Methods of treating organ diseases or conditions with ASK1 inhibitors

Abstract

The present invention relates to the use of apoptosis signal-regulating kinase-1 (ASK-1) inhibitor compounds for the treatment of organ diseases and disorders, wherein the organ diseases or disorders are selected from liver, heart, kidney, pancreas, spleen or skin diseases or disorders.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 368,961, filed on July 20, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] A variety of disease processes can affect organs (eg, liver, kidneys, heart, pancreas, spleen, and skin), including liver injury, acute kidney injury, and cardiac disease. Summary of the invention

[0004] There is still a need for novel new compounds to treat these organ diseases. ASK1 inhibitors can be used to treat these organ diseases. The orally administered ASK1 inhibitors described herein show preferential distribution to the liver and kidneys, and reach organ concentrations that are several times higher than plasma concentrations. The injectable administration of the ASK1 inhibitors described herein also shows preferential distribution to the liver and kidneys, and is therefore suitable for treating patients for whom the injectable administration route is superior to the oral route, including patients who are comatose, have difficulty swallowing, or require a rapid onset of pharmacological activity. Therefore, in some embodiments, the ASK1 inhibitors described herein can be used to treat organ diseases.

[0005] In one aspect, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that inhibits ASK1, or a pharmaceutically acceptable salt or solvate thereof.

[0006] In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof:

[0007]

[0008]

[0009] in

[0010] for

[0011] R 1 for

[0012] Z is C(R 9 ) 2 ;

[0013] R 5 Selected from halogen and C 1-6 alkyl;

[0014] Each R 25 are independently selected from halogen, -OR 6 、-N(R 6 ) 2 、-C(=O)OR 6 、-C(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 and C 1-9 Heteroaryl, the C 1-9 The heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl; wherein C 1-9 Heteroaryl is optionally selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 One, two or three substituents in the cycloalkyl group;

[0015] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-pyrazole and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein the heteroaryl is selected from imidazolyl, pyrazolyl and pyrrolyl, wherein C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 One, two or three substituents are substituted;

[0016] Each R8 are independently selected from hydrogen and C 1 -C 6 alkyl;

[0017] Each R 9 is hydrogen;

[0018] Each R 13 are independently selected from hydrogen and C 1 -C 6 alkyl;

[0019] Each R 14 Independently selected from C 1 -C 6 alkyl;

[0020] n is 0, 1 or 2; and

[0021] p is 0 or 1.

[0022] In some embodiments, n is 1.

[0023] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-pyrazole and C 3 -C 8 Cycloalkyl.

[0024] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein the heteroaryl is selected from imidazolyl, pyrazolyl and pyrrolyl, wherein C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R13 )C(=O)R 14 is substituted by a substituent.

[0025] In some embodiments, R 25 for

[0026]

[0027] In some embodiments, R 25 for

[0028] In some embodiments, provided herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof:

[0029]

[0030] in

[0031] for

[0032] Z is O, S, C(=O), N(R 8 ) or C(R 9 ) 2 ;

[0033] R 1 and R 3 are each independently selected from hydrogen, halogen, -CN, -OH, -OR 6 、-SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0034] R 2 Selected from hydrogen, halogen, -CN, -OH, -SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 )2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted in the 2 and R 3 Not all are hydrogen;

[0035] Each R 4 and each R 5 are each independently selected from halogen, -CN and C 1-6 alkyl;

[0036] R 5a Selected from hydrogen and C 1 -C 6 alkyl;

[0037] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 heterocyclic ring; or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 heteroaryl;

[0038] Each R 7 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0039] R 8 Selected from hydrogen and C 1 -C 6 alkyl;

[0040] Each R 9 are independently selected from hydrogen, halogen and C 1 -C 6 alkyl;

[0041] Each R13 are independently selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 13 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic ring;

[0042] Each R 14 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0043] n is 0, 1 or 2;

[0044] p is 0, 1, 2 or 3; and

[0045] q is 0, 1, or 2.

[0046] In some embodiments, R 2 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0047] In some embodiments, R 2 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0048] In some embodiments, R 2 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0049] In some embodiments, R 2 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0050] In some embodiments, R 2 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 In some embodiments, R 2 for

[0051] Where R 11 C 1-C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0052] In some embodiments, R 2 for Where R 12 For halogenated, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0053] In some embodiments, R 2 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0054] In some embodiments, R 2 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0055] In some embodiments, R 2 for

[0056]

[0057] In some embodiments, R 2 for

[0058]

[0059] Where R 10 It is a heteroaryl group.

[0060] In some embodiments, R 3 In some embodiments, R 3 C 1 -C 6 alkyl.

[0061] In some embodiments, R 3 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0062] In some embodiments, R 3 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0063] In some embodiments, R 3 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0064] In some embodiments, R 3is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0065] In some embodiments, R 3 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0066] In some embodiments, R 3 for

[0067] Where R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0068] In some embodiments, R 3 for

[0069] Each R 12 are independently halogenated, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0070] In some embodiments, R 3 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0071] In some embodiments, R 3 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0072] In some embodiments, R 3 for

[0073]

[0074] In some embodiments, R 3 for

[0075]

[0076] Where R 10 It is a heteroaryl group.

[0077] In some embodiments, R 3 For-OR 6 , and R 6 Selected from C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl and -C 1 -C 6 Alkyl-C 2-9 In some embodiments, R 2 In some embodiments, R 2 C 1 -C 6 alkyl.

[0078] In some embodiments, R 1 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0079] In some embodiments, R 1 Selected from C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0080] In some embodiments, R 1 Selected from C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 1 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0081] In some embodiments, R 1is selected from triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0082] In some embodiments, R 1 is selected from triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally selected from halogenated, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0083] In some embodiments, R 1 for

[0084]

[0085] In some embodiments, R 1 for

[0086] In some embodiments, R 1 for

[0087]

[0088] In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof:

[0089]

[0090] in

[0091] for

[0092] R 1 for

[0093] Z is O, S, C(=O), N(R 8 ) or C(R 9 ) 2 ;

[0094] X is O or S;

[0095] R 2 C 3-6 Cycloalkyl;

[0096] R 3 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0097] Each R 4 are independently selected from hydrogen, halo, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0098] or an R 4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O)2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0099] Each R 5 independently selected from halogen and C 1-6 alkyl;

[0100] R 5a Selected from hydrogen and C 1 -C 6 alkyl;

[0101] R 25 Selected from halogen, -CN, -OH, -OR 6 、-SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0102] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 heterocyclic ring; or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 heteroaryl;

[0103] Each R 7 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0104] R 8 Selected from hydrogen and C 1 -C 6 alkyl;

[0105] Each R 9 are independently selected from hydrogen, halogen and C 1 -C 6 alkyl;

[0106] Each R 13 are independently selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 13 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic ring;

[0107] Each R 14 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0108] n is 0, 1, 2, 3 or 4;

[0109] p is 0, 1, 2 or 3; and

[0110] q is 0, 1, or 2.

[0111] In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof:

[0112]

[0113] in

[0114] for

[0115] R 1 for

[0116] Z is O, S, C(=O), N(R 8 ) or C(R9 ) 2 ;

[0117] X is O or S;

[0118] R 2 C 3-6 Cycloalkyl;

[0119] R 3 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0120] Each R 4 are independently selected from hydrogen, halo, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0121] or an R 4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0122] Each R 5 independently selected from halogen and C 1-6 alkyl;

[0123] R 5a Selected from hydrogen and C 1 -C 6 alkyl;

[0124] Each R 25 independently selected from halogen, -CN, -OH, -OR 6 、-SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0125] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl, -C 3 -C 8 Cycloalkyl-phenyl and C 2-9 Heterocyclic ring, in which C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl, -C 3 -C 8 Cycloalkyl-phenyl and C 2-9 The heterocyclic ring is optionally selected from halo, -OR8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 One, two or three substituents are substituted;

[0126] Each R 7 Independently selected from C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring, in which C 3 -C 8 Cycloalkyl and C 2-9 The heterocyclic ring is optionally selected from halo, oxo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 One, two or three substituents are substituted;

[0127] Each R 8 are independently selected from hydrogen and C 1 -C 6 alkyl;

[0128] Each R 9 are independently selected from hydrogen, halogen and C 1 -C 6 alkyl;

[0129] Each R 13 are independently selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 13 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic ring;

[0130] Each R 14 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0131] n is 0, 1, 2, 3 or 4;

[0132] p is 0, 1, 2 or 3; and

[0133] q is 0, 1, or 2.

[0134] In some embodiments, R 25 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0135] In some embodiments, R 25 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0136] In some embodiments, R 25 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0137] In some embodiments, R 25 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0138] In some embodiments, R 25 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0139] In some embodiments, R 25 for

[0140] Each R 11 Independently for C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0141] In some embodiments, R 25 for Each R 12 are independently hydrogen, halo, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0142] In some embodiments, R 25 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0143] In some embodiments, R 25 is selected from pyrimidine, pyrazine and pyridazine; wherein pyrimidine, pyrazine and pyridazine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0144] In some embodiments, R 25 Selected from halogen, -OR 6 、-N(R 6 ) 2 , C 1-6 wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halogenated, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0145] In some embodiments, R 25 Selected from halogen, -OR 6 、-N(R 6 ) 2 , C 1-6 Alkyl and unsubstituted pyridine.

