Methods of treating organ diseases or disorders 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 diseases and disorders of an organ, wherein the disease or disorder of the organ is selected from diseases or disorders of the liver, heart, kidney, pancreas, spleen, or skin.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 368,961, filed July 20, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] A variety of disease processes, including liver injury, acute kidney injury, and heart disease, can affect organs such as the liver, kidneys, heart, pancreas, spleen, and skin. Summary of the Invention

[0003] There is still a need for novel new compounds for treating diseases of these organs. ASK1 inhibitors can be useful for treating diseases of these organs. Orally administered ASK1 inhibitors described herein exhibit preferential distribution to the liver and kidney, achieving organ concentrations several times higher than plasma concentrations. Injectable administration of the ASK1 inhibitors described herein also exhibits preferential distribution to the liver and kidney, and is therefore suitable for treating patients for whom the injectable administration route is preferable to the oral route (including patients who are unconscious, have difficulty swallowing, or require rapid onset of pharmacological activity). Thus, in some embodiments, the ASK1 inhibitors described herein are useful for treating diseases of organs.

[0004] In one aspect, the present specification describes a method for treating an organ disease or disorder in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound that inhibits ASK1, or a pharmaceutically acceptable salt or solvate thereof.

[0005] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a compound of formula IIa

[0006] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0007] [ka] teeth,

[0008] [ka] and R 1 teeth

[0009] [ka] and Z is C(R 9 )2, R 5 is halogen and C 1-6 is selected from the group consisting of alkyl, Each R 25 are independently 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 selected from pyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. 1-9 heteroaryl; C 1-9 Heteroaryl is optionally selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-8cycloalkyl; Each R 6 are independently selected from the group consisting of 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 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 forming a heteroaryl, wherein the heteroaryl is selected from imidazolyl, pyrazolyl, and pyrrolyl, wherein C 2-9 Heterocycle 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 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 8 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is hydrogen, Each R 13 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 14 is independently selected from the group consisting of C1-C6 alkyl; n is 0, 1, or 2; p is 0 or 1.

[0010] In some embodiments, n is 1.

[0011] In some embodiments, R 25 is -C(=O)N(R 6 )2, and each R 6is independently selected from the group consisting of hydrogen, C1-C6 alkyl, —C1-C6 alkyl-O—C1-C6 alkyl, —C1-C6 alkyl-pyrazole, and C3-C8 cycloalkyl.

[0012] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 forming a heteroaryl, wherein heteroaryl is selected from imidazolyl, pyrazolyl, and pyrrolyl, wherein C 2-9 Heterocycle or C 2-9 Heteroaryl is optionally -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 with one substituent selected from the group consisting of:

[0013] In some embodiments, R 25 teeth,

[0014] [ka] is.

[0015] In some embodiments, R 25 teeth,

[0016] [ka] is.

[0017] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a compound of formula I

[0018] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0019] [ka] teeth,

[0020] [ka] and Z is O, S, C(=O), N(R 8 ) or C(R 9 )2, R 1 and R 3 are each independently hydrogen, halogen, -CN, -OH, -OR 6 , -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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 Heterocycle, C 6-10 Aryl, C1-9 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: R 2 represents hydrogen, halogen, -CN, -OH, -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: R 2 and R 3 is not simultaneously hydrogen, Each R 4 and each R 5 are each independently a halogen, -CN, and C1-6 is selected from the group consisting of alkyl, R 5a is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles, or two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 forming a heteroaryl, Each R 7 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; R 8 is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; Each R 13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, or two R on the same heteroatom 13 However, together with the heteroatoms to which they are attached, 2-9 forming a heterocyclic ring, Each R 14 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0021] In some embodiments, R 2 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl; 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0022] In some embodiments, R 2 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0023] In some embodiments, R 2 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0024] In some embodiments, R 2 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0025] In some embodiments, R 2 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 In some embodiments, R is substituted with 1 or 2 substituents selected from the group consisting of cycloalkyl. 2 teeth,

[0026] [ka] where R 11 is C1-C6 alkyl or C3-C6 cycloalkyl.

[0027] In some embodiments, R 2 teeth,

[0028] [ka] where R 12 is halo, C1-C6 alkyl, or C3-C6 cycloalkyl, and m is 1 or 2.

[0029] In some embodiments, R2 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0030] In some embodiments, R 2 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0031] In some embodiments, R 2 teeth,

[0032] [ka] is.

[0033] In some embodiments, R 2 teeth,

[0034] [ka] where R 10 is heteroaryl.

[0035] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C1-C6 alkyl.

[0036] In some embodiments, R 3 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 Heteroaryl-cycloalkyl is defined herein as C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0037] In some embodiments, R 3 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0038] In some embodiments, R 3 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0039] In some embodiments, R 3 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0040] In some embodiments, R 3 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0041] In some embodiments, R 3 teeth,

[0042] [ka] where R 11 is C1-C6 alkyl or C3-C6 cycloalkyl.

[0043] In some embodiments, R 3 teeth,

[0044] [ka] where each R12 is independently halo, C1-C6 alkyl, or C3-C6 cycloalkyl, and m is 1 or 2.

[0045] In some embodiments, R 3 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0046] In some embodiments, R 3 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0047] In some embodiments, R 3 teeth,

[0048] [ka] is.

[0049] In some embodiments, R 3 teeth,

[0050] [ka] where R 10 is heteroaryl.

[0051] In some embodiments, R 3 HA-OR 6 and R 6 is C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, and -C1-C6 alkyl-C 2-9 In some embodiments, R is selected from the group consisting of:2 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl.

[0052] In some embodiments, R 1 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0053] In some embodiments, R 1 is C 1-9 Heteroaryl and Fused C 5-9 heteroaryl-cycloalkyl; 1-9Heteroaryl 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0054] In some embodiments, R 1 is C 1-9 Heteroaryl and Fused C 5-9 heteroaryl-cycloalkyl; 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 Heterocycle, 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)2R 13 , -S(=O)2-N(R 13 )2, -N(R 13 )2, -N(R 13 )C(=O)R14 , and -N(R 13 )S(=O)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0055] In some embodiments, R 1 is selected from the group consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole, and the triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0056] In some embodiments, R 1 is selected from the group consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole, and the triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0057] In some embodiments, R1 teeth

[0058] [ka] is.

[0059] In some embodiments, R 1 teeth

[0060] [ka] is.

[0061] In some embodiments, R 1 teeth

[0062] [ka] is.

[0063] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a compound of formula II

[0064] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0065] [ka] teeth,

[0066] [ka] and R 1 teeth,

[0067] [ka] and Z is O, S, C(=O), N(R 8 ), or C(R 9 )2, X is O or S, R 2 is C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl; Each R 4 are independently hydrogen, halo, C 1-6 Alkyl, and C 3-6 cycloalkyl; Or one R 4 and another R 2 , R 3 , or R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 5 are independently halogen and C 1-6 is selected from the group consisting of alkyl, R 5a is selected from the group consisting of hydrogen and C1-C6 alkyl; R 25 is halogen, -CN, -OH, -OR 6 , -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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 Heterocycle, 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 Heterocycle, 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 3-8Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles, or two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 forming a heteroaryl, Each R 7 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; R 8 is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; Each R 13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, or two R on the same heteroatom 13 However, together with the heteroatoms to which they are attached, 2-9 forming a heterocyclic ring, Each R 14is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0068] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a compound of formula III

[0069] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0070] [ka] teeth,

[0071] [ka] and R 1 teeth,

[0072] [ka] and Z is O, S, C(=O), N(R 8 ) or C(R 9 )2, X is O or S; R 2 is C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl; Each R 4are independently hydrogen, halo, C 1-6 Alkyl, and C 3-6 cycloalkyl; Or one R 4 and another R 2 , R 3 , or R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 5 are independently halogen and C 1-6 is selected from the group consisting of alkyl, R 5a is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 25 are independently halogen, -CN, -OH, -OR 6 , -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7, -S(=O)2N(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 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, -C3-C8 cycloalkyl-phenyl, and C 2-9 heterocycle, wherein C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, -C3-C8 cycloalkyl-phenyl, and C 2-9 The heterocycle may optionally be selected from the group consisting of 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 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Form a heteroaryl, where C 2-9 Heterocycle 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 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R7 are independently C1-C6 alkyl, C3-C8 cycloalkyl, and C 2-9 heterocycle, C3-C8 cycloalkyl and C 2-9 The heterocycle is optionally substituted with 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 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 8 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; Each R 13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, or two R on the same heteroatom 13 However, together with the heteroatoms to which they are attached, 2-9 forming a heterocyclic ring, Each R 14 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0073] In some embodiments, R 25 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 Heteroaryl-cycloalkyl is defined herein as C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0074] In some embodiments, R 25 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0075] In some embodiments, R 25 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0076] In some embodiments, R 25 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0077] In some embodiments, R 25 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0078] In some embodiments, R 25 teeth,

[0079] [ka] and each R 11 is independently C1-C6 alkyl or C3-C6 cycloalkyl.

