houses the components of the kit. The packaging materials may be made from materials that can maintain the sterility of the components and are commonly used for such purposes (e.g., paper, corrugated cardboard, glass, plastic, foil, ampoules, vials, tubes, etc.). Product labels or product inserts may include “printed materials,” e.g., paper or cardboard, or those separate from or attached to the components, kit or packaging materials (e.g., a box), or those attached to ampoules, tubes, or vials containing the kit components. The label or package insert may further include computer-readable media, optical discs such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or electrical storage media such as RAM and ROM, or hybrids thereof, such as magnetic / optical storage media, flash media, or memory-type cards. The product label or package insert may include identification information for one or more of its components, dosage, mechanism of action, and clinical pharmacology of the active ingredient, including pharmacokinetics (PK) and pharmacodynamics (PD). The product label or package insert may include manufacturer information, lot number, manufacturer's address, date, and information identifying the indicated conditions, disorders, diseases, or symptoms for which the kit components can be used. The product label or package insert may include instructions for clinicians or subjects for using one or more kit components in a method, treatment protocol, or therapeutic regimen. The instructions may include dosage, frequency, or duration, and instructions for performing any of the methods described herein. The product label or package insert may include information on potential side effects and / or warnings.Packs and / or dispensers may be accompanied by instructions for administration. Packs or dispensers may also be accompanied by notices relating to the form of container prescribed by the government agency that regulates the manufacture, use, or sale of the drug, which reflect agency approval of the form of the drug for human or veterinary administration. Such notices may be, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug, or an approved product insert. [Examples]

[0103] Example 1 - Assay of necroptosis and apoptosis In this example, the therapeutic potential of the compounds described herein for inhibiting necroptosis or apoptosis is determined by the method described in Gan et al. (2018) Am. J. Transplant. 19: 686-698. In short, B6 and Cyp-D - / - Microangiocytes (MVECs) are grown in complete endothelial growth medium-2 (EGM-2 medium) supplemented with fetal bovine serum and growth factors in a 96-well flat-bottom plate until confluence is reached for 24 hours. Test reagents and control reagents are added to each well, and cell death is assessed using either SYTOX Green Nucleic Acid Stain (100 nmol / L; Thermo Fisher Scientific, Waltham, MA) or 7-aminoactinomycin D (eBioscience). Cell death is monitored using an IncuCyte Zoom System (Essen BioScience, Ann Arbor, MI) or a CytoFLEX flow cytometer (Beckman, Coulter, Brea, CA).

[0104] Cells are treated with 100 ng / ml of tumor necrosis factor and smac mimetic (100 nmol / L) to induce cell death in the presence or absence of caspase-8 inhibitors (i.e., Z-Ile-Glu-Asp-fluoromethyl ketone (10-30 μmol / L)), caspase-3 inhibitors (Z-Asp-Glu-Val-Asp-fluoromethyl ketone (DEVD, 10-30 μmol / L)), and / or caspase-9 inhibitors (Z-Leu-Glu-His-Asp-fluoromethyl ketone (LEHD, 10-30 μmol / L)) to inhibit caspase-mediated apoptosis. The smac mimetic reagent is added to suppress the function of inhibitors of apoptotic proteins (IAPs) that promote apoptosis. Cells are treated with a RIPK1 inhibitor (necrostatin-1s (NEC-1s, 10-30 μmol / L)) and / or an MLKL inhibitor (GW806742X (50-1000 nmol / L, SYNkinase, San Diego, CA)) to inhibit necroptosis. Cells are treated with S-15176 (Sigma-Aldrich) to inhibit mitochondrial permeability transition events. Cyclosporine A (CsA) is added as a positive control as an inhibitor of TNF-induced necroptosis cell death. Compounds of formulas I, II, III, or IV are added as test reagents to assay their ability to inhibit necroptosis and / or apoptosis.