[0146] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0147] In some embodiments, R 25 for

[0148]

[0149] In some embodiments, R 25 for

[0150]

[0151] Where R 10 It is a heteroaryl group.

[0152] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 One, two or three substituents are substituted.

[0153] In some embodiments, R 25 for

[0154] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl.

[0155] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and the two R 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl.

[0156] In some embodiments, R 25 for

[0157] In some embodiments, R 25 For-OR 6 , and R 6 Selected from C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl and -C 1 -C 6 Alkyl-C 2-9 Heterocyclic ring.

[0158] In some embodiments, R 1 for

[0159] In some embodiments, R 1 for

[0160] In some embodiments, R 1 for

[0161] In some embodiments, R 1 for

[0162] In some embodiments, R 1 for

[0163] In some embodiments, for In some embodiments, p is 0.

[0164] In some embodiments, for In some embodiments, for In some embodiments, q is 0.

[0165] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, Z is C(R 9 ) 2 In some embodiments, R 9 For H.

[0166] In a further aspect, described herein are pharmaceutical compositions comprising a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0167] In another aspect, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0168] In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is a liver disease or condition. In some embodiments, described herein is a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is a liver disease or condition selected from liver damage, drug-induced liver damage, liver failure, fulminant or acute liver failure, and chronic acute liver failure. Examples of fulminant liver failure include fulminant liver failure due to drug overdose (e.g., acetaminophen overdose), fulminant liver failure due to poisoning associated with wild mushroom death caps (wild mushroomamanita phalloide) or carbon tetrachloride illness. Examples of acute liver failure include acute liver failure due to poisoning associated with, for example, herbal supplements, acute liver failure due to surgical ischemia-reperfusion injury (liver transplantation, partial resection), acute liver failure due to vascular disease, acute liver failure due to metabolic disease (acute fatty liver of pregnancy), and acute liver failure due to septic shock. Examples of acute-on-chronic failure include acute-on-chronic liver failure due to alcoholic hepatitis, acute-on-chronic liver failure due to autoimmune hepatitis, acute-on-chronic liver failure due to viral hepatitis, and acute-on-chronic liver failure due to cirrhosis. In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is a cardiac disease or condition.In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is a cardiac disease or condition selected from ischemia-reperfusion injury, ischemia, coronary artery disease, cardiovascular dysfunction caused by sepsis, drug-induced cardiotoxicity, viral myocarditis, and cardiac transplant complications. In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is a kidney disease or condition. In some embodiments, described herein are methods of treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is a kidney disease or condition, which is acute kidney injury. In some embodiments, described herein are methods of treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is a kidney disease or disorder due to acute kidney injury caused by hypovolemia, hypotension, renal vasoconstriction, glomerular efferent arteriolar vasodilation, prolonged renal ischemia, prolonged renal sepsis, prolonged nephrotoxins, kidney transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, or intratubular obstruction.

[0169] In some embodiments of the methods described herein, the compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered by injectable delivery. In some embodiments of the methods described herein, the compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments of the methods described herein, the compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered by intraperitoneal delivery.

[0170] In some embodiments, the methods described herein further comprise administering a second therapeutic agent. In some embodiments, the second therapeutic agent is selected from N-acetylcysteine, a corticosteroid, and a vasopressor.

[0171] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION

[0172] ASK1 is a membrane-proximal MAP3K (MAP-kinase-kinase-kinase) located upstream of pathways that play important roles in the cellular response to environmental stresses, including ischemia and inflammation. The downstream ASK1 cascade includes the c-Jun and p38 pathways, which are known to respond to UV and oxidative damage and lead to apoptosis and inflammation. ASK1 is a promising therapeutic target for organ diseases, including liver injury, kidney injury, and heart disease. As a positive regulator of mitochondrial apoptosis, ASK1 is tightly regulated and activated by multiple cell damage signals, such as receptor-acting inflammatory cytokines (e.g., TNFa and LPS), calcium, and intracellular sensors (e.g., the redox sensor thioredoxin and the ER stress-responsive IRE1).

[0173] ASK1 modulation is a promising therapeutic target for liver injury. Liver injury includes, but is not limited to, drug-induced liver injury, fulminant liver failure, acute liver failure, and acute-on-chronic liver failure. Drug-induced liver failure includes, but is not limited to, liver failure caused by antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Fulminant liver failure can be caused by a variety of causes, including, but not limited to, acetaminophen overdose and poisoning. Poisoning may be associated with the wild mushroom Amanita phalloides, carbon tetrachloride, and herbal supplements, including, but not limited to, kava, ephedra, skullcap, and pennyroyal. Acute liver failure may be caused by surgical ischemia-reperfusion injury (liver transplantation, partial resection), vascular disease (such as, but not limited to, Budd-Chiari syndrome), metabolic disease (such as, but not limited to, Wilson's disease and acute fatty liver of pregnancy), and septic shock. Acute-on-chronic liver failure can be caused by a variety of causes, including but not limited to alcoholic hepatitis, autoimmune hepatitis and viral hepatitis (including but not limited to hepatitis A, hepatitis B and hepatitis E), Epstein-Barr virus, cytomegalovirus and herpes simplex virus.

[0174] ASK1 modulation is a promising therapeutic target for acute kidney injury, which can be caused by a variety of causes, including but not limited to hypovolemia, hypotension, renal vasoconstriction, vasodilation of the glomerular efferent arterioles, prolonged renal ischemia, renal transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, and intratubular obstruction.

[0175] ASK1 modulation is a promising therapeutic target for cardiac diseases and conditions including, but not limited to, ischemia-reperfusion injury, ischemia, septic shock, cardiotoxicity, and viral myocarditis, or due to cardiac transplantation.

[0176] In some embodiments, the ASK1 inhibitors described herein are delivered orally or by injection. The ASK1 inhibitors described herein show preferential distribution to the liver and kidneys after oral administration or injection, and reach organ concentrations several times higher than plasma concentrations. In some embodiments, injectable administration is advantageous for treating patients for whom the injectable route of administration is superior to the oral route, including patients who are comatose, have difficulty swallowing, or require rapid onset of pharmacological activity.

[0177] Furthermore, in some embodiments, the ASK1 inhibitors described herein can be used as adjuncts to systemic treatment with N-acetylcysteine, corticosteroids, and vasopressors (such as, but not including, vasopressin and catecholamines).

[0178] Certain terms

[0179] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise stated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, unless otherwise stated, "or" or "and" are used to represent "and / or". In addition, the use of the term "including" and other forms (such as "include", "includes" and "included") is not restrictive. The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subject matter described.

[0180] "Alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety can be branched or straight chain. "Alkyl" can have 1 to 15 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 15" refers to each integer in a given range; for example, "1 to 15 carbon atoms" means that the alkyl can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 15 carbon atoms, although this definition also covers the case of the term "alkyl" without specifying a numerical range). In one aspect, the alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc.

[0181] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR 2 , wherein R refers to the rest of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. Non-limiting examples of alkenyl groups include -CH=CH 2 、-C(CH 3 )=CH 2 、-CH=CHCH 3 、-C(CH 3 )=CHCH 3 and –CH 2 CH=CH 2 .

[0182] The term "alkynyl" refers to a class of alkyl groups in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH 3 、-C≡CCH 2 CH 3 、-CH 2 C≡CH.

[0183] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each atom (i.e., skeleton atom) forming the ring is a carbon atom. Cycloalkyl can be saturated, or partially unsaturated. Cycloalkyl can be fused to an aromatic ring, and the point of attachment is located on the carbon of a non-aromatic ring carbon atom. Cycloalkyl includes groups having 3 to 10 ring atoms. In some embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl can be substituted or unsubstituted. According to the structure, cycloalkyl can be a monoradical or a diradical (i.e., cycloalkylidene, such as, but not limited to, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl, etc.). In one aspect, cycloalkyl is C 3 -C 6 Cycloalkyl.

[0184] The term "aromatic" refers to a planar ring with a non-localized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic is optionally substituted. The term "aromatic" includes cycloalkylaryl ("aryl", such as phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (such as pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl is optionally substituted. Depending on the structure, an aryl group can be a monoradical or a diradical (e.g., an arylene group).

[0185] The term "heteroaryl" or "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include the following moieties:

[0186]

[0187] In some embodiments, the heteroaryl group contains 0-3 N atoms in the ring. In some embodiments, the heteroaryl group contains 1-3 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-3 N atoms, 0-1 O atoms and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is a monocyclic or bicyclic heteroaryl group. In some embodiments, the heteroaryl group is C 1 -C 9 In some embodiments, the monocyclic heteroaryl is C 1 -C 5In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C 6 -C 9 Heteroaryl. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (ie, a heteroarylene group).

[0188] "Heterocycle" or "heterocycloalkyl" refers to a cycloalkyl group in which at least one of the carbon atoms of the cycloalkyl group is replaced by nitrogen (unsubstituted or substituted, e.g., -NH-, -N(alkyl)-), oxygen (-O-), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)-). 2 -) substitution. The group may be fused to an aryl or heteroaryl group. In some embodiments, the heterocycloalkyl group is selected from oxazolidinone, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and dihydroindole. The term heteroalicyclic also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In one aspect, the heterocycloalkyl group is C 2 -C 10 In another aspect, the heterocycloalkyl group is C 4 -C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-3 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-3 N atoms, 0-3 O atoms, and 0-1 S atoms in the ring.

[0189] The term "halo" or "halogen" or "halide" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to form between the remaining identified groups.