[0080] In some embodiments, R 25 teeth,

[0081] [ka] and each R 12is independently hydrogen, halo, C1-C6 alkyl, or C3-C6 cycloalkyl; and m is 1 or 2.

[0082] In some embodiments, R 25 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0083] In some embodiments, R 25 is selected from the group consisting of pyrimidine, pyrazine, and pyridazine, and the pyrimidine, pyrazine, and pyridazine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0084] In some embodiments, R 25 is halogen, -OR 6 , -N(R 6 )2, C 1-6 alkyl, pyrazole, imidazole, thiazole, and pyridine, wherein pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0085] In some embodiments, R 25 is halogen, -OR 6 , -N(R 6 )2, C 1-6 alkyl, and unsubstituted pyridine.

[0086] In some embodiments, R 25 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0087] In some embodiments, R 25 teeth,

[0088] [ka] is.

[0089] In some embodiments, R 25 teeth,

[0090] [ka] where R 10 is heteroaryl.

[0091] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Form a heteroaryl, where C 2-9 Heterocycle 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 1, 2, or 3 substituents selected from the group consisting of:

[0092] In some embodiments, R 25 teeth,

[0093] [ka] is.

[0094] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Forming a heteroaryl.

[0095] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Forming a heteroaryl.

[0096] In some embodiments, R 25 teeth,

[0097] [ka] is.

[0098] In some embodiments, R 25 HA-OR 6 and R 6 is C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, and -C1-C6 alkyl-C 2-9 heterocycles.

[0099] In some embodiments, R 1 teeth,

[0100] [ka] is.

[0101] In some embodiments, R 1 teeth,

[0102] [ka] is.

[0103] In some embodiments, R 1 teeth,

[0104] [ka] is.

[0105] In some embodiments, R 1 teeth,

[0106] [ka] is.

[0107] In some embodiments, R 1 teeth,

[0108] [ka] is.

[0109] In some embodiments,

[0110] [ka] teeth,

[0111] [ka] In some embodiments, p is 0.

[0112] In some embodiments,

[0113] [ka] teeth,

[0114] [ka] In some embodiments,

[0115] [ka] teeth,

[0116] [ka] In some embodiments, q is 0.

[0117] 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 is H.

[0118] 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.

[0119] In another aspect, described herein is a method of treating an organ disease or disorder in a subject in need thereof, the method 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 is a method of treating an organ disease or disorder in a subject in need thereof, the method 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.

[0120] 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, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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, 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, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, 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. In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need of such treatment, 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 liver disease or disorder. In some embodiments, described herein is a method for treating an organ disease or disorder in a subject in need of such treatment, 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 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. Examples of fulminant hepatic failure include fulminant hepatic failure due to drug overdose, such as acetaminophen overdose, fulminant hepatic failure due to poisoning with the wild-type mushroom Amanita phalloides, or carbon tetrachloride injury.Examples of acute liver failure include, for example, acute liver failure due to herbal supplement poisoning, acute liver failure due to surgical ischemia-reperfusion injury (liver transplant, 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 exacerbated liver failure include acute exacerbated liver failure due to alcoholic hepatitis, acute exacerbated liver failure due to autoimmune hepatitis, acute exacerbated liver failure due to viral hepatitis, and acute exacerbated liver failure due to cirrhosis. In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof is described, 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 cardiac disease or disorder. In some embodiments, described is a method for treating organ disease or disorder in a subject in need of such treatment, 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 cardiac disease or disorder selected from the group consisting of ischemia-reperfusion injury, ischemia, coronary artery disease, cardiovascular dysfunction due to sepsis, drug-induced cardiotoxicity, viral myocarditis, and complications resulting from heart transplantation.In some embodiments, described is a method for treating organ disease or disorder in a subject in need of such treatment, 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. In some embodiments, a method 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 that is acute kidney injury.In some embodiments, methods are described 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, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is hypovolemia, hypotension, renal vasoconstriction, glomerular efferent arteriolar dilation, prolonged renal ischemia, prolonged renal sepsis, prolonged renal nephrotoxin, renal transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, or acute kidney injury due to intratubular obstruction.

[0121] In some embodiments of the method described herein, the compound of Formula I, Formula II, Formula IIa, or Formula III, or their pharmaceutically acceptable salts or solvates, is administered by injectable delivery.In some embodiments of the method described herein, the compound of Formula I, Formula II, Formula IIa, or Formula III, or their pharmaceutically acceptable salts or solvates, is administered by intravenous delivery, and the intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump.In some embodiments of the method described herein, the compound of Formula I, Formula II, Formula IIa, or Formula III, or their pharmaceutically acceptable salts or solvates, is administered by intraperitoneal delivery.

[0122] In some embodiments, the methods described herein further comprise administering a second therapeutic agent, hi some embodiments, the second therapeutic agent is selected from N-acetylcysteine, a corticosteroid, and a hypertensive agent.

[0123] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It will be understood, however, 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 disclosure will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0124] ASK1 is a membrane-proximal MAP3K (MAP-kinase-kinase-kinase) upstream of a pathway that plays a key role in cellular responses to environmental stress, 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, leading to apoptosis and inflammation. ASK1 is a promising therapeutic target for organ diseases, including liver injury, kidney injury, and heart disease. ASK1, a positive regulator of mitochondrial apoptosis, is precisely regulated and activated by diverse cell damage signals, such as receptor-acting inflammatory cytokines (e.g., TNFα and LPS), calcium and intracellular sensors (e.g., the redox sensor thioredoxin, and the ER stress-responsive IRE1).

[0125] Regulation of ASK1 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-chronic liver failure. Drug-induced liver failure includes, but is not limited to, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants, which lead to liver failure. Fulminant liver failure can be due to various causes, including, but not limited to, acetaminophen overdose and poisoning. Poisoning can be due to the wild-type mushroom Amanita phalloides, carbon tetrachloride, and herbal supplements, including, but not limited to, kava, ephedra, skullcap, and pennyroyal. Acute liver failure can result from surgical ischemia-reperfusion injury (liver transplant, partial resection), vascular diseases, including, but not limited to, Budd-Chiari syndrome, metabolic diseases, including, but not limited to, Wilson's disease and acute fatty liver of pregnancy, and septic shock. Acute exacerbated liver failure can be due to a variety of causes, including, but not limited to, alcoholic hepatitis, autoimmune hepatitis, and viral hepatitis, including, but not limited to, hepatitis A, B, and E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus.

[0126] ASK1 regulation is a promising therapeutic target for acute kidney injury, which can be caused by various factors, including but not limited to hypovolemia, hypotension, renal vasoconstriction, glomerular efferent arteriolar vasodilation, prolonged renal ischemia, renal transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, and intratubular obstruction.

[0127] ASK1 regulation is a promising therapeutic target for cardiac disease and disorder.Heart disease and disorder include but are not limited to ischemia-reperfusion injury, ischemia, septic shock, cardiotoxicity and viral myocarditis or heart transplantation-induced disease and disorder.

[0128] In some embodiments, the ASK1 inhibitor described herein is delivered orally or by injection.The ASK1 inhibitor described herein exhibits preferential distribution to the liver and kidney after oral or injection, and achieves organ concentrations several times higher than plasma concentrations.In some embodiments, injectable administration is advantageous for treating patients, including those who are unconscious, have difficulty swallowing, or require rapid onset of pharmacological activity, where injectable administration route is preferable to oral route.

[0129] Additionally, in some embodiments, the ASK1 inhibitors described herein are useful as adjuvants for systemic treatment with N-acetylcysteine, corticosteroids, and hypertensive agents such as, but not limited to, vasopressin and catecholamines.

[0130] Specific Terms Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used unless otherwise indicated. In this application, the use of "or" or "and" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the specific inventions described.

[0131] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be branched or straight-chain. An "alkyl" group may have 1 to 15 carbon atoms (whenever it appears herein, a numerical range such as "1 to 15" refers to each integer within the given range; for example, "1 to 15 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 15 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified). In one aspect, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, and the like.

[0132] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR, where R refers to the remainder 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, -C(CH)=CH, -CH=CHCH, -C(CH)=CHCH, and -CHCH=CH.

[0133] The term "alkynyl" refers to a species of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3-C≡CCH2CH3, and -CH2C≡CH.

[0134] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, where each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. A cycloalkyl can be saturated or partially unsaturated. A cycloalkyl can also be fused to an aromatic ring, where the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A cycloalkyl group can be substituted or unsubstituted. Depending on the structure, the cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group such as, but not limited to, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cycloethane-1,1-diyl, cyclohexane-1,1-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl, etc.). In one aspect, the cycloalkyl is a C3-C6 cycloalkyl.