[0105] Example 2 - Specific Non-Limitative Embodiments A1 A method for inhibiting, reducing, delaying, or preventing rejection of transplanted organs, wherein formula I;

[0106] [ka]

[0107] The step of administering a composition containing a therapeutically effective amount of a compound having the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, During the ceremony: R 2is selected from the group consisting of H and methyl; R 3 is a trifluoromethyl or other fluorosubstituted alkyl group; L 3 is a carbonyl group; R at each appearance 6 These are independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, substituted heterocyclic, halogen, cyano, cyanoalkyl, nitro, amino, amidino, carbamate, S(O) n R 7 and C(O)R 8 Selected from the group consisting of, or two adjacent R 6 It bonds to the adjacent phenyl moiety, forming an optionally substituted heteroaryl or heteroalkyl ring; R 7 H, R 9 NH2, HNR 9 or NR 9 R 10 and; R 8 OH, OR 9 NH2, NHR 9 or NR 9 R 10 and; R at each appearance 9 and R 10 These are independently and optionally substituted alkyl groups; n=1 or 2 method.

[0108] A2 R when each appearance 6 These include alkyl, substituted alkyl, hydroxyl, alkoxy, substituted alkoxy, halogen and C(O)R 8 A method according to Embodiment A1, selected from the group consisting of the following.

[0109] A3 R when each appearance 6The method according to Embodiment A2, wherein is selected from the group consisting of methyl, methoxy, perfluoromethyl, perfluoromethoxy, hydroxyl, Cl, F, and I.

[0110] A4 The compound is given by formula II;

[0111] [ka]

[0112] It has the structure of or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same, in which formula: (i)R A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 It is methyl, and R B4 is methyl; or (ii)R A2 , R A3 , R A5 and R A6 H is R A4 It is methoxy, and R B2 It is methyl, and R B4 is methyl; or (iii)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 H is R B4 is H; or (iv)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 It is methyl, and R B4 is methyl; or (v)R A2 , R A4 , R A5 and R A6 H is RA3 It is methoxy, and R B2 H is R B4 is H; or (vi)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 H is R B4 is methyl; or (vii)R A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 H is R B4 is methyl; or (viii)R A2 , R A3 , R A4 , R A5 and R A6 H is R B2 It is methyl, and R B4 is H; or (ix)R A2 , R A4 , R A5 and R A6 H is R A3 It is methoxy, and R B2 It is methyl, and R B4 is H; or (x)R A2 , R A3 , R A5 and R A6 H is R A4 COOH and R B2 It is methyl, and R B4 is methyl; or (xi)R A2 , R A4 and R A5 H is R A3 and R A6 is hydroxyl, and R B2 It is methyl, and R B4 is methyl; or (xii)R A2 , R A4 and R A6 H is R A3 and R A5 is hydroxyl, and R B2 It is methyl, and R B4 is methyl; or (xiii)R A2 , R A4 and R A5 H is R A3 It is methoxy, and R A6 F is R B2 H is R B4 is Cl; or (xiv)R A3 and R A5 H is R A2 and R A6 F is R A4 is hydroxyl, and R A6 F is R B2 H is R B4 is F; or (xv)R A2 , R A4 and R A6 H is R A3 is hydroxyl, and R A5 F is R B2 H is R B4 is F; or (xvi)R A2 , R A5 and R A6 H is R A3 and R A4 Together they form -O-CH2-O-, and R A5 F is R B2 H is R B4 F is The method described in Embodiment A1.

[0113] A5 R A2 , R A4 , R A5 and R A6 H is RA3 It is methoxy, and R B2 It is methyl, and R B4 The method according to Embodiment A4, wherein is methyl.

[0114] A6 The subject is an organ transplant recipient, and the method is one of the embodiments A1 to A5 described above.

[0115] A7 The subject is an organ donor, and the method is one of the embodiments A1 to A5 described above.

[0116] B1 A method for inhibiting, reducing, delaying, or preventing rejection of a transplanted organ, comprising the step of administering a composition comprising a therapeutically effective amount of a compound comprising a structure selected from any one of formulas I to IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof to a subject.

