Methods and compositions for modulating splicing

Abstract

Described herein are small molecule splice modulator compounds that modulate the splice of gene-encoded mRNA (e.g., pre-mRNA), pharmaceutical compositions comprising the same, and methods of using the small molecule splice modulator compounds to modulate splice and treat diseases and conditions.

Description

[0001] This application is a divisional application of a patent application with application number 202080026934.6, application date February 3, 2020, and name “Methods and compositions for regulating splicing”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 801,206 filed on February 5, 2019, U.S. Provisional Application No. 62 / 801,231 filed on February 5, 2019, U.S. Provisional Application No. 62 / 801,208 filed on February 5, 2019, U.S. Provisional Application No. 62 / 801,212 filed on February 5, 2019, and U.S. Provisional Application No. 62 / 801,231 filed on February 5, 2019. ,236, U.S. Provisional Application No. 62 / 801,387 filed on February 5, 2019, U.S. Provisional Application No. 62 / 800,691 filed on February 4, 2019, U.S. Provisional Application No. 62 / 800,720 filed on February 4, 2019, and U.S. Provisional Application No. 62 / 800,779 filed on February 4, 2019, the disclosures of which are incorporated herein by reference in their entirety. Background Art

[0004] Most protein-coding genes in the human genome are composed of multiple exons (coding regions) separated by introns (non-coding regions). Gene expression produces a single precursor messenger RNA (pre-mRNA). The intron sequence is then removed from the pre-mRNA by a process called splicing, which results in mature messenger RNA (mRNA). By comprising different exon combinations, alternative splicing produces multiple mRNAs encoding different protein isoforms. Spliceosomes (intracellular complexes of various proteins and ribonucleoproteins) catalyze splicing.

[0005] Current therapeutic approaches for directing and controlling mRNA expression require methods such as gene therapy, genome editing, or various oligonucleotide technologies (antisense, RNAi, etc.). Gene therapy and genome editing act upstream of mRNA transcription by influencing the DNA code and thereby altering mRNA expression. Oligonucleotides modulate the effects of RNA through canonical base / base hybridization. The appeal of this approach lies in the design of the oligonucleotide's basic pharmacophore, which can be defined in a straightforward manner by base pairing with known target sequences. Each of these therapeutic modalities faces significant technical, clinical, and regulatory challenges. Some limitations of oligonucleotides as therapeutic agents (e.g., antisense, RNAi) include unfavorable pharmacokinetics, insufficient oral bioavailability, and insufficient blood-brain barrier penetration, the latter of which prevents delivery to the brain or spinal cord after parenteral administration for the treatment of diseases (e.g., neurological diseases, brain cancer). Furthermore, without sophisticated delivery systems (such as lipid nanoparticles), oligonucleotides are not effectively absorbed into solid tumors. Furthermore, most oligonucleotides absorbed into cells and tissues remain in non-functional compartments (e.g., endosomes) and are unable to enter the cytoplasm and / or nucleus where their targets are located.

[0006] In addition, in order to anneal to the target, oligonucleotide therapy requires complementary base pairs close to the target. The method assumes that the pre-mRNA sequence exists in the cell as a linear chain of RNA. However, pre-mRNA is rarely linear; it has a complex secondary and tertiary structure. In addition, cis-acting elements (such as protein binding elements) and trans-acting factors (such as splicing complex components) can produce additional two-dimensional and three-dimensional complexity (for example, by combining with pre-mRNA). These features may be the effectiveness and efficacy limitations of oligonucleotide therapy. Summary of the Invention

[0007] Novel small molecule splicing regulators (SMSMs) as described herein do not have the above limitations, nor do they greatly limit the structure and spatial barriers of oligonucleotide therapy (e.g., by blocking hybridization with pre-mRNA targets). Small molecules are crucial for revealing the mechanism, regulation, and function of many cellular processes (including DNA replication / transcription and translation). Although several recent reports have described the screening of small molecule splicing effectors, only a small amount of constitutive or alternative splicing regulators have been identified, and many small molecule inhibitors lack specificity, lack selectivity, lack efficacy, display toxicity, or are orally unavailable. Targeting RNA transcriptome with small molecule regulators represents an undeveloped therapeutic method for treating a variety of RNA-mediated diseases. Therefore, there is still a need to develop small molecule RNA regulators for use as therapeutic agents. Novel regulators for splicing or splicing-dependent processes are needed in the art. Provided herein are small molecule splicing regulators and uses thereof that meet this demand.