[0135] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. Aromatics are optionally substituted. The term "aromatic" includes both cycloalkylaryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., 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 of the atoms forming the ring is a carbon atom. Aryl groups are optionally substituted. Depending on the structure, aryl groups can be monoradicals or diradicals (i.e., arylene groups).

[0136] The term "heteroaryl," or alternatively, "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:

[0137] [ka] and the like. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. In some embodiments, a heteroaryl contains 0 to 3 N atoms in the ring. In some embodiments, a heteroaryl contains 1 to 3 N atoms in the ring. In some embodiments, a heteroaryl contains 0 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, a heteroaryl is a monocyclic or bicyclic heteroaryl. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl. Depending on the structure, a heteroaryl group can be a single-ended radical or a double-ended radical (i.e., a heteroarylene group).

[0138] A "heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group in which at least one of the carbon atoms of the cycloalkyl is replaced with nitrogen (unsubstituted or substituted, e.g., -NH-, -N(alkyl)-), oxygen (-O-), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)-). The radical can be fused with an aryl or heteroaryl. In some embodiments, heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is C-C10 Heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-3 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0139] The term "halo" or alternatively "halogen" or "halide" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term "bond" or "single bond" refers to a chemical bond between two atoms or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a single bond, the referenced group is absent, thereby allowing for the formation of a single bond between the remaining specified groups.

[0140] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0141] 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, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, amino, including mono- and di-substituted amino groups, and protected derivatives thereof. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) include oxo (=O).

[0142] In certain embodiments, the compounds provided herein possess one or more stereocenters, and each center independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof. Where appropriate, stereoisomers may be obtained by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. In some embodiments, the halogen is F or Cl. In some embodiments, the halogen is F.

[0143] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula I, Formula II, Formula IIa, or Formula III, as well as active metabolites of these compounds that have the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated forms.

[0144] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means having no lasting adverse effects on the health of the subject being treated.

[0145] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as a compound of Formula I, II, IIa, or III described herein, or a pharmaceutically acceptable salt thereof, and an auxiliary agent are both administered to a patient at the same time in the form of a single entity or dosage. The term "unfixed combination" means that the active ingredients, such as a compound of Formula I, II, IIa, or III described herein, or a pharmaceutically acceptable salt thereof, and an auxiliary agent are administered to a patient simultaneously, concurrently, or sequentially as separate entities without any specific intervening time limit, such that administration provides an effective level of the two compounds to the patient's body. The latter term also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0146] The term "subject" or "patient" includes any member of the class of mammals, including, but not limited to, humans, non-human primates such as chimpanzees, and other apes and monkeys, livestock such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents, such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0147] The terms "treat," "treating," or "treatment" as used herein include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition, prophylactically and / or therapeutically.

[0148] method 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

[0149] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0150] [ka] teeth,

[0151] [ka] and Z is O, S, C(=O), N(R 8 ) or C(R 9 )2, R 1 and R 3 are each independently hydrogen, halogen, -CN, -OH, -OR 6 , -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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, C2-6 Alkynyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: R 2 represents hydrogen, halogen, -CN, -OH, -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and R is substituted with 1, 2, or 3 substituents selected from the group consisting of 2 and R 3is not simultaneously hydrogen, Each R 4 and each R 5 are each independently a halogen, -CN, and C 1-6 is selected from the group consisting of alkyl, R 5a is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles, or two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 forming a heteroaryl, Each R 7 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; R 8 is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; Each R 13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, or two R on the same heteroatom 13 However, together with the heteroatoms to which they are attached, 2-9 forming a heterocyclic ring, Each R 14 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0152] In some embodiments, R2 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0153] In some embodiments, R 2 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0154] In some embodiments, R 2 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0155] In some embodiments, R 2is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0156] In some embodiments, R 2 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0157] In some embodiments, R 2 teeth,

[0158] [ka] and each R 11 is C1-C6 alkyl or C3-C6 cycloalkyl, and R 11a is —CN, —OH, C1-C6 alkyl, or C3-C6 cycloalkyl, and u is 0, 1, or 2.

[0159] In some embodiments, R 2 teeth,

[0160] [ka] where R 11 is C1-C6 alkyl or C3-C6 cycloalkyl.

[0161] In some embodiments, R 2 teeth,

[0162] [ka] [ka] is.

[0163] In some embodiments, R 2 teeth,

[0164] [ka] where each R 12 is independently halo, C1-C6 alkyl, or C3-C6 cycloalkyl, and m is 1 or 2.

[0165] In some embodiments, R 2 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0166] In some embodiments, R 2 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0167] In some embodiments, R 2 teeth,

[0168] [ka] is.

[0169] In some embodiments, R 2 teeth,

[0170] [ka] where R 10 is heteroaryl.

[0171] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C1-C6 alkyl.

[0172] In some embodiments, R 3 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl; 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, -C(=O)R14 , -C(=O)OR 13 , -C(=O)N(R 13 )2, -S(=O)R 14 , -S(=O)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0173] In some embodiments, R 3 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0174] In some embodiments, R 3 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles and C 1-9Heteroaryl 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0175] In some embodiments, R 3 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0176] In some embodiments, R 3 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0177] In some embodiments, R 3 teeth,

[0178] [ka] and each R 11 is C1-C6 alkyl or C3-C6 cycloalkyl, and R 11a is —CN, —OH, C1-C6 alkyl, or C3-C6 cycloalkyl, and u is 0, 1, or 2.

[0179] In some embodiments, R 3 teeth,

[0180] [ka] where R 11 is C1-C6 alkyl or C3-C6 cycloalkyl.

[0181] In some embodiments, R 3 teeth,

[0182] [ka] is.

[0183] In some embodiments, R 3 teeth,

[0184] [ka] where each R 12 is independently halo, C1-C6 alkyl, or C3-C6 cycloalkyl, and m is 1 or 2.

[0185] In some embodiments, R 3 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0186] In some embodiments, R 3 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0187] In some embodiments, R 3 teeth,

[0188] [ka] is.

[0189] In some embodiments, R 3 teeth,

[0190] [ka] where R 10 is heteroaryl.

[0191] In some embodiments, R 3 HA-OR 6 and R 6 is C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, and -C1-C6 alkyl-C 2-9In some embodiments, R is selected from the group consisting of: 2 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl.

[0192] In some embodiments, R 1 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0193] In some embodiments, R 1 is C 1-9 Heteroaryl and Fused C 5-9heteroaryl-cycloalkyl; 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0194] In some embodiments, R 1 is C 1-9 Heteroaryl and Fused C 5-9 heteroaryl-cycloalkyl; 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 Heterocycle, 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)2R 13 , -S(=O)2-N(R 13 )2, -N(R13 )2, -N(R 13 )C(=O)R 14 , and -N(R 13 )S(=O)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0195] In some embodiments, R 1 is selected from the group consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole, and the triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0196] In some embodiments, R 1 is selected from the group consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole, and the triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0197] In some embodiments, R 1 teeth,

[0198] [ka] where R 15 is C 1-6 Alkyl or C 3-8 cycloalkyl, and R 16 is hydrogen, halo, -CN, C 1-6 Alkyl or C 3-8 It is cycloalkyl.

[0199] In some embodiments, R 1 teeth,

[0200] [ka] where R 15 is C 1-6 Alkyl or C 3-8 is cycloalkyl, and R 16 Halo, -CN, C 1-6 Alkyl, or C 3-8 It is cycloalkyl.

[0201] In some embodiments, R 1 teeth,

[0202] [ka] [ka] is.

[0203] In some embodiments, R 1 teeth,

[0204] [ka] is.

[0205] In some embodiments, R 1 teeth,

[0206] [ka] where 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 Heterocycle, 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)2R 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)2R 13 and 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 Heterocycle, 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)2R 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)2R 13wherein 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, and 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 It is cycloalkyl.

[0207] 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, and each R 18 are independently hydrogen, halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, or C 1-6 It is haloalkyl.

[0208] In some embodiments, each R 17 are independently hydrogen, halo, -CN, or C 1-6 alkyl, and each R 18 are independently hydrogen, halo, -CN, or C 1-6 It is alkyl.

[0209] In some embodiments, R 1 teeth

[0210] [ka] is.