[0117] Composition B2 is formula IV;

[0118] [ka]

[0119] The method according to Embodiment B1, comprising a therapeutically effective amount of a compound containing the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0120] B3 The method according to embodiment B1 or B2, wherein the subject is an organ transplant recipient.

[0121] B4 The subject is the method described in Embodiments B1, B2, or B3, which requires organ transplantation.

[0122] The B5 composition is administered during, before, or after organ transplantation to a subject, according to any one of Embodiments B1 to B4.

[0123] B5.1 The method described in Embodiment B1 or B2, wherein the subject is an organ donor.

[0124] B5.2 The method according to Embodiment B5.1, wherein the composition is administered to the organ transplant recipient before organ transplantation.

[0125] B6 The method according to any one of Embodiments B1 to B5.2, wherein the rejection reaction inhibited, reduced, delayed, or prevented is acute graft rejection.

[0126] B7 The method according to any one of embodiments B1 to B5, wherein the rejection reaction inhibited, reduced, delayed, or prevented is chronic graft rejection.

[0127] C1 An ex vivo or in vitro method for preparing an organ for transplantation to an organ transplant recipient, comprising the step of contacting the organ with a composition comprising an effective amount of a compound containing a structure selected from any one of formulas I to IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0128] The method according to Embodiment C1, wherein the organ C2 is not attached to or connected to the subject.

[0129] The organ C3 is separated or extracted from the subject by the method according to Embodiment C1 or C2.

[0130] C4 The method according to any one of embodiments C1 to C3, wherein the contact step includes perfusing the organ with the composition.

[0131] D1 An in situ method for preparing an organ for transplantation, comprising the step of contacting an organ of an organ donor with a composition comprising an effective amount of a compound comprising a structure selected from any one of formulas I to IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0132] The method according to Embodiment D1, wherein the D2 organ is brought into contact with the composition before being removed from the organ donor.

[0133] The method according to Embodiment D1 or D2, wherein the D3 organ is operably connected to an organ donor.

[0134] The method according to any one of Embodiments D1 to D3, wherein the step of contacting comprises perfusion of the composition into the organ.

[0135] The method according to any one of Embodiments D1 to D4, wherein the organ donor is alive.

[0136] The method according to any one of Embodiments D1 to D5, wherein the organ donor is brain dead.

[0137] The method according to any one of Embodiments D1 to D5, wherein the organ donor is dead.

[0138] A method for inhibiting, reducing, delaying or preventing reperfusion injury of a transplanted organ in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising a structure selected from any one of Formulas I to IV or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0139] The method according to Embodiment E1, wherein the composition is administered to the subject during, before or after transplantation of the organ into the subject.

[0140] The method according to Embodiment E1 or E2, wherein the subject is an organ transplant recipient.

[0141] A method for inhibiting, reducing, delaying or preventing cell death of cells in an organ, comprising administering to the organ or a subject operably connected to the organ a therapeutically effective amount of a composition comprising a structure selected from any one of Formulas I to IV or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0142] The method according to Embodiment F1, wherein the F2 composition is administered to an organ transplant recipient during, before, or after organ transplantation.

[0143] F2.1 The method according to embodiment F1 or F2, wherein the subject is an organ donor.

[0144] F2.2 The method according to embodiment F1 or F2, wherein the subject is an organ transplant recipient.

[0145] F3 cell death is a method described in Embodiments F1 to F2.2, comprising apoptosis, necrosis, necroptosis, or autophagy.

[0146] G1 An ex vivo or in vitro method for inhibiting, reducing, delaying, or preventing cell death in organs, comprising the step of contacting the organ with a composition comprising an effective amount of a compound comprising a structure selected from any one of formulas I to IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0147] The method according to Embodiment G1, wherein the organ G2 is not attached to or connected to the subject.

[0148] G2.2 The method is the method described in Embodiment G1 or G2, which is performed after the organ has been removed from the organ donor and before the organ has been transplanted to the organ transplant recipient.