[0190] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is typically a recognized chemical entity embedded in or attached to a molecule.

[0191] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino (including mono- and di-substituted amino), and protected derivatives thereof. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH 2 、-NH(CH 3 )、-N(CH3 ) 2 、-OH、-CO 2 H, -CO 2 Alkyl, -C(=O)NH 2 、-C(=O)NH(alkyl)、-C(=O)N(alkyl) 2 、-S(=O) 2 NH 2 、-S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH 2 、-OH、-NH(CH 3 )、-N(CH 3 ) 2 、-CH 3 、-CH 2 CH 3 , -CF 3 、-OCH 3 and-OCF 3 In some embodiments, the substituent group is substituted with one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (non-cyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) include oxo (=0).

[0192] In certain embodiments, the compounds presented herein have one or more stereocenters, and each center is independently present in the R or S configuration. The compounds presented herein include all diastereoisomers, enantiomers and epimers and their appropriate mixtures. If desired, stereoisomers are obtained by, for example, stereoselective synthesis and / or by a method for separating stereoisomers using a chiral chromatographic column. In some embodiments, halogen is F or Cl. In some embodiments, halogen is F.

[0193] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also referred to as polymorphs) or pharmaceutically acceptable salts of compounds having the structure of Formula I, Formula II, Formula IIa or Formula III, and active metabolites of these compounds having the same active type. In some cases, the compound may exist in the form of tautomers. All tautomers are included within the scope of the compounds proposed herein. In certain embodiments, the compounds described herein exist in a solvated form formed with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). In other embodiments, the compounds described herein exist in a non-solvated form.

[0194] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0195] The term "drug combination" as used herein refers to a product produced by mixing or combining more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to active ingredients (e.g., compounds of Formula I, Formula II, Formula IIa, or Formula III, or pharmaceutically acceptable salts thereof and combination agents) being applied to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to active ingredients (e.g., compounds of Formula I, Formula II, Formula IIa, or Formula III, or pharmaceutically acceptable salts thereof and combination agents) being applied to the patient sequentially as separate entities simultaneously, jointly, or without specific interval time limits, wherein such administration provides effective levels of two compounds in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more active ingredients.

[0196] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; livestock, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a human.

[0197] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, such as arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or prophylactically and / or therapeutically arresting the symptoms of the disease or condition.

[0198] method

[0199] In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof:

[0200]

[0201] in

[0202] for

[0203] Z is O, S, C(=O), N(R 8 ) or C(R 9 ) 2 ;

[0204] R 1 and R 3 are each independently selected from hydrogen, halogen, -CN, -OH, -OR 6 、-SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0205] R 2 Selected from hydrogen, halogen, -CN, -OH, -SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 )2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted in the 2 and R 3 Not all are hydrogen;

[0206] Each R 4 and each R 5are each independently selected from halogen, -CN and C 1-6 alkyl;

[0207] R 5a Selected from hydrogen and C 1 -C 6 alkyl;

[0208] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 heterocyclic ring; or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 heteroaryl;

[0209] Each R 7 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0210] R 8 Selected from hydrogen and C 1 -C 6 alkyl;

[0211] Each R 9 are independently selected from hydrogen, halogen and C 1 -C 6 alkyl;

[0212] Each R 13 are independently selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 13 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic ring;

[0213] Each R 14 Independently selected from C 1 -C 6Alkyl and C 3 -C 8 Cycloalkyl;

[0214] n is 0, 1 or 2;

[0215] p is 0, 1, 2 or 3; and

[0216] q is 0, 1, or 2.

[0217] In some embodiments, R 2 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0218] In some embodiments, R 2 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0219] In some embodiments, R 2 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13One or two substituents are substituted.

[0220] In some embodiments, R 2 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0221] In some embodiments, R 2 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0222] In some embodiments, R 2 for

[0223] Each R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl; R 11a -CN, -OH, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and u is 0, 1 or 2.

[0224] In some embodiments, R2 for

[0225]

[0226] Where R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0227] In some embodiments, R 2 for

[0228]

[0229]

[0230] In some embodiments, R 2 for Each R 12 are independently halogenated, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0231] In some embodiments, R 2 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0232] In some embodiments, R 2 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0233] In some embodiments, R 2 for

[0234]

[0235] In some embodiments, R 2 for

[0236] Where R 10 It is a heteroaryl group.

[0237] In some embodiments, R 3 In some embodiments, R 3 C 1 -C 6 alkyl.

[0238] In some embodiments, R 3 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0239] In some embodiments, R 3 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0240] In some embodiments, R 3 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0241] In some embodiments, R 3 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0242] In some embodiments, R 3 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0243] In some embodiments, R 3 for

[0244] Each R 11 It is C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl; R 11a -CN, -OH, C 1 -C 6 Alkyl or C 3 -C6 cycloalkyl; and u is 0, 1 or 2.

[0245] In some embodiments, R 3 for

[0246] Where R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0247] In some embodiments, R 3 for

[0248]

[0249] In some embodiments, R 3 for Each R 12 are independently halogenated, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0250] In some embodiments, R 3 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0251] In some embodiments, R 3 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0252] In some embodiments, R 3 for

[0253]

[0254] In some embodiments, R 3 for Where R 10 It is a heteroaryl group.

[0255] In some embodiments, R 3 For-OR 6 , and R 6 Selected from C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl and -C 1 -C 6 Alkyl-C 2-9 In some embodiments, R 2 In some embodiments, R 2 C 1 -C 6 alkyl.

[0256] In some embodiments, R 1 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 )2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0257] In some embodiments, R 1 Selected from C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0258] In some embodiments, R 1 Selected from C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0259] In some embodiments, R 1 is selected from triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0260] In some embodiments, R 1is selected from triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally selected from halogenated, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0261] In some embodiments, R 1 for

[0262] Where R 15 C 1-6 Alkyl or C 3-8 cycloalkyl; and R 16 is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0263] In some embodiments, R 1 for

[0264] Where R 15 C 1-6 Alkyl or C 3-8 cycloalkyl; and R 16 For halogenated, -CN, C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0265] In some embodiments, R 1 for

[0266]

[0267]

[0268] In some embodiments, R 1 for

[0269]

[0270] In some embodiments, R 1 for

[0271]

[0272] Each R 17 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 ; Each R 18 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 ; v is 0, 1, 2, 3, 4, 5, or 6; and w is 0, 1, 2, 3, or 4. In some embodiments, each R 17 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl or C 3-8 Cycloalkyl; each R 18 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl or C 3-8 Cycloalkyl.

[0273] In some embodiments, each R 17 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH or C 1-6 haloalkyl; each R 18 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH or C 1-6 Halogenated alkyl.

[0274] In some embodiments, each R 17 are independently hydrogen, halo, -CN or C 1-6 Alkyl; each R 18 are independently hydrogen, halo, -CN or C 1-6 alkyl.

[0275] In some embodiments, R 1 for

[0276]

[0277] In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof:

[0278]

[0279] in

[0280] for

[0281] R 1 for

[0282] Z is O, S, C(=O), N(R 8 ) or C(R 9 ) 2 ;

[0283] X is O or S;

[0284] R 2 C 3-6 Cycloalkyl;

[0285] R 3 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0286] Each R 4are independently selected from hydrogen, halo, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0287] or an R 4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0288] Each R 5 independently selected from halogen and C 1-6 alkyl;

[0289] R 5a Selected from hydrogen and C 1 -C 6 alkyl;

[0290] R 25 Selected from halogen, -CN, -OH, -OR 6 、-SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0291] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 heterocyclic ring; or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 heteroaryl;

[0292] Each R 7 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0293] R 8 Selected from hydrogen and C 1 -C 6 alkyl;

[0294] Each R 9 are independently selected from hydrogen, halogen and C 1 -C 6 alkyl;

[0295] Each R 13 are independently selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 13 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic ring;

[0296] Each R 14 Independently selected from C 1 -C6 Alkyl and C 3 -C 8 Cycloalkyl;

[0297] n is 0, 1, 2, 3 or 4;

[0298] p is 0, 1, 2 or 3; and

[0299] q is 0, 1, or 2.

[0300] In some embodiments, R 25 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0301] In some embodiments, R25 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0302] In some embodiments, R 25 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0303] In some embodiments, R 25 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0304] In some embodiments, R 25 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0305] In some embodiments, R 25 for

[0306] Each R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl; R 11a For –CN, -OH, C1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and u is 0, 1 or 2.

[0307] In some embodiments, R 25 for

[0308] Where R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0309] In some embodiments, R 25 for

[0310]

[0311]

[0312] In some embodiments, R 25 for Where R 12 For halogenated, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0313] In some embodiments, R 25 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0314] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0315] In some embodiments, R 25 for

[0316]

[0317] In some embodiments, R 25 for

[0318]

[0319] Where R 10 It is a heteroaryl group.

[0320] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and the two R 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl.

[0321] In some embodiments, R 25 for

[0322] In some embodiments, R 25 For-OR 6 , and R 6 Selected from C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl and -C 1 -C 6 Alkyl-C 2-9 Heterocyclic ring.

[0323] In some embodiments, for In some embodiments, p is 0.

[0324] In some embodiments, for In some embodiments, for In some embodiments, q is 0.

[0325] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, Z is C(R 9 ) 2 In some embodiments, R 9 For H.

