MTORC1 modulators and uses thereof

Abstract

The present disclosure provides compounds and salts showing high selectivity and inhibitory activity against mTORC1 and uses thereof for treating diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 001,187, filed on March 27, 2020; U.S. Provisional Patent Application No. 63 / 001,144, filed on March 27, 2020; U.S. Provisional Patent Application No. 63 / 001,177, filed on March 27, 2020; U.S. Provisional Patent Application No. 63 / 019,176, filed on May 1, 2020; U.S. Provisional Patent Application No. 63 / 054,763, filed on July 21, 2020; U.S. Provisional Patent Application No. 63 / 054,762, filed on July 21, 2020; and U.S. Provisional Patent Application No. 63 / 054,768, filed on July 21, 2020; the entire contents of each of which are incorporated herein by reference. Background Art

[0003] The therapeutic potential of rapamycin has been demonstrated in many chronic diseases ranging from Alzheimer's disease and Parkinson's disease to diabetes and cardiovascular disease. However, the prohibitive safety profile of rapamycin for long-term treatment has limited its use in treating various diseases. As an FDA-approved compound, rapamycin inhibits mTOR signaling, thereby leading to life extension in many species, but it can induce adverse effects such as peripheral edema, hypercholesterolemia, mucosal ulceration, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia and thrombocytopenia. In view of the complications associated with rapamycin, new agents are needed. Summary of the Invention

[0004] In a first aspect, the present disclosure provides a compound represented by the structure of Formula I:

[0005]

[0006] or a pharmaceutically acceptable salt thereof, wherein:

[0007] R 1 Selected from -OH, 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxy, 3 to 10 membered heterocyclic ring and C 3-10carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0008] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0009] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy; and

[0010] R 4’ Selected from

[0011] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0012] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form

[0013] R 20 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0014] R 21 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 carbon ring;

[0015] R 22 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 Carbocyclic ring and -P(=O)(R 24 )2;

[0016] R 23 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 carbon ring;

[0017] R 24 is an optionally substituted C1-C6 alkyl group;

[0018] R 100 Selected from:

[0019] Hydrogen and -(CH2-CH2-G) y -V; and

[0020] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0021] C 3-20Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0022] R 110’ Selected from:

[0023] Hydrogen, -(CH2-CH2-G) y -V, -S(O)R 51’ 、-S(O)2R 51’ 、-C(O)R 51’ 、-C(O)N(R 51’ )2 and -C(O)OR 51’ ;as well as

[0024] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31)2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0025] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 alkynyl; or

[0026] R 100 and R 110’ Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not an unsubstituted morpholine, and when R 6 and R 7 When one of them is selected from hydroxyl and C1-C6 alkoxy or when R 6 and R 7 Unite to form When R 100 and R 110 The 3-10 membered heterocyclic ring formed is further optionally substituted with one or more =0;

[0027] R 120 Selected from:

[0028] Hydrogen, -(CH2-CH2-G) y -V; and

[0029] C 3-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings;

[0030] C 3-20 saturated carbocyclic and 3- to 20-membered heterocyclic rings, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 alkynyl; or

[0031] C substituted by one or more substituents independently selected from the following 1-2 Alkyl: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31)2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings;

[0032] Each G is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0033] Each D is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0034] Each y is selected from 3-20;

[0035] Each z is selected from 1-20;

[0036] Each V is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0037] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0038] Each R 31 are independently selected from hydrogen, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings; and

[0039] R 32 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0040] where R 20 、R 21 、R 22 、R 23 、R 24 、R 51’ Optional substituents on V and T are independently selected at each occurrence from:

[0041] Halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0042] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30)2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0043] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 30 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0044] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0045] R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocycle, optionally substituted 3-10 membered heterocycle, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30alkyl;

[0046] q is selected from 1 to 6;

[0047] Each p is selected from 1 or 2;

[0048] Each n is selected from 3 to 7; and

[0049] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl).

[0050] In certain embodiments, the present disclosure provides a method of treating a disease comprising chronically administering a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) to a subject in need thereof.

[0051] In certain embodiments, the present disclosure provides a method for treating a disease, wherein the disease is selected from a chronic disease. The chronic disease can be selected from a disease in which mTORC1 is overactivated. The chronic disease can be selected from a disease in which the chronic disease will benefit from mTORC1 inhibition. In certain embodiments, the chronic disease can be selected from a neurodegenerative disease, a neurocutaneous disease, a neurodevelopmental disorder, an mTOR disease, a tau disease, a cognitive disorder, epilepsy, autism spectrum disorder, an autoimmune disease, a metabolic disease, a cancer, a disease in which autophagy is impaired, an infectious disease, a cardiovascular disease, a muscle atrophy, an inflammatory disease, a kidney disease, a lung disease, an eye disease, or an aging disease that leads to overactivation of mTORC1, including reduced immune activity in the elderly. The chronic disease can be an mTOR disease, such as tuberous sclerosis.

[0052] In certain embodiments, the present disclosure provides a method of treating a disease, wherein the compound may be a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG).

[0053] In a second aspect, the present disclosure provides a compound represented by the structure of formula (X):

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein:

[0056] L is selected from optionally substituted C 1-8 alkylene;

[0057] R 1 It is a carboxylic acid or a carboxylic acid isostere;

[0058] R 2is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0059] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl; and

[0060] R 4 Selected from and an optionally substituted 3- to 10-membered heterocycle, and when L is an optionally substituted C 3-8 When alkylene, R 4 further selected from methoxy; and when -LR 1 When it is ethyl acetate, tert-butyl acetate, benzyl acetate or methyl 2-phenylacetate, R 4 Not methoxy;

[0061] where R 4 The optionally substituted heterocycle may be substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, =O, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy C1-C6 alkyl;

[0062] z is 0, 1, 2, 3, 4, or 5;

[0063] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0064] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form

[0065] R 25 is independently selected at each occurrence from hydrogen, optionally substituted C1-C6 alkyl, -D-(CH2-CH2-G) y -V, optionally substituted C 3-20 carbocyclic and optionally substituted 3- to 20-membered heterocyclic rings;

[0066] When R 25 When C1-C6 alkyl is optionally substituted, the substituents on C1-C6 alkyl are independently selected from halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C(O)N(R 31 )2、-OC(O)N(R 31 )2、-C(O)OR 31 、-P(O)(R 31 )2. -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-10 Alkyl-CN, -OC 1-10 Alkyl-C(O)OR 31 、C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings;

[0067] When R 25 is optionally substituted C 3-20 When it is a carbocyclic ring or an optionally substituted 3- to 20-membered heterocyclic ring, C 3-20 The substituents on the carbocyclic and 3- to 20-membered heterocyclic rings are independently selected at each occurrence from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0068] wherein D is selected from a bond or -O-;

[0069] Each G is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0070] Each y is selected from 1-20;

[0071] Each V is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0072] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -OSi(C1-C6 alkyl)3, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0073] R' and R'' at each occurrence are independently selected from hydrogen, halogen, -OR 31 and optionally one or more independently selected from halogen and -OR 31 Substituents substituted C 1-8 alkyl; and

[0074] R 31 is independently selected at each occurrence from hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -OSi(C1-C6 alkyl)3, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-10 Alkyl-OH, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 carbocyclic and 3- to 12-membered heterocyclic rings.

[0075] R 32 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings; and

[0076] wherein the substituents on V and L are independently selected at each occurrence from:

[0077] Halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0078] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 30 、C 2-6 Alkenyl and C 2-6 Alkynyl.

[0079] In certain embodiments, the present disclosure provides a method of treating a disease, comprising administering, e.g., chronically administering, a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG) to a subject in need thereof.

[0080] In certain embodiments, the present disclosure provides a method for treating a disease, wherein the disease is selected from a chronic disease. The chronic disease can be selected from a disease in which mTORC1 is overactivated. The chronic disease can be selected from a disease in which the chronic disease will benefit from mTORC1 inhibition. In certain embodiments, the chronic disease can be selected from a neurodegenerative disease, a neurocutaneous disease, a neurodevelopmental disorder, an mTOR disease, a tau disease, a cognitive disorder, epilepsy, autism spectrum disorder, an autoimmune disease, a metabolic disease, a cancer, a disease in which autophagy is impaired, an infectious disease, a cardiovascular disease, a muscle atrophy, an inflammatory disease, a kidney disease, a lung disease, an eye disease, or an aging disease that leads to overactivation of mTORC1, including reduced immune activity in the elderly. The chronic disease can be an mTOR disease, such as tuberous sclerosis.

[0081] In certain embodiments, the present disclosure provides a method of treating a disease, wherein the compound may be a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG).

[0082] In a third aspect, the present disclosure provides a compound represented by the structure of formula L:

[0083]

[0084] or a pharmaceutically acceptable salt thereof, wherein:

[0085] R 1 Selected from 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted by one or more independently selected R 33 Substituents substituted;

[0086] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0087] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl; and

[0088] R 4 yes

[0089] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0090] R 6 and R 7 Each independently selected from hydrogen, hydroxyl and C 1-6 alkoxy; or

[0091] R 6 and R 7 Unite to form

[0092] R 20 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0093] R 21 is selected from optionally substituted C1-C6 alkyl and optionally substituted 3 to 7 membered heterocycle;

[0094] R 22 is selected from hydrogen, optionally substituted C1-C6 alkyl, -Si(R 24 )3 and -P(=O)(R 24 )2;

[0095] R 23 is selected from optionally substituted C1-C6 alkyl and optionally substituted 3 to 7 membered heterocycle;

[0096] R 24 is an optionally substituted C1-C6 alkyl group;

[0097] where R 20、R 21 、R 22 、R 23 and R 24 The substituents on each occurrence are independently selected from:

[0098] Halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0099] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0100] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 30 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0101] Each p is selected from 1 or 2;

[0102] Each n is selected from 3 to 7;

[0103] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl);

[0104] R 30 independently selected at each occurrence from:

[0105] hydrogen; and

[0106] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -OSi(C1-C6 alkyl)3, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and haloalkyl rings;

[0107] z is selected from 0-2;

[0108] R' and R'' are independently selected from hydrogen, halogen, -OR 31 and optionally one or more independently selected from halogen and -OR 31Substituents substituted C 1-3 alkyl;

[0109] Ring A is selected from optionally substituted C3-C5 carbocycles and optionally substituted 3- to 5-membered heterocycles, wherein the substituents on Ring A are independently selected at each occurrence from:

[0110] Halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ) and -CN;

[0111] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0112] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31)2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0113] R 31 is independently selected at each occurrence from hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 carbocyclic and 3- to 12-membered heterocyclic rings; and

[0114] R 33 is independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkyl, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl.

[0115] In certain embodiments, the present disclosure provides a method of treating a disease comprising chronically administering a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG) to a subject in need thereof.

[0116] In certain embodiments, the present disclosure provides a method for treating a disease, wherein the disease is selected from a chronic disease. The chronic disease can be selected from a disease in which mTORC1 is overactivated. The chronic disease can be selected from a disease in which the chronic disease will benefit from mTORC1 inhibition. In certain embodiments, the chronic disease can be selected from a neurodegenerative disease, a neurocutaneous disease, a neurodevelopmental disorder, an mTOR disease, a tau disease, a cognitive disorder, epilepsy, autism spectrum disorder, an autoimmune disease, a metabolic disease, a cancer, a disease in which autophagy is impaired, an infectious disease, a cardiovascular disease, a muscle atrophy, an inflammatory disease, a kidney disease, a lung disease, an eye disease, or an aging disease that leads to overactivation of mTORC1, including reduced immune activity in the elderly. The chronic disease can be an mTOR disease, such as tuberous sclerosis.

[0117] In certain embodiments, the present disclosure provides a method of treating a disease, wherein the compound may be a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG).

[0118] Incorporation by reference

[0119] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If a publication, patent, or patent application incorporated herein by reference conflicts with the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0120] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, variations, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein can be used to practice the present invention. It is intended that the following claims define the scope of the invention, and methods and structures within the scope of these claims and their equivalents are covered by the claims.

[0121] definition

[0122] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference.

[0123] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0124] The term "C x-y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl is intended to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight-chain and branched-chain alkyl groups. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. For example, –C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which are optionally substituted.

[0125] The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to an unsaturated aliphatic group analogous to the alkyl groups described above in length and possible substitution, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having from x to y carbons in the alkenylene chain. For example, –C 2-6 Alkenylene - may be selected from ethenylene, propenylene, butenylene, pentenylene and hexenylene, any of which are optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. Term - C x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain having from x to y carbon atoms in the chain. For example, -C 2-6 Alkynylene-can be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which are optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0126] "Alkylene" refers to a linear divalent hydrocarbon chain that is attached to the rest of the molecule and consists solely of carbon and hydrogen, contains no unsaturation, and preferably has from one to twelve carbon atoms, such as methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule and to the radical group via a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are respectively through a terminal carbon. The alkylene chain may be optionally substituted with one or more substituents such as those described herein.

[0127] "Alkenylene" refers to a straight, divalent hydrocarbon chain that is attached to the rest of the molecule and consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule by a single bond and to the radical group by a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are each through a terminal carbon. The alkenylene chain may be optionally substituted with one or more substituents such as those described herein.

[0128] "Alkynylene" refers to a straight, divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms, which connects the rest of the molecule to a radical. The alkynylene chain is attached to the rest of the molecule by a single bond and to the radical by a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical are respectively through a terminal carbon. The alkynylene chain may be optionally substituted with one or more substituents such as those described herein.

[0129] As used herein, the term "carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can include 3-10 membered monocycles, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is an aryl group. In some embodiments, the carbocycle is a cycloalkyl group. In some embodiments, the carbocycle is a cycloalkenyl group. In an exemplary embodiment, an aromatic ring such as a phenyl group can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. When valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles can be fused, bridged, or spirocyclic ring systems. The carbocycle can optionally be substituted with one or more substituents such as those described herein. As used herein, the term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. Where valence permits, the heterocycle can be attached to the rest of the molecule via any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle such as a pyridyl group can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. The bicyclic heterocycle can be a fused, bridged or spiro ring system.The heterocycle can be optionally substituted with one or more substituents such as those described herein.

[0130] The term "heteroaryl" includes aromatic monocyclic ring structures whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings. The term "heteroaryl" also includes polycyclic ring systems having two or more rings, wherein two or more atoms are shared by two adjacent rings, and wherein at least one ring is heteroaromatic, e.g., the other rings may be aromatic or non-aromatic carbocyclic or heterocyclic rings. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0131] The term "substituted" refers to a substituent that replaces one or more carbon atoms of a compound or a substitutable heteroatom, such as NH or NH2. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such substitutions conform to the permissible valences of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo a transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo group, an imino group, or a thio group. As used herein, the term "substituted" is considered to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different.

[0132] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t Ra (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a)2 (where t is 1 or 2); where each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a Where valence permits, it may be optionally substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R cis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents may themselves be substituted, if appropriate.

[0133] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0134] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0135] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0136] The terms "subject," "individual," and "patient" are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a human (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a male child, a female child) who is hospitalized under the care of a physician or other health care provider, as an outpatient, or in other clinical settings. In certain embodiments, a subject may not be under the care or prescription of a physician or other health care provider.

[0137] As used herein, the phrase "a subject in need thereof" refers to a subject as described below who suffers from, or is at risk of, a condition to be treated prophylactically or therapeutically with a compound or salt described herein.

[0138] The term "administer" or "administered" or "administers" or "administering" is defined as providing a composition to a subject by any route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal administration. In certain embodiments, an oral route of administration of the composition may be used. The term "administering" a compound should be understood to mean providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof.

[0139] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or salt described herein that is sufficient to achieve the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo); or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition; the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a specific response in the target cell, such as a decrease in proliferation or downregulation of the activity of a target protein. The specific dose may vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0140] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a preventive benefit. In certain embodiments, treatment involves administering a compound or composition disclosed herein to a subject. The therapeutic benefit may include the eradication or improvement of the underlying condition being treated. In addition, the therapeutic benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, such as by observing an improvement in the subject, even though the subject may still be suffering from the underlying condition. In certain embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a specific disease, or to a subject reporting one or more physiological symptoms of a disease, although a diagnosis of the disease may not yet have been made. Treatment may include, for example, alleviating, delaying, or alleviating the severity of one or more symptoms of a disease or illness, or it may include reducing the frequency of symptoms experienced by a patient of a disease, defect, disorder, or adverse condition. Treatment may be used herein to refer to a method that results in a certain level of treatment or improvement of a disease or disorder, and a range of results directed to the target may be considered, including but not limited to preventing the disorder completely.

[0141] In certain embodiments, the terms "prevent" or "preventing" as used in connection with a disease or condition may refer to a compound reducing the occurrence of the condition or disorder in a treated sample relative to an untreated control sample, or delaying the onset of or reducing the severity of one or more symptoms of the condition or disorder relative to an untreated control sample.

[0142] "Therapeutic effect," as the term is used herein, encompasses therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping, or reversing the progression of a disease or disorder, or any combination thereof.