[0211] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a compound of formula II

[0212] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0213] [ka] teeth,

[0214] [ka] and R 1 teeth

[0215] [ka] and Z is O, S, C(=O), N(R 8 ) or C(R 9 )2, X is O or S; R 2 is C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl; Each R 4 are independently hydrogen, halo, C 1-6 Alkyl, and C 3-6 cycloalkyl; Or one R 4 and another R 2 , R 3 , or R 4and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 5 are independently halogen and C 1-6 is selected from the group consisting of alkyl, R 5a is selected from the group consisting of hydrogen and C1-C6 alkyl; R 25 is halogen, -CN, -OH, -OR 6 , -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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 6C(=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 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles, or two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 forming a heteroaryl, Each R 7 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; R 8 is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; Each R 13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, or two R on the same heteroatom 13 However, together with the heteroatoms to which they are attached, 2-9 forming a heterocyclic ring, Each R 14 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0216] In some embodiments, R 25 is C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 Heteroaryl-cycloalkyl is defined herein as C 3-8Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0217] In some embodiments, R 25 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 13 , -S(=O)2-N(R 13 )2, -N(R13 )2, -N(R 13 )C(=O)R 14 , and -N(R 13 )S(=O)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0218] In some embodiments, R 25 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0219] In some embodiments, R 25 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0220] In some embodiments, R 25 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0221] In some embodiments, R 25 teeth,

[0222] [ka] and each R 11 is C1-C6 alkyl or C3-C6 cycloalkyl, and R 11a is —CN, —OH, C1-C6 alkyl, or C3-C6 cycloalkyl, and u is 0, 1, or 2.

[0223] In some embodiments, R 25 teeth,

[0224] [ka] where R 11 is C1-C6 alkyl or C3-C6 cycloalkyl.

[0225] In some embodiments, R 25 teeth,

[0226] [ka] [ka] is.

[0227] In some embodiments, R 25 teeth,

[0228] [ka] where R 12 is halo, C1-C6 alkyl, or C3-C6 cycloalkyl, and m is 1 or 2.

[0229] In some embodiments, R 25 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0230] In some embodiments, R 25 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0231] In some embodiments, R 25 teeth,

[0232] [ka] is.

[0233] In some embodiments, R 25 teeth,

[0234] [ka] where R 10 is heteroaryl.

[0235] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Forming a heteroaryl.

[0236] In some embodiments, R 25 teeth,

[0237] [ka] is.

[0238] In some embodiments, R 25 HA-OR 6 and R 6 is C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, and -C1-C6 alkyl-C 2-9 heterocycles.

[0239] In some embodiments,

[0240] [ka] teeth,

[0241] [ka] In some embodiments, p is 0.

[0242] In some embodiments,

[0243] [ka] teeth,

[0244] [ka] In some embodiments,

[0245] [ka] teeth,

[0246] [ka] In some embodiments, q is 0.

[0247] 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 is H.

[0248] In some embodiments, R 1 teeth,

[0249] [ka] and In the formula, R 2 is C 3-6 is cycloalkyl, and R 3 is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, and each R 4 are independently hydrogen, halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl; or one R 4 and another R2 , R 3 , or R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0250] In some embodiments, R 1 teeth,

[0251] [ka] and In the formula, R 3 is C 1-6 Alkyl, and C 3-6 cycloalkyl, and each R 4 are independently hydrogen, halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0252] In some embodiments, R 1 teeth,

[0253] [ka] is.

[0254] In some embodiments, R 1 teeth,

[0255] [ka] is.

[0256] In some embodiments, R 1 teeth,

[0257] [ka] is.

[0258] In some embodiments, R 1 teeth,

[0259] [ka] where R 2 and R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R13 , -S(=O)2-N(R 13 )2, -N(R 13 )2, -N(R 13 )C(=O)R 14 , and -N(R 13 )S(=O)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0260] In some embodiments, R 1 teeth,

[0261] [ka] where X is O, N, or S, and each R 19 are independently halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and y is 0, 1, 2, 3, or 4.

[0262] In some embodiments, R 1 teeth,

[0263] [ka] where X is O, N, or S.

[0264] In some embodiments, R 1 teeth,

[0265] [ka] where X is N.

[0266] In some embodiments, R 1 teeth,

[0267] [ka] where X is O or S; 1 R 4 and another R 2 , R 3 , or R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0268] In some embodiments, R 1 teeth

[0269] [ka] is.

[0270] In some embodiments, R 1 teeth,

[0271] [ka] is.

[0272] In some embodiments, a method for treating an organ disease or disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a compound of formula III

[0273] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0274] [ka] teeth,

[0275] [ka] and R 1 teeth,

[0276] [ka] and Z is O, S, C(=O), N(R 8 ) or C(R 9 )2, X is O or S; R2 is C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl; Each R 4 are independently hydrogen, halo, C 1-6 Alkyl, and C 3-6 cycloalkyl; Or one R 4 and another R 2 , R 3 , or R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 5 are independently halogen and C 1-6 is selected from the group consisting of alkyl, R 5a is selected from the group consisting of hydrogen and C1-C6 alkyl; Each R25 are independently halogen, -CN, -OH, -OR 6 , -SR 6 , -S(=O)R 7 , -NO2, -N(R 6 )2, -S(=O)2R 7 , -NHS(=O)2R 7 , -S(=O)2N(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 Heterocycle, 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 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, -C3-C8 cycloalkyl-phenyl, and C 2-9 heterocycle, wherein C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, -C3-C8 cycloalkyl-phenyl, and C 2-9 The heterocycle may optionally be selected from the group consisting of 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 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Form a heteroaryl, where C 2-9 Heterocycle or C 2-9 Heteroaryl is optionally selected from halo, -OR 8 , -SR 8 , -N(R 8 )2, -C 1-6Alkyl, -OC 1-6 Alkyl, -C(=O)R 14 , -C(=O)OR 13 , and -N(R 13 )C(=O)R 14 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 7 are independently C1-C6 alkyl, C3-C8 cycloalkyl, and C 2-9 heterocycle, wherein C3-C8 cycloalkyl and C 2-9 The heterocycle is optionally substituted with 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 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R 8 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; Each R 13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, or two R on the same heteroatom 13 However, together with the heteroatoms to which they are attached, 2-9 forming a heterocyclic ring, Each R 14 is independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0277] In some embodiments, R 25 is C3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocycle, C 6-10 Aryl, C 1-9 Heteroaryl, and fused C 5-9 Heteroaryl-cycloalkyl is defined herein as C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0278] In some embodiments, R 25 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles and C 1-9 Heteroaryl is optionally selected from halo, -CN, C 1-6 Alkyl, -C 1-6Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0279] In some embodiments, R 25 is C 2-9 Heterocycles and C 1-9 heteroaryl; 2-9 Heterocycles 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 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0280] In some embodiments, R 25 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with one or two substituents selected from the group consisting of:

[0281] In some embodiments, R 25 is selected from the group consisting of pyrazole, imidazole, thiazole, and pyridine, and the pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0282] In some embodiments, R 25 teeth,

[0283] [ka] and each R 11 is C1-C6 alkyl or C3-C6 cycloalkyl, and R 11ais —CN, —OH, C1-C6 alkyl, or C3-C6 cycloalkyl, and u is 0, 1, or 2.

[0284] In some embodiments, R 25 teeth,

[0285] [ka] where R 11 is C1-C6 alkyl or C3-C6 cycloalkyl.

[0286] In some embodiments, R 25 teeth,

[0287] [ka] is.

[0288] In some embodiments, R 25 teeth,

[0289] [ka] where R 12 is halo, C1-C6 alkyl, or C3-C6 cycloalkyl, and m is 1 or 2.

[0290] In some embodiments, R 25 is selected from the group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.

[0291] In some embodiments, R 25 is selected from the group consisting of pyrimidine, pyrazine, and pyridazine, and the pyrimidine, pyrazine, and pyridazine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0292] In some embodiments, R 25 is halogen, -OR 6 , -N(R 6 )2, C 1-6 alkyl, pyrazole, imidazole, thiazole, and pyridine, wherein pyrazole, imidazole, thiazole, and pyridine are optionally selected from the group consisting of halo, C 1-6 Alkyl, and C 3-8 cycloalkyl.

[0293] In some embodiments, R 25 is halogen, -OR 6 , -N(R 6 )2, C 1-6 alkyl, and unsubstituted pyridine.

[0294] In some embodiments, R 25 is -C(=O)N(R 6 )2, and each R 6 are independently hydrogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-C 2-9 Heterocycle, -C1-C6 alkyl-C 2-9 Heteroaryl, C3-C8 cycloalkyl, and C 2-9 heterocycles.

[0295] In some embodiments, R 25 teeth,

[0296] [ka] and

[0297] In some embodiments, R 25 teeth,

[0298] [ka] where R 10 is heteroaryl.

[0299] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R on the same heteroatom 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Form a heteroaryl, where C 2-9 Heterocycle 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 1, 2, or 3 substituents selected from the group consisting of:

[0300] In some embodiments, R 25 teeth,

[0301] [ka] is.

[0302] In some embodiments, R 25 is -C(=O)N(R 6 )2, and two R 6 However, together with the heteroatoms to which they are attached, 2-9 Heterocycle or C 2-9 Forming a heteroaryl.