[0008] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0009]

[0010] in

[0011] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0012] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0013] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0014] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0015] X is –O-, –S-, or –NR 3 -;

[0016] Z is CR 2 ;

[0017] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0018] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0019] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0020] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0021] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0022] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0023] R 15 and R 18 are identical and are selected from hydrogen and deuterium;

[0024] a is 0 or 1;

[0025] b is 0;

[0026] c is 1; and

[0027] d is 0 or 1.

[0028] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0029]

[0030] in

[0031] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0032] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0033] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0034] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0035] X is –O-, –S-, or –NR 3 -;

[0036] Z is CR 2 ;

[0037] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0038] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0039] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0040] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0041] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0042] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0043] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0044] a is 0 or 1;

[0045] b is 0;

[0046] c is 1; and

[0047] d is 0 or 1.

[0048] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0049]

[0050] in

[0051] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0052] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0053] R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0054] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0055] X is –O-, –S-, or –NR 3 -;

[0056] Z is CR 2 ;

[0057] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0058] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0059] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0060] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0061] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0062] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0063] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0064] a is 0 or 1;

[0065] b is 0;

[0066] c is 1; and

[0067] d is 0 or 1.

[0068] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0069]

[0070] in

[0071] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0072] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0073] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0074] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0075] X is –O-, –S-, or –NR 3 -;

[0076] Z is CR2 ;

[0077] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0078] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0079] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0080] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0081] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0082] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0083] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0084] a is 0 or 1;

[0085] b is 0;

[0086] c is 1; and

[0087] d is 0 or 1.

[0088] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0089]

[0090] in

[0091] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0092] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0093] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0094] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0095] X is

[0096] Z is N or CR 2 ;

[0097] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0098] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0099] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0100] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0101] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0102] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0103] R 15 and R 18 are identical and are selected from hydrogen and deuterium;

[0104] a is 0 or 1;

[0105] b is 0;

[0106] c is 1; and

[0107] d is 0 or 1.

[0108] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0109]

[0110] in

[0111] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0112] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0113] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0114] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0115] X is

[0116] Z is N or CR 2 ;

[0117] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0118] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0119] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0120] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0121] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0122] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0123] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0124] a is 0 or 1;

[0125] b is 0;

[0126] c is 1; and

[0127] d is 0 or 1.

[0128] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0129]

[0130] in

[0131] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0132] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0133] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0134] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0135] X is

[0136] Z is N or CR 2 ;

[0137] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0138] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0139] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0140] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0141] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0142] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0143] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0144] a is 0 or 1;

[0145] b is 0;

[0146] c is 1; and

[0147] d is 0 or 1.

[0148] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0149]

[0150] in

[0151] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0152] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0153] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0154] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0155] X is

[0156] Z is N or CR2 ;

[0157] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0158] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0159] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0160] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0161] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0162] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0163] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0164] a is 0 or 1;

[0165] b is 0;

[0166] c is 1; and

[0167] d is 0 or 1.

[0168] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0169]

[0170] in

[0171] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0172] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0173] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0174] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0175] X is and Z is N or CR 2 ;or

[0176] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0177] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0178] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0179] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0180] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0181] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0182] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0183] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0184] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0185] a is 0 or 1;

[0186] b is 0;

[0187] c is 1; and

[0188] d is 0 or 1.

[0189] In one embodiment, the compound of Formula (I) has the structure of Formula (Ia):

[0190]

[0191] In one embodiment, the compound of Formula (I) has the structure of Formula (Ib):

[0192]

[0193] In one embodiment, the compound of Formula (I) has the structure of Formula (Ic):

[0194]

[0195] In one embodiment, the compound of Formula (I) has the structure of Formula (Id):

[0196]

[0197] In one embodiment, the compound of Formula (I) has the structure of Formula (Ie):

[0198]

[0199] In one embodiment, the compound of Formula (I) has the structure of Formula (If):

[0200]

[0201] Provided herein are compounds of formula (II) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0202]

[0203]

[0204] in

[0205] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0206] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0207] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0208] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0209] is a single bond or a double bond;

[0210] X is and Z is C; or

[0211] X is and Z is N or CR 2 ;

[0212] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0213] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0214] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0215] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0216] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0217] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0218] R 15 and R 18 are identical and are selected from hydrogen and deuterium;

[0219] a is 0 or 1;

[0220] b is 0;

[0221] c is 1; and

[0222] d is 0 or 1.

[0223] Provided herein are compounds of formula (II) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0224]

[0225] in

[0226] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0227] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0228] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0229] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0230] is a single bond or a double bond;

[0231] X is and Z is C; or

[0232] X is and Z is N or CR 2 ;

[0233] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0234] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0235] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0236] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0237] Each R 4are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0238] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0239] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0240] a is 0 or 1;

[0241] b is 0;

[0242] c is 1; and

[0243] d is 0 or 1.