[0143] As used in relation to a biologically active agent, the term "selective inhibition" or "selectively inhibit" means that the agent is able to preferentially reduce target signaling activity over off-target signaling activity by interacting directly or indirectly with the target.

[0144] introduction

[0145] The mechanistic target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and acts as a master regulator of cell metabolism, growth, proliferation, and survival. Specifically, mTOR complex 1 (mTORC1) positively regulates cell growth and proliferation by promoting many anabolic processes including the biosynthesis of proteins, lipids, and organelles, and by limiting catabolic processes such as autophagy. Much of the knowledge about mTORC1 function comes from the use of the bacterial macrolide rapamycin.

[0146] Rapamycin is thought to directly inhibit mTORC1 and indirectly inhibit mTORC2 after long-term treatment. Recent evidence has revealed that inhibition of mTORC1 leads to effects associated with lifespan extension, whereas inhibition of mTORC2 is unrelated to longevity and leads to several adverse effects of rapamycin, such as impaired insulin sensitivity, impaired glucose homeostasis, and dysregulation of lipids.

[0147] Studies of rapamycin and related rapamycin analogs have revealed that these compounds form binary complexes with FKB binding proteins such as FKBP12 and FKBP51. This binary complex can allosterically inhibit the functionality of mTORC1 by binding to the FRB domain of mTOR. FKBP12 and FKBP51 direct binding assays provide a method for assessing the relative binding affinity of rapamycin analogs for a given FKBP. Without wishing to be bound by any particular mechanistic theory, it is preferred that the binding of rapamycin analogs to FKB proteins, such as FKBP12 or FKBP51, is similar, equivalent, or stronger than the binding of rapamycin to the FKB protein.

[0148] The ternary complex formation assay provides a method to assess the relative binding affinity of rapamycin analogs / FKB binary complexes to the FRB domain of mTOR. The different binding affinities exhibited by rapamycin analogs / FKB complexes to mTOR relative to the known rapamycin analogs, rapamycin and everolimus, can result in different pharmacological and safety profiles.

[0149] In certain aspects, the present disclosure provides compounds and salts thereof and methods of use for treating diseases. In certain embodiments, the compounds described herein are referred to as rapamycin analogs, which refer to the common core structure of the compounds described herein relative to rapamycin. In certain aspects, the compounds described herein show similar direct binding properties relative to known compounds such as rapamycin and everolimus, such as similar or improved FKB binding. In certain aspects, the compounds described herein show altered ternary binding affinity relative to known compounds such as rapamycin or everolimus, such as reduced binding affinity to the FRB domain of mTOR.

[0150] In certain embodiments, the compounds or salts of the present disclosure are evaluated for direct binding to FKBP12 and / or FKBP51. In certain embodiments, the compounds or salts of the present disclosure are evaluated for ternary complex formation with MTORC1 and FKBP12. In certain embodiments, the compounds or salts thereof have strong binding to FKBP12 and / or FKBP51.

[0151] In certain aspects, the compounds of the present disclosure are grouped into compound groups 1, 2, and 3. Each of these compound groups describes a different group of chemical structures. Any repetition of a variable in one group relative to another group is not intended to imply that the variable can be interchanged with a variable in one of the other groups. For example, in the compounds of group 1, R 1 The description applies only to compounds in Group 1 and not to Group 2 or Group 3.

[0152] Compound Group 1

[0153] In a first aspect, the present disclosure provides a compound represented by the structure of Formula I:

[0154]

[0155] or a pharmaceutically acceptable salt thereof, wherein:

[0156] R 1 Selected from -OH, 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxy, 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from:

[0157] Hydroxyl, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy;

[0158] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0159] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy; and

[0160] R 4’ Selected from

[0161] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0162] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form

[0163] R 20 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0164] R 21 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 carbon ring;

[0165] R 22 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 Carbocyclic ring and -P(=O)(R 24 )2;

[0166] R 23 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 carbon ring;

[0167] R 24 is an optionally substituted C1-C6 alkyl group;

[0168] R 100 Selected from:

[0169] Hydrogen and -(CH2-CH2-G) y -V; and

[0170] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0171] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0172] R 110’ Selected from:

[0173] Hydrogen, -(CH2-CH2-G) y -V, -S(O)R 51’ 、-S(O)2R 51’ 、-C(O)R 51’ 、-C(O)N(R 51’ )2 and -C(O)OR 51’ ; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0174] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 alkynyl; or

[0175] R 100 and R 110’ Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not an unsubstituted morpholine, and when R 6 and R 7 When one of them is selected from hydroxyl and C1-C6 alkoxy or when R 6 and R 7 Unite to form When R 100 and R 110 The 3-10 membered heterocyclic ring formed is further optionally substituted with one or more =0;

[0176] R 120 Selected from:

[0177] Hydrogen, -(CH2-CH2-G) y -V; and

[0178] C 3-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0179] C 3-20 saturated carbocyclic and 3- to 20-membered heterocyclic rings, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 alkynyl; or

[0180] C substituted by one or more substituents independently selected from the following 1-2 Alkyl: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings;

[0181] Each G is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0182] Each D is independently selected from -O-, -NR32 -, -S- or -SO2-;

[0183] Each y is selected from 3-20;

[0184] Each z is selected from 1-20;

[0185] Each V is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0186] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0187] Each R 31 are independently selected from hydrogen, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings; and

[0188] R 32 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0189] where R 20 、R 21 、R 22 、R 23 、R 24 、R 51’ Optional substituents on V and T are independently selected at each occurrence from:

[0190] Halogen, -OR 30 、-N(R 30)2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0191] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0192] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 30 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0193] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0194] R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocycle, optionally substituted 3-10 membered heterocycle, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 alkyl;

[0195] q is selected from 1 to 6;

[0196] Each p is selected from 1 or 2;

[0197] Each n is selected from 3 to 7; and

[0198] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl).

[0199] In some embodiments, the compound of formula (I) is represented by formula (IZ):

[0200]

[0201] or a pharmaceutically acceptable salt thereof, wherein:

[0202] R 1 Selected from -OH, 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxy, 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from:

[0203] Hydroxyl, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy;

[0204] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0205] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy; and

[0206] R 4 Selected from

[0207] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0208] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form

[0209] R 20 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0210] R 21 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 carbon ring;

[0211] R 22 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 Carbocyclic ring and -P(=O)(R 24 )2;

[0212] R 23 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 carbon ring;

[0213] R 24 is an optionally substituted C1-C6 alkyl group;

[0214] R 100 Selected from:

[0215] Hydrogen and -(CH2-CH2-G) y -V; and

[0216] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0217] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0218] R 110 Selected from:

[0219] Hydrogen, -(CH2-CH2-G) y -V, -S(O)R 51 、-S(O)2R 51 、-C(O)R 51 、-C(O)N(R 51 )2 and -C(O)OR 51 ;as well as

[0220] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0221] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 alkynyl; or

[0222] R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not an unsubstituted morpholine, and when R 6 and R 7 When one of them is selected from hydroxyl and C1-C6 alkoxy or when R 6 and R 7 Unite to form When R 100 and R 110 The 3-10 membered heterocyclic ring formed is further optionally substituted with one or more =0;

[0223] R 120 Selected from:

[0224] Hydrogen, -(CH2-CH2-G) y -V; and

[0225] C 3-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0226] C 3-20 saturated carbocyclic and 3- to 20-membered heterocyclic rings, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R31 、C 2-6 Alkenyl and C 2-6 alkynyl; or

[0227] C substituted by one or more substituents independently selected from the following 1-2 Alkyl: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings;

[0228] Each G is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0229] Each D is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0230] Each y is selected from 3-20;

[0231] Each z is selected from 1-20;

[0232] Each V is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0233] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0234] Each R 31 are independently selected from hydrogen, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings; and

[0235] R 32 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0236] where R 20 、R 21 、R 22 、R 23 、R 24 、R 51 Optional substituents on V and T are independently selected at each occurrence from:

[0237] Halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0238] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0239] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 30 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0240] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Carbocyclic and 3- to 10-membered heterocyclic rings;

[0241] R 51 is independently selected at each occurrence from -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 alkyl;

[0242] q is selected from 1 to 6;

[0243] Each p is selected from 1 or 2;

[0244] Each n is selected from 3 to 7; and

[0245] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl).

[0246] In certain embodiments, the compound of formula (I) is represented by formula (IA): or a salt thereof.

[0247] In certain embodiments, the compound of formula (I) is represented by formula (IB): or a salt thereof.

[0248] In certain embodiments, the compound of formula (I) is represented by formula (IC): or a salt thereof.

[0249] In certain embodiments, the compound of formula (I) is represented by formula (ID): or a salt thereof.

[0250] In certain embodiments, the compound of formula (I) is represented by formula (IE): or a salt thereof.

[0251] In certain embodiments, the compound of formula (I) is represented by formula (IF): or a salt thereof.

[0252] In certain embodiments, the compound of formula (I) is represented by formula (IG): or a salt thereof.

[0253] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ By R 51 express.

[0254] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100’ By R 100 express.

[0255] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4’ It is R 4 .

[0256] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), Depend on express.

[0257] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100 and R 110’ Together with the nitrogen to which they are attached, they form a 3-10 membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy.

[0258] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100 and R 110’ Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not an unsubstituted morpholine.

[0259] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100 and R 110’Together with the nitrogen to which they are attached, they form a 3-5 membered saturated heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy.

[0260] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), when R 6 and R 7 Unite to form And R 1 When it is hydroxyl, R 4 no And when R 6 and R 7 Unite to form And R 1 yes When R 4 no In some cases, R 4 no In some cases, R 4 no In some cases, R 4 no In some cases, R 4 No

[0261] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100 and R 110’ They do not combine with the nitrogen to which they are attached to form a 3-10 membered ring.

[0262] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes In some embodiments, R 100 Selected from R 110 The same part, such as R 100 is ethyl, and R 110 In some embodiments, R 100 Different from R 110 In some embodiments, R 100 is H. In some embodiments, R 110 Selected from: -(CH2-CH2-G)y -V; and C optionally substituted by one or more substituents independently selected from the following 1-10 Alkyl: halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 carbocyclic rings and 3- to 20-membered heterocyclic rings.

[0263] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 110 Selected from -(CH2-CH2-G) y -V. In some embodiments, -(CH2-CH2-G) y In some embodiments, y is from 1 to 1000. In some embodiments, y is from 1 to 800. In some embodiments, y is from 1 to 500. In some embodiments, y is from 1 to 300. In some embodiments, y is from 1 to 100. In some embodiments, y is from 1 to 50. In some embodiments, y is from 1 to 25. In some embodiments, y is from 3 to 1000. In some embodiments, y is from 10 to 1000. In some embodiments, y is from 50 to 1000. In some embodiments, y is from 100 to 1000. In some embodiments, y is from 200 to 1000. In some embodiments, y is from 500 to 1000. In some embodiments, R 110 -(CH2-CH2-G) y -V y is 3 to 10. In some embodiments, R 110 -(CH2-CH2-G) y -V y is 5 to 10. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

[0264] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 110 Selected from -(CH2-CH2-G) y -V, where -(CH2-CH2-G) y -V's G is -O-. In some embodiments, R 110 -(CH2-CH2-G) y Each G of -V is -NR 32 -. In some embodiments, -NR 32 - Each R 32 are independently selected from hydrogen; and C 1-10 Alkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0265] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 110 Selected from -(CH2-CH2-G) y -V, where R 110 Each V is optionally substituted -C1-C 10 In some embodiments, R 110 Each V of is optionally substituted -C1-C6 alkyl. In some embodiments, R 110 The -C1-C6 alkyl group on V is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30)2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN.

[0266] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 110 The -C1-C6 alkyl group on V is replaced by one or more independently selected from -OR 30 and -N(R 30 ) 2 is substituted with a substituent. In some embodiments, R 110 The -C1-C6 alkyl group on V is replaced by one or more -N(R 30 )2 is substituted. In some embodiments, R 110 The -C1-C6 alkyl group on V is replaced by one or more -OR 30 In some embodiments, each R 30 selected from hydrogen; and C 1-5 Alkyl, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0267] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-, 4-, 5-, 7-, or 8-membered heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy. In some embodiments, the 3- to 8-membered heterocyclic ring is unsaturated. In some embodiments, the 3- to 8-membered heterocyclic ring is saturated.

[0268] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 and R 110Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not an unsubstituted morpholine, and when R 6 and R 7 When one of them is selected from hydroxyl and C1-C6 alkoxy or when R 6 and R 7 Unite to form When R 100 and R 110 The 3-10 membered heterocyclic ring formed is further optionally substituted with one or more =0.

[0269] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is a substituted morpholine, and when R 6 and R 7 When one of them is selected from hydroxyl and C1-C6 alkoxy or when R 6 and R 7 Unite to form When R 100 and R 110 The 3-10 membered heterocyclic ring formed is further optionally substituted with one or more =0.

[0270] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 and R 110Together with the nitrogen to which they are bound, a heterocycle is formed. The heterocycle may be selected from a 3-10 membered heterocycle, a 3-8 membered heterocycle, a 3-6 membered heterocycle, a 3-5 membered heterocycle, a 4-10 membered heterocycle, a 4-8 membered heterocycle, a 4-6 membered heterocycle, and a 4-5 membered heterocycle, any of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxyl, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, =O, and C1-C6 alkoxy. In some embodiments, the heterocycle is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy. In some embodiments, the heterocycle is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, =O, and C1-C6 alkoxy. In some embodiments, the heterocycle is unsaturated. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is aromatic. In some embodiments, the heterocycle further comprises at least a second heteroatom. In some embodiments, the second heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the second heteroatom is selected from nitrogen and sulfur. In some embodiments, the second heteroatom is selected from oxygen and sulfur. In some embodiments, the second heteroatom is selected from nitrogen and oxygen. In some embodiments, the second heteroatom is sulfur. In some embodiments, the second heteroatom is nitrogen. In some embodiments, the second heteroatom is oxygen.

[0271] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not And when R 6 and R 7 When one of them is selected from hydroxyl and C1-C6 alkoxy or when R 6 and R 7 Unite to form When R 100 and R 110 The 3-10 membered heterocyclic ring formed is further optionally substituted with one or more =0.

[0272] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combined with the nitrogen to which they are attached, they form aziridine, 2H-aziridine, azetidine, 2,3-dihydroazetidine, 1,3-diazetidine, pyrrolidine, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, pyrazolidine, imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole , 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 2,4-thiazolidinedione, succinimide, oxazine, thiomorpholine, thiazine, 2-oxazolidinone, hydantoin, cytosine, thymine, uracil, thiomorpholine dioxide, piperidine, pyridine, piperazine, pyridazine, pyrimidine, pyrazine, triazine, 2,3-dihydroaza 2,5-Dihydroazepine 4,5-Dihydroazepine Aza 2H-aza 3H-aza 4H-aza 1,2-diazepine 1,3-diazepine 1,4-diazepine 1,4-Thiazepine Azocane and azocine, each optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy.

[0273] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110Combine with the nitrogen to which they are attached to form aziridine, 2H-aziridine, azetidine, 2,3-dihydroazetidine, 1,3-diazetidine, pyrrolidine, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, pyrazolidine, imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, oxazole, isoxazole, Isothiazole, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 2,4-thiazolidinedione, succinimide, oxazine, thiomorpholine, thiazine, 2-oxazolidinone, hydantoin, cytosine, thymine, uracil, thiomorpholine dioxide, piperidine, pyridine, piperazine, pyridazine, pyrimidine, pyrazine, triazine, 2,3-dihydroazepine 2,5-Dihydroazepine 4,5-Dihydroazepine Aza 2H-aza 3H-aza 4H-aza 1,2-diazepine 1,3-diazepine 1,4-diazepine 1,4-Thiazepine Azoline, azocine, 1,2-thiazetidine, isothiazolidine and imidazolidine, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy.

[0274] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110Combine with the nitrogen to which they are attached to form aziridine, 2H-aziridine, azetidine, 2,3-dihydroazetidine, 1,3-diazetidine, pyrrolidine, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, pyrazolidine, imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, oxazole, isoxazole, Isothiazole, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, 2,4-thiazolidinedione, succinimide, oxazine, thiomorpholine, thiazine, 2-oxazolidinone, hydantoin, cytosine, thymine, uracil, thiomorpholine dioxide, piperidine, pyridine, piperazine, pyridazine, pyrimidine, pyrazine, triazine, 2,3-dihydroazepine 2,5-Dihydroazepine 4,5-Dihydroazepine Aza 2H-aza 3H-aza 4H-aza 1,2-diazepine 1,3-diazepine 1,4-diazepine 1,4-Thiazepine Azoline, azocine, 1,2-thiazetidine, isothiazolidine and imidazolidine, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, =O and C1-C6 alkoxy.