[0303] In some embodiments, R 25 teeth,

[0304] [ka] is.

[0305] In some embodiments, R 25 HA-OR 6 and R 6 is C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, and -C1-C6 alkyl-C 2-9 heterocycles.

[0306] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0307] In some embodiments, Z is C(R 9 )2. In some embodiments, Z is C(R 9 )2, and each R 9 is H.

[0308] 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 is C1-C6 alkyl.

[0309] In some embodiments,

[0310] [ka] teeth,

[0311] [ka] In some embodiments, p is 0.

[0312] In some embodiments,

[0313] [ka] teeth,

[0314] [ka] In some embodiments,

[0315] [ka] teeth,

[0316] [ka] In some embodiments, q is 0.

[0317] In some embodiments, R 1 teeth,

[0318] [ka] and In the formula, R 2 is C 3-6 is cycloalkyl, and R 3 is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, and each R 4 are independently hydrogen, halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, or one R 4 and another R 2 , R 3 , or R 4 and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, and 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, C2-9 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0319] In some embodiments, R 1 teeth,

[0320] [ka] and In the formula, R 3 is C 1-6 Alkyl, and C 3-6 cycloalkyl; Each R 4 are independently hydrogen, halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0321] In some embodiments, R 1 teeth,

[0322] [ka] is.

[0323] In some embodiments, R 1 teeth,

[0324] [ka] is.

[0325] In some embodiments, R 1 teeth,

[0326] [ka] is.

[0327] In some embodiments, R 1 teeth,

[0328] [ka] is.

[0329] In some embodiments, R 1 teeth,

[0330] [ka] is.

[0331] In some embodiments, R 1 teeth,

[0332] [ka] is.

[0333] In some embodiments, R 1 teeth,

[0334] [ka] is.

[0335] In some embodiments, R 1 teeth,

[0336] [ka] is.

[0337] In some embodiments, R 1 teeth,

[0338] [ka] where R 2 and R 4 together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, 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 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0339] In some embodiments, R 1 teeth,

[0340] [ka] where X is O, N, or S, and each R 19 are independently halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 and y is 0, 1, 2, 3, or 4.

[0341] In some embodiments, R 1 teeth,

[0342] [ka] where X is O, N, or S.

[0343] In some embodiments, R 1 teeth,

[0344] [ka] where X is N.

[0345] In some embodiments, R 1 teeth,

[0346] [ka] and X is O or S; 1 R 4 and another R 2 , R 3 , or R 4and together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, N, and S, wherein the 5- or 6-membered ring is a saturated, unsaturated, or aromatic ring, wherein the 5- or 6-membered ring optionally contains halo, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-9 Heterocycle, 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)2R 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)2R 13 is substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0347] In some embodiments, R 1 teeth

[0348] [ka] is.

[0349] In some embodiments, R 1 teeth,

[0350] [ka] is.

[0351] In some embodiments, presented 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.

[0352] In some embodiments, there are methods for treating organ diseases or disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there are methods for treating organ diseases or disorders 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, there are methods for treating organ diseases or disorders 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, there are methods for treating organ diseases or disorders 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, there 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.

[0353] In some embodiments, there 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, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, kidney disease or disorder, pancreatic disease or disorder, spleen disease or disorder, and skin disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, and kidney disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder and kidney disease or disorder.

[0354] In some embodiments, there 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, wherein the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, kidney disease or disorder, pancreatic disease or disorder, spleen disease or disorder, and skin disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, and kidney disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder and kidney disease or disorder.

[0355] In some embodiments, there 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, wherein the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, kidney disease or disorder, pancreatic disease or disorder, spleen disease or disorder, and skin disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, and kidney disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder and kidney disease or disorder.

[0356] In some embodiments, there 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, wherein the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, kidney disease or disorder, pancreatic disease or disorder, spleen disease or disorder, and skin disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, and kidney disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder and kidney disease or disorder.

[0357] In some embodiments, there 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, wherein the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, kidney disease or disorder, pancreatic disease or disorder, spleen disease or disorder, and skin disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder, heart disease or disorder, and kidney disease or disorder. In some embodiments, the organ disease or disorder is selected from liver disease or disorder and kidney disease or disorder.

[0358] 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

[0359] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0360] 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

[0361] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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 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.

[0362] 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

[0363] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0364] 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

[0365] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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 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.

[0366] 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

[0367] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0368] 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:

[0369] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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 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.

[0370] 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:

[0371] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0372] 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:

[0373] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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 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.

[0374] 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:

[0375] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0376] 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:

[0377] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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 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.

[0378] In some embodiments, there is a method for treating a disease or disorder of an organ 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.

[0379] In some embodiments, there 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 described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the organ disease or disorder is selected from 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 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.

[0380] In some embodiments, described herein are methods for treating an organ disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from Table 1.

[0381] 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 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 a liver disease or disorder, a heart disease or disorder, and a kidney disease or disorder.

[0382] [Table 1-1] [Table 1-2] [Table 1-3]

[0383] 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 exacerbated liver failure. In some embodiments, the fulminant liver failure is caused by a drug overdose, acetaminophen overdose, poisoning by the wild-type mushroom Amanita phalloides, or carbon tetrachloride injury. In some embodiments, the acute liver failure is caused by poisoning, surgical ischemia-reperfusion injury, vascular disease, metabolic disease, pregnancy, or septic shock. In some embodiments, the acute exacerbated liver failure is caused by alcoholic hepatitis, autoimmune hepatitis, viral hepatitis, or cirrhosis.

[0384] 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 caused by the wild-type mushroom Amanita phalloides or carbon tetrachloride injury, acute liver failure due to poisoning with herbal supplements including kava, ephedra, skullcap, and pennyroyal, acute liver failure due to surgical ischemia-reperfusion injury (liver transplant, partial resection), acute liver failure due to vascular disease such as Budd-Chiari syndrome, acute liver failure due to metabolic disease such as Wilson's disease, acute fatty liver of pregnancy, acute liver failure due to septic shock, acute exacerbation of liver failure due to alcoholic hepatitis, acute-chronic liver failure due to autoimmune hepatitis, and acute exacerbation of liver failure due to viral hepatitis, e.g., hepatitis A, hepatitis B, and hepatitis E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus.

[0385] In some embodiments, the liver disease or disorder is drug-induced liver injury. 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 with the wild-type mushroom Amanita phalloides or carbon tetrachloride poisoning. In some embodiments, the liver disease or disorder is acute liver failure due to poisoning with herbal supplements including kava, ephedra, skullcap, and pennyroyal. In some embodiments, the liver disease or disorder is acute liver failure due to surgical ischemia-reperfusion injury (liver transplant, partial resection). In some embodiments, the liver disease or disorder is acute liver failure due to vascular disease such as Budd-Chiari syndrome. In some embodiments, the liver disease or disorder is acute liver failure due to metabolic disease such as 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 exacerbated liver failure due to alcoholic hepatitis. In some embodiments, the liver disease or disorder is acute exacerbation of liver failure due to autoimmune hepatitis, hi some embodiments, the liver disease or disorder is acute exacerbation of liver failure due to viral hepatitis, such as hepatitis A, hepatitis B, hepatitis E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus.

[0386] In some embodiments, the organ disease or disorder is a cardiac disease or disorder. In some embodiments, the cardiac disease or disorder is selected from ischemia-reperfusion injury, cardiovascular dysfunction from ischemia, coronary artery disease, sepsis, drug-induced cardiotoxicity, viral myocarditis, and complications resulting from cardiac transplantation. In some embodiments, the cardiac disease or disorder is ischemia-reperfusion injury. In some embodiments, the ischemia-reperfusion injury results from acute ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), cardiopulmonary bypass, and extracorporeal circulation, or a combination thereof. In some embodiments, the cardiac disease or disorder is ischemia. Examples of ischemia include, but are not limited to, coronary artery disease and cardiac ischemia. In some embodiments, the cardiac disease or disorder is coronary artery disease. In some embodiments, the cardiac disease or disorder is cardiovascular dysfunction from sepsis. In some embodiments, the cardiac disease or disorder is drug-induced cardiotoxicity. In some embodiments, the toxicity is due to doxorubicin. In some embodiments, the cardiac disease or disorder is viral myocarditis, hi some embodiments, the cardiac disease or disorder is a complication resulting from a heart transplant.