[0326] In some embodiments, R 1 for

[0327]

[0328] Where R 2 C 3-6 Cycloalkyl; R 3 Selected from Hydrogen C 1-6 Alkyl and C 3-6 Cycloalkyl; each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; or one R 4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0329] In some embodiments, R 1 for

[0330]

[0331]

[0332] Where R 3 Selected from C 1-6 Alkyl and C 3-6 cycloalkyl; and each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0333] In some embodiments, R 1 for

[0334]

[0335] In some embodiments, R 1 for

[0336] In some embodiments, R 1 for

[0337] In some embodiments, R 1 for Where R 2 and R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0338] In some embodiments, R 1 for

[0339]

[0340] Where X is O, N or S; each R 19 are independently halogenated, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 ; and y is 0, 1, 2, 3 or 4.

[0341] In some embodiments, R 1 for

[0342]

[0343] Wherein X is O, N or S.

[0344] In some embodiments, R 1 for

[0345]

[0346] Where X is N.

[0347] In some embodiments, R 1 for

[0348] wherein X is O or S; and

[0349] One R4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0350] In some embodiments, R 1 for

[0351]

[0352] In some embodiments, R 1 for

[0353] In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof:

[0354]

[0355] in

[0356] for

[0357] R 1 for

[0358] Z is O, S, C(=O), N(R 8 ) or C(R 9 ) 2 ;

[0359] X is O or S;

[0360] R 2 C 3-6 Cycloalkyl;

[0361] R 3 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0362] Each R 4 are independently selected from hydrogen, halo, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0363] or an R 4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0364] Each R 5 independently selected from halogen and C 1-6 alkyl;

[0365] R 5a Selected from hydrogen and C 1 -C 6 alkyl;

[0366] Each R 25 independently selected from halogen, -CN, -OH, -OR 6 、-SR 6 、-S(=O)R 7 、-NO 2 、-N(R 6 ) 2 、-S(=O) 2 R 7 、-NHS(=O) 2 R 7 、-S(=O) 2 N(R 6 ) 2 、-C(=O)R 7 、-C(=O)OR 6 、-OC(=O)R 7 、-C(=O)N(R 6 ) 2 、-OC(=O)N(R 6 ) 2 、-NR 6 C(=O)N(R 6 ) 2 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 6 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted;

[0367] Each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl, -C 3 -C 8 Cycloalkyl-phenyl and C 2-9 Heterocyclic ring, in which C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl, -C 3 -C 8 Cycloalkyl-phenyl and C 2-9 The heterocyclic ring is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 One, two or three substituents are substituted;

[0368] Each R 7 Independently selected from C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring, in which C 3 -C 8 Cycloalkyl and C 2-9 The heterocyclic ring is optionally selected from halo, oxo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 substituted with one, two or three substituents;

[0369] Each R 8 are independently selected from hydrogen and C 1 -C 6 alkyl;

[0370] Each R 9 are independently selected from hydrogen, halogen and C 1 -C 6 alkyl;

[0371] Each R 13 are independently selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl; or two R on the same heteroatom 13 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic ring;

[0372] Each R 14 Independently selected from C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0373] n is 0, 1, 2, 3 or 4;

[0374] p is 0, 1, 2 or 3; and

[0375] q is 0, 1, or 2.

[0376] In some embodiments, R 25 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl; wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl and fused C 5-9 Heteroaryl-cycloalkyl is optionally selected from halo, -CN, C 1-6Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 is substituted with one, two or three substituents.

[0377] In some embodiments, R 25 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13One, two or three substituents are substituted.

[0378] In some embodiments, R 25 Selected from C 2-9 Heterocyclic and C 1-9 Heteroaryl; wherein C 2-9 Heterocyclic and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0379] In some embodiments, R 25 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One or two substituents are substituted.

[0380] In some embodiments, R 25 is selected from pyrazole, imidazole, thiazole and pyridine; wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0381] In some embodiments, R 25 for

[0382]

[0383] Each R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl; R 11a For –CN, -OH, C 1 -C 6 Alkyl or C 3 -C 6 cycloalkyl; and u is 0, 1 or 2.

[0384] In some embodiments, R 25 for

[0385]

[0386] Where R 11 C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl.

[0387] In some embodiments, R 25 for

[0388]

[0389]

[0390] In some embodiments, R 25 for Where R 12 For halogenated, C 1 -C6 Alkyl or C 3 -C 6 cycloalkyl; and m is 1 or 2.

[0391] In some embodiments, R 25 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole and unsubstituted pyridine.

[0392] In some embodiments, R 25 is selected from pyrimidine, pyrazine and pyridazine; wherein pyrimidine, pyrazine and pyridazine are optionally selected from halo, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0393] In some embodiments, R 25 Selected from halogen, -OR 6 、-N(R 6 ) 2 , C 1-6 wherein pyrazole, imidazole, thiazole and pyridine are optionally selected from halogenated, C 1-6 Alkyl and C 3-8 One or two substituents in the cycloalkyl group are substituted.

[0394] In some embodiments, R 25 Selected from halogen, -OR 6 、-N(R 6 ) 2 , C 1-6 Alkyl and unsubstituted pyridine.

[0395] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and each R 6 are independently selected from hydrogen, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 2-9 Heterocyclic, -C 1 -C 6 Alkyl-C 2-9 Heteroaryl, C 3 -C 8 Cycloalkyl and C 2-9 Heterocyclic ring.

[0396] In some embodiments, R 25 for

[0397]

[0398] In some embodiments, R 25 for

[0399]

[0400] Where R 10 It is a heteroaryl group.

[0401] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 ) 2 , -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 is substituted with one, two or three substituents.

[0402] In some embodiments, R 25 for

[0403] In some embodiments, R 25 -C(=O)N(R 6 ) 2 , and the two R 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl.

[0404] In some embodiments, R 25 for

[0405] In some embodiments, R 25 For-OR 6 , and R 6 Selected from C 1 -C 6Alkyl, -C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl and -C 1 -C 6 Alkyl-C 2-9 Heterocyclic ring.

[0406] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0407] In some embodiments, Z is C(R 9 ) 2 In some embodiments, Z is C(R 9 ) 2 And each R 9 For H.

[0408] In some embodiments, Z is N(R 8 In some embodiments, Z is N(R 8 ) and each R 8 is H. In some embodiments, Z is N(R 8 ) and each R 8 C 1 -C 6 alkyl.

[0409] In some embodiments, for In some embodiments, p is 0.

[0410] In some embodiments, for In some embodiments, for In some embodiments, q is 0.

[0411] In some embodiments, R 1 for

[0412]

[0413] Where R 2 C 3-6 Cycloalkyl; R 3 Selected from Hydrogen C 1-6 Alkyl and C 3-6 Cycloalkyl; each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; or one R 4 and another R 2 , R 3 or R4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0414] In some embodiments, R 1 for

[0415]

[0416] Where R 3 Selected from C 1-6 Alkyl and C 3-6 cycloalkyl; and

[0417] Each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0418] In some embodiments, R 1 for

[0419]

[0420] In some embodiments, R 1 for

[0421] In some embodiments, R 1 for

[0422] In some embodiments, R 1 for

[0423] In some embodiments, R 1 for

[0424] In some embodiments, R 1 for

[0425] In some embodiments, R 1 for

[0426] In some embodiments, R 1 for

[0427] In some embodiments, R 1 for Where R 2 and R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13One, two or three substituents are substituted.

[0428] In some embodiments, R 1 for

[0429] Where X is O, N or S; each R 19 are independently halogenated, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 ; and y is 0, 1, 2, 3 or 4.

[0430] In some embodiments, R 1 for

[0431]

[0432] Wherein X is O, N or S.

[0433] In some embodiments, R 1 for

[0434]

[0435] Where X is N.

[0436] In some embodiments, R 1 for

[0437] wherein X is O or S; and

[0438] One R 4 and another R 2 , R 3 or R 4 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5- or 6-membered ring is saturated, unsaturated or aromatic; and wherein the 5- or 6-membered ring is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R 14 、-C(=O)OR 13 、-C(=O)N(R 13 ) 2 、-S(=O)R 14 、-S(=O) 2 R 13 、-S(=O) 2 -N(R 13 ) 2 、-N(R 13 ) 2 、-N(R 13 )C(=O)R 14 and -N(R 13 )S(=O) 2 R 13 One, two or three substituents are substituted.

[0439] In some embodiments, R 1 for

[0440]

[0441] In some embodiments, R 1 for

[0442] In some embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0443] In some embodiments, a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof.

[0444] In some embodiments, a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition and a kidney disease or condition.

[0445] In some embodiments, it is a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition and a kidney disease or condition.

[0446] In some embodiments, it is a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition and a kidney disease or condition.

[0447] In some embodiments are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition and a kidney disease or condition.

[0448] In some embodiments, it is a method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition and a kidney disease or condition.

[0449] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof.

[0450] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is a liver disease or condition, a heart disease or condition, or a kidney disease or condition described herein.

[0451] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof.

[0452] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from the group consisting of a liver disease or disorder, a heart disease or disorder, a kidney disease or disorder, a pancreatic disease or disorder, a spleen disease or disorder, and a skin disease or disorder. In some embodiments, the organ disease or disorder is selected from the group consisting of a liver disease or disorder, a heart disease or disorder, and a kidney disease or disorder. In some embodiments, the organ disease or disorder is a liver disease or disorder, a heart disease or disorder, or a kidney disease or disorder described herein.

[0453] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof.

[0454] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is a liver disease or condition, a heart disease or condition, or a kidney disease or condition described herein.