[0275] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combined with the nitrogen to which they are attached to form azetidine, 1,2-thiazetidine, isothiazolidine and imidazolidine, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, =O, when R 6 and R 7 One of them is selected from hydroxyl and C1-C6 alkoxy or R 6 and R 7 Unite to form

[0276] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combine with the nitrogen to which they are bound to form And R 6 and R 7 One of them is selected from hydroxyl and C1-C6 alkoxy or R 6 and R 7 Unite to form

[0277] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combine with the nitrogen to which they are bound to form At this time R 6 and R 7 One of them is selected from hydroxyl and C1-C6 alkoxy or R 6 and R 7 Unite to form

[0278] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combine with the nitrogen to which they are bound to form And R 1 Not selected

[0279] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combine with the nitrogen to which they are bound to form At this time R 1 Not selected

[0280] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combine with the nitrogen to which they are bound to form At this time R 1 Not selected

[0281] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combine with the nitrogen to which they are bound to form At this time R 1 Not selected

[0282] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes and R 100 and R 110 Combined with the nitrogen to which they are attached to form azetidin-2-one, thiazetidine 1,1-dioxide or isothiazolidine 1,1-dioxide, any of which is substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy.

[0283] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 is hydrogen or C 1-10 alkyl; and R 110 Selected from -(CH2-CH2-G) y -V, -S(O)R 51 、-S(O)2R 51 、-C(O)R 51、-C(O)N(R 51 )2 and -C(O)OR 51 ; or R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, and =O.

[0284] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 is hydrogen or C 1-10 alkyl; and R 110 Selected from -(CH2-CH2-G) y -V, -S(O)R 51 and -S(O)2R 51 ; or R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, and =O.

[0285] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 is hydrogen or C 1-10 alkyl; and R 110 Selected from -S(O)R 51 and -S(O)2R 51 ; or R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, and =O.

[0286] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R100 is hydrogen or C 1-10 alkyl; and R 110 Selected from -S(O)R 51 and -S(O)2R 51 ; or R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, and =O.

[0287] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51 is independently selected at each occurrence from -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 Alkyl; wherein q is independently selected from 1 to 6 at each occurrence, each D is independently selected from -O-, -NR 32 -, -S- or -SO2-; each z is selected from 1-20; and each T is selected from hydrogen and optionally substituted -C1-C6 alkyl. In some embodiments, R 51 is independently selected at each occurrence from -((CH2) q -CH2-D) z -T. In some embodiments, R 51 is optionally substituted C 5-30 In some embodiments, q is independently selected at each occurrence from 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, q is 1 to 5. In some embodiments, q is 1 to 4. In some embodiments, q is 1 to 3. In some embodiments, q is 1 to 2. In some embodiments, q is 6. In some embodiments, q is 5. In some embodiments, q is 4. In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, D is independently selected at each occurrence from -O-, -NR 32 In some embodiments, D is independently selected at each occurrence from -O-, -NR 32 In some embodiments, D is independently selected at each occurrence from -O- or -NR 32. In some embodiments, D is independently selected at each occurrence from -O-. In some embodiments, z is selected from 1 to 500. In some embodiments, z is selected from 1 to 50. In some embodiments, z is selected from 1 to 300. In some embodiments, z is selected from 3 to 500. In some embodiments, z is selected from 3 to 250. In some embodiments, z is selected from 3 to 50. In some embodiments, z is selected from 3 to 25. In some embodiments, z is selected from 3 to 20. In some embodiments, z is selected from 3 to 10. In some embodiments, z is selected from 3. In some embodiments, z is selected from 20. In some embodiments, T is selected from hydrogen and optionally substituted -C1-C6 alkyl. In some embodiments, T is hydrogen. In some embodiments, T is selected from optionally substituted -C1-C6 alkyl. In some embodiments, T is selected from unsubstituted -C1-C6 alkyl. In some embodiments, -NR 32 -R 32 Selected from hydrogen and C 1-10 In some embodiments, R 4 Selected from In some embodiments, -NR 32 -R 32 In some embodiments, -NR 32 -R 32 Selected from C 1-10 alkyl.

[0288] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51 is independently selected at each occurrence from -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 Alkyl; wherein q is independently selected from 1 to 6 at each occurrence, each D is independently selected from -O-, -NR 32 -, -S- or -SO2-; each z is selected from 1-20; and each T is selected from hydrogen and optionally substituted -C1-C6 alkyl.

[0289] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51 is independently selected at each occurrence from -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 Alkyl; wherein q is independently selected from 1 to 6 at each occurrence, each D is independently selected from -O-, -NR32 -, -S- or -SO2-; each z is selected from 3-20; and each T is selected from hydrogen and optionally substituted -C1-C6 alkyl. In some embodiments, R 51 is optionally substituted C 5-30 In some embodiments, R 51 Selected from C 5-30 Alkyl, selected from optionally substituted C 5-25 Alkyl, optionally substituted C 5-20 Alkyl, optionally substituted C 5-15 Alkyl and optionally substituted C 5-10 In some embodiments, R 51 is optionally substituted C 5-10 In some embodiments, C 5-30 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN. In some embodiments, C 5-30 The alkyl group is optionally substituted with one or more substituents selected from: -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 , -NO2 and -CN. In some embodiments, C 5-30 The alkyl group is optionally substituted with one or more groups selected from -OR30 In some embodiments, each R 30 independently selected at each occurrence from hydrogen and C 1-10 In some embodiments, -OR 30 R 30 independently selected from hydrogen and C 1-10 In some embodiments, -OR 30 R 30 Independently selected from C 1-10 alkyl.

[0290] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51 Selected from C 3-8 In some embodiments, R 51 It is C 3-6 In some embodiments, R 51 Selected from C 3-6 Cycloalkyl.

[0291] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes where R 100 is hydrogen or C 1-10 alkyl; and R 110 Selected from -S(O)2R 51 ; or R 100 and R 110 Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, and =O.

[0292] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100 and R 110 Each is further independently selected from -SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, -CN, optionally substituted C 3-20 Carbocyclic and optionally substituted 3 to 20 membered heterocyclic rings, in which case R 1 In some embodiments, for compounds or salts of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 100 and R 110 Each is further independently selected from -S(O)R 31 、-S(O)2R 31 , -NO2, -CN, optionally substituted C 3-20 Carbocyclic and optionally substituted 3 to 20 membered heterocyclic rings, in which case R 1 In some embodiments, R 100 and R 110 Each is further independently selected from -S(O)R 31 and -S(O)2R 31 , at this time R 1 In some embodiments, each R 31 is independently selected at each occurrence from hydrogen; and C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 In some embodiments, C 1-10 The alkyl group is optionally substituted by one or more independently selected from -OC 1-10 The alkyl group is substituted with a substituent.

[0293] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes In some embodiments, R 4 R 120 Selected from: hydrogen, -(CH2-CH2-G) y -V; and C optionally substituted by one or more substituents independently selected from the following 3-10 Alkyl: halogen, -OR 31 、-SR 31、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and C 3-20 saturated carbocyclic and 3- to 20-membered heterocyclic rings, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 Alkynyl.

[0294] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 4 R 120 It's hydrogen.

[0295] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 4 R 120 Yes -(CH2-CH2-G) y -V.

[0296] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 4 R 120is C optionally substituted by one or more substituents independently selected from the following 3-10 Alkyl: halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-NO2、-CN、C 3-20 In some embodiments, R 4 R 120 It is C 3-10 Alkyl, optionally substituted with one or more substituents independently selected from: -OR 31 、-SR 31 and -N(R 31 )2, where each R 31 are independently selected from hydrogen and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0297] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 4 R 120 is C substituted by one or more substituents independently selected from the following 1-2 Alkyl: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 carbocyclic rings and 3- to 20-membered heterocyclic rings.

[0298] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 yes And R 120 Selected from -(CH2-CH2-G) y -V, where R 120 -(CH2-CH2-G) y In some embodiments, y is from 1 to 1000. In some embodiments, y is from 1 to 800. In some embodiments, y is from 1 to 500. In some embodiments, y is from 1 to 300. In some embodiments, y is from 1 to 100. In some embodiments, y is from 1 to 50. In some embodiments, y is from 1 to 25. In some embodiments, y is from 3 to 1000. In some embodiments, y is from 10 to 1000. In some embodiments, y is from 50 to 1000. In some embodiments, y is from 100 to 1000. In some embodiments, y is from 200 to 1000. In some embodiments, y is from 500 to 1000. In some embodiments, R 120 -(CH2-CH2-G) y -V y is 3 to 10. In some embodiments, R 120 -(CH2-CH2-G) y -V y is 5 to 10. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

[0299] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2 and C1-C6 alkoxy. 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -NO2 and C1-C6 alkoxy.

[0300] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 2is selected from hydrogen and C1-C6 alkoxy. 2 In some embodiments, R 2 Yes-OMe.

[0301] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy and C1-C6 alkoxy. 3 is selected from hydrogen and C1-C6 alkoxy.

[0302] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 3 In some embodiments, R 3 Yes-OMe.

[0303] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2 and C1-C6 alkoxy.

[0304] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 5 It is a hydroxyl group.

[0305] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 6 and R 7 are each independently selected from hydrogen and hydroxy. 6 and R 7 In some embodiments, R 6 is hydrogen, and R 7 In some embodiments, R 6 and R 7 Unite to form

[0306] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from and an optionally substituted 3- to 10-membered heterocycle. In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from hydroxyl groups.

[0307] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from Optionally substituted C 3-10 carbocyclic and optionally substituted 3- to 10-membered heterocyclic rings.

[0308] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from and an optionally substituted 3- to 10-membered heterocyclic ring.

[0309] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from -OH.

[0310] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from: -OH, an optionally substituted 3- to 10-membered heterocyclic ring and an optionally substituted C 3-10 Carbon ring.

[0311] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from: -OH, and an optionally substituted 3- to 10-membered heterocyclic ring.

[0312] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 is an optionally substituted 3- to 10-membered heterocycle. In some embodiments, the optionally substituted heterocycle is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycle. In some embodiments, the optionally substituted 3- to 10-membered heterocycle is a 3- or 4-membered heterocycle, a 5- or 6-membered heterocycle, a 7- or 8-membered heterocycle, or a 9- or 10-membered heterocycle.

[0313] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 is an optionally substituted 5- to 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, nitrogen, sulfur, boron, phosphorus, silicon, selenium, and any combination thereof. In some embodiments, the optionally substituted 5- to 6-membered heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof.

[0314] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 The optionally substituted 5- to 6-membered heterocyclic ring of contains at least 1 nitrogen. In some embodiments, R 1 The optionally substituted 5- to 6-membered heterocyclic ring is selected from Any of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy. In some embodiments, one or more substituents are independently selected from the group consisting of hydroxy, =O, C1-C6 alkyl, 3 to 8 membered heterocycle, and C 3-8 carbocyclic ring, wherein the 3 to 8 membered heterocyclic ring and C 3-8 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy.

[0315] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 yes In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 is selected from optionally substituted C1-C6 alkyl and -P(=O)(R 24 )2.

[0316] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 It's hydrogen.

[0317] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 Yes -P(=O)(R 24 )2, and R 24 Selected from optionally substituted C 1-10 In some embodiments, R 1 yes

[0318] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 is a C1-C6 alkyl group optionally substituted by one or more substituents selected from: -N(R 30 )2、-(O-CH2-(CH2) p ) n -W, –OR 30 , optionally substituted C 3-10 carbocyclic and optionally substituted 3- to 10-membered heterocyclic rings, and R 30 is selected from hydrogen and optionally substituted C 1-10 In some embodiments, R 1 R 22 is a C1-C6 alkyl group substituted by one or more substituents selected from the group consisting of: -N(R 30 )2、-(O-CH2-(CH2) p) n -W and –OR 30 .

[0319] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 is one or more selected from -N(R 30 ) 2 is substituted with a C1-C6 alkyl group. In some embodiments, R 1 yes

[0320] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 is one or more selected from -(O-CH2-(CH2) p ) nIn some embodiments, n is 1 to 1000. In some embodiments, n is 1 to 800. In some embodiments, n is 1 to 500. In some embodiments, n is 1 to 300. In some embodiments, n is 1 to 100. In some embodiments, n is 1 to 50. In some embodiments, n is 1 to 25. In some embodiments, n is 3 to 1000. In some embodiments, n is 10 to 1000. In some embodiments, n is 50 to 1000. In some embodiments, n is 100 to 1000. In some embodiments, n is 200 to 1000. In some embodiments, n is 500 to 1000. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100. In some embodiments, p is from 1 to 1000. In some embodiments, p is from 1 to 800. In some embodiments, p is from 1 to 500. In some embodiments, p is from 1 to 300. In some embodiments, p is from 1 to 100. In some embodiments, p is from 1 to 50. In some embodiments, p is from 1 to 25. In some embodiments, p is from 3 to 1000. In some embodiments, p is from 10 to 1000. In some embodiments, p is from 50 to 1000. In some embodiments, p is from 100 to 1000. In some embodiments, p is from 200 to 1000. In some embodiments, p is from 500 to 1000. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

[0321] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 is one or more selected from -(O-CH2-(CH2) p ) n -W and –OR 30 In some embodiments, R 1 Selected from:

[0322] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22is selected from optionally substituted C 3-10 In some embodiments, the optionally substituted C1-C6 alkyl group is 3-10 The carbon ring is selected from C 3-6 In certain embodiments, C 3-6 In certain embodiments, the carbocyclic ring is unsaturated. 3-6 The carbocyclic ring is saturated. In some embodiments, the optionally substituted C 3-6 The carbon ring is selected from In some embodiments, R 1 R 22 is a C1-C6 alkyl group substituted with a phenyl group. 1 Selected from:

[0323] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 22 is a C1-C6 alkyl group substituted by one or more substituents selected from an optionally substituted 3 to 6 membered heterocycle. In some embodiments, the optionally substituted 3 to 6 membered heterocycle contains at least one heteroatom selected from N, O, S and any combination thereof.

[0324] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 22 is C1-C6 alkyl substituted by one or more substituents selected from optionally substituted 3 to 8 membered heterocyclic rings. 22 is a C2-C3 alkyl group substituted by one or more substituents selected from an optionally substituted 3 to 8 membered heterocyclic ring. 1 R 22 is C1-C6 alkyl substituted by one or more substituents selected from optionally substituted 3 to 8 membered heterocyclic rings, wherein the optionally substituted 3 to 8 membered heterocyclic rings contain at least one heteroatom selected from N and O. In some embodiments, R 22 The 3 to 8 membered heterocyclic ring of is saturated. 22 The 3 to 8 membered heterocyclic ring is substituted by one or more substituents selected from the following: -S(O)2R 30 、C 1-6 Alkyl and -OR 30 In some embodiments, -S(O)2R 30 R 30 Selected from C1-10 Alkyl, and -OR 30 R 30 Selected from hydrogen and C 1-6 In some embodiments, R 1 R 22 is a C1-C6 alkyl group substituted by one or more substituents selected from an optionally substituted 3- to 6-membered heterocyclic ring, wherein the optionally substituted 3- to 6-membered heterocyclic ring contains at least one heteroatom selected from N and O. In some embodiments, the 3- to 6-membered heterocyclic ring is substituted by one or more substituents selected from an optionally substituted C 1-6 Alkyl and -OR 30 In some embodiments, R 1 Selected from:

[0325]

[0326] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0327] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0328]

[0329] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 yes In some embodiments, R 1 R 20 is selected from hydrogen and optionally substituted C1-C3 alkyl. 1 R 21 is selected from hydrogen and optionally substituted C1-C3 alkyl. 1 R 21 is optionally substituted C 1-10 In some embodiments, R 1 R 21 is C substituted with one or more substituents selected from the following 1-10Alkyl: -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, optionally substituted C 3-10 In some embodiments, R 1 Selected from:

[0330]

[0331] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 yes where R 1 R 21 is an optionally substituted 3- to 7-membered heterocyclic ring. In some embodiments, the 3- to 7-membered heterocyclic ring is replaced by one or more selected from -OR 30 and optionally substituted C 1-10 In some embodiments, R 1 Selected from:

[0332] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 yes In some embodiments, R 1 R 23 is an optionally substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is substituted with one or more substituents selected from: -OR 30 、-N(R 30 ) 2. optionally substituted C 1-10 Alkyl, optionally substituted C 3-10 In some embodiments, R 1 Selected from:

[0333] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 R 23 is an optionally substituted 3- to 7-membered heterocyclic ring. In some embodiments, the 3- to 7-membered heterocyclic ring is replaced by one or more optionally substituted C1-10 In some embodiments, R 1 Selected from:

[0334] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0335]

[0336]

[0337] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0338]

[0339] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0340]

[0341] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0342] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from:

[0343] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG):

[0344] R 1 Selected from

[0345] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0346] R 3 Selected from optionally substituted C1-C6 alkoxy groups, such as R 3 is a C1-C6 alkoxy group, and preferably, R 3 is -OCH3;

[0347] R 4’ Selected from

[0348] R 5 is selected from hydroxy and optionally substituted C1-C6 alkoxy, such as R 5 is a C1-C6 alkoxy group, and preferably, R 5 It is hydroxyl;

[0349] R 6 and R 7 Unite to form

[0350] R 22 Selected from C1-C6 alkyl groups, such as R 22 is C2-C4 alkyl, wherein the C1-C6 alkyl or C2-C4 alkyl is substituted by an optionally substituted saturated 3 to 8 membered heterocycle, oxo, -OC 1-10 Alkyl, -NR 30 -S(O)2R 30 、-SO2-N(R 30 )2 or -S(O)2R 30 , where R 22 The substituents on the 3 to 8 membered saturated heterocyclic ring are independently selected from -NR 52 -SO2-R 30 、-SO2-N(R 52 )2、-S(O)2R 30 、C 1-6 Alkyl, C 1-6 Hydroxyalkyl and -OR 30 , and where -S(O)2R 30 R 30 Selected from C 1-10 Alkyl, and -OR 30 R 30 Selected from hydrogen and C 1-6 alkyl;

[0351] R100 Selected from hydrogen and C 1-10 alkyl;

[0352] R 110’ Selected from -S(O)2R 51’ , where R 51’ Selected from substituted C 1-4 Alkyl, -((CH2) q -CH2-D) z -T, optionally substituted C 1-30 Alkyl, optionally substituted C 3-8 Carbocyclic and optionally substituted 3-10 membered heterocyclic rings;

[0353] R 52 Selected from hydrogen and C 1-10 alkyl;

[0354] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0355] q is selected from 1 to 6;

[0356] Each z is selected from 1-20; and

[0357] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl.