[0387] In some embodiments, the organ disease or disorder is a kidney disease or disorder. In some embodiments, the kidney disease or disorder is acute kidney injury. In some embodiments, the acute kidney injury is due to hypovolemia, hypotension, renal vasoconstriction, glomerular efferent arteriolar dilation, prolonged renal ischemia, prolonged renal sepsis, prolonged renal nephrotoxins, renal transplantation, acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, and intratubular obstruction. In some embodiments, the hypovolemia is due to hemorrhage, severe burns, and gastrointestinal fluid loss such as diarrhea, vomiting, and high ostomy output. In some embodiments, the hypotension is due to reduced cardiac output such as cardiogenic shock, large pulmonary embolism, and acute coronary syndrome. In some embodiments, the hypotension is due to systemic vasodilation such as septic shock, anaphylaxis, anesthesia administration, and hepatic syndrome. In some embodiments, renal vasoconstriction is caused by nonsteroidal anti-inflammatory drugs (NSAIDs), iodinated contrast agents, amphotericin B, calcineurin inhibitors, and hepatic syndrome. In some embodiments, glomerular efferent arteriolar vasodilation is caused by ACE inhibitors and angiotensin receptor blockers. In some embodiments, acute tubular necrosis is caused by ischemia due to prolonged prerenal injury; drugs such as aminoglycosides, vancomycin, amphotericin B, and pentamidine; rhabdomyolysis; and intravascular hemolysis. In some embodiments, acute interstitial nephritis is caused by drugs such as β-lactam antibiotics, penicillin, NSAIDs, proton pump inhibitors (PPIs), and 5-ASA; infections; and autoimmune diseases (systemic lupus erythematosus (SLE) and IgG-related disease). In some embodiments, the glomerulonephritis is due to anti-glomerular basement membrane disease, immune complex-mediated diseases such as SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy, and Henoch-Schonlein purpura. In some embodiments, the intraductal obstruction is due to monoclonal gammopathy seen in multiple myeloma, tumor lysis syndrome, or toxins such as ethylene glycol.

[0388] In some embodiments, described herein are methods for treating organ diseases or disorders 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 compound is administered by injectable delivery. In some embodiments, described herein are methods for treating organ diseases or disorders 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 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 a disease or disorder of an organ 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 compound is administered by intraperitoneal delivery.

[0389] 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, wherein the compound is administered by injectable delivery. 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, 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 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, wherein the compound is administered by intraperitoneal delivery.

[0390] 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, wherein the compound is administered by injectable delivery. 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, 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 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, wherein the compound is administered by intraperitoneal delivery.

[0391] In some embodiments, described herein is a method for treating organ diseases or disorders in a subject in need of such treatment, 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 is a method for treating organ diseases or disorders in a subject in need of such treatment, 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 the intravenous delivery is selected from bolus injection, intravenous drip, and infusion pump. In some embodiments, described herein is a method for treating organ diseases or disorders in a subject in need of such treatment, 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.

[0392] 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, wherein the compound is administered by injectable delivery. 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, 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 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, wherein the compound is administered by intraperitoneal delivery.

[0393] Compound synthesis The compounds used in the methods described herein are made by the procedures described in U.S. WO 2018 / 0291002, which is incorporated herein by reference in its entirety, or by known organic synthesis techniques starting from commercially available chemicals and / or compounds described in the chemical literature. Starting materials used in the synthesis of the compounds described herein are either synthesized or obtained from commercial sources such as Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, etc. The compounds described herein, and other related compounds with different substituents, are described herein or in the "Advanced Organic Chemistry" section of March 1999, Vol. 4, No. 1, pp. 111-114, 1999. th Ed., (Wiley 1992), Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 thEd.,Vols. A and B (Plenum 2000,2001), and Green and Wuts,PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). General methods for the preparation of compounds can be modified using appropriate reagents and conditions to introduce the various components found in the formulae presented herein. Detailed descriptions of techniques applicable to the creation and removal of protecting groups are found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., 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 disclosures.

[0394] Further forms of the compound In one aspect, the compounds described herein possess one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis-, trans-, syn-, anti-, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, resolution of the enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by 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.

[0395] "Pharmaceutically acceptable," as used herein, refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or deleteriously interacting with any of the components of the composition in which it is included.

[0396] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid. Pharmaceutically acceptable salts can also be obtained by reacting a compound described herein with a base to form a salt.

[0397] The compounds described herein may be formed and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, (1) acid addition salts, which are 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, etc. salt), 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-phenyl and (2) acid addition salts such as propionate, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, muconate, butyrate, phenyl acetate, phenylbutyrate, and valproate, and salts formed when an acidic proton in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, or potassium salt), an alkaline earth ion (e.g., magnesium or calcium salt), or an aluminum ion (e.g., aluminum salt). Optionally, the compounds described herein may be coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine.In other examples, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine salts, lysine salts, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0398] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol.The solvates of the compounds described herein can be conveniently prepared or formed during the process described herein.In addition, the compounds provided herein can exist in both solvated and non-solvated forms.

[0399] Administration route Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection, as well as intramuscular, subcutaneous, intravenous, and intramedullary injection.

[0400] In certain embodiments, the compounds described herein are administered locally rather than systemically, often as a depot or sustained-release formulation, for example, via injection of the compound directly into an organ. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, an extended-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0401] 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 via 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 via intravenous delivery, wherein the 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 via 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 via intravenous delivery, wherein the 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 the 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 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 the 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 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 the intravenous delivery is selected from a bolus injection, an intravenous drip, and an infusion pump.

[0402] Pharmaceutical Compositions / Formulations In some embodiments, the compound described herein is formulated into pharmaceutical composition.The pharmaceutical composition is formulated in a conventional manner with one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compound into pharmaceutically usable preparation.Suitable preparation depends on the route of administration selected. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0403] Provided herein are pharmaceutical compositions 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 excipient. In some embodiments, there are pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, there are pharmaceutical compositions comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, there are pharmaceutical compositions comprising a compound of Formula IIa, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, there are pharmaceutical compositions 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 in which the compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt thereof, is mixed with other active ingredients as a combination therapy. In other embodiments, the pharmaceutical composition includes other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts for regulating osmotic pressure, and / or buffers. In yet another embodiment, the pharmaceutical composition includes other useful substances.

[0404] In some embodiments, the compounds described herein can be used as adjuvants for systemic treatment with N-acetylcysteine, corticosteroids, and vasoconstrictors. In some embodiments, the compounds described herein can be used as adjuvants for systemic treatment with N-acetylcysteine. In some embodiments, the compounds described herein can be used as adjuvants for systemic treatment with corticosteroids. In some embodiments, the compounds described herein can be used as adjuvants for systemic treatment with vasoconstrictors, including, but not limited to, vasopressin and catecholamines.

[0405] Pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula I, Formula II, Formula IIa, or Formula III with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavorings, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. Pharmaceutical compositions facilitate administration of the compound to a mammal.

[0406] In certain embodiments, the therapeutically effective amount will vary 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 described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0407] The pharmaceutical formulations described herein are administered to a subject by a suitable route, 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 dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0408] 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 means of conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes, by way of example only.

[0409] Pharmaceutical compositions include at least one compound of Formula I, Formula II, Formula IIa, or Formula III as an active ingredient, in free acid or free base form, or in the form of a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein include the use of N-oxides (where appropriate), crystalline forms, amorphous phases, as well as active metabolites of these compounds that have the same type of activity. In some embodiments, the compounds described herein exist in unsolvated or solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0410] In some embodiments, solid oral dosage forms are prepared by mixing a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt thereof, with carrier materials such as antioxidants, flavoring agents, and binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0411] In some embodiments, the solid dosage forms disclosed herein are in the form of a tablet (including a suspension tablet, a fast-dissolving tablet, a bite-disintegrating tablet, a rapid-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder, a capsule, a solid dispersion, a solid solution, a bioerodible dosage form, a controlled-release formulation, a pulsed-release dosage form, a multiparticulate dosage form, beads, pellets, or granules. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation is in the form of a capsule.

[0412] 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, individual unit dosages include a film coating. These formulations are manufactured by conventional formulation techniques.

[0413] Traditional formulation techniques include, for example, (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, for example, one or a combination of methods such as spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tabletting, extrusion, etc.

[0414] In some embodiments, the compound of Formula I, Formula II, or Formula III, or its pharmaceutically acceptable salt, is formulated into a pharmaceutical composition suitable for intravitreal, intramuscular, subcutaneous, or intravenous injection.In one aspect, the formulation suitable for intravitreal, intramuscular, subcutaneous, or intravenous injection comprises a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension, or emulsion, and a sterile injectable solution or sterile powder for reconstitution into dispersion.In some embodiments, the formulation suitable for subcutaneous injection contains additives such as preservatives, wetting agents, emulsifiers, and dispersants.

[0415] In some embodiments, the compound of formula I, formula II or formula III or its pharmaceutically acceptable salt is formulated into a pharmaceutical composition suitable for intravenous injection.In some embodiments, the compound of formula II or formula IIa or its pharmaceutically acceptable salt 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.