[0455] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof.

[0456] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is a liver disease or condition, a heart disease or condition, or a kidney disease or condition described herein.

[0457] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof.

[0458] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a heart disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is a liver disease or condition, a heart disease or condition, or a kidney disease or condition described herein.

[0459] In some embodiments are methods for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0460] In some embodiments are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or condition is selected from a liver disease or condition, a cardiac disease or condition, a kidney disease or condition, a pancreatic disease or condition, a spleen disease or condition, and a skin disease or condition. In some embodiments, the organ disease or condition is selected from a liver disease or condition, a cardiac disease or condition, and a kidney disease or condition. In some embodiments, the organ disease or condition is a liver disease or condition, a cardiac disease or condition, or a kidney disease or condition described herein.

[0461] In some embodiments, described herein are methods for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from Table 1.

[0462] In some embodiments, described herein are methods for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from Table 1, wherein the organ disease or disorder is selected from a liver disease or disorder, a cardiac disease or disorder, a kidney disease or disorder, a pancreatic disease or disorder, a spleen disease or disorder, and a skin disease or disorder. In some embodiments, the organ disease or disorder is selected from a liver disease or disorder, a cardiac disease or disorder, and a kidney disease or disorder.

[0463] Table 1:

[0464]

[0465]

[0466]

[0467] In some embodiments, the organ disease or disorder is a liver disease or disorder. In some embodiments, the liver disease or disorder is selected from liver injury, drug-induced liver injury, liver failure, fulminant or acute liver failure, and acute-on-chronic liver failure. In some embodiments, fulminant liver failure is due to drug overdose, due to acetaminophen overdose, due to poisoning associated with wild mushroom death caps, or due to carbon tetrachloride disorders. In some embodiments, acute liver failure is due to poisoning, due to surgical ischemia-reperfusion injury, due to vascular disease, due to metabolic disease, due to pregnancy, or due to septic shock. In some embodiments, acute-on-chronic liver failure is due to alcoholic hepatitis, due to autoimmune hepatitis, due to viral hepatitis, or due to cirrhosis.

[0468] In some embodiments, the liver disease or disorder is selected from drug-induced liver injury, fulminant hepatic failure due to acetaminophen overdose, fulminant hepatic failure due to poisoning associated with wild mushroom death cap or carbon tetrachloride illness, acute liver failure due to poisoning associated with herbal supplements (including kava, ephedra, skullcap, and mint), acute liver failure due to surgical ischemia-reperfusion injury (liver transplantation, partial resection), acute liver failure due to vascular disease (e.g., Budd-Chiari syndrome), acute liver failure due to metabolic disease (e.g., Wilson's disease, acute fatty liver of pregnancy), acute liver failure due to septic shock, acute-on-chronic liver failure due to alcoholic hepatitis, acute-on-chronic liver failure due to autoimmune hepatitis, and acute-on-chronic liver failure due to viral hepatitis (e.g., hepatitis A, hepatitis B, and hepatitis E), Epstein-Barr virus, cytomegalovirus, and herpes simplex virus.

[0469] In some embodiments, the liver disease or disorder is drug-induced liver damage. In some embodiments, the liver disease or disorder is fulminant liver failure due to acetaminophen overdose. In some embodiments, the liver disease or disorder is fulminant liver failure due to poisoning associated with wild mushroom death caps or carbon tetrachloride illness. In some embodiments, the liver disease or disorder is acute liver failure due to poisoning associated with herbal supplements, including kava, ephedra, scutellaria and pennyroyal. In some embodiments, the liver disease or disorder is acute liver failure due to surgical ischemia-reperfusion injury (liver transplantation, partial resection). In some embodiments, the liver disease or disorder is acute liver failure due to vascular disease (e.g., Budd-Chiari syndrome). In some embodiments, the liver disease or disorder is acute liver failure due to metabolic diseases (e.g., Wilson's disease and acute fatty liver of pregnancy). In some embodiments, the liver disease or disorder is acute liver failure due to septic shock. In some embodiments, the liver disease or disorder is acute-on-chronic liver failure due to alcoholic hepatitis. In some embodiments, the liver disease or disorder is acute-on-chronic liver failure due to autoimmune hepatitis. In some embodiments, the liver disease or disorder is acute-on-chronic liver failure due to viral hepatitis (e.g., hepatitis A, hepatitis B, and hepatitis E), Epstein-Barr virus, cytomegalovirus, and herpes simplex virus.

[0470] In some embodiments, the organ disease or condition is a heart disease or condition. In some embodiments, the heart disease or condition is selected from ischemia-reperfusion injury, ischemia, coronary artery disease, cardiovascular dysfunction caused by sepsis, drug-induced cardiotoxicity, viral myocarditis and complications caused by heart transplantation. In some embodiments, the heart disease or condition is ischemia-reperfusion injury. In some embodiments, ischemia-reperfusion injury is caused by acute ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), cardiopulmonary bypass and extracorporeal circulation or a combination thereof. In some embodiments, the heart disease or condition is ischemia. Examples of ischemia include but are not limited to coronary artery disease and myocardial ischemia. In some embodiments, the heart disease or condition is coronary artery disease. In some embodiments, the heart disease or condition is cardiovascular dysfunction caused by sepsis. In some embodiments, the heart disease or condition is cardiotoxicity caused by drugs. In some embodiments, drug toxicity is caused by doxorubicin. In some embodiments, the heart disease or condition is viral myocarditis. In some embodiments, the cardiac disease or disorder is a complication of a cardiac transplant.

[0471] In some embodiments, organ disease or disorder is kidney disease or disorder. In some embodiments, kidney disease or disorder is acute kidney injury. In some embodiments, acute kidney injury is due to hypovolemia, hypotension, renal vasoconstriction, glomerular efferent arteriolar vasodilation, long-term renal ischemia, long-term renal sepsis, long-term nephrotoxins, renal transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis and tubular obstruction. In some embodiments, hypovolemia is due to bleeding, severe burns and gastrointestinal fluid loss (such as diarrhea, vomiting, high stoma output). In some embodiments, hypotension is due to reduced cardiac output (such as cardiogenic shock, massive pulmonary embolism and acute coronary syndrome). In some embodiments, hypotension is due to systemic vasodilation, such as septic shock, allergic reaction, anesthesia administration and hepatorenal syndrome. In some embodiments, renal vasoconstriction is due to nonsteroidal anti-inflammatory drugs (NSAIDs), iodinated contrast agents, amphotericin B, calcineurin inhibitors and hepatorenal syndrome. In some embodiments, glomerular efferent arteriolar vasodilation is due to ACE inhibitors and angiotensin receptor blockers. In some embodiments, acute tubular necrosis is due to ischemia caused by: long-term prerenal injury; drugs, such as aminoglycosides, vancomycin, amphotericin B, pentamidine; rhabdomyolysis; and intravascular hemolysis. In some embodiments, acute interstitial nephritis is due to drugs such as β-lactam antibiotics, penicillins, NSAIDs, proton pump inhibitors (PPI), 5-ASA, infection and autoimmune conditions (systemic lupus erythematosus (SLE), IgG-related diseases). In some embodiments, glomerulonephritis is due to anti-glomerular basement membrane disease, immune complex-mediated diseases (e.g., SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy and Henoch-Schonlein purpura). In some embodiments, the intratubular obstruction is due to monoclonal gammopathy, tumor lysis syndrome, toxins (eg, ethylene glycol) as seen in multiple myeloma.

[0472] In some embodiments, described herein are methods for treating organ diseases or conditions in subjects in need, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by injectable delivery. In some embodiments, described herein are methods for treating organ diseases or conditions in subjects in need, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intravenous delivery, wherein the intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments, described herein are methods for treating organ diseases or conditions in subjects in need, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intraperitoneal delivery.

[0473] In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by injectable delivery. In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intraperitoneal delivery.

[0474] In some embodiments, described herein are methods for treating organ diseases or conditions in subjects in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by injectable delivery. In some embodiments, described herein are methods for treating organ diseases or conditions in subjects in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments, described herein are methods for treating organ diseases or conditions in subjects in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intraperitoneal delivery.

[0475] In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by injectable delivery. In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intraperitoneal delivery.

[0476] In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by injectable delivery. In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments, described herein are methods for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered by intraperitoneal delivery.

[0477] Compound synthesis

[0478] The compound used in the method described herein is made according to the steps disclosed in US2018 / 0291002, which is incorporated herein by reference as a whole, or by known organic synthesis techniques, from commercially available chemicals and / or from the compounds described in chemical literature. The starting material for synthesizing the compound described herein is synthesized or obtained from commercial sources, such as but not limited to Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, etc. The compound described herein and other related compounds with different substituents are synthesized using described herein or other known techniques and materials, and the other known techniques and materials are included in March, Advanced Organic Chemistry 4th Edition, (Wiley 1992);Carey and Sundberg, Advanced Organic Chemistry 4th Edition, A Volume and B Volume (Plenum 2000, 2001) and Green and Wuts, Protective Groups in Organic Synthesis 3rd Edition, (Wiley 1999) those found. The various moieties found in the formulas provided herein can be introduced by modifying the general methods for preparing compounds using appropriate reagents and conditions. A detailed description of techniques suitable for creating protecting groups and their removal is described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0479] Further forms of compounds

[0480] In one aspect, the compounds described herein have one or more stereocenters, and each stereocenter is independently present in the R or S configuration. The compounds proposed herein include all diastereoisomers, enantiomers and epimer forms and appropriate mixtures thereof. The compounds and methods provided herein include all cis-, trans-, syn-, anti-, entgegen (E) and zusammen (Z) isomers and appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating diastereomers and recovering optically pure enantiomers. In some embodiments, the covalent diastereomeric derivatives of the compounds described herein are used to separate enantiomers. In another embodiment, diastereomers are separated by separation / resolving techniques based on solubility differences. In other embodiments, separation of stereoisomers is carried out by chromatography or by forming diastereomeric salts and separation by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0481] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to an individual without causing adverse biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0482] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid. A pharmaceutically acceptable salt is also obtained by reacting a compound described herein with a base to form a salt.