[0358] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG): R 51’ is independently selected at each occurrence from -((CH2) q -CH2-D) z -T, optionally substituted C 1-30 Alkyl, optionally substituted C 3-8 In some embodiments, R 51’ is independently selected at each occurrence from -((CH2) q -CH2-D)z -T, optionally substituted C 3-8 In some embodiments, R 51’ is independently selected at each occurrence from -((CH2) q -CH2-D) z -T, C 3-8 carbocyclic rings and 3-10 membered heterocyclic rings.

[0359] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG): R 51’ Selected from -((CH2) q -CH2-D) z -T. In some embodiments, R 51’ Selected from C 1-30 In some embodiments, R 51’ Selected from unsubstituted C 1-30 In some embodiments, R 51’ Selected from C 3-8 In some embodiments, R 51’ Selected from unsubstituted C 3-6 In some embodiments, R 51’ Selected from C 3-5 In some embodiments, R 51’ In some embodiments, R 51’ In some embodiments, each D is independently selected from -O-. In some embodiments, z is selected from 1-10. In some embodiments, T is selected from hydrogen and C1-C6 alkyl. In some embodiments, R 51’ The optionally substituted C 1-30 Alkyl, optionally substituted C 3-8 The optional substituents on the carbocyclic and optionally substituted 3-10 membered heterocyclic rings are independently selected at each occurrence from:

[0360] Halogen, -OR 30’ 、-N(R 30’ )2、-(O-CH2-(CH2) p ) n -W, -SR 30’ 、-C(O)R 30’ 、-C(O)N(R 30’ )2、-N(R 30’ )C(O)R 30’ 、-C(O)OR 30’、-OC(O)R 30’ 、-S(O)R 30’ 、-S(O)2R 30’ 、-P(O)(OR 30’ )2、-OP(O)(OR 30’ )2, -NO2, =O, =S, =N(R 30’ ) and -CN;

[0361] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30’ 、-SR 30’ 、-N(R 30’ )2、-C(O)R 30’ 、-C(O)N(R 30’ )2、-N(R 30’ )C(O)R 30’ 、-C(O)OR 30’ 、-OC(O)R 30’ 、-S(O)R 30’ 、-S(O)2R 30’ 、-P(O)(OR 30’ )2、-OP(O)(OR 30’ )2, -NO2, =O, =S, =N(R 30’ ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0362] as well as

[0363] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30’ 、-SR 30’ 、-N(R 30’ )2、-C(O)R 30’ 、-C(O)N(R 30’ )2、-N(R 30’ )C(O)R 30’ 、-C(O)OR 30’ 、-OC(O)R 30’ 、-S(O)R 30’ 、-S(O)2R 30’ 、-P(O)(OR 30’ )2、-OP(O)(OR 30’ )2, -NO2, =O, =S, =N(R 30’ ),-CN, C 1-6Alkyl, C 1-6 Alkyl-R 30’ 、C 2-6 Alkenyl and C 2-6 Alkynyl.

[0364] In some embodiments, R 51’ R 30’ is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0365] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG);

[0366] R 1 Selected from: -OH and

[0367] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0368] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy; and

[0369] R 4’ Selected from

[0370] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;

[0371] R 6 and R 7 Unite to form

[0372] R 22 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 Carbocyclic ring and -P(=O)(R 24 )2;

[0373] R 100 Selected from:

[0374] Hydrogen and -(CH2-CH2-G) y -V; and

[0375] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0376] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0377] R 110’ Selected from:

[0378] Hydrogen, -(CH2-CH2-G) y -V, -S(O)R 51’ 、-S(O)2R 51’ 、-C(O)R 51’ 、-C(O)N(R 51’ )2 and -C(O)OR 51’ ;as well as

[0379] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31、-P(O)(OR 31 )2、-OP(O)(OR 31 )2、-NO2、-CN、C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings; and

[0380] C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 31 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0381] or

[0382] R 100 and R 110’ Together with the nitrogen to which they are attached, they form a 3-10 membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkoxy, wherein when R 1 When it is a hydroxyl group, R 100 and R 110 The ring formed is not an unsubstituted morpholine

[0383] Each G is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0384] Each D is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0385] Each y is selected from 3-20;

[0386] Each z is selected from 1-20;

[0387] Each V is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0388] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0389] Each R 31 are independently selected from hydrogen, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings; and

[0390] R 32 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0391] where R 22 、R 51 Optional substituents on V and T are independently selected at each occurrence from:

[0392] Halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0393] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0394] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C2-6 Alkynyl;

[0395] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0396] R 51’ is independently selected at each occurrence from optionally substituted C 3-8 Carbocycle, optionally substituted 3-10 membered heterocycle, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 alkyl;

[0397] Among them C 3-10 The carbocyclic and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0398] q is selected from 1 to 6;

[0399] Each p is selected from 1 or 2;

[0400] Each n is selected from 3 to 7; and

[0401] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl).

[0402] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG),

[0403] R 1 Selected from

[0404] R 22 is selected from optionally substituted C1-C6 alkyl;

[0405] where R 22 The substituents on each occurrence are independently selected from: -S(O)R 30 and -S(O)2R 30 , preferably -S(O)2R 30 ;

[0406] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy;

[0407] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy;

[0408] R 4’ Selected from

[0409] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy;

[0410] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form Preferably, R 6 and R 7 Unite to form

[0411] R 100 Selected from:

[0412] Hydrogen and

[0413] C 1-10 alkyl;

[0414] R 110’ Selected from:

[0415] -S(O)R51’ and -S(O)2R 51’ , preferably S(O)2R 51’ ;

[0416] R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocycle, optionally substituted 3-10 membered heterocycle, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 alkyl;

[0417] where R 51’ and the substituents on T are independently selected at each occurrence from:

[0418] Halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0419] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings,

[0420] Each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings;

[0421] Each D is independently selected from -O-;

[0422] q is selected from 1 to 6;

[0423] Each z is selected from 1-20;

[0424] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl.

[0425] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), -OH and where R 22 is one or more selected from –(O-CH2-(CH2) p ) n -W and –OR 30 a C1-C6 alkyl group substituted with a substituent of

[0426] R 4’ Selected from where R 100 Selected from: hydrogen and C 1-10 alkyl; and

[0427] R 110’ Selected from: -S(O)R 51’ and -S(O)2R 51’ , preferably S(O)2R 51’ .

[0428] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from: -OH and

[0429] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 yes And R 22 is selected from optionally substituted C1-C6 alkyl, preferably optionally substituted C 2-4 In some embodiments, R 22 is optionally substituted C 2-3 alkyl.

[0430] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 yes And R 22 is selected from substituted C1-C6 alkyl, preferably substituted C 2-4 alkyl.

[0431] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 22 The substituents on 30 、-(O-CH2-(CH2) p ) n -W, -S(O)R 30 、-S(O)2R 30 , =O, =S, =N(R 30 ) and -CN.

[0432] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 22 The optional substituents on are independently selected from -OR 30 、-S(O)2R 30 And = O.

[0433] In some embodiments, for a compound or salt of Formula (I), (IZ), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), -OR 30 and -S(O)2R 30 R 30 independently selected from hydrogen and C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0434] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), -OR 30 and -S(O)2R 30 R 30 independently selected at each occurrence from hydrogen and C 1-10 alkyl.

[0435] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from

[0436] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 1 Selected from

[0437] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4’ yes In some cases, R 100 Selected from: hydrogen and C 1-10 alkyl.

[0438] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 110’ Selected from: hydrogen, -S(O)R 51’ and -S(O)2R 51’ In some cases, R 110’ Selected from: -S(O)2R 51’ .

[0439] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocycle, optionally substituted 3-10 membered heterocycle, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 alkyl.

[0440] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocyclic ring, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 alkyl.

[0441] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocyclic ring and -((CH2) q -CH2-D) z -T.

[0442] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), wherein R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocycle, optionally substituted 3-10 membered heterocycle, -((CH2) q -CH2-D) z -T and optionally substituted C 5-30 In some cases, z is 3-10. In some cases, z is 3-8. In some cases, z is 4-8. In some cases, z is 5-10.

[0443] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3 to 6 membered heterocyclic rings. In some cases, R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings.

[0444] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, saturated C 3-6 carbocyclic and saturated 5- to 6-membered heterocyclic rings.

[0445] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl and saturated C3-6 Carbon ring.

[0446] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ C 1-4 The alkyl group is substituted with one or more substituents independently selected from: -OR 30 、C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0447] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ C 1-4 The alkyl group is replaced by one or more selected from -OR 30 and saturated C 3-6 The carbocyclic ring is substituted with a substituent.

[0448] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ C 1-4 Alkyl is independently selected from one or more -OR 30 and -((CH2) q -CH2-D) z -T, wherein z is 3 to 20, D is -O-, and T is selected from hydrogen and optionally substituted -C1-C6 alkyl.

[0449] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ C 1-4 Alkyl is composed of one or more independently selected from -((CH2) q -CH2-D) z -T, wherein z is 1 to 20, D is -O-, and T is selected from hydrogen and optionally substituted -C1-C6 alkyl.

[0450] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ -((CH2) q -CH2-D) z -Z of T is selected from 1 to 10. In some cases, z is selected from 1 to 5. In some cases, z is selected from 3 to 5.

[0451] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ -OR 30 R 30 Selected from hydrogen and C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0452] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ -OR 30 R 30 Selected from C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted by one or more independently selected from -OC 1-10 The alkyl group is substituted with a substituent.

[0453] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 51’ -OR 30 R 30 Selected from C 1-3 Alkyl, where C 1-10 The alkyl group is optionally substituted by one or more independently selected from -OC 1-3 The alkyl group is substituted with a substituent.

[0454] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 Selected from

[0455] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 Selected from

[0456] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 Selected from In some cases, R 4 Selected from

[0457] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 Selected from

[0458] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 Selected from

[0459] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R 4 Selected from

[0460] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG),

[0461] R 1 Selected from

[0462] R 22 is selected from optionally substituted C1-C6 alkyl;

[0463] where R 22 The substituents on each occurrence are independently selected from: -S(O)R 30 and -S(O)2R 30 , preferably -S(O)2R 30 , where R 30 independently selected at each occurrence from hydrogen and C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0464] In some embodiments, for a compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG),

[0465] R 1 Selected from -OH and

[0466] R 2 Selected from optionally substituted C1-C6 alkoxy, preferably -OCH3;

[0467] R 3 is selected from optionally substituted C1-C6 alkoxy, preferably -OCH3; and

[0468] R 4’ Selected from

[0469] R 5 is selected from hydroxy and optionally substituted C1-C6 alkoxy, preferably -OH;

[0470] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form Preferably

[0471] R 22 is selected from optionally substituted C1-C6 alkyl;

[0472] R 100 Selected from:

[0473] Hydrogen and

[0474] C 1-10 alkyl;

[0475] R 110’ Selected from:

[0476] Hydrogen and -S(O)2R 51’ , preferably -S(O)2R 51’ ;

[0477] where R 22 、R 51’ and the optional substituents on T are independently selected at each occurrence from:

[0478] Halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n-W, -NO2, =O, =S, -S(O)2R 30 and -CN;

[0479] as well as

[0480] C 3-10 Carbocyclic and 3-6 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl, -OC 1-6 alkyl;

[0481] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl;

[0482] R 51’ is independently selected at each occurrence from substituted C 1-4 Alkyl, optionally substituted C 3-8 Carbocyclic ring and -((CH2) q -CH2-D) z -T;

[0483] Each D is independently selected from -O-;

[0484] Each T is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0485] z is selected from 1 to 10;

[0486] q is selected from 1 to 6;

[0487] Each p is selected from 1 or 2;

[0488] Each n is selected from 3 to 7; and

[0489] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl).

[0490] In some embodiments, the compound or salt of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) is selected from:

[0491]

[0492]

[0493] Compound Group 2

[0494] In a second aspect, the present disclosure provides a compound represented by the structure of Formula X:

[0495]

[0496] or a pharmaceutically acceptable salt thereof, wherein:

[0497] L is selected from optionally substituted C 1-8 alkylene;

[0498] R 1 It is a carboxylic acid or a carboxylic acid isostere;

[0499] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0500] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl; and

[0501] R 4 Selected from and an optionally substituted 3- to 10-membered heterocycle, and when L is an optionally substituted C 3-8 When alkylene, R 4 further selected from methoxy; and when -LR 1 When it is ethyl acetate, tert-butyl acetate, benzyl acetate or methyl 2-phenylacetate, R 4 Not methoxy;

[0502] where R4 The optionally substituted heterocycle may be substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, =O, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy C1-C6 alkyl;

[0503] z is 0, 1, 2, 3, 4, or 5;

[0504] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0505] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form

[0506] R 25 is independently selected at each occurrence from hydrogen, optionally substituted C1-C6 alkyl, -D-(CH2-CH2-G) y -V, optionally substituted C 3-20 carbocyclic and optionally substituted 3- to 20-membered heterocyclic rings,

[0507] When R 25 When C1-C6 alkyl is optionally substituted, the substituents on C1-C6 alkyl are independently selected from halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C(O)N(R 31 )2、-OC(O)N(R 31 )2、-C(O)OR 31 、-P(O)(R 31 )2. -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-10 Alkyl-CN, -OC 1-10 Alkyl-C(O)OR 31 、C 2-10 Alkenyl, C 2-10Alkynyl, C 3-20 Carbocyclic and 3- to 20-membered heterocyclic rings;

[0508] When R 25 is optionally substituted C 3-20 When it is a carbocyclic ring or an optionally substituted 3- to 20-membered heterocyclic ring, C 3-20 The substituents on the carbocyclic and 3- to 20-membered heterocyclic rings are independently selected at each occurrence from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0509] wherein D is selected from a bond or -O-;

[0510] Each G is independently selected from -O-, -NR 32 -, -S- or -SO2-;

[0511] Each y is selected from 1-20;

[0512] Each V is selected from hydrogen and optionally substituted -C1-C6 alkyl;

[0513] R 30 is independently selected at each occurrence from hydrogen; C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -OSi(C1-C6 alkyl)3, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0514] R' and R'' at each occurrence are independently selected from hydrogen, halogen, -OR 31 and optionally one or more independently selected from halogen and -OR 31 Substituents substituted C 1-8 alkyl; and

[0515] R 31 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -OSi(C1-C6 alkyl)3, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-10 Alkyl-OH, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0516] R 32 is independently selected at each occurrence from: hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings; and

[0517] wherein the substituents on V and L are independently selected at each occurrence from:

[0518] Halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0519] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0520] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0521] In certain embodiments, the compound of formula (X) is represented by formula (XA): or a salt thereof.

[0522] In certain embodiments, the compound of formula (X) is represented by formula (XB): or a salt thereof.

[0523] In certain embodiments, the compound of formula (X) is represented by formula (XC): or a salt thereof.

[0524] In certain embodiments, the compound of formula (X) is represented by formula (XD): or a salt thereof.

[0525] In certain embodiments, the compound of formula (X) is represented by formula (XE): or a salt thereof.

[0526] In certain embodiments, the compound of formula (X) is represented by formula (XF): or a salt thereof.

[0527] In certain embodiments, the compound of formula (X) is represented by formula (XG): or a salt thereof.

[0528] In certain embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 is a carboxylic acid isostere. The carboxylic acid functional group can be an important component of the pharmacophore; however, the presence of this moiety can also lead to significant drawbacks, including metabolic instability, toxicity, and limited passive diffusion across biological membranes. To avoid potential drawbacks while retaining the desirable properties of the carboxylic acid moiety, R 1 It may be selected from carboxylic acid isosteres. Carboxylic acid isosteres are chemical moieties that exhibit similar or improved physical and biological properties relative to a carboxylic acid group.

[0529] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1The carboxylic acid isostere is selected from the group consisting of esters, hydroxamic acids, hydroxamates, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfones, sulfonamides, acylsulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinediones, oxazolidinediones, oxadiazole-5(4H)-ones, thiadiazole-5(4H)-thiones, oxathiadiazole-2-oxides, oxadiazole-5(4H)-thiones, isoxazoles, tetramic acids, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acids, and substituted phenols.