[0416] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, and such penetrants are generally known in the art.

[0417] In certain embodiments, delivery systems for pharmaceutical compounds can be used, such as, for example, nanoparticles, implants, mucoadhesives, liposomes, and emulsions. In certain embodiments, the compositions provided herein can 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.

[0418] In some embodiments, the compounds described herein may be administered topically and may be formulated into a variety of topically administrable compositions such as solutions, suspensions, sprays, lotions, gels, pastes, medicated sticks, foams, balms, creams, or ointments. Such pharmaceutical compounds may include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0419] Combination therapy In certain instances, it will be appropriate to administer at least one compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0420] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant may have minimal therapeutic effect by itself, but when combined with another therapeutic agent, the overall therapeutic effect on the patient is enhanced). Alternatively, in some embodiments, the effect 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 a therapeutic effect.

[0421] In one 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.

[0422] In some embodiments, the second therapeutic agent is an antibacterial agent. In some embodiments, the second therapeutic agent is an antidiabetic agent selected from a biguanide, a sulfonylurea, a meglitinide, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and an α-glucosidase inhibitor.

[0423] 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.

[0424] In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be merely the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0425] In certain embodiments, various therapeutically effective doses of the compounds disclosed herein are utilized in the formulation of pharmaceutical compositions and / or treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agents, such as additional therapeutically effective drugs or adjuvants. Therapeutically effective dosages of the drugs and other agents used in combination treatment regimens can be determined by means similar to those described above for the active agents themselves. Additionally, the prevention / treatment methods described herein encompass the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination treatment regimens encompass treatment regimens in which administration of a compound of Formula I, Formula II, Formula IIa, or Formula III, or a pharmaceutically acceptable salt thereof, is initiated before, during, or after treatment with the second agent and continues at any time during or after the end of treatment with the second agent. This also includes treatments 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 at the same time or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment also includes periodic treatments that are started and stopped at various times to aid in the clinical management of the patient.

[0426] It is understood that dosage regimens to treat, prevent, or ameliorate the condition for which relief is sought will be modified according to a variety of factors (e.g., the disease, disorder, or illness from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0427] With respect to the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-drug utilized, the particular drug utilized, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered either simultaneously or sequentially with the one or more other therapeutic agents.

[0428] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.

[0429] The compounds of Formula I, Formula II, Formula IIa, or Formula III, or pharmaceutically acceptable salts thereof, and combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administering compositions containing the compounds varies. Thus, in one embodiment, the compounds described herein are used as prophylactics to prevent the onset of a disease or condition and are administered continuously to subjects prone to a disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for as long as necessary to treat the condition. In some embodiments, the required duration of treatment varies, and the treatment duration is tailored to the specific needs of each subject. For example, in a specific embodiment, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, from about 1 month to about 5 years. [Example]

[0430] These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0431] Example 1: Organ distribution of ASK1 inhibitors in rats after intravenous administration The objective 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 intravenously injected with 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. 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 U.S. WO 2018 / 0291002, which is incorporated herein by reference in its entirety.

[0432] Blood samples (approximately 120 μL) were collected from the retroorbital plexus of three rats under light isoflurane anesthesia 1 hour after IV injection. Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 40°C. Samples were stored at -70±10°C until biopsy. Animals were immediately sacrificed, and the abdominal vena cava was then incised and perfused transcardially with 10 mL of saline. Tissue samples were separated, rinsed three times with ice-cold saline (approximately 5-10 mL of saline in a disposable Petri dish for 5-10 seconds each time), dried on absorbent paper, and weighed. Tissue samples (liver, heart, kidney, pancreas, spleen, and skin) were homogenized using ice-cold phosphate-buffered saline (pH -7.4). The total homogenate volume was five times the tissue weight. All homogenates were stored below −70±10°C until bioanalysis.

[0433] Plasma, liver, heart, kidney, pancreas, spleen, and skin samples were quantified by a fit-for-purpose LC-MS / MS method.

[0434] Following a single intravenous administration 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 at a 10 mg / kg dose 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, and skin: 0.46.

[0435] Example 2: Organ distribution of ASK1 inhibitors in rats after oral administration The objective 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. Triplicate 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 0.1% Tween 80 and 99.9% HPMC (0.5% w / v in water) at a dose of 300 mg / kg.

[0436] Blood samples (approximately 120 μL) were collected from the retroorbital plexus of three rats under light isoflurane anesthesia 1 hour after PO administration. Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 40°C. Samples were stored at -70±10°C until bioanalysis. Animals were immediately sacrificed, and the abdominal vena cava was then incised and perfused transcardially with 10 mL of saline. Tissue samples were separated, rinsed three times with ice-cold saline (each rinse was performed for 5–10 seconds in a disposable Petri dish using approximately 5–10 mL of saline), dried on absorbent paper, and weighed. Tissue (liver, heart, and kidney) samples were homogenized using ice-cold phosphate-buffered saline (pH -7.4). The total homogenate volume was five times the tissue weight. All homogenates were stored below -70±10°C until bioanalysis.

[0437] Plasma, liver, heart, kidney, pancreas, spleen, and skin samples were quantified by a fit-for-purpose LC-MS / MS method.

[0438] Following a single oral administration 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 at a dose of 300 mg / kg to male Sprague Dawley rats, plasma and tissue concentrations were quantifiable at 1 hour. Tissue-to-plasma ratios at 1 hour were liver: 13.77, heart: 1.13, and kidney: 7.47.

[0439] Example 3: Efficacy of intravenous treatment with ASK1 inhibitors in liver injury due to acute alcoholic hepatitis (AH) The purpose of the study was to evaluate whether an IV-administered ASK1 inhibitor could reduce liver damage caused by acute alcoholic hepatitis (AH).

[0440] C57Bl / 6 male mice were treated with pyrazole for 2 days to induce CYP2E expression before administration of the ASK1 inhibitor and lipopolysaccharide (LPS) for 7 days. On day 3, the 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 twice (3 hours apart) via intravenous tail vein injection at 0.3 and 3 mg / kg or vehicle. LPS was administered intraperitoneally 30 minutes after the first dose of 2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morpholine-4-carbonyl)isoindolin-1-one. LPS administration emulates inflammation caused by intestinal bacteria penetrating the intestinal wall following heavy drinking. Twenty-four hours after LPS administration, plasma was collected for ALT analysis to assess the reduction of liver injury after intravenous treatment with ASK1 inhibitors.

[0441] 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 reduced liver injury, as reflected by a 74–85% reduction in plasma ALT levels.

[0442] Example 4: Efficacy of intravenous treatment with ASK1 inhibitors in fulminant hepatitis using an acetaminophen overdose model The objective of the study was to evaluate whether the ASK1 inhibitors described herein administered IV could reduce liver injury caused by acetaminophen (APAP) overdose plasma ALT and reduce hepatic biomarkers of ASK1 signaling in a mouse model.

[0443] C57Bl / 6 male mice acclimated for 7 days were intravenously injected via the tail vein with the ASK1 inhibitors described herein at doses ranging from 0.1 to 10 mg / kg or vehicle 30 minutes before APAP injection (300 mg / kg i.p.). At 6 or 24 hours, animals were anesthetized with CO2 or isoflurane, and blood was collected via cardiac puncture into a heparinized syringe for subsequent determination of alanine aminotransferase (ALT) activity. Phospho-JNK, phospho-p38, total JNK and p38, and β-actin were quantified by Western blot using liver samples.

[0444] Example 5: Phase II Study - Evaluation of an ASK1 Inhibitor in Patients at Risk for Developing Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI) The study will be designed to include patients scheduled for cardiac surgery who are considered to be at high risk of developing CSA-AKI.

[0445] Stage 1 consisted of 140 patients randomized in a 1:1:1:1 ratio to placebo or one of three ASK1 inhibitor dose arms (approximately 35 patients per treatment arm): 1. Pre-operative placebo, followed by three post-operative placebo doses, or 2. A low dose of an ASK1 inhibitor before surgery, followed by three post-operative doses at lower doses, or 3. A medium dose of an ASK1 inhibitor before surgery, followed by three postoperative doses at lower doses, or 4. A high dose of an ASK1 inhibitor before surgery, followed by three lower doses post-surgery.

[0446] Study treatment (ASK1 inhibitor or placebo) consisted of one 60-minute IV infusion administered preoperatively, followed by a 60-minute IV infusion administered starting early postoperatively, followed by two additional 60-minute IV infusions administered on consecutive days after cardiac surgery.

[0447] The primary endpoint for evaluating efficacy in patients receiving an ASK1 inhibitor compared with patients receiving a placebo will be the proportion of patients who develop CSA-AKI as measured by the Kidney Disease Improving Global Outcomes (KDIGO) criteria: • An increase in serum creatinine (SCr) by ≥ 0.3 mg / dl (> 26.5 μmol / l) within 48 hours after surgery, or An increase in SCr of ≥ 1.5 times baseline measured during the preceding 7 days, or Urinary output <0.5 ml / kg / h for 6 hours after surgery • If at least one of these measures was present by the 7-day assessment, the patient would be considered to have developed CSA-AKI.