[0483] The compounds described herein can be formed and / or used as pharmaceutically acceptable salts. The types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid to form a salt, such as hydrochloride, hydrobromide, sulfate, phosphate, metaphosphate, etc.; or with an organic acid to form a salt, such as acetate, propionate, hexanoate, cyclopentanepropionate, glycolate, pyruvate, lactate, malonate, succinate, malate, maleate, fumarate, trifluoroacetate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, 2-naphthalenesulfonate, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylate, glucoheptonate, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylate), 3-phenylpropionate, trimethylacetate, tert-butylacetate, dodecyl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, muconate, butyrate, phenylacetate, phenylbutyrate, valproate, etc.; (2) salts formed by replacing the acidic protons present in the parent compound with metal ions, such as alkali metal ions (such as lithium salts, sodium salts or potassium salts), alkaline earth metal ions (such as magnesium salts or calcium salts) or aluminum ions (such as aluminum salts). In some cases, the compounds described herein can be coordinated with organic bases to form salts, such as, but not limited to, ethanolamine salts, diethanolamine salts, triethanolamine salts, tromethamine salts, N-methylglucamine salts, dicyclohexylamine salts, or tris(hydroxymethyl)methylamine salts. In other cases, the compounds described herein can form salts with amino acids, such as, but not limited to, arginine salts, lysine salts, and the like. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0484] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and can be formed during crystallization with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed in the process described herein. In addition, the compounds provided herein can exist in unsolvated forms as well as solvated forms.

[0485] Route of administration

[0486] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, aural, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0487] In certain embodiments, the compounds as described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a depot preparation or a sustained release formulation. In a specific embodiment, the long-acting preparation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered with a targeted drug delivery system, for example, with liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to the organ and selectively absorbed by the organ. In yet other embodiments, the compounds as described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compounds described herein are administered topically.

[0488] In some embodiments described herein, a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery. In some embodiments described herein, a therapeutically effective amount of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments described herein, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery. In some embodiments described herein, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments described herein, a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery. In some embodiments described herein, a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and an infusion pump. In some embodiments described herein, a therapeutically effective amount of a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery. In some embodiments described herein, a therapeutically effective amount of a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and an infusion pump. In some embodiments described herein, a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery. In some embodiments described herein, a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof by intravenous delivery, wherein intravenous delivery is selected from bolus injection, intravenous drip, and an infusion pump.

[0489] Pharmaceutical compositions / preparations

[0490] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients, which assist in processing the active compound into a pharmaceutically usable product. The appropriate formulation depends on the selected route of administration. The summary of the pharmaceutical composition described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0491] Provided herein is a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula IIa or Formula III or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In some embodiments, a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a compound of Formula II or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a compound of Formula IIa or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the compounds described herein are administered as pharmaceutical compositions, wherein a compound of Formula I, Formula II, Formula IIa or Formula III or a pharmaceutically acceptable salt thereof is mixed with other active ingredients, as in combination therapy. In other embodiments, the pharmaceutical composition comprises other medicines or medicaments, carriers, adjuvants, preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In still other embodiments, the pharmaceutical composition comprises other therapeutically valuable substances.

[0492] In some embodiments, the compounds described herein may be used as adjuncts to systemic treatments with N-acetylcysteine, corticosteroids, and vasopressors. In some embodiments, the compounds described herein may be used as adjuncts to systemic treatments with N-acetylcysteine. In some embodiments, the compounds described herein may be used as adjuncts to systemic treatments with corticosteroids. In some embodiments, the compounds described herein may be used as adjuncts to systemic treatments with vasopressors, including but not limited to vasopressin and catecholamines.

[0493] As used herein, pharmaceutical compositions refer to a mixture of a compound of Formula I, Formula II, Formula IIa or Formula III or a pharmaceutically acceptable salt thereof and other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. Pharmaceutical compositions facilitate administration of compounds to mammals.

[0494] The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0495] The pharmaceutical formulations described herein are administered to a subject by an appropriate route of administration, including but not limited to oral, parenteral (e.g., intravenous, intravitreal, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. The pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsed release formulations, multi-particulate formulations, and mixed immediate and controlled release formulations.

[0496] Pharmaceutical compositions comprising a compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0497] The pharmaceutical composition will include at least one compound of Formula I, Formula II, Formula IIa or Formula III as an active ingredient in the form of a free acid or free base or a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, and active metabolites of these compounds with the same active type. In some embodiments, the compounds described herein exist in a non-solvated form or in a solvated form formed with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). The solvated forms of the compounds proposed herein are also considered to be disclosed herein.

[0498] In some embodiments, solid oral dosage forms are prepared by combining a compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt thereof, with one or more of the following: an antioxidant, a flavoring agent, and a carrier material (e.g., a binder, a suspending agent, a disintegrant, a filler, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, and a diluent).

[0499] In some embodiments, the solid dosage forms disclosed herein are in the form of tablets (including suspension tablets, fast-melt tablets, chewable disintegrating tablets, rapidly disintegrating tablets, effervescent tablets or caplets), pills, powders, capsules, solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsed release dosage forms, multi-particulate dosage forms, beads, pellets, granules. In other embodiments, the pharmaceutical preparation is in powder form. In other embodiments, the pharmaceutical preparation is in tablet form. In other embodiments, the pharmaceutical preparation is in capsule form.

[0500] In some embodiments, solid dosage forms, such as tablets, effervescent tablets and capsules, are prepared by mixing particles of a compound of Formula I, Formula II, Formula IIa or Formula III or a pharmaceutically acceptable salt thereof with one or more pharmaceutical excipients to form a bulk blend composition. The bulk blend is easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. In some embodiments, a single unit dose includes a film coating. These preparations are manufactured by conventional formulation techniques.

[0501] Conventional formulation techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0502] In some embodiments, the compound of Formula I, Formula II or Formula III or a pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition suitable for intravitreal, intramuscular, subcutaneous or intravenous injection. In one aspect, formulations suitable for intravitreal, intramuscular, subcutaneous or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. In some embodiments, formulations suitable for subcutaneous injection contain additives such as preservatives, wetting agents, emulsifiers and dispersants.

[0503] In some embodiments, the compound of Formula I, Formula II or Formula III or a pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition suitable for intravenous injection. In some embodiments, the compound of Formula II or Formula IIa or a pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition suitable for intravenous injection. Examples of intravenous injection include, but are not limited to, bolus injection, intravenous drip, and infusion pump.

[0504] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0505] In certain embodiments, delivery systems of pharmaceutical compounds may be used, such as nanoparticles, implants, mucoadhesives, liposomes, and emulsions. In certain embodiments, compositions provided herein may also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0506] In some embodiments, the compounds described herein can be administered topically and can be formulated into various topically administrable compositions, such as solutions, suspensions, sprays, lotions, gels, pastes, sticks, foams, balms, creams or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0507] Combination therapy

[0508] In certain cases, it is appropriate to administer at least one compound of Formula I, Formula II, Formula Ha, or Formula III, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0509] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administering an adjuvant (i.e., the adjuvant may have minimal therapeutic benefit by itself, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0510] In a specific embodiment, a compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of Formula I, Formula II, Formula IIa or Formula III, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0511] In some embodiments, the second therapeutic agent is an antidiabetic agent. In some embodiments, the second therapeutic agent is an antidiabetic agent selected from biguanides, sulfonylureas, meglitinides, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT2) inhibitors and alpha-glucosidase inhibitors.

[0512] In some embodiments, the second therapeutic agent is N-acetylcysteine. In some embodiments, the second therapeutic agent is a corticosteroid. In some embodiments, the second therapeutic agent is a vasopressor. In some embodiments, the vasopressor is vasopressin or a catecholamine. In some embodiments, the vasopressor is vasopressin. In some embodiments, the vasopressor is a catecholamine.

[0513] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0514] In certain embodiments, when the compounds disclosed herein are co-administered with one or more additional agents (e.g., additional therapeutically effective drugs, adjuvants, etc.), different therapeutically effective doses of the compounds disclosed herein will be used in the preparation of pharmaceutical compositions and / or in the treatment regimen. The therapeutically effective doses of the drugs and other agents used in the combined treatment regimen can be determined by methods similar to those described above for the active substance itself. In addition, the prevention / treatment methods described herein include the use of metronomic administration, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combined treatment regimen includes a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt thereof, which is administered before, during, or after treatment with a second agent, and continues to any time during treatment with the second agent or after treatment with the second agent. It also includes a treatment regimen in which a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered simultaneously or at different times and / or at intervals that are gradually reduced or increased during the treatment period. The combined treatment further includes periodic treatments that start and stop at different times to assist in the clinical management of patients.