[0530] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 The carboxylic acid isostere is selected from the group consisting of hydroxamic acid, hydroxamate, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfone, sulfonamide, acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid and substituted phenols.

[0531] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 Selected from: esters, carboxylic acids, hydroxamic acids, hydroxamates, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfones, sulfonamides, acylsulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinediones, oxazolidinediones, oxadiazole-5(4H)-ones, thiadiazole-5(4H)-thiones, oxathiadiazole-2-oxides, oxadiazole-5(4H)-thiones, isoxazoles, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acids, and substituted phenols.

[0532] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 Selected from the group consisting of: carboxylic acids, hydroxamic acids, hydroxamates, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfones, acylsulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinediones, oxazolidinediones, oxadiazole-5(4H)-ones, thiadiazole-5(4H)-thiones, oxathiadiazole-2-oxides, oxadiazole-5(4H)-thiones, isoxazoles, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acids, and substituted phenols.

[0533] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), when -LR 1 R 1 When R is selected from the group consisting of carboxylic acid, hydroxamic acid, hydroxamate, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfone, acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid and substituted phenol, R 4 Not methoxy.

[0534] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), when -LR 1 R 1 When R is selected from the group consisting of esters, carboxylic acids, hydroxamic acids, hydroxamates, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfones, acylsulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinediones, oxazolidinediones, oxadiazole-5(4H)-ones, thiadiazole-5(4H)-thiones, oxathiadiazole-2-oxides, oxadiazole-5(4H)-thiones, isoxazoles, tetramic acids, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acids, and substituted phenols, R 4 Not methoxy.

[0535] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on In some embodiments, when -LR 1 Depend on When R 4 In some embodiments, when -LR 1 Depend on In some embodiments, when -LR 1 Depend on Indicates that, and L is selected from C 3-8 In some embodiments, when -LR 1 Depend on Indicates that, and L is selected from C 1-2 When L is an alkylene group, L is substituted.

[0536] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on In some embodiments, R 41 Selected from C 1-6 In some embodiments, R 41 It is C 1-6 In some embodiments, R 41 It is C 1-4 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, R 41 In some embodiments, -LR 1 yes In some embodiments, -LR 1 yes In some embodiments, -LR 1 yes In some embodiments, when -LR 1 Depend on When L is selected from C 2-8 In some embodiments, when -LR 1 Depend on When L is a C1 alkylene group, R 4 In some embodiments, -LR 1 Depend on Indicates that R 4 In some embodiments, when -LR 1 When it is ethyl acetate, tert-butyl acetate, benzyl acetate or methyl 2-phenylacetate, R 4 In some embodiments, when -LR 1 Selected from When R 4 In some embodiments, when -LR1 yes When R 4 In some embodiments, when -LR 1 yes When R 4 In some embodiments, when -LR 1 yes When R 4 In some embodiments, when -LR 1 yes When R 4 Not methoxy.

[0537] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is a hydroxamate. In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0538] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 Selected from: hydroxamic acid, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfone, acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-thione, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid and substituted phenol.

[0539] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 Is a hydroxamic acid. In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0540] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0541] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0542] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is a sulfonic acid. In some embodiments, -LR 1 Depend on In some embodiments, R 1 The carboxylic acid isostere may be a salt, such as -LR 1 Depend on express.

[0543] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0544] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 Is a sulfonamide. In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0545] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0546] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0547] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is a sulfonylurea. In some embodiments, -LR 1 Depend on express.

[0548] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0549] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0550] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1is a thiazolidinedione. In some embodiments, -LR 1 Depend on express.

[0551] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0552] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is oxadiazol-5(4H)-one. In some embodiments, -LR 1 Depend on express.

[0553] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is thiadiazole-5(4H)-thione. In some embodiments, -LR 1 Depend on express.

[0554] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0555] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is oxadiazole-5(4H)-thione. In some embodiments, -LR 1 Depend on express.

[0556] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1R 1 In some embodiments, -LR 1 Depend on express.

[0557] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on express.

[0558] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is cyclopentane 1,3-dione. In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0559] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is cyclopentane 1,2-dione. In some embodiments, -LR 1 Depend on express.

[0560] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0561] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 R 1 is a substituted phenol. In some embodiments, -LR 1 The substituted phenol is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -S-, -S(O)-, and -S(O)2-. In some embodiments, -LR 1 Depend on express.

[0562] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 The substituted phenol is substituted with one or more substituents selected from halogen. 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0563] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on In some embodiments, -LR 1 Depend on express.

[0564] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 Depend on express.

[0565] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 Depend on express.

[0566] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), -LR 1 Depend on express.

[0567] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted C 1-8 In some embodiments, the optionally substituted C 1-8 The alkylene group is selected from methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), when L is an optionally substituted C 1-2 When alkylene, R 4 In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、=O、C 1-10 Alkyl, C 1-10 In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-N(R30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-(O-CH2-(CH2) p ) n -W、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、C 1-10 Alkyl, C 1-10 In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、C 1-10 Alkyl, C 1-10 In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is unsubstituted, for example, L is methylene, ethylene, or propylene.

[0568] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted C 1-8 Alkylene, wherein L is optionally replaced by one or more independently selected from -(O-CH2-(CH2) p ) n -W is substituted with a substituent, wherein each p is selected from 1 or 2; each n is selected from 3-7; and each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl).

[0569] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), when L is optionally substituted C 3-8 When alkylene, R 4 Further selected from methoxy.

[0570] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted C 3-8 Alkylene, the C 3-8 The alkylene group is selected from propylene, butylene, pentylene, hexylene, heptylene and octylene, any of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、=O、C 1-10 Alkyl, C 1-10 In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、C 1-10 Alkyl, C 1-10 Haloalkyl and -CN.

[0571] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is substituted C1-8 In some embodiments, the substituted C 1-8 The alkylene group is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene.

[0572] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), when L is substituted C 3-8 When alkylene, R 4 Further selected from methoxy.

[0573] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is C substituted with one or more substituents independently selected from the group consisting of 3-8 Alkylene: halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、C 1-10 Alkyl, C 1-10 Haloalkyl and -CN.

[0574] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is C substituted with one or more substituents independently selected from the group consisting of 3-8 Alkylene: halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-NO2、=O、C 1-10 Alkyl, C 1-10 Haloalkyl and -CN.

[0575] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2 and C1-C6 alkoxy. 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -NO2 and C1-C6 alkoxy.

[0576] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 2 is selected from hydrogen and C1-C6 alkoxy. 2 In some embodiments, R 2 Yes-OMe.

[0577] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy and C1-C6 alkoxy. 3 is selected from hydrogen and C1-C6 alkoxy.

[0578] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 3 In some embodiments, R 3 Yes-OMe.

[0579] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2 and C1-C6 alkoxy.

[0580] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 5 It is a hydroxyl group.

[0581] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 6 and R 7 are each independently selected from hydrogen, hydroxyl and C1-C6 alkoxy. 6 and R 7 are each independently selected from hydrogen and hydroxy. 6 and R 7 In some embodiments, R 6 is hydrogen, and R 7 In some embodiments, R 6 is hydrogen, and R 7 Yes. In some embodiments, R 6 and R 7 Unite to form

[0582] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from and an optionally substituted 3- to 10-membered heterocyclic ring.

[0583] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 yes In some embodiments, z is 0, 1, 2, 3, 4, or 5. In some embodiments, z is 1, 2, 3, 4, or 5. In some embodiments, z is 1, 2, or 3. In some embodiments, z is 2, 3, or 4. In some embodiments, when z is 0, R 25 is selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 In some embodiments, when z is 1, R 25 is selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered heterocycle and optionally substituted C 3-10 Carbon ring.

[0584] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), Each R' and R'' is independently selected from hydrogen, -OR 31 and optionally one or more -OR31 Substituted C 1-3 In some embodiments, R' and R" are the same substituent, for example, R' is methyl and R" is methyl, or R' is hydrogen and R" is hydrogen. In some embodiments, each R' and R" is independently selected from different substituents, for example, R' is methyl and R" is ethyl. In some embodiments, each R' and R" is independently selected from hydrogen and optionally substituted by one or more -OR 31 Substituted C 1-3 In some embodiments, R' and R" are each optionally substituted with one or more -OR 31 Substituted C 1-3 In some embodiments, R' and R" are each hydrogen.

[0585] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 is selected from hydrogen, optionally substituted C1-C6 alkyl, -D-(CH2-CH2-G) y -V, an optionally substituted 3- to 10-membered heterocyclic ring and an optionally substituted C 3-10 Carbon ring.

[0586] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 In some embodiments, R 4 yes

[0587] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 is an optionally substituted C1-C6 alkyl. 25 The optionally substituted C1-C6 alkyl group is replaced by one or more selected from -OH and -OC 1-6 In some embodiments, R 4 Selected from: In some embodiments, R 4 yes

[0588] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 is a compound selected from -P(O)(R 31 ) 2 is a substituted C1-C6 alkyl. In some embodiments, -P(O)(R 31 )2 of R 31 is one or more selected from -OH and -OC 1-6 Alkyl substituents substituted C 1-6 In some embodiments, R 4 Depend on express.

[0589] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 Yes-D-(CH2-CH2-G) y -V. In some embodiments, D is a bond. In some embodiments, D is -O-. In some embodiments, -D-(CH2-CH2-G) y -V is 1 to 1000. In some embodiments, y is 1 to 800. In some embodiments, y is 1 to 500. In some embodiments, y is 1 to 300. In some embodiments, y is 1 to 100. In some embodiments, y is 1 to 50. In some embodiments, y is 1 to 25, such as 1 to 10 or 1 to 8. In some embodiments, y is 3 to 1000. In some embodiments, y is 10 to 1000. In some embodiments, y is 50 to 1000. In some embodiments, y is 100 to 1000. In some embodiments, y is 200 to 1000. In some embodiments, y is 500 to 1000. In some embodiments, R 25 -D-(CH2-CH2-G) y -V y is 3 to 10. In some embodiments, R 25 -D-(CH2-CH2-G) y -V y is 5 to 10. In some embodiments, y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100. In some embodiments, y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

[0590] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2-G) y -V represents, and -D-(CH2-CH2-G) y -V's G at each occurrence is -O-. In some embodiments, R 4 Selected from In some embodiments, R 4 Selected from

[0591] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2-G) y -V represents. In some embodiments, D is selected from a bond or -O-. In some embodiments, D is a bond. In some embodiments, D is -O-. In some embodiments, when z is 0, D is a bond. In some embodiments, when z is 1, D is a bond. In some embodiments, when z is 2, D is a bond. In some embodiments, when D is -O-, z is selected from 1, 2, 3, 4, or 5. In some embodiments, when D is -O-, z is selected from 2, 3, 4, or 5.

[0592] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2) y -V represents, and -D-(CH2-CH2-G) y -V's G is -NR every time it appears 32 -. In some embodiments, -NR 32 - Each R 32 are independently selected from hydrogen; and C 1-10 Alkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0593] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2-G) y -V represents, and V is an optionally substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl of V is optionally replaced by one or more independently selected from -(O-CH2-(CH2) p ) n -W is substituted with a substituent, wherein

[0594] Each p is selected from 1 or 2; each n is selected from 3 to 7; and each W is selected from hydrogen, -OH, -C1-C4 alkyl, and -O(C1-C4 alkyl).

[0595] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2-G) y -V represents, and V is an optionally substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl of V is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 30 、-N(R 30 )2、-SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN.

[0596] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2-G) y-V represents, and V is an optionally substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl of V is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN.

[0597] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 By -D-(CH2-CH2-G) y -V represents, and V is one or more independently selected from -OR 30 and -N(R 30 ) 2 is a substituted C1-C6 alkyl group. In some embodiments, V is a substituted C1-C6 alkyl group having one or more independently selected from -OR 30 The substituents are substituted C1-C6 alkyl, wherein R 30 selected from hydrogen; and C 1-5 Alkyl, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0598] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25is an optionally substituted 3 to 6 membered heterocyclic ring. In some embodiments, the 3 to 6 membered heterocyclic ring is saturated. In some embodiments, the 3 to 6 membered heterocyclic ring is unsaturated. In some embodiments, the optionally substituted 3 to 6 membered heterocyclic ring contains at least one heteroatom selected from nitrogen, oxygen, sulfur and any combination thereof. In some embodiments, the optionally substituted 3 to 6 membered heterocyclic ring contains at least one heteroatom selected from N and O, wherein the 3 to 6 membered heterocyclic ring is optionally replaced by C 1-6 In some embodiments, R 4 Selected from

[0599] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 is optionally substituted C 3-10 In some embodiments, R 25 is optionally substituted C 3-6 In some embodiments, C 3-6 The carbocyclic ring is saturated. In some embodiments, C 3-6 The carbocyclic ring is unsaturated. In some embodiments, R 4 Selected from:

[0600] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 yes

[0601] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0602] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R4 yes In some embodiments, R 4 yes

[0603] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0604] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 Selected from: In some embodiments, R 4 yes

[0605] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), when R 1 When it is hydroxyl, R 4 no In some embodiments, R 4 no

[0606] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from: In some embodiments, R 4 Selected from In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0607] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0608] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from: In some embodiments, R 4 From In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0609] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is selected from optionally substituted C 1-6 alkylene;

[0610] R 1 It is sulfone;

[0611] R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy;

[0612] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy; and

[0613] R 4 Selected from and an optionally substituted 3- to 10-membered heterocyclic ring, preferably

[0614] where R 4 The optionally substituted heterocycle may be substituted by one or more substituents selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, =O, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy C1-C6 alkyl;

[0615] z is 0, 1, 2, 3, 4, or 5;

[0616] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy;

[0617] R 6 and R 7 Each independently selected from hydrogen, hydroxy and C1-C6 alkoxy; or R 6 and R 7 Unite to form Preferably, R 6 and R 7 Unite to form

[0618] In some embodiments, for compounds or salts of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), L is selected from optionally substituted C 1-5Alkylene.

[0619] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 Selected from carboxylic acids, esters, sulfones and sulfonic acids.

[0620] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), the ester is composed of -C(O2)(C 1-6 Alkyl) represents, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NO2, =O, -OC 1-6 Alkyl, and sulfone is composed of -S(O)2C 1-6 Alkyl represents a C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NO2, =O, -OC 1-6 alkyl.

[0621] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 Selected from

[0622] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 In some embodiments, R 1 Selected from In some cases, R 1 Selected from

[0623] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 Selected from

[0624] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 1 is selected from sulfones and esters. In some cases, R 1 Selected from

[0625] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 yes wherein R' and R'' at each occurrence are independently selected from hydrogen, hydroxyl and -OR 31 , where R 31 It is C 1-10 In some cases, z is selected from 1, 2, and 3.

[0626] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 25 Selected from hydrogen and -D-(CH2-CH2-G) y -V, wherein D is -O-, G is -O-, y is 1-3, and V is selected from -C1-C6 alkyl and hydrogen.

[0627] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 It's a methoxy group.

[0628] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from

[0629] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from

[0630] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from

[0631] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from

[0632] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from In some cases, R 4 Selected from

[0633] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG),

[0634] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG),

[0635] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0636]

[0637] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0638] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0639] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0640] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0641] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0642] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0643] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0644] In some embodiments, for a compound or salt of Formula (X), (XA), (XB), (XC), (XD), (XE), (XF), or (XG), R 4 Selected from:

[0645] In some embodiments, the compound or salt of formula (I) is selected from:

[0646]

[0647]

[0648] Compound Group 3

[0649] In a third aspect, the present disclosure provides a compound represented by the structure of formula (L):

[0650]

[0651] or a pharmaceutically acceptable salt thereof, wherein:

[0652] R 1 Selected from 3 to 10 membered heterocyclic ring and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted by one or more independently selected R 33 Substituents substituted;

[0653] R 2is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0654] R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl; and

[0655] R 4 yes

[0656] R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl;

[0657] R 6 and R 7 Each independently selected from hydrogen, hydroxyl and C 1-6 alkoxy; or

[0658] R 6 and R 7 Unite to form

[0659] R 20 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0660] R 21 is selected from optionally substituted C1-C6 alkyl and optionally substituted 3 to 7 membered heterocycle;

[0661] R 22 is selected from hydrogen, optionally substituted C1-C6 alkyl, -Si(R 24 )3 and -P(=O)(R 24 )2;

[0662] R 23 is selected from optionally substituted C1-C6 alkyl and optionally substituted 3 to 7 membered heterocycle;

[0663] R 24 is an optionally substituted C1-C6 alkyl group;

[0664] where R 20 、R 21 、R 22 、R 23 and R 24 The substituents on each occurrence are independently selected from:

[0665] Halogen, -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, -SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ) and -CN;

[0666] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0667] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 30 、-SR 30 、-N(R 30 )2、-C(O)R 30 、-C(O)N(R 30 )2、-N(R 30 )C(O)R 30 、-C(O)OR 30 、-OC(O)R 30 、-S(O)R 30 、-S(O)2R 30 、-P(O)(OR 30 )2、-OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ),-CN, C 1-6 Alkyl, C 1-6 Alkyl-R 30 、C 2-6 Alkenyl and C 2-6 Alkynyl;

[0668] Each p is selected from 1 or 2;

[0669] Each n is selected from 3 to 7;

[0670] Each W is selected from hydrogen, -OH, -C1-C4 alkyl and -O(C1-C4 alkyl);

[0671] R 30 independently selected at each occurrence from:

[0672] hydrogen; and

[0673] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -OSi(C1-C6 alkyl)3, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and haloalkyl rings;

[0674] z is selected from 0-2;

[0675] R' and R'' are independently selected from hydrogen, halogen, -OR 31 and optionally one or more independently selected from halogen and -OR 31 Substituents substituted C 1-3 alkyl;

[0676] Ring A is selected from optionally substituted C3-C5 carbocycles and optionally substituted 3- to 5-membered heterocycles, wherein the substituents on Ring A are independently selected at each occurrence from:

[0677] Halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ) and -CN;

[0678] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; and

[0679] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-SR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-S(O)R 31 、-S(O)2R 31 、-P(O)(OR 31 )2、-OP(O)(OR 31 )2, -NO2, =O, =S, =N(R 31 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0680] R 31 is independently selected at each occurrence from hydrogen; and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 carbocyclic and 3- to 12-membered heterocyclic rings; and

[0681] R 33is independently selected at each occurrence from hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkyl, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyC1-C6 alkyl.