[0149] G3 The contact step is the method according to any one of Embodiments G1 to G2.2, which includes perfusing the organ with the composition.

[0150] G4 Cell death is a method according to any one of Embodiments G1 to G3, comprising apoptosis, necrosis, necroptosis, or autophagy.

[0151] An in situ method for inhibiting, reducing, delaying, or preventing cell death in an H1 organ, comprising the step of contacting the organ of interest with a composition comprising an effective amount of a compound having a structure selected from any one of formulas I to IV.

[0152] The method according to Embodiment H1, wherein the subject is an organ donor, and the organ is brought into contact with the composition before the organ is removed from the organ donor.

[0153] The method according to embodiment H1 or H2, wherein the H3 organ is operably connected to the subject or organ donor.

[0154] The method according to any one of embodiments H1 to H3, wherein the step of contacting includes perfusing the composition to the organ.

[0155] H5 The subject or organ donor is alive, as described in any one of Embodiments H1 to H4.

[0156] H6 The method according to any one of embodiments H1 to H5, wherein the subject or organ donor is brain dead.

[0157] H7 Cell death is a method according to any one of Embodiments H1 to H6, comprising apoptosis, necrosis, necroptosis, or autophagy.

[0158] I1 A pharmaceutical composition for use in carrying out the method described in any one of Embodiments A1 to H7, comprising a compound comprising a structure selected from any one of Formulas I, II, III, and IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0159] The method according to any one of Embodiments A1 to I1, wherein the organ is a solid organ, tissue, body part, or a part thereof.

[0160] J1.1 The method according to Embodiment J1, wherein the organ is a solid organ or a part thereof.

[0161] The method according to embodiment J1.1, wherein the solid organ is selected from the kidney, liver, heart, lung, pancreas, intestine, or a part thereof.

[0162] The method according to any one of embodiments A1 to J1.2, wherein the subject is a mammal.

[0163] The method according to any one of embodiments A1 to J1.2, wherein the subject is a primate.

[0164] The method according to any one of embodiments A1 to J1.2, wherein the subject is a human.

[0165] The method according to any one of embodiments A1 to J4, wherein the composition further comprises an immunosuppressant.

[0166] The method according to embodiment J5, wherein the immunosuppressant is selected from one or more of a calcineurin inhibitor, cyclosporine, cyclosporine A, an antiproliferative agent, a steroid, a corticosteroid, cyclophilin D, necrostatin-1 (Nec-1), imifidase, alginic acid heme, and an anti-inflammatory agent.

[0167] A method for inhibiting, reducing, delaying, or preventing transplant organ rejection, damage, or cell death in a subject, comprising administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0168] An ex vivo or in vitro method for preparing an organ for transplantation into a subject, comprising contacting the organ with a composition comprising an effective amount of a compound comprising the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0169] K3 An in situ or in vivo method for preparing an organ for transplantation, comprising the step of contacting the organ with a composition containing an effective amount of a compound comprising the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, prior to excision from a donor subject.

[0170] A method for inhibiting, reducing, delaying, or preventing reperfusion injury of a transplanted organ in a K4 subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0171] A method for inhibiting, reducing, delaying, or preventing cell death of transplanted organ cells in a K5 subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0172] A method, either ex vivo or in vitro, for inhibiting, reducing, delaying, or preventing cell death in organs, comprising the step of contacting the organ with a composition comprising an effective amount of a compound having the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0173] An in situ method for inhibiting, reducing, delaying, or preventing cell death in organs, comprising the step of contacting the organ with a composition containing an effective amount of a compound comprising the structure of formula IV or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, prior to excision from a donor subject.

[0174] The method according to Embodiment K1, wherein an effective amount of the K8 compound is administered to the organ before transplantation into the subject.

[0175] The compound having the structure of formula K9 IV is administered to the organ before extraction from the donor subject, according to the method of embodiment K8.