[0448] Secondary outcome measures ●Incidence of AKI [Time frame: 7 days] Severity of AKI [Timeframe: 7 days] ●AKI stage determination is defined as follows: ■ Stage 1: SCr increased 1.5 to 1.9 times baseline or ≥ 0.3 mg / dL (≥ 26.5 μmol / L), and urine output was < 0.5 ml / kg / hr for 6 to 12 hours. ■ Stage 2: SCr is 2.0 to 2.9 times baseline, and urine output is <0.5 ml / kg / h for ≥12 hours. Stage 3: SCr 3.0 times higher than baseline, or SCr increasing to ≥ 5.0 mg / dL (≥ 353.6 μmol / L), or initiation of renal replacement therapy, or eGFR 1.73 m in patients < 18 years of age. 2 decreased urine output to <35 ml / min for ≥24 hours, urine output <0.3 ml / kg / h for ≥24 hours, or anuria for ≥12 hours. ■Absence of AKI is considered the best outcome, and stage 3 is the worst outcome. Duration of AKI [time frame: 7 days or postoperative release]

[0449] Inclusion criteria: Male or female, and >18 years old. Scheduled for non-urgent coronary and / or valvular surgery requiring CPB, including: ■ Coronary artery bypass graft (CABG) only, ■ Aortic valve replacement or repair only, with or without aortic root repair; ■ Mitral, tricuspid, or pulmonary valve replacement or repair only; ■ Simultaneous replacement of several heart valves, ■ CABG with replacement or repair of the aortic, mitral, tricuspid, or pulmonary valve; ■ CABG with heart valve replacement or repair. ●Having any of the following risk factors for CSA-AKI: eGFR ≥ 20 and < 30 ml / min / 1.73 m2, or eGFR ≥ 30 and < 60 ml / min / 1.73 m2 and one of the following additional risk factors (other than age ≥ 75 years) OR eGFR ≥ 60 ml / min / 1.73 m2 and two of the following additional risk factors: Additional risk factors ■ Age ≥ 75 years old, ■ Combination of valve surgery and coronary artery surgery, ■ Previous cardiac surgery with sternotomy, ■ Report of NYHA class III or IV within 1 year before surgery; ■ Left ventricular ejection fraction (LVEF) ≤ 35% on invasive or noninvasive cardiac imaging (echocardiography, nuclear imaging, CT, MRI, or angiography performed within 90 days before surgery) (patients meet the risk factors if their LVEF is ≤ 35% on invasive or noninvasive imaging). Diabetes requiring insulin ■ Diabetes mellitus not requiring insulin and urinalysis (medical history or dipstick) reveals proteinuria of ≥ +2 or more. ■ Preoperative anemia (hemoglobin <11 g / dl in both men and women).

[0450] Exclusion criteria: Weight >174 kg or >383 lbs, - AKI (KDIGO criteria) is present at the time of screening, Surgery performed without CPB, • Surgery performed under conditions of circulatory arrest or hypothermia with a rectal temperature <28°C (82.4°F), ●eGFR(MDRD)<20ml / min / 1.73m2, Surgery for aortic dissection, Surgery to correct major congenital heart defects (e.g., tetralogy of Fallot, transposition of the great arteries, single ventricle, Ebstein's anomaly; bicuspid aortic valve is not considered a congenital heart defect), Previous organ transplants, ●Dialysis dependence, administration of iodinated contrast within 24 hours before cardiac surgery; - Patients who have received contrast within 24 hours and have AKI as defined by the KDIGO criteria Cardiogenic shock or hemodynamic instability within 24 hours prior to surgery, including the induction period of anesthesia (defined as a systolic blood pressure <80 mmHg, a pulse >120 beats per minute (bpm), and the need for inotropes, vasodilators, or other mechanical devices such as an intra-aortic balloon pump (IABP)). Meet one of the following requirements within seven days of cardiac surgery: ■ Defibrillators or long-term pacemakers; ■Mechanical artificial respiration, ■ Intra-aortic balloon counterpulsation (IABP), ■Left ventricular assist device (LVAD), ■ Other forms of mechanical circulatory support (MCS), Cardiopulmonary resuscitation within 14 days prior to cardiac surgery History of cancer within the past 5 years, except for non-invasive carcinoma of the cervix or properly treated basal cell carcinoma of the skin known or suspected sepsis at the time of screening, known or suspected glomerulonephritis or interstitial nephritis at the time of screening; Endocarditis confirmed or treated within the past 30 days before cardiac surgery - Other active infections requiring antibiotic treatment, liver dysfunction, defined as total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN) at screening, or Child-Pugh class C liver disease (see Appendix 6) or worse; -any congenital coagulation disorder, Pregnancy or lactation, If the patient has a "Do Not Resuscitate" (DNR) status, known hypersensitivity to the investigational drug or any of its excipients; Treatment with an investigational drug or participation in an interventional clinical trial of an investigational drug within 60 days prior to the first dose; • any disease process or confounding variables that, in the investigator's opinion, may inappropriately alter the results of the study; • Inability to comply with research protocol requirements.

[0451] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are encompassed within the spirit and scope of this application and the appended claims.

Claims

1. 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 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, 【Chemistry 2】 teeth, 【Chemistry 3】 and R １ teeth 【Chemistry 4】 and Z is C(R ９ ) ２ and R ５ is a halogen and C １－６ is selected from the group consisting of alkyl, Each R ２５ are independently 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 selected from pyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. １－９ heteroaryl, wherein C １－９ Heteroaryl is optionally selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－８ substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl; Each R ６ are independently hydrogen, C １ -C ６ Alkyl, -C １ -C ６ Alkyl-O-C １ -C ６ Alkyl, -C １ -C ６ Alkyl-pyrazoles, and C ３ -C ８ cycloalkyl, or two R on the same heteroatom ６ However, together with the heteroatom to which they are attached, ２－９ Heterocycle or C ２－９ forming a heteroaryl, said heteroaryl being selected from imidazolyl, pyrazolyl, and pyrrolyl; ２－９ Heterocycle 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 and is substituted with 1, 2, or 3 substituents selected from the group consisting of: Each R ８ are independently hydrogen and C １ -C ６ is selected from the group consisting of alkyl, Each R ９ is hydrogen, Each R １３ are independently hydrogen and C １ -C ６ is selected from the group consisting of alkyl, Each R １４ are independently １ -C ６ is selected from the group consisting of alkyl, n is 0, 1, or 2; p is 0 or 1; method.

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

3. R ２５ is -C(=O)N(R ６ ) ２ and each R ６ are independently hydrogen, C １ -C ６ Alkyl, -C １ -C ６ Alkyl-O-C １ -C ６ Alkyl, -C １ -C ６ Alkyl-pyrazoles, and C ３ -C ８ 3. The method of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from the group consisting of cycloalkyl.

4. R ２５ is -C(=O)N(R ６ ) ２ and two R on the same heteroatom ６ However, together with the heteroatom to which they are attached, ２－９ Heterocycle or C ２－９ forming a heteroaryl, said heteroaryl being selected from imidazolyl, pyrazolyl, and pyrrolyl; ２－９ Heterocycle or C ２－９ Heteroaryl is optionally —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 3. The method of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is substituted with one substituent selected from the group consisting of:

5. R ２５ but, 【Chemistry 5】 5. The method of claim 4, wherein:

6. R ２５ but, 【Chemistry 6】 6. The method of claim 5, wherein:

7. The compound is 【Chemistry 7】 2. The method of claim 1, wherein:

8. The compound is 【Chemistry 8】 2. The method of claim 1, wherein:

9. The compound is 【Chemistry 9】 2. The method of claim 1, wherein:

10. The compound is 【Chemistry 10】 2. The method of claim 1, wherein:

11. The compound is 【Chemistry 11】 2. The method of claim 1, wherein:

12. 1. A method for treating a disease or disorder of an organ in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein said compound: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 A method selected from the following.

13. 13. The method of any one of claims 1 to 12, wherein the organ disease or disorder is selected from 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. 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. 15. The method of claim 14, wherein the organ disease or disorder is a liver disease or disorder.

16. 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 exacerbated liver failure.

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

18. 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, cardiovascular dysfunction from sepsis, drug-induced cardiotoxicity, viral myocarditis, and complications resulting from cardiac transplantation.

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

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

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

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

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

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

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

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

27. 27. The method of claim 26, wherein the second therapeutic agent is selected from N-acetylcysteine, a corticosteroid, and a hypertensive agent.

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