[0682] In certain embodiments, the compound of formula (L) is represented by formula (LA): or a salt thereof.

[0683] In certain embodiments, the compound of formula (L) is represented by formula (LB): or a salt thereof.

[0684] In certain embodiments, the compound of formula (L) is represented by formula (LC): or a salt thereof.

[0685] In certain embodiments, the compound of formula (L) is represented by formula (LD): or a salt thereof.

[0686] In certain embodiments, the compound of formula (L) is represented by formula (LE): or a salt thereof.

[0687] In certain embodiments, the compound of formula (L) is represented by formula (LF): or a salt thereof.

[0688] In certain embodiments, the compound of formula (L) is represented by formula (LG): or a salt thereof.

[0689] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 In some embodiments, z is selected from 0, 1, or 2. In some embodiments, z is selected from 0 and 1. In some embodiments, z is selected from 0 and 2. In some embodiments, z is selected from 1 and 2. In some embodiments, z is selected from optionally substituted -CH2- and optionally substituted -CH2CH2-.

[0690] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), z is 0, and R 4 It is represented by:

[0691] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), z is 1, and R 4 It is represented by:

[0692] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), z is 2, and R 4 It is represented by:

[0693] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Each R' and R'' is independently selected from hydrogen, halogen, -OR 31 and optionally one or more independently selected from halogen and -OR 31 Substituents substituted C 1-3 In some embodiments, z is 1, and R' and R" are the same substituent, for example, R' is methyl and R" is methyl, or R' is hydrogen and R" is hydrogen. In some embodiments, z is 1, and R' and R" are independently selected from different substituents, for example, R' is methyl and R" is ethyl. In some embodiments, each R' and R" are independently selected from hydrogen and C 1-3 In some embodiments, each of R' and R" is independently selected from hydrogen, halogen, and -OR 31 In some embodiments, z is 1, and R' and R" are each hydrogen.

[0694] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from an optionally substituted C3-C5 carbocycle, such as an optionally substituted C3-C4 carbocycle, an optionally substituted C3 carbocycle, an optionally substituted C4 carbocycle, or an optionally substituted C5 carbocycle. In some embodiments, the optionally substituted carbocycle is unsaturated. In some embodiments, the optionally substituted carbocycle is saturated.

[0695] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 3- to 5-membered heterocycle, such as an optionally substituted 3- to 4-membered heterocycle, an optionally substituted 3-membered heterocycle, an optionally substituted 4-membered heterocycle, or an optionally substituted 5-membered heterocycle. In some embodiments, the optionally substituted heterocycle is unsaturated. In some embodiments, the optionally substituted heterocycle is saturated.

[0696] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from optionally substituted C3-C5 carbocycles and optionally substituted 3-5 membered heterocycles, wherein each substituent is independently selected from: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2 and -CN; and C optionally substituted by one or more substituents independently selected from the following 1-3 Alkyl: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、-N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 、-NO2、-CN、C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings.

[0697] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from optionally substituted C3-C5 carbocycles and optionally substituted 3- to 5-membered heterocycles, wherein one or more substituents are independently selected from: C 1-3 Alkyl, which is optionally substituted with one or more -OR 31 Substituent substitution.

[0698] In some embodiments, for the compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted C3-C5 carbocycle selected from: Any of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings.

[0699] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 yes wherein z is selected from 1 and 2. In some embodiments, z is selected from 0, 1, and 2. In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 yes wherein z is selected from 0, 1, and 2. In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 yes wherein z is selected from 0, 1, and 2. In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0700] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the C3 carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0701] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the C3 carbocyclic ring is substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0702] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the C4 carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31)2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0703] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the C4 carbocyclic ring is substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0704] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the C5 carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31, -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0705] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the C5 carbocyclic ring is substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0706] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 3- to 5-membered heterocyclic ring wherein one or more substituents are independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 In some embodiments, the optionally substituted 3 to 5 membered heterocyclic ring is saturated. In some embodiments, the optionally substituted 3 to 5 membered heterocyclic ring is unsaturated.

[0707] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the 3- to 5-membered heterocyclic ring comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, boron, phosphorus, silicon, selenium, and any combination thereof. In some embodiments, the 3- to 5-membered heterocyclic ring comprises at least one heteroatom selected from oxygen, nitrogen, and sulfur.

[0708] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a 3-membered heterocyclic ring wherein the heterocyclic ring comprises one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, Ring A is a 3-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0709] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a 4-membered heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31)2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0710] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 4-membered heterocyclic ring containing 1 oxygen atom, wherein the 4-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S and -CN. In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-6 In some embodiments, R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0711] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a substituted 4-membered heterocyclic ring containing 1 oxygen atom, wherein the 4-membered heterocyclic ring is substituted with one or more substituents independently selected from the group consisting of halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S and -CN. In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-10 In some embodiments, R 4 Selected from:

[0712] In some embodiments, for the compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted 4-membered heterocyclic ring contains 1 or 2 heteroatoms selected from nitrogen and sulfur.

[0713] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 4-membered heterocyclic ring containing 1 or 2 nitrogen atoms. In some embodiments, the optionally substituted 4-membered heterocyclic ring is selected from azetidine, 2,3-dihydroazetadiene, azetadiene, 1,3-diazetidine, and 1,4-diazetidine, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-10 Alkyl and hydrogen.

[0714] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 4-membered heterocycle selected from azetidine, 1,3-diazetidine, and 1,4-diazetidine, any of which are optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-10 Alkyl and hydrogen.

[0715] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 4-membered heterocycle selected from 2,3-dihydroazetidine and azetidine, either of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-10 Alkyl and hydrogen.

[0716] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted azetidine optionally substituted by one or more independently selected from C 1-10 The alkyl group is substituted with a substituent, the C 1-10 Each alkyl group is optionally substituted by one or more independently selected from -OR 31 In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-10 In some embodiments, R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R4 yes In some embodiments, R 4 Selected from: In some embodiments, R 4 yes

[0717] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring comprising at least one heteroatom selected from nitrogen, oxygen, sulfur, and any combination thereof. In some embodiments, Ring A is an optionally substituted 5-membered heterocyclic ring comprising 4 heteroatoms selected from nitrogen, oxygen, sulfur, and any combination thereof.

[0718] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocycle containing 4 nitrogen atoms. In some embodiments, Ring A is an optionally substituted tetrazole, optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0719] In some embodiments, for the compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring comprising 3 heteroatoms selected from nitrogen, oxygen, sulfur, and any combination thereof.

[0720] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the optionally substituted 5-membered heterocyclic ring is selected from 1,2,4-triazole, 1,2,3-triazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, and 1,2,5-thiadiazole, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0721] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the optionally substituted 5-membered heterocyclic ring is selected from pyrazolidine, imidazolidine, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,3-dioxolane, oxazole, isoxazole, thiazole, isothiazole, 1,2-oxathiolane, and 1,3-oxathiolane, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0722] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is a substituted 5-membered heterocyclic ring containing 2 oxygen atoms, wherein the optionally substituted 5-membered heterocyclic ring is selected at each occurrence from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 2-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0723] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), when R 1 When it is hydroxyl, R 4 no In some embodiments, R 4 no

[0724] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is selected from pyrrolidine, 3-pyrroline, 2-pyrroline, 2H-pyrrole, 1H-pyrrole, tetrahydrofuran, furan, tetrahydrothiophene, and thiophene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0725] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring containing 1 oxygen atom, wherein the optionally substituted 5-membered heterocyclic ring is selected from tetrahydrofuran and furan, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0726] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocycle selected from optionally substituted by one or more independently selected from halogen, -OR 31 and C1-10 In some embodiments, the optionally substituted 5-membered heterocycle is tetrahydrofuran, which is optionally substituted by one or more independently selected from halogen, -OR 31 and C 1-10 In some embodiments, -OR 31 R 31 Selected from hydrogen and C 1-10 In some embodiments, R 4 Selected from In some embodiments, R 4 Selected from In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0727] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring containing 1 nitrogen atom, wherein the optionally substituted 5-membered heterocyclic ring is selected from pyrrolidine, 3-pyrroline, 2-pyrroline, 2H-pyrrole, and 1H-pyrrole, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 , -NO2, =O, =S, -CN, C3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0728] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted 5-membered heterocycle is selected from pyrrolidine, 3-pyrroline, 2-pyrroline, 2H-pyrrole, and 1H-pyrrole, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 ; and C 1-10 Alkyl, each of which is optionally substituted by one or more independently selected from OR 31 In some embodiments, -OR 31 R 31 In each occurrence, independently selected from C 1-10 In some embodiments, R 4 Selected from: In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0729] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is an optionally substituted 5-membered heterocyclic ring containing 1 sulfur atom, wherein the optionally substituted 5-membered heterocyclic ring is selected from tetrahydrothiophene and thiophene, either of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31 )2、-C(O)R 31 、-C(O)N(R 31 )2、N(R 31 )C(O)R 31 、-C(O)OR 31 、-OC(O)R 31 , -NO2, =O, -CN; and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 31 、-N(R 31)2、-C(O)R 31 , -NO2, =O, =S, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0730] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the optionally substituted 5-membered heterocycle is tetrahydrothiophene, which is optionally substituted by one or more independently selected from -OR 31 , =O and C 1-10 In some embodiments, R 4 Selected from In some embodiments, R 4 From In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0731] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 Selected from

[0732] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2 and C1-C6 alkoxy. 2 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -NO2 and C1-C6 alkoxy.

[0733] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 2 is selected from hydrogen and C1-C6 alkoxy. 2 In some embodiments, R 2 Yes-OMe.

[0734] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 3 is selected from hydrogen and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy and C1-C6 alkoxy. 3 is selected from hydrogen and C1-C6 alkoxy.

[0735] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 3 In some embodiments, R 3 Yes-OMe.

[0736] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 5 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, -CN, -NO2 and C1-C6 alkoxy.

[0737] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 5 It is a hydroxyl group.

[0738] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 6 and R 7 are each independently selected from hydrogen and hydroxy. 6 and R 7 In some embodiments, R 6 is hydrogen, and R 7 In some embodiments, R 6 and R 7 Unite to form

[0739] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from and an optionally substituted 3- to 10-membered heterocycle. In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from hydroxyl groups.

[0740] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 is an optionally substituted 3- to 10-membered heterocycle. In some embodiments, the optionally substituted heterocycle is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycle. In some embodiments, the optionally substituted 3- to 10-membered heterocycle is a 3- or 4-membered heterocycle, a 5- or 6-membered heterocycle, a 7- or 8-membered heterocycle, or a 9- or 10-membered heterocycle.

[0741] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 is an optionally substituted 5- to 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, nitrogen, sulfur, boron, phosphorus, silicon, selenium, and any combination thereof. In some embodiments, the optionally substituted 5- to 6-membered heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof.

[0742] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 The optionally substituted 5- to 6-membered heterocyclic ring of contains at least one heteroatom selected from nitrogen. 1 The optionally substituted 5- to 6-membered heterocyclic ring is selected from Any of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, 3 to 10 membered heterocycle and C 3-10 carbocyclic ring, wherein the 3 to 10-membered heterocyclic ring and C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy. In some embodiments, one or more substituents are independently hydroxy, =O, C1-C6 alkyl, 3 to 8 membered heterocycle, and C1-C6 alkyl. 3-8 carbocyclic ring, wherein the 3 to 8 membered heterocyclic ring and C 3-8 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, -CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy.

[0743] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 yes In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is selected from hydrogen, optionally substituted C1-C6 alkyl and -P(=O)(R 24 )2.

[0744] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 It's hydrogen.

[0745] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22Yes -P(=O)(R 24 )2, and R 24 Selected from optionally substituted C 1-10 In some embodiments, R 1 yes

[0746] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is a C1-C6 alkyl group optionally substituted by one or more substituents selected from: -N(R 30 )2、-(O-CH2-(CH2) p ) n -W, –OR 30 , optionally substituted C 3-10 carbocyclic and optionally substituted 3- to 10-membered heterocyclic rings, and R 30 is selected from hydrogen and optionally substituted C 1-10 In some embodiments, R 1 R 22 is a C1-C6 alkyl group substituted by one or more substituents selected from the group consisting of: -N(R 30 )2、-(O-CH2-(CH2) p ) n -W and –OR 30 .

[0747] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is one or more selected from -N(R 30 ) 2 is substituted with a C1-C6 alkyl group. In some embodiments, R 1 yes

[0748] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is one or more selected from -(O-CH2-(CH2) p ) nIn some embodiments, n is 1 to 1000. In some embodiments, n is 1 to 800. In some embodiments, n is 1 to 500. In some embodiments, n is 1 to 300. In some embodiments, n is 1 to 100. In some embodiments, n is 1 to 50. In some embodiments, n is 1 to 25. In some embodiments, n is 3 to 1000. In some embodiments, n is 10 to 1000. In some embodiments, n is 50 to 1000. In some embodiments, n is 100 to 1000. In some embodiments, n is 200 to 1000. In some embodiments, n is 500 to 1000. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100. In some embodiments, p is from 1 to 1000. In some embodiments, p is from 1 to 800. In some embodiments, p is from 1 to 500. In some embodiments, p is from 1 to 300. In some embodiments, p is from 1 to 100. In some embodiments, p is from 1 to 50. In some embodiments, p is from 1 to 25. In some embodiments, p is from 3 to 1000. In some embodiments, p is from 10 to 1000. In some embodiments, p is from 50 to 1000. In some embodiments, p is from 100 to 1000. In some embodiments, p is from 200 to 1000. In some embodiments, p is from 500 to 1000. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 100.

[0749] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is one or more selected from -(O-CH2-(CH2) p ) n -W and –OR 30 In some embodiments, R 1 Selected from:

[0750] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is selected from optionally substituted C 3-10In some embodiments, the optionally substituted C1-C6 alkyl group is 3-10 The carbon ring is selected from C 3-6 In certain embodiments, C 3-6 In certain embodiments, the carbocyclic ring is unsaturated. 3-6 The carbocyclic ring is saturated. In some embodiments, the optionally substituted C 3-6 The carbon ring is selected from In some embodiments, R 1 R 22 is a C1-C6 alkyl group substituted with a phenyl group. 1 Selected from:

[0751] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is a C1-C6 alkyl group substituted by one or more substituents selected from an optionally substituted 3 to 6 membered heterocycle. In some embodiments, the optionally substituted 3 to 6 membered heterocycle contains at least one heteroatom selected from N, O, S and any combination thereof.