[0176] The compound having the structure of formula K10 IV is administered to the organ after excision from the donor subject and before transplantation to the subject, according to the method of embodiment K8 or K9.

[0177] The K11 compound is administered intravenously or intra-arterially to the subject by the method described in Embodiments K1, K3, K4, K5, K7, K8 to K10.

[0178] The method according to Embodiment K11, wherein the K12 compound is further administered orally to the subject before and / or after the receipt of the transplanted organ.

[0179] The K13 compound is administered topically to an organ and / or in a perfusion fluid, as described in Embodiments K2, K6, K8 to K10.

[0180] The entire contents of each patent, patent application, publication, or other reference or document cited herein shall be incorporated by reference only. In the event of any conflict, this specification, including its definitions, shall prevail.

[0181] Citations of patents, patent applications, publications, or other documents do not constitute an endorsement of any of the foregoing as appropriate prior art, nor do they constitute an endorsement of the content or date of such publications or documents.

[0182] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0183] All features disclosed herein can be combined in any combination. Each feature disclosed herein can be replaced by an alternative feature that serves the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, the disclosed features (e.g., antibodies) are examples of a group of equivalent or similar features.

[0184] Where used herein, all numbers or numerical ranges include integers and values ​​or fractions of integers within that range unless the context explicitly indicates otherwise. Furthermore, where an enumeration of values ​​is given herein (e.g., about 50%, 60%, 70%, 80%, 85%, or 86%), the enumeration includes all its intermediate and fractional values ​​(e.g., 54%, 85.4%). Thus, for example, a reference to identity of 80% or more includes 81.1%, 81.2%, 81.3%, 81.4%, 81.5%, etc., as well as 82.1%, 82.2%, 82.3%, 82.4%, 82.5%, etc., in addition to 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, etc.

[0185] References to integers that include "greater than" or "less than" the reference number encompass any number greater than or less than the reference number, respectively. For example, a reference to less than 100 includes all numbers up to 1, such as 99, 98, 97, etc., and a reference to less than 10 includes all numbers up to 1, such as 9, 8, 7, etc.

[0186] As used herein, all numbers or numerical ranges include, unless the context explicitly indicates otherwise, the values ​​and integer fractions within such ranges, as well as integer fractions within such ranges. For example, a reference to a numerical range such as 1 to 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc. Similarly, a reference to the range 1 to 50 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to 50, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., and 2.1, 2.2, 2.3, 2.4, 2.5, etc.

[0187] A reference to a range encompasses a range that combines the boundary values ​​of different ranges within that range. Therefore, to explain a reference to a range, for example, 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150-200, 200-250, 250-300, 300-400, 400-500, 500-750, 750-1,000, 1,000-1,500, 1,500-2,000, 2,000-2,500 The ranges 2,500-3,000, 3,000-3,500, 3,500-4,000, 4,000-4,500, 4,500-5,000, 5,500-6,000, 6,000-7,000, 7,000-8,000, or 8,000-9,000 include ranges such as 10-50, 50-100, 100-1,000, 1,000-3,000, and 2,000-4,000.

[0188] Modifications can be made to the foregoing without departing from the basic aspects of the present technology. Although the present technology is described in great detail with reference to one or more specific embodiments, those skilled in the art will recognize that modifications can be made to the embodiments specifically disclosed herein, and that these modifications and improvements fall within the scope and spirit of the present technology.

[0189] Some embodiments of the Art described herein can preferably be carried out in the absence of elements not specifically disclosed herein. Accordingly, in some embodiments, the terms “comprising” or “comprises” can be replaced with “consisting essentially of” or “consisting of” or their grammatical variations. The terms “a” or “an” can refer to one or more elements that they modify unless it is clearly stated in the context that one or more elements are being described (for example, “a reagent” may mean one or more reagents). The term “about” as used herein refers to a value within 10% (i.e., plus or minus 10%) of an underlying parameter, and the use of the term “about” at the beginning of a string of values ​​modifies each value (i.e., “about 1, 2 and 3” refers to about 1, about 2 and about 3). For example, a weight of “about 100 grams” may include weights between 90 grams and 110 grams. As used herein, the term “substantially” refers to value modifiers meaning “at least 95%”, “at least 96%”, “at least 97%”, “at least 98%”, or “at least 99%”, and may include 100%. For example, a composition that is substantially free of X may contain less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of X, and / or X may not be present or detectable in the composition.