[0244] Provided herein are compounds of formula (II) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0245]

[0246] in

[0247] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0248] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0249] R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0250] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0251] is a single bond or a double bond;

[0252] X is and Z is C; or

[0253] X is and Z is N or CR 2 ;

[0254] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0255] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0256] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0257] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0258] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0259] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0260] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0261] a is 0 or 1;

[0262] b is 0;

[0263] c is 1; and

[0264] d is 0 or 1.

[0265] In one aspect, described herein are compounds having the structure of Formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0266]

[0267] in

[0268] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0269] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0270] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0271] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0272] is a single bond or a double bond;

[0273] X is and Z is C; or

[0274] X is and Z is N or CR 2 ;

[0275] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0276] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0277] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0278] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0279] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0280] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0281] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0282] a is 0 or 1;

[0283] b is 0;

[0284] c is 1; and

[0285] d is 0 or 1.

[0286] In one embodiment, the compound of formula (II) has the structure of formula (IIa):

[0287]

[0288] In one embodiment, the compound of formula (II) has the structure of formula (lib):

[0289]

[0290] In one embodiment, the compound of formula (II) has the structure of formula (IIc):

[0291]

[0292] In one embodiment, the compound of formula (II) has the structure of formula (IIaa):

[0293]

[0294] In one embodiment, the compound of formula (II) has the structure of formula (IIbb):

[0295]

[0296] In one embodiment, the compound of formula (II) has the structure of formula (IIcc):

[0297]

[0298] In one embodiment, the compound of formula (II) has the structure of formula (IId):

[0299]

[0300] In one embodiment, the compound of formula (II) has the structure of formula (IIe):

[0301]

[0302] In one embodiment, the compound of formula (II) has the structure of formula (IIf):

[0303]

[0304] In one embodiment, the compound of formula (II) has the structure of formula (IIdd):

[0305]

[0306] In one embodiment, the compound of formula (II) has the structure of formula (IIee):

[0307]

[0308] In one embodiment, the compound of formula (II) has the structure of formula (III):

[0309]

[0310] In one aspect, described herein are compounds having the structure of Formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0311]

[0312] in

[0313] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0314] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0315] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0316] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0317] X is and Z is N or CR 2 ;or

[0318] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0319] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0320] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0321] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0322] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0323] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0324] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0325] R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R20 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0326] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0327] a is 0 or 1;

[0328] b is 0;

[0329] c is 1; and

[0330] d is 0 or 1.

[0331] In one aspect, described herein are compounds having the structure of Formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0332]

[0333] in

[0334] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0335] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0336] R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0337] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0338] is a single bond or a double bond;

[0339] X is and Z is C; or

[0340] X is and Z is N or CR 2 ;

[0341] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0342] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0343] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0344] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0345] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0346] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0347] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0348] a is 0 or 1;

[0349] b is 0;

[0350] c is 1; and

[0351] d is 0 or 1.

[0352] Also provided herein are methods of modulating splicing comprising contacting a compound described herein with a cell, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA.

[0353] Provided herein are methods of treating a disease or condition comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0354] Provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0355] Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the preparation of a medicament for treating a condition or disease.

[0356] Incorporated by Reference

[0357] All publications, patents, and patent applications mentioned in this specification are incorporated 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. DETAILED DESCRIPTION

[0358] Certain specific details of this specification are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will appreciate that the present disclosure can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily confusing the description of the embodiments. Unless the context requires otherwise, in the subsequent description and claims, the term "including" and its variants (e.g., "comprising") should be interpreted in an open, inclusive sense, i.e., "including but not limited to". In addition, the titles provided herein are for convenience only and do not explain the scope or meaning of the disclosure claimed.

[0359] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise.

[0360] Unless otherwise defined, 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 disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0361] definition