[0752] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 22 is a C1-C6 alkyl group substituted by one or more substituents selected from an optionally substituted 3- to 6-membered heterocyclic ring, wherein the optionally substituted 3- to 6-membered heterocyclic ring contains at least one heteroatom selected from N and O. In some embodiments, the 3- to 6-membered heterocyclic ring is substituted by one or more substituents selected from an optionally substituted C 1-6 Alkyl and -OR 30 In some embodiments, R 1 Selected from:

[0753]

[0754] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0755] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0756]

[0757] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 yes In some embodiments, R 1 R 20 is selected from hydrogen and optionally substituted C1-C3 alkyl. 1 R 21 is selected from hydrogen and optionally substituted C1-C3 alkyl. 1 R 21 is optionally substituted C 1-10 In some embodiments, R 1 R 21 is C substituted with one or more substituents selected from the following 1-10 Alkyl: -OR 30 、-N(R 30 )2、-(O-CH2-(CH2) p ) n -W, optionally substituted C 3-10 In some embodiments, R 1 Selected from:

[0758]

[0759] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 yes where R 1 R 21 is an optionally substituted 3- to 7-membered heterocyclic ring. In some embodiments, the 3- to 7-membered heterocyclic ring is replaced by one or more selected from -OR 30 and optionally substituted C 1-10 In some embodiments, R 1 Selected from:

[0760] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 yes In some embodiments, R 1 R 23 is an optionally substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is substituted with one or more substituents selected from: -OR 30 、-N(R 30 ) 2. optionally substituted C 1-10 Alkyl, optionally substituted C 3-10 In some embodiments, R 1 Selected from:

[0761] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 R 23 is an optionally substituted 3- to 7-membered heterocyclic ring. In some embodiments, the 3- to 7-membered heterocyclic ring is replaced by one or more optionally substituted C 1-10 In some embodiments, R 1 yes

[0762] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0763]

[0764]

[0765] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0766]

[0767] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0768]

[0769] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0770] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from:

[0771] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from: -OH and In some cases, R 1 yes And R 22 is selected from optionally substituted C1-C6 alkyl, preferably optionally substituted C 2-4 In some cases, R 1 yes And R 22 is selected from substituted C1-C6 alkyl, preferably substituted C 2-4 In some cases, R 22 The substituents on 30 、-(O-CH2-(CH2) p ) n -W, -S(O)R 30 、-S(O)2R 30 、=O、=S、=N(R 30 ) and -CN. In some cases, R 22 The optional substituents on are independently selected from -OR 30 、-S(O)2R 30 and =0. In some cases, R 22 The optional substituents on are independently selected from -OR 30 and -S(O)2R 30 In some cases, -OR 30 and -S(O)2R 30 R 30 independently selected from hydrogen and C 1-10 Alkyl, wherein the C1-10 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings. In some cases, -OR 30 and -S(O)2R 30 R 30 independently selected at each occurrence from hydrogen and C 1-10 alkyl.

[0772] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 1 Selected from In some cases, R 1 Selected from

[0773] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R' and R" at each occurrence are independently selected from hydrogen.

[0774] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from optionally substituted C3-C5 carbocycles and optionally substituted 4- to 5-membered heterocycles, wherein the optional substituents on Ring A are independently selected at each occurrence from halogen, ═O, —OH, —OC 1-3 In some cases, ring A is selected from optionally substituted saturated C3-C5 carbocycles and optionally substituted saturated 4- to 5-membered heterocycles, wherein the optional substituents on ring A are independently selected at each occurrence from halogen, =O, -OH, -OC 1-3 In some cases, for the compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), the 4- to 5-membered heterocyclic ring includes at least one heteroatom selected from oxygen and sulfur.

[0775] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 Selected from

[0776] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 Selected from

[0777] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 Selected from

[0778] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from unsubstituted C3-C5 carbocycle and optionally substituted 4- to 5-membered heterocycle, wherein the optional substituents on the 4- to 5-membered heterocycle are independently selected at each occurrence from halogen, ═O, —OH, —OC 1-3 Alkyl and -CN.

[0779] In some embodiments, for a compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), R 4 Selected from

[0780] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from an optionally substituted C3-C5 carbocycle.

[0781] In some embodiments, for compounds or salts of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG), Ring A is selected from an unsubstituted C3-C5 carbocycle. In some cases, z is selected from 0 and 1. In some cases, R 4 Selected from

[0782] In some embodiments, the compound or salt of Formula (L), (LA), (LB), (LC), (LD), (LE), (LF), or (LG) is selected from:

[0783]

[0784]

[0785]

[0786] Compound groups 1, 2 and 3

[0787] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are also intended to include all Z, E and tautomeric forms.

[0788] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to designate a racemic mixture. "Diastereomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over another can be determined.

[0789] When stereochemistry is not specified, the molecules with stereo centers described herein include isomers, such as enantiomers and diastereomers; mixtures of enantiomers, including racemates; mixtures of diastereomers; and other mixtures thereof, as long as they can be prepared by those of ordinary skill in the art by routine experiments. In certain embodiments, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by splitting a mixture of a racemate or diastereomers. If possible, the splitting of a mixture of a racemate or diastereomer can be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, a mixture of two enantiomers enriched in one of the two enantiomers can be purified by recrystallization and / or wet grinding to provide a further optically enriched form of the main enantiomer.

[0790] In certain embodiments, the compositions of the present disclosure may comprise two or more enantiomers or diastereomers of a compound, wherein a single enantiomer or diastereomer comprises at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, such as an enantiomer, that is substantially free of its stereoisomers can be obtained by resolving a racemic mixture using a method such as using an optically active resolving agent to form diastereomers (Stereochemistry of Carbon Compounds, (1962), E.L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113 (3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another method for separation of enantiomers is to use a Diacel chiral column and elution with an organic mobile phase, such as is performed by Chiral Technologies (www.chiraltech.com) on a fee-for-service basis.

[0791] "Tautomers" refer to molecules in which a proton can potentially shift from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist as tautomers. In cases in which tautomerism is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0792]

[0793] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14 In one embodiment, the compound is enriched in C content. In a specific embodiment, the compound is deuterated in at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0794] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a structure having the present invention except that a hydrogen is replaced by a deuterium or tritium, or a carbon is replaced by a 13 C or 14 C-enriched carbon-substituted compounds are within the scope of the present disclosure.

[0795] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Use 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F.17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br and 125 All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0796] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom replacement. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0797] Deuterium-substituted compounds were synthesized using various methods such as those described in Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0798] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0799] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0800] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficiently acidic functional groups, sufficiently basic functional groups, or both functional groups can react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those having quaternary nitrogen, can form salts with appropriate counterions, for example, halides such as bromide, chloride, or fluoride, particularly bromide.

[0801] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0802] In certain embodiments, the compound or the salt of the compound may be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented as an ester or carbonate, or the carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted to the disclosed medicament under physiological conditions. A method for preparing a prodrug is to include one or more selected portions that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of specific target cells in a host animal such as a host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0803] Prodrugs are often useful because, in some cases, they can be easier to administer than the parent drug. They can, for example, be made bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cell permeability of a compound relative to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed as reversible drug derivatives to act as modulators to enhance drug transport to site-specific tissues or to increase drug retention within cells.

[0804] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0805] Synthetic chemistry transformations and methods useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0806] Pharmaceutical formulations of compounds of Groups 1, 2 and 3

[0807] The compounds or salts of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) can be formulated into any suitable pharmaceutical formulation. The pharmaceutical formulations disclosed herein typically contain an active ingredient (e.g., a compound or salt of any of the formulae described herein) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, antioxidants, solubilizers, and excipients.

[0808] In certain embodiments, the compound or salt of any one of the formulas or subformulas described herein (e.g., formula (I) of the first aspect, formula (X) of the second aspect, formula (L) of the third aspect, etc.) is formulated with an agent that inhibits the degradation of the compound or salt. In certain embodiments, the compound or salt is formulated with one or more antioxidants. Acceptable antioxidants include, but are not limited to, citric acid, d, 1-α-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, and propyl gallate. In certain embodiments, the formulation contains 0.1 to 30%, 0.5 to 25%, 1 to 20%, 5 to 15% or 7 to 12% (wt / wt) CCI-779, 0.5 to 50%, 1 to 40%, 5 to 35%, 10 to 25% or 15 to 20% (wt / wt) water-soluble polymer, 0.5 to 10%, 1 to 8% or 3 to 5% (wt / wt) surfactant, and 0.001% to 1%, 0.01% to 1% or 0.1% to 0.5% (wt / wt) antioxidant. In certain embodiments, the antioxidant of the formulation of the present invention will be used at a concentration within the range of 0.001% to 3% wt / wt.

[0809] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I) of the first aspect, Formula (X) of the second aspect, Formula (L) of the third aspect, etc.) is formulated with a pH adjuster to maintain a pH of about 4 to about 6. Acceptable pH adjusters include, but are not limited to, citric acid, sodium citrate, dilute HCl, and other weak acids or bases capable of buffering a solution containing a compound or salt of the present disclosure to a pH in the range of about 4 to about 6.

[0810] In certain embodiments, compounds or salts of any of the formulae or subformulae described herein (e.g., Formula (I) of the first aspect, Formula (X) of the second aspect, Formula (L) of the third aspect, etc.) are formulated with a chelating agent or other material capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA) and its salts, which can enhance the stability of compounds or salts of any of the formulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.).

[0811] Pharmaceutical preparations can be provided in any suitable form, which may depend on the route of administration. In some embodiments, pharmaceutical compositions disclosed herein may be formulated into dosage forms for administration to a subject. In some embodiments, pharmaceutical compositions are formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation and / or intraperitoneal administration. In some embodiments, dosage forms are formulated for oral administration. For example, pharmaceutical compositions may be formulated in the form of pills, tablets, capsules, inhalants, liquid suspensions, liquid emulsions, gels or powders. In some embodiments, pharmaceutical compositions may be formulated into unit doses in liquid, gel, semi-liquid, semi-solid or solid forms.

[0812] The amount of the compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L)), etc.) will depend on the mammal being treated, the severity of the condition or disorder, the rate of administration, the disposition of the compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L)), etc.), and the judgment of the prescribing physician.

[0813] In some embodiments, a pharmaceutically acceptable carrier for a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), Formula (I), Formula (X), Formula (L), etc.) may include a physiologically acceptable compound that is an antioxidant.

[0814] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising at least one compound or salt of any one of the formulas or subformulas described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) and a pharmaceutical excipient suitable for oral administration. The composition can be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second dose.

[0815] Pharmaceutical compositions of the present disclosure suitable for oral administration can be presented as discrete dosage forms such as hard or soft capsules, cachets, lozenges, troches or tablets, or liquids or aerosol sprays (each containing a predetermined amount of active ingredient in powdered or granular form), solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the pharmaceutical methods that generally include the step of bringing one or more active ingredients into association with a carrier. In general, the compositions are prepared by uniformly and intimately admixing one or more active ingredients with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired appearance. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing one or more active ingredients in a free-flowing form (such as a powder or granules), optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surfactant or dispersant, in a suitable machine. Molded tablets can be prepared by molding a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.), moistened with an inert liquid diluent, in a suitable machine.

[0816] In some embodiments, the present disclosure provides a pharmaceutical composition for injection, comprising a compound or salt of any one of the formulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) and a pharmaceutical excipient suitable for injection. The components and amounts of the composition are as described herein.

[0817] In certain embodiments, the compounds or salts of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) can be formulated for injection as aqueous or oily suspensions; emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil; as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0818] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using a surfactant. Preventing the effects of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0819] Pharmaceutical compositions can also be prepared from a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999).

[0820] The present disclosure also provides a kit. The kit may include a compound or salt of any one of the formulas or subformulas described herein (e.g., formula (I), formula (X), formula (L), etc.) and one or more additional agents in a suitable package, and may include written materials such as instructions for use, clinical research discussions, side effect lists, etc. Such kits may also include instructions or determine the activity and / or advantages of the composition, and / or describe information on administration, application, side effects, drug interactions, such as scientific references, package inserts, clinical trial results, and / or an overview of these information, etc.; or other information useful to health care providers. Such information may be based on the results of various studies, such as the use of experimental animals, involving research on in vivo models and research based on human clinical trials. The kit may also contain another agent. In some embodiments, a compound or salt of any one of the formulas or subformulas described herein (e.g., formula (I), formula (X), formula (L), etc.) and the agent are provided in a separate container within the kit as a separate composition. In some embodiments, the compound or salt of any one of the formulas or subformulas described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) and the agent are provided in a container in a kit as a single composition. Suitable packaging and additional supplies (e.g., measuring cups for liquid preparations, foil packaging materials to minimize air exposure, etc.) are known in the art and may be included in the kit. The kits described herein can be provided, sold, and / or promoted to health providers, including physicians, nurses, pharmacists, prescribing officials, etc. In some embodiments, the kits can also be sold directly to consumers.

[0821] Therapeutic applications of compounds of Groups 1, 2 and 3

[0822] In one aspect, the present disclosure provides a method of inhibiting mTORC1, comprising administering a compound or salt of any one of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.). In one aspect, the present disclosure provides a method of inhibiting mTORC1 without significantly modulating mTORC2, comprising administering a compound or salt of any one of the formulae (e.g., Formula (I), Formula (X), Formula (L), etc.). In certain embodiments, the compounds and salts of the present disclosure do not significantly inhibit mTORC2.

[0823] Without being bound by any particular mechanism, the compounds or salts of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) may exhibit reduced side effects relative to rapamycin. In particular, the compounds or salts of the present disclosure may not significantly affect the gastrointestinal and / or cardiac systems. In certain embodiments, the compounds of the present disclosure may be administered in larger doses or over longer periods of time compared to the prescribed dosage or time frame for rapamycin. For example, with respect to a predetermined time frame, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) may be administered daily, every other day, once a week, or once every two weeks for a period of time such as 2 months or longer, 4 months or longer, 6 months or longer, 1 year or longer, or even 2 years or longer. For example, with respect to intended dosing, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) may be administered at a dose that is 30% or greater, 50% or greater, 80% or greater than the indicated dosing of rapamycin for the same indication.

[0824] In certain embodiments, a compound or salt of any one of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent tauopathy (including but not limited to Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration (FTLD) (including but not limited to FTLD-17), behavioral variant FTD, primary progressive aphasia (semantic, agrammatic or oligoword variant), argyrophilic grain disease, Pick's disease ( disease), globular glial tauopathies, primary age-related tauopathies (including neurofibrillary tangle dementia), chronic traumatic encephalopathy (CTE) - traumatic brain injury and aging-related tau astrogliopathy), mTOR diseases (including but not limited to tuberous sclerosis complex (TSC)), mTOR diseases associated with seizures, focal cortical dysplasia (FCD), ganglioglioma, hemimegalencephaly, neurofibromatosis 1, Sturge-Weber syndrome, Cowden syndrome syndrome), PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy), familial multiple discoid fibrosis (FMDF), epilepsy / seizures (both inherited and acquired forms of the disease, such as familial focal epilepsy, epileptic spasms, infantile spasms (IS), status epilepticus (SE), temporal lobe epilepsy (PLE), and absence epilepsy), rare diseases associated with dysfunction of mTORC1 activity (e.g., lymphangioleiomyomatosis (LAM), Leigh's syndrome, Friedrich's ataxia, Diamond-Blackfan anemia, and leukemia). anemia, etc.), metabolic diseases (e.g., obesity, type II diabetes, etc.), autoimmune and inflammatory diseases (e.g., systemic lupus erythematosus (SLE), multiple sclerosis (MS), psoriasis, etc.), cancer, fungal infections, proliferative diseases, maintenance of immunosuppression, transplant rejection, traumatic brain injury, autism, lysosomal storage diseases and neurodegenerative diseases associated with excessive mTORC1 activity (e.g., Parkinson's disease, Huntington's disease, etc.), accumulation of abnormal compounds, dysfunction of the autophagy mechanism, and generally include but are not limited to conditions that can be regulated by selective inhibition of the mTORC1 pathway.

[0825] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent a tauopathy selected from the group consisting of progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia, Lyto-Bodig disease (Guam Parkinsonism-dementia complex), tangle-dominant dementia (with NFTs similar to those in Alzheimer's disease, but without plaques), gangliogliomas and gangliocytomas, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Pick's disease, corticobasal degeneration (tau protein is deposited as inclusions within swollen or "ballooned" neurons), Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and frontotemporal lobar degeneration.

[0826] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent a tauopathy selected from the group consisting of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration (FTLD) (including but not limited to FTLD-17), behavioral variant FTD, primary progressive aphasia (semantic, agrammatic, or oligoword variant), argyrophilic grain disease, Pick's disease, globular glial tauopathy, primary age-related tauopathy (including neurofibrillary tangle dementia), chronic traumatic encephalopathy (CTE)-traumatic brain injury, and aging-associated tau astrocytopathy.

[0827] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent an mTOR disease. An mTOR disease may be, for example, tuberous sclerosis, focal cortical dysplasia, or PTEN (phosphatase and tensin homolog) disease. An mTOR disease may be a disease or condition described elsewhere herein.