[0515] It should be understood that the dosage regimen for treating, preventing or improving the condition being sought to be alleviated is modified according to a variety of factors (e.g., the disease, disorder or condition suffered by the subject; the age, weight, sex, diet and medical condition of the subject). Therefore, in some cases, the dosage regimen actually adopted will be different, and in some embodiments deviate from the dosage regimen described herein.

[0516] For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more additional therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more additional therapeutic agents.

[0517] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided, by way of example only, in a single unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0518] The compound of formula I, formula II, formula IIa or formula III or its pharmaceutically acceptable salt and combination therapy are applied before, during or after the occurrence of the disease or condition, and the timing of applying the composition containing the compound is different. Therefore, in one embodiment, the compound described herein is used as a prophylactic and is continuously administered to a subject with a tendency to develop a condition or disease to prevent the occurrence of the disease or condition. In another embodiment, the compound and composition are applied to the subject as quickly as possible during or after the onset of symptoms. In a specific embodiment, after the onset of a disease or condition is detected or suspected, the compound described herein is applied as soon as possible, and continues for the duration required for the treatment of the disease. In some embodiments, the duration required for treatment is different, and the duration is adjusted to suit the specific needs of each subject. For example, in a specific embodiment, the compound described herein or a preparation containing the compound is administered for at least 2 weeks, from about 1 month to about 5 years.

[0519] Example

[0520] These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0521] Example 1: Organ distribution of ASK1 inhibitors in rats after intravenous administration

[0522] The aim of this study was to investigate the organ (liver, heart, kidney, pancreas, spleen and skin) distribution of an ASK1 inhibitor in male Sprague Dawley rats after a single intravenous (IV) administration at a dose of 10 mg / kg. Three rats were administered a solution formulation of the ASK1 inhibitor 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one in 5% NMP, 15% Solutol HS-15, 20% PEG-400 and 60% HpBetaCD at a dose of 10 mg / kg intravenously. 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one was prepared as described in US2018 / 0291002, which is incorporated herein by reference in its entirety.

[0523] Blood samples (about 120 μL) were collected from the retroorbital plexus of a group of three rats under mild isoflurane anesthesia 1 hour after IV injection. Plasma was collected immediately after blood collection by centrifugation at 4000 rpm for 10 minutes at 40°C, and the samples were stored at -70 ± 10°C until bioanalysis. The animals were killed, and the abdominal vena cava was immediately cut open, and 10 mL of saline was used to perfuse the whole body from the heart. After separation, the tissue samples were rinsed three times in ice-cold saline (for each rinse, about 5-10 ml of saline was used in a disposable culture dish for 5-10 seconds), dried on blotting paper and weighed. Tissue (liver, heart, kidney, pancreas, spleen and skin) samples were homogenized using ice-cold phosphate buffered saline (pH-7.4). The total homogenate volume was five times the weight of the tissue. All homogenates were stored below -70 ± 10°C until bioanalysis.

[0524] Plasma, liver, heart, kidney, pancreas, spleen, and skin samples were quantified by appropriate LC-MS / MS methods.

[0525] Following a single intravenous administration of a 10 mg / kg dose of the ASK1 inhibitor 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one to male Sprague Dawley rats, plasma and tissue concentrations were quantifiable at 1 hour. Tissue to plasma ratios at 1 hour were: liver: 9.37; heart: 1.11; kidney: 5.99; pancreas: 0.99; spleen: 0.89; skin: 0.46.

[0526] Example 2: Organ distribution of ASK1 inhibitors in rats after oral administration

[0527] The aim of this study was to investigate the organ (liver, heart, kidney) distribution of an ASK1 inhibitor in male Sprague Dawley rats after a single oral (PO) administration at a dose of 300 mg / kg. Three rats were orally administered a suspension formulation of the ASK1 inhibitor 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one in a formulation of 0.1% Tween 80 and 99.9% HPMC (0.5% w / v in water) at a dose of 300 mg / kg.

[0528] Blood samples (approximately 120 μL) were collected from the retro-orbital plexus of a group of three rats under mild isoflurane anesthesia 1 hour after PO administration. Plasma was collected immediately after blood collection by centrifugation at 4000 rpm for 10 minutes at 40°C, and the samples were stored at -70 ± 10°C until bioanalysis. The animals were sacrificed, and the abdominal vena cava was immediately cut and the whole body was perfused from the heart with 10 mL of normal saline. After separation, the tissue samples were rinsed three times in ice-cold normal saline (for each rinse, about 5-10 mL of normal saline was used in a disposable culture dish for 5-10 seconds), dried on blotting paper and weighed. Tissue (liver, heart, kidney) samples were homogenized using ice-cold phosphate buffered saline (pH-7.4). The total homogenate volume was five times the weight of the tissue. All homogenates were stored below -70 ± 10°C until bioanalysis.

[0529] Plasma, liver, heart, kidney, pancreas, spleen, and skin samples were quantified by appropriate LC-MS / MS methods.

[0530] After a single oral administration of 300 mg / kg dose of the ASK1 inhibitor 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one to male Sprague Dawley rats, plasma and tissue concentrations were quantifiable at 1 hour. The tissue to plasma ratios at 1 hour were: liver: 13.77; heart: 1.13; kidney: 7.47.

[0531] Example 3: Efficacy of intravenous treatment with ASK1 inhibitors in liver damage due to acute alcoholic hepatitis (AH)

[0532] The aim of this study was to evaluate whether IV administration of an ASK1 inhibitor could attenuate liver damage due to acute alcoholic hepatitis (AH).

[0533] C57Bl / 6 male mice acclimated for 7 days were treated with pyrazole for 2 days to induce CYP2E before administration of ASK1 inhibitor and lipopolysaccharide (LPS). On day 3, ASK1 inhibitor 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one was administered via tail vein IV injection at doses of 0.3 and 3 mg / kg or vehicle was injected twice (3 hours apart). LPS was administered intraperitoneally 30 minutes after the first administration of 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one. LPS administration mimics inflammation caused by penetration of the intestinal wall by enteric bacteria after binge drinking. 24 h after LPS administration, plasma was collected for ALT analysis to assess the reduction of liver injury after intravenous treatment with ASK1 inhibitors.

[0534] Intravenous treatment with the ASK1 inhibitor 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one significantly attenuated liver injury as reflected by a 74-85% reduction in plasma ALT levels.

[0535] Example 4: Efficacy of intravenous treatment with an ASK1 inhibitor in a model of fulminant hepatitis caused by acetaminophen overdose

[0536] The aim of this study was to evaluate whether IV administration of the ASK1 inhibitor described herein could reduce liver injury due to acetaminophen (APAP) excess plasma ALT and reduce hepatic biomarkers of ASK1 signaling in a mouse model.

[0537] C57Bl / 6 male mice acclimated for 7 days were injected IV via the tail vein with the ASK1 inhibitors described herein at a dose range of 0.1-10 mg / kg or vehicle 30 minutes before APAP injection (300 mg / kg ip). 2 Animals were anesthetized with 1% or isoflurane and blood was drawn into heparinized syringes by cardiac puncture, followed by determination of alanine aminotransferase (ALT) activity. Liver samples were used to quantify phosphorylated JNK, phosphorylated p38, total JNK and p38, and β-actin by Western blotting.

[0538] Example 5: Phase II Study - Evaluation of ASK1 Inhibitors in Patients at Risk for Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI)

[0539] This study was designed to enroll patients scheduled for cardiac surgery who were considered to be at increased risk for developing CSA-AKI.

[0540] Phase 1 included 140 patients randomized in a 1:1:1:1 ratio (approximately 35 patients per treatment group) to placebo or one of three (3) ASK1 inhibitor dose groups:

[0541] 1. Placebo before surgery, followed by three (3) placebo doses after surgery, or

[0542] 2. A low dose of an ASK1 inhibitor before surgery, followed by three (3) low doses after surgery, or

[0543] 3. A medium dose of an ASK1 inhibitor before surgery, followed by three (3) lower doses after surgery, or

[0544] 4. A high dose of ASK1 inhibitor before surgery, followed by three (3) lower doses after surgery.

[0545] Study treatment (ASK1 inhibitor or placebo) will consist of one 60-minute IV infusion administration prior to surgery, followed by one 60-minute IV infusion administration beginning in the early postoperative period, and then two (2) additional 60-minute IV infusion administrations on consecutive days following cardiac surgery.

[0546] The primary endpoint for efficacy evaluation in patients receiving the ASK1 inhibitor will be the proportion of patients who develop CSA-AKI compared with those who received placebo, as measured by the Kidney Disease Improving Global Outcomes (KDIGO) criteria, as follows:

[0547] An increase in serum creatinine (SCr) ≥0.3 mg / dL (>26.5 micromol / L) within 48 hours of surgery; or

[0548] An increase in serum creatinine (SCr) to ≥1.5 times the baseline measured in the previous seven days; or

[0549] Urine output <0.5 mL / kg / hour within 6 hours postoperatively

[0550] ●If at least one of these measurements was present during the 7-day assessment, the patient was considered to have CSA-AKI.