Claims

1. A method for inhibiting, reducing, delaying, or preventing rejection, damage, or cell death of a transplanted organ in a subject, comprising formula I; 【Chemistry 1】 The step of administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, During the ceremony: R ２ is selected from the group consisting of H and methyl; R ３ is a trifluoromethyl or other fluorosubstituted alkyl group; L ３ is a carbonyl group; R at each appearance ６ These are independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, substituted heterocyclic, halogen, cyano, cyanoalkyl, nitro, amino, amidino, carbamate, S(O) ｎ R ７ and C(O)R ８ Selected from the group consisting of, or two adjacent R ６ It bonds to the adjacent phenyl moiety, forming an optionally substituted heteroaryl or heteroalkyl ring; R ７ is H, R ９ , NH ２ , HNR ９ or NR ９ R １０ and; R ８ OH, OR ９ NH ２ NHR ９ Or NR ９ R １０ And; R at each appearance ９ and R １０ These are independently and optionally substituted alkyl groups; n = 1 or 2, method.

2. The aforementioned compound is of formula IV; 【Chemistry 2】 The method according to claim 1, comprising the structure or a pharmaceutically acceptable salt thereof, stereoisomer, or tautomer.

3. An ex vivo or in vitro method for preparing organs for transplantation into a subject, wherein formula IV; 【Transformation 3】 A method comprising the step of contacting the organ with a composition comprising an effective amount of a compound including the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same.

4. An in situ or in vivo method for preparing organs for transplantation, wherein, prior to extraction from a donor subject, formula IV; 【Chemistry 4】 A method comprising the step of contacting the organ with a composition comprising an effective amount of a compound including the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same.

5. A method for inhibiting, reducing, delaying, or preventing reperfusion injury of transplanted organs in a subject, comprising formula IV; 【Transformation 5】 A method comprising the step of administering to a subject a composition comprising a therapeutically effective amount of a compound including the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same.

6. A method for inhibiting, reducing, delaying, or preventing cell death of transplanted organ cells in a subject, comprising formula IV; 【Transformation 6】 A method comprising the step of administering to a subject a composition comprising a therapeutically effective amount of a compound including the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same.

7. An ex vivo or in vitro method for inhibiting, reducing, delaying, or preventing cell death in organs, comprising formula IV; 【Transformation 7】 A method comprising the step of contacting the organ with a composition comprising an effective amount of a compound including the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same.

8. An in situ method for inhibiting, reducing, delaying, or preventing cell death in organs, wherein, before excision from a donor subject, formula IV; 【Transformation 8】 A method comprising the step of contacting the organ with a composition comprising an effective amount of a compound including the structure or a pharmaceutically acceptable salt, stereoisomer, or tautomer of the same.

9. The method according to claim 2, wherein an effective amount of the compound having the structure of formula IV is administered to the organ before transplantation to the subject.

10. The method according to claim 9, wherein the compound having the structure of formula IV is administered to the organ before extraction from the donor subject.

11. The method according to claim 9 or 10, wherein the compound having the structure of formula IV is administered to the organ after excision from the donor subject and before transplantation to the subject.

12. The method according to any one of claims 1, 2, 4, 5, 6, 8, 9 to 11, wherein the compound is administered intravenously or intra-arterially to the subject.

13. The method according to claim 12, wherein the compound is further administered orally to the subject before and / or after the receipt of the transplanted organ.

14. The method according to any one of claims 3, 7, 9 to 11, wherein the compound is administered locally to the organ and / or in a perfusion fluid.

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