[0828] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent cancer. Non-limiting examples of cancer may include acute lymphoblastic leukemia (ALL); acute myeloid leukemia; adrenocortical carcinoma; childhood cerebellar or cerebral astrocytoma; basal cell carcinoma; bladder cancer; bone tumors, osteosarcoma / malignant fibrous histiocytoma; brain cancer; brain tumors such as cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, optic tract and hypothalamic glioma; brain stem glioma; breast cancer; bronchial adenoma / carcinoid; Burkitt's lymphoma (Burkitt's lymphoma; cerebellar astrocytoma; cervical cancer; bile duct cancer; chondrosarcoma; chronic lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disorders; colon cancer; cutaneous T-cell lymphoma; endometrial cancer; ependymoma; esophageal cancer; eye cancers, such as intraocular melanoma and retinoblastoma; gallbladder cancer; glioma; hairy cell leukemia; head and neck cancer; heart cancer; hepatocellular (liver) cancer; Hodgkin lymphoma; hypopharyngeal cancer; islet cell carcinoma (endocrine pancreas); Kaposi sarcoma sarcoma); kidney cancer (renal cell carcinoma); laryngeal cancer; leukemias, such as acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia; cancers of the lip and oral cavity; liposarcoma; lung cancers, such as non-small cell lung cancer and small cell lung cancer; lymphomas, such as AIDS-related Burkitt lymphoma; cutaneous T-cell Hodgkin and non-Hodgkin lymphomas, macroglobulinemia, malignant fibrous histiocytoma of bone / osteosarcoma; melanoma; Merkel cell carcinoma; mesothelioma; multiple myeloma / plasma cell neoplasms; mycosis fungoides; myeloproliferative disorders myeloproliferative disorders; myelosuppressive syndromes; myeloproliferative disorders; chronic myeloproliferative disorders; nasal and paranasal sinus cancer; nasopharyngeal cancer; neuroblastoma; oligodendroglioma; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer; pancreatic cancer; parathyroid cancer; pharyngeal cancer; pheochromocytoma; pituitary adenoma; plasmacytoma; pleuropulmonary blastoma; prostate cancer; rectal cancer; renal cell carcinoma (kidney cancer); transitional cell carcinoma of the renal pelvis and ureter; rhabdomyosarcoma; salivary gland cancer; Ewing family of tumor sarcomas; Kaposi's sarcoma; soft tissue sarcoma; uterine sarcoma; Sézary syndrome syndrome); skin cancer (non-melanoma); skin cancer; small bowel cancer; soft tissue sarcoma; squamous cell carcinoma; metastatic squamous neck cancer with occult primary; stomach cancer; testicular cancer; pharyngeal cancer; thymoma and thymic carcinoma; thymoma; thyroid cancer; childhood thyroid cancer; uterine cancer; vaginal cancer; Waldenstrom's macroglobulinemia; Wilms tumor, and any combination thereof.

[0829] In certain embodiments, a compound or salt of any one of the formulae or subformulae described herein (e.g., formula (I) of the first aspect, formula (X) of the second aspect, formula (L) of the third aspect, etc.) is administered to a subject in need thereof to treat and / or prevent seizures and / or seizure-related disorders. Seizure-related disorders may include, but are not limited to, West syndrome, focal cortical dysplasia (FCD), tuberous sclerosis complex (TSC), childhood absence epilepsy, benign focal epilepsy of childhood, juvenile myoclonic epilepsy (JME), temporal lobe epilepsy, frontal lobe epilepsy, refractory epilepsy, Lennox-Gastaut syndrome, occipital lobe epilepsy, Proteus syndrome, hemimegalencephaly syndrome (HMEG), megalencephaly syndrome (MEG), megalencephaly-capillary malformation (MCAP), megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), and PTEN disorders.

[0830] Compounds according to any of the therapeutic compounds disclosed herein are used to treat and / or prevent conditions (e.g., liver and kidney conditions) that include fibrotic and / or inflammatory processes. Conditions may include, but are not limited to, liver fibrosis (which may occur in end-stage liver disease); cirrhosis; liver failure due to toxicity; non-alcoholic hepatic steatosis or NASH; and alcohol-related steatosis. Another example may be renal fibrosis, which may occur due to acute kidney injury, chronic kidney disease, or diabetic nephropathy may induce renal fibrosis and inflammation. Conditions may include polycystic kidney disease, ischemia / reperfusion injury, transplantation, adriamycin nephropathy, unilateral ureteral obstruction (UUO), glomerulopathy, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), lupus mesangial proliferative nephritis.

[0831] Compounds according to any of the therapeutic compounds disclosed herein are useful for treating and / or preventing acute or chronic organ or tissue transplant rejection, e.g., heart, lung, combined heart-lung, liver, kidney, pancreas, skin or corneal transplants, preventing graft-versus-host disease, such as after bone marrow transplantation, etc.

[0832] Compounds according to any of the therapeutic compounds disclosed herein are useful in the treatment and / or prevention of autoimmune diseases and / or inflammatory disorders, particularly including inflammatory disorders whose etiology may include an autoimmune component, such as arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis, and arthritis deformans) and rheumatic diseases. Examples may include autoimmune blood disorders (including, for example, hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Stevens-Johnson syndrome, and inflammatory bowel disease. syndrome), idiopathic sprue, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and Crohn's disease), endocrine eye diseases, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes mellitus (type 1 diabetes), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change disease), and juvenile dermatomyositis.

[0833] The compound according to any of the therapeutic compounds disclosed herein is used to treat and / or prevent a mitochondrial disease or disorder.

[0834] The compounds according to any of the therapeutic compounds disclosed herein are useful for treating and / or preventing smooth muscle cell proliferation and migration leading to vascular intimal thickening, vascular occlusion, obstructive coronary atherosclerosis, or restenosis.

[0835] In certain embodiments, the present disclosure provides a method for treating a disease characterized by overactivation of mTORC1. The following references include methods for assessing mTORC (e.g., mTORC1) activity: T. O'Reilly et al., Translational Oncology, v3, i2, pp. 65-79, (2010); J. Peralba, Clinical Cancer Research, v9, i8, pp. 2887-2892 (2003); DR Moore et al., Acta Physiologica, v201, i3, pp. 365-372 (2010); M. Dieterlen., Clinical Cytometry, v82B, i3, pp. 151-157, (2012); the contents of each of the references are incorporated herein by reference.

[0836] In certain embodiments, the present disclosure provides a method for treating age-related diseases. It has been determined that regulating mTORC1 signaling can extend lifespan and delay the onset of age-related diseases in a wide range of organisms, from flies to mammals, thereby potentially providing therapeutic options for preventing or treating age-related diseases in humans. In a recent clinical study, Mannick et al. (mTOR inhibition improves immune function in the elderly, Sci Transl Med. 2014 Dec 24; 6(268):268ra179. doi:10.1126 / scitranslmed.3009892) may have shown that mTOR inhibition improves immune function in the elderly.

[0837] In certain embodiments, the present disclosure provides a method for treating mitochondrial diseases. Mitochondrial myopathy and mitochondrial stress can be mitochondrial disorders as described in Chinnery, PF (2015); EMBO Mol. Med. 7, 1503-1512; Koopman, WJ et al., 10 (2016); EMBO Mol. Med. 8, 311-327 and Young, MJ and Yound and Copeland, WC (2016); Curr. Opin. Genet. Dev. 38, 52-62.

[0838] In certain embodiments, the present disclosure provides a method for treating a disease in which autophagy is impaired. In some cases, these may include impaired autophagy leading to mitochondrial damage, lysosomal storage diseases, cancer, Crohn's disease, and the like. In some cases, impaired autophagy may be as described in Jiang P. and Mizushima, N., Autophagy and human diseases, Cell Research, Vol. 24, pp. 69-79 (2014).

[0839] In certain embodiments, the compounds or salts of the present disclosure are used to induce heterodimerization of the FRB domains of FKBP12 and mTOR. Chemical induction of dimerization (CID) can be used as a biological tool to manipulate specific molecules, such as peptides and polypeptides, in cells at precise times and spatially to control specific activities. The uses of CID include experimental studies to illustrate cell systems and therapeutic uses to regulate cell-based therapies. Exemplary uses include activating cells for promoting implantation, treating diseases or illnesses, or controlling or regulating the activity of therapeutic cells expressing chimeric antigen receptors or recombinant T cell receptors. The compounds of the present disclosure can be used to develop inducible systems or molecular switches to control cell signaling.

[0840] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent diabetic nephropathy, kidney-related complications of type 1 diabetes and type 2 diabetes, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), kidney diseases associated with cyst formation or cystogenesis, focal segmental glomerulosclerosis (FSGS) and other diseases associated with nephrosclerosis (glomerulopathy, IgA nephropathy, lupus mesangial proliferative nephritis), laminopathy, age-related macular degeneration (AMD), diabetic macular edema, diabetic retinopathy, glaucoma, age-related retinal diseases, aging of the immune system, respiratory tract infections, urinary tract infections, heart failure, osteoarthritis, arterial pulmonary hypertension (PAH) and / or chronic obstructive pulmonary disease (COPD).

[0841] In certain embodiments, a compound or salt of any of the formulae or subformulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.) is administered to a subject in need thereof to treat and / or prevent lymphangioleiomyomatosis (LAM) and / or polycystic kidney disease.

[0842] The use of rapamycin as a dimerizing agent is limited by side effects associated with mTOR inhibition. mTOR inhibition can lead to reduced cell growth and proliferation and possible immunosuppression. In contrast, the compounds of the present disclosure may offer advantages over rapamycin due to their high selectivity for mTOR1 over mTOR2. mTOR2 inhibition is associated with the negative side effects associated with rapamycin. The currently described compounds are selective for mTOR1 and have minimal effects on mTOR2.

[0843] The term "multimerize" or multimerization refers to the dimerization of two peptides or polypeptides, or the multimerization of more than two peptides or polypeptides, such as the dimerization of FKBP12 and the FRB domain of mTOR.

[0844] The inducible multimerization system based on FKBP12 / FRB can also be incorporated into chimeric antigen receptor (CAR) T cells that can be used, for example, in immunotherapy applications. One type of immunotherapy is adoptive cell transfer, in which the immune cells of the subject are collected and modified in vitro, such as T cells modified by CAR, to provide specific and targeted tumor cell killing when the modified cells are returned to the body. T cells from the patient's blood can be extracted and genetically engineered to express CAR on the cell surface. The components of CAR generally include an extracellular antibody-derived single-chain variable fragment (scFv) that specifically recognizes a target tumor cell antigen, and one or more multicellular T cell-derived signaling sequences fused with the scFv. The combination of scFv region and antigen results in activation of T cells by the signaling domain of CAR. In certain embodiments, the compound of the present disclosure can be administered to cells to activate CAR-T cells with a multimerization system based on FKBP12 / FRB. In certain embodiments, the present disclosure provides a method for activating the growth of cells, such as CAR-T cells, containing an FKBP protein fusion and a FRB fusion protein, by contacting the cells with a compound or salt of any one of the formulae described herein (e.g., Formula (I), Formula (X), Formula (L), etc.).

[0845] In some cases, it is beneficial to increase the activity of therapeutic cells. For example, co-stimulatory polypeptides can be used to enhance the activation of T cells and CAR-expressing T cells for antigens, which will increase the effectiveness of adoptive immunotherapy. These treatments are, for example, used to treat tumors to achieve elimination, and for treating cancer and blood disorders, but these therapies may have negative side effects. Too active on-target effects, such as those for large tumor masses, can lead to cytokine storms with tumor lysis syndrome (TLS), cytokine release syndrome (CRS) or macrophage activation syndrome (MAS). In some cases of adverse events induced by therapeutic cells, there is a need to quickly and nearly completely eliminate therapeutic cells. If there is a need to reduce the number of transferred CAR-T cells, then inducible ligands can be administered to the treated object, thereby specifically inducing the apoptosis of modified T cells. For example, multimeric forms of ligand binding domains FRB and / or FKBP12 or variants thereof fused to caspase proteins and expressed in modified therapeutic cells, such as those described in WO 2020 / 076738, can serve as scaffolds that allow caspase units to spontaneously dimerize and activate upon recruitment by FRB and / or FKBP12 using chemical inducers such as compounds or salts of any one of the formulae described herein (e.g., formula (I), formula (X), formula (L), etc.). In certain embodiments, the present disclosure provides a method of inhibiting the growth of cells containing an FKBP protein fusion and a FRB fusion protein by contacting the cells with a compound or salt of any one of the formulae described herein (e.g., formula (I), formula (X), formula (L), etc.).

[0846] Example

[0847] The following examples are provided to illustrate, but not to limit, the claimed invention. It will be appreciated that these methods of preparation are illustrative and not limiting. Numerous other methods of producing the rapamycin analogs described herein will be readily available to those skilled in the art using the teachings provided herein.

[0848] When specified, absolute stereochemistry is assigned by analogy based on analytical data for rapamycin (eg, at C16 and C28 for compounds described elsewhere herein).

[0849] Example 1: NMR spectroscopy

[0850] Recorded on a Bruker Avance III NMR spectrometer at 400 MHz 1 H NMR spectra. Samples were prepared in deuterated chloroform (CDCl3) or dimethyl sulfoxide (DMSO-d6), and the raw data were processed using MNova NMR software.

[0851] Example 2: UPLC-MS analysis

[0852] LCMS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity i-Class Sample Manager-FL, an Acquity i-Class Binary Solvent Manager, and an Acquity i-Class UPLC Column Manager. UV detection was achieved using an Acquity i-Class UPLC PDA detector (scanning from 210–400 nm), while mass detection was achieved using an Acquity QDa detector (mass scanning from 100–1250 Da; simultaneous positive and negative modes). A Waters Acquity UPLC CSH C18 column (2.1 × 100 mm; particle size 1.7 μm) was used to achieve separation of the analytes.

[0853] Samples were prepared by dissolving (with or without sonication) into 1 mL of MeOH or MeCN. The resulting solutions were filtered through a 0.2 μm syringe filter before submission for analysis. All solvents (including formic acid) were used at HPLC grade.

[0854] Details of the analytical methods used for this work are presented below.

[0855] Method 1: 0.1% v / v formic acid in water [eluent A]; 0.1% v / v formic acid in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 μL, and 1.5 min equilibration time between samples.

[0856] Table 1: UPLC-MS parameters

[0857] Time (min) Eluent A (%) Eluent B (%) 0.00 50 50 10 0 100 10.10 50 50 12 5 95

[0858] Example 3: Preparative HPLC

[0859] Method 1: The compound was purified by reverse phase column chromatography on a Gemini NX C18 (30 mm x 150 mm, 5 μm) cartridge using a H2O (0.2% formic acid): MeCN gradient elution. The gradient was selected based on the analytical separation.

[0860] Example 4: SFC

[0861] Use the following method to perform SFC:

[0862] Method 1: Greensep 2EP (19 mm x 100 mm, 5 μm); CO2 / MeCN. Gradient selected based on analytical separation.

[0863] Synthesis of intermediates

[0864] Example 5: Synthesis of 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonyl chloride

[0865] Under reflux, 1-bromo-2-[2-(2-methoxyethoxy)ethoxy]ethane (2.50g, 11.0mmol) and sodium sulfite [NaSO] (1.39g, 11.0mmol) in HO (13.4mL) were stirred and heated for 18h. The mixture was concentrated under reduced pressure, then dissolved in ethanol (20mL) and concentrated to dryness. A 1:1 mixture (20mL) of TBME / hexanes was added, and the mixture was again concentrated to dryness. This final step was repeated to produce 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sodium sulfonate (in the form of a mixture with sodium bromide) as a solid, which was used without analysis or purification. POCl (6.8mL, 74.1mmol) was added, and the mixture was heated at 70°C for 4h, then stirred at room temperature overnight. The mixture was carefully added to ice-H2O (50 mL), and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonyl chloride) (1.90 g, 70%) as an oil.

[0866] 1 H NMR (400MHz, CDCl3) δ4.14–4.04(m,2H),3.99(t,J=6.0Hz,2H),3.78–3.69(m,2H),3.69–3.61(m,4H),3.55(dd,J=5.7,3.4Hz,2H),3.38(s,3H).

[0867] Example 6: Synthesis of N-tert-butyl-2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide

[0868] At -20 ° C, 2- [2- (2- methoxyethoxy) ethoxy] ethane -1- sulfonyl chloride (0.84 g, 2.21 mmol) was added dropwise to a solution of tert-butylamine (0.70 mL, 4.43 mmol) in THF (4.4 mL). The mixture was allowed to warm to room temperature and stirred overnight. The resulting precipitate was filtered, the filter cake was washed with THF (10 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-100% EtOAc / hexanes; dyed with acidic vanillin solution) to produce N- tert-butyl -2- [2- (2- methoxyethoxy) ethoxy] ethane -1- sulfonamide (0.144 g, 23%) as an oil. 1 H NMR (400MHz, CDCl3) δ4.77(s,1H),3.90(t,J=5.8Hz,2H),3.64(d,J=11.5Hz,6H),3.59–3.54(m,2H),3.38(s,3H),3.30(t,J=5.8Hz,2H),1.37(s,9H).

[0869] Example 7: Synthesis of 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide

[0870] To N-tert-butyl-2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide (144 mg, 0.51 mmol) in DCM (2 mL) was added TFA (0.39 mL, 5.1 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and then azeotroped with toluene (2×10 mL) and DCM (10 mL) to give 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-sulfonamide as an oil that still contained some TFA but was used without further purification. 1 H NMR (400MHz, CDCl3) δ4.06–3.95(m,2H),3.75–3.58(m,9H),3.43(s,3H),3.40–3.34(m,2H).

[0871] Example 8: Synthesis of 3-methanesulfonylpropyl trifluoromethanesulfonate

[0872]

[0873] 3-methanesulfonylpropane-1-ol (2.00 g, 14.5 mmol) and 2,6-lutidine (1.80 mL, 15.2 mmol) were dissolved in anhydrous DCM (25 mL) and cooled to -30 ° C. Trifluoromethanesulfoni...

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

3. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

4. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

5. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

6. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

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

8. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

9. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

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

11. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

12. The compound or salt of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

Images