[0551] Secondary outcome measures:

[0552] Incidence of AKI (time frame: 7 days)

[0553] Severity of AKI (time frame: 7 days)

[0554] The stages of AKI are defined as follows:

[0555] ■ Stage 1: SCr is 1.5-1.9 times the baseline or increases by ≥0.3 mg / dL (≥26.5 μmol / L), and urine output is <0.5 ml / kg / hr for 6-12 hours

[0556] Stage 2: SCr is 2.0-2.9 times the baseline, and urine output is <0.5 ml / kg / h for ≥12 hours

[0557] ■Stage 3: SCr is 3.0 times the baseline or SCr increases to ≥5.0 mg / dL (≥353.6 μmol / L) or renal replacement therapy is started or in patients <18 years old, eGFR decreases to <35 ml / min / 1.73 m^2, urine output <0.3 ml / kg / h for ≥24 hours or anuria lasts ≥12 hours.

[0558] ■No AKI is considered the best outcome, while stage 3 is considered the worst outcome.

[0559] Duration of AKI (time frame: 7 days or until discharge from surgery)

[0560] Inclusion criteria :

[0561] Male or female, and aged >18 years.

[0562] ●Planning for a non-urgent coronary and / or valvular procedure requiring CPB, including:

[0563] ■Coronary artery bypass grafting (CABG) alone;

[0564] ■Aortic valve replacement or repair alone, with or without aortic root repair;

[0565] ■ Mitral valve, tricuspid valve or pulmonary valve replacement or repair alone;

[0566] ■Replace multiple heart valves simultaneously;

[0567] ■CABG combined with aortic, mitral, tricuspid, or pulmonary valve replacement or repair;

[0568] ■CABG is performed together with heart valve replacement or repair.

[0569] ●The following risk factors for CSA-AKI:

[0570] eGFR ≥ 20 and < 30 ml / min / 1.73 m2 or

[0571] eGFR ≥ 30 and < 60 ml / min / 1.73 m2 and one of the following additional risk factors (except age ≥ 75 years) or

[0572] eGFR ≥ 60 ml / min / 1.73 m2 and two of the following additional risk factors

[0573] ●Other risk factors:

[0574] Age ≥ 75 years;

[0575] ■Combined valve and coronary artery surgery;

[0576] ■Previous cardiac surgery with sternotomy;

[0577] ■ Documented NYHA class III or IV within 1 year before surgery;

[0578] ■Left ventricular ejection fraction (LVEF) ≤ 35% as measured by invasive or noninvasive diagnostic cardiac imaging (echocardiography, nuclear imaging, computed tomography, magnetic resonance imaging, or angiography) within 90 days before surgery. (Patients meet risk factors if LVEF is ≤ 35% as measured by any invasive or noninvasive imaging procedure.)

[0579] ■ Diabetes requiring insulin treatment;

[0580] ■ Diabetes mellitus not requiring insulin therapy and urinalysis showing ≥+2 proteinuria (medical history or dipstick);

[0581] ■ Preoperative anemia (hemoglobin <11 g / dl in men and women).

[0582] Exclusion criteria :

[0583] Weight > 174 kg or 383 lbs;

[0584] ●Presence of AKI at screening (KDIGO criteria);

[0585] ●Performing surgery without CPB;

[0586] ●Surgery was performed under conditions of circulatory arrest or hypothermia, with rectal temperature <28°C (82.4°F);

[0587] ●eGFR(MDRD)<20ml / min / 1.73m2;

[0588] ●Aortic dissection surgery;

[0589] ●Surgery to correct a major congenital heart defect (eg, tetralogy of Fallot, transposition of the great vessels, univentricular heart, Ebstein's anomaly. A bicuspid aortic valve is not considered a congenital heart defect.);

[0590] ●Previous organ transplant;

[0591] ●Dialysis dependence;

[0592] ●Administering iodinated contrast media within 24 hours before cardiac surgery;

[0593] If contrast material was received within 24 hours before and AKI was defined according to KDIGO criteria;

[0594] Cardiogenic shock or hemodynamic instability within 24 hours before surgery (including induction of anesthesia), defined as systolic blood pressure <80 mm Hg and pulse >120 beats per minute (bpm) and the need for inotropes or vasopressors or other mechanical devices such as intra-aortic balloon counter-pulsation (IABP);

[0595] Any of the following within seven (7) days before cardiac surgery:

[0596] ■Defibrillator or permanent pacemaker,

[0597] Mechanical ventilation,

[0598] ■Intra-aortic balloon pump (IABP),

[0599] Left ventricular assist device (LVAD),

[0600] ■Other forms of mechanical circulatory support (MCS);

[0601] ●Cardiopulmonary resuscitation within 14 days before heart surgery;

[0602] ●A known history of cancer within the past 5 years, except for carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin;

[0603] ●Known or suspected sepsis at screening;

[0604] ● Known or suspected glomerulonephritis or interstitial nephritis at screening;

[0605] ● Endocarditis diagnosed or treated within 30 days before cardiac surgery;

[0606] ●Other current active infections requiring antibiotic treatment;

[0607] Hepatic insufficiency, defined as total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN) or Child Pugh class C liver disease (see Appendix 6) or higher at screening;

[0608] ●Any congenital coagulation disorder;

[0609] ●Pregnancy or breastfeeding;

[0610] If the patient is on a “do not resuscitate” (DNR) order;

[0611] ●Known allergy to the study drug or any of its excipients;

[0612] ●Received study drug treatment or participated in interventional trials within 60 days before the first dose of study drug;

[0613] Any disease process or confounding variable that the investigator believes would inappropriately alter the study results;

[0614] ●Unable to comply with the requirements of the study protocol.

[0615] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are to be included within the spirit and purview of this application and the scope of the appended claims.

Claims

1. A method for treating an organ disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa or a pharmaceutically acceptable salt or solvate thereof: in for R 1 for Z is C(R 9 )2; R 5 Selected from halogen and C 1-6 alkyl; Each R 25 are independently selected from halogen, -OR 6 、-N(R 6 )2, -C(=O)OR 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)N(R 6 )2 and C 1-9 Heteroaryl, the C 1-9 Heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl; wherein said C 1-9 Heteroaryl is optionally selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 One, two or three substituents in the cycloalkyl group; Each R 6 independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-pyrazole and C3-C8 cycloalkyl; or two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein the heteroaryl is selected from imidazolyl, pyrazolyl and pyrrolyl, wherein the C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 、-SR 8 、-N(R 8 2. -C 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 One, two or three substituents are substituted; Each R 8 Independently selected from hydrogen and C1-C6 alkyl; Each R 9 is hydrogen; Each R 13 Independently selected from hydrogen and C1-C6 alkyl; Each R 14 Independently selected from C1-C6 alkyl; n is 0, 1 or 2; and p is 0 or 1.

2. The method according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

3. The method according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 25 -C(=O)N(R 6 )2, and each R 6 Independently selected from hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-pyrazole and C3-C8 cycloalkyl.

4. The method according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 25 -C(=O)N(R 6 )2, and two R on the same heteroatom 6 Together with the heteroatom to which they are attached, they form C 2-9 Heterocyclic or C 2-9 Heteroaryl, wherein the heteroaryl is selected from imidazolyl, pyrazolyl and pyrrolyl, wherein the C 2-9 Heterocyclic or C 2-9 Heteroaryl is optionally selected from -OR 8 、-SR 8 、-N(R 8 2. -C 1-6 Alkyl, -C(=O)R 14 、-C(=O)OR 13 and -N(R 13 )C(=O)R 14 is substituted by a substituent.

5. The method according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 25 for 6. The method according to claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 25 for 7. The method according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 8. The method according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 9. The method according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 10. The method according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 11. The method according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 12. A method for treating an organ disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof selected from:

13. The method of any one of claims 1-12, wherein the organ disease or disorder is selected from the group consisting of a liver disease or disorder, a heart disease or disorder, a kidney disease or disorder, a pancreatic disease or disorder, a spleen disease or disorder, and a skin disease or disorder.

14. The method of claim 13, wherein the organ disease or disorder is selected from a liver disease or disorder, a heart disease or disorder, and a kidney disease or disorder.

15. The method of claim 14, wherein the organ disease or disorder is a liver disease or disorder.

16. The method of claim 15, wherein the organ disease or disorder is a liver disease or disorder selected from liver injury, drug-induced liver injury, liver failure, fulminant or acute liver failure, and acute-on-chronic liver failure.

17. The method of claim 14, wherein the organ disease or disorder is a cardiac disease or disorder.

18. The method of claim 17, wherein the organ disease or disorder is a cardiac disease or disorder selected from ischemia-reperfusion injury, ischemia, coronary artery disease, sepsis-induced cardiovascular dysfunction, drug-induced cardiotoxicity, viral myocarditis, and complications from cardiac transplantation.

19. The method of claim 14, wherein the organ disease or disorder is a kidney disease or disorder.

20. The method of claim 19, wherein the kidney disease or disorder is acute kidney injury.

21. The method of claim 20, wherein the renal disease or disorder is acute kidney injury due to hypovolemia, hypotension, renal vasoconstriction, glomerular efferent arteriolar vasodilation, chronic renal ischemia, chronic renal sepsis, chronic nephrotoxins, renal transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, or intratubular obstruction.

22. The method of any one of claims 1-21, wherein the compound is administered by injectable delivery.

23. The method of claim 22, wherein the injectable delivery is intravenous delivery.

24. The method of claim 23, wherein the intravenous delivery is selected from the group consisting of bolus injection, intravenous drip, and infusion pump.

25. The method of claim 22, wherein the injectable delivery is intraperitoneal delivery.

26. The method of any one of claims 1-25, further comprising administering a second therapeutic agent.

27. The method of claim 26, wherein the second therapeutic agent is selected from the group consisting of N-acetylcysteine, corticosteroids, and vasopressors.

Images