[0362] The terms "disclosed compounds," "compounds of the present disclosure," "small molecule steric modulators," "small molecule splicing modulators," "steric modulators," "splicing modulators," "compounds that modify splicing," and "splicing-modifying compounds," "SMSMs," or "small molecules that bind to target RNAs" are used interchangeably herein and refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. The terms "disclosed compounds," "compounds of the present disclosure," "small molecule steric modulators," "small molecule splicing modulators," "steric modulators," "splicing modulators," "compounds that modify splicing," and "splicing-modifying compounds," "SMSMs," or "small molecules that bind to target RNAs" refer to small molecule compounds that bind to cellular components (e.g., DNA, RNA, pre-mRNA, proteins, RNPs, snRNAs, carbohydrates, lipids, cofactors, nutrients, and / or metabolites) and modulate the splicing of a target polynucleotide (e.g., pre-mRNA). For example, SMSM can be directly or indirectly bound to a target polynucleotide, such as RNA (e.g., pre-mRNA), via a mutated, non-mutated, protruding and / or abnormal splicing site, thereby causing regulation of the splicing of the target polynucleotide. For example, SMSM can be directly or indirectly bound to a protein, such as a spliceosomal protein or a ribonucleoprotein, thereby causing regulation of the spatial regulation of the protein and the splicing of the target RNA. For example, SMSM can be directly or indirectly bound to a spliceosomal component, such as a spliceosomal protein or snRNA, thereby causing regulation of the spatial regulation of the spliceosomal protein or snRNA and the splicing of the target polynucleotide. These terms explicitly exclude compounds consisting of oligonucleotides. These terms include small molecule compounds that can be bound to one or more secondary or tertiary structural elements of the target RNA. These sites include RNA triplexes, 3WJs, 4WJs, parallel Y knots, hairpins, raised loops, pseudoknots, internal loops, and other high-order RNA structural motifs.

[0363] As used herein, the term "RNA" (ribonucleic acid) refers to naturally occurring or synthetic oligoribonucleotides independent of their source (e.g., RNA can be produced by humans, animals, plants, viruses, or bacteria, or can be of synthetic origin), biological context (e.g., RNA can be in the nucleus, circulating in the blood, in vitro, in a cell lysate, or in isolated or purified form), or physical form (e.g., RNA can be single-stranded, double-stranded, or triple-stranded (including RNA-DNA hybrids), can include epigenetic modifications, natural post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, can be bound to, for example, metal ions, small molecules, proteins such as chaperones or cofactors, or can be in a denatured, partially denatured, or folded state, including any natural or non-natural secondary or tertiary structure, such as quadruplexes, hairpins, triplexes, three-way junctions (3WJs), four-way junctions (4WJs), parallel Y-junctions, hairpins, bulged loops, pseudoknots, and internal loops, etc., as well as any transient form or structure adopted by the RNA). In some embodiments, the length of the RNA is 20, 22, 50, 75 or 100 or more nucleotides. In some embodiments, the length of the RNA is 250 or more nucleotides. In some embodiments, the length of the RNA is 350, 450, 500, 600, 750 or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000 or more nucleotides. In some embodiments, the length of the RNA is between 250 and 1,000 nucleotides. In some embodiments, the RNA is pre-RNA, pre-miRNA or pre-transcript. In some embodiments, the RNA is a noncoding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), ribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudogene, viral RNA, fungal RNA, parasitic RNA, or bacterial RNA.

[0364] As used herein, the term "target polynucleotide" or "target RNA" refers to any type of polynucleotide or RNA having a splice site that can be modulated by the small molecule compounds described herein. For example, a "target polynucleotide" or "target RNA" can have a secondary or tertiary structure that can bind to a small molecule compound described herein.

[0365] As used herein, "steric alteration," "steric modification," or "steric modulation" refers to a change in the spatial orientation of chemical moieties relative to one another. One of ordinary skill in the art will recognize that steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsion, steric inhibition of resonance, and steric inhibition of protonation.

[0366] Any open valence appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein represents the presence of hydrogen unless otherwise indicated.

[0367] The definitions described herein apply regardless of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein may be appended to form chemically related combinations, such as "heterocycloalkylaryl," "haloalkylheteroaryl," "arylalkylheterocycloalkyl," or "alkoxyalkyl." The last member of the combination is the group to which the remainder of the molecule is bound. In terms of literal sequence, the other members of the combination are attached to the bound group in reverse order, for example, the combination of arylalkylheterocycloalkyl refers to a heterocycloalkyl group substituted with an alkyl group substituted with an aryl group.

[0368] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitution, ie, replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0369] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0370] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule.

[0371] The term "substituted" means that the specified group bears one or more substituents. Where any group may bear multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the possible substituents. When referring to the number of substituents, the term "one or more" refers to the maximum possible number of substitutions, i.e., replacement of one hydrogen by a substituent up to the replacement of all hydrogens by a substituent.

[0372] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethyl acetate (EtOAc); butanol (n-BuOH); 1,2-dichloroethane (DCE); dichloromethane (CH2Cl2, DCM); diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogen chloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr); N-methyl-2-pyrrolidone (NMP); iodomethane (MeI); n-propanol (n-PrOH); p-methoxybenzyl (PMB); triethylamine (Et3N); [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; (Pd(dppf)Cl2); sodium ethanethiolate (EtSNa); sodium acetate (NaOAc); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF).

[0373] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x By way of example only, a group designated "C1-C4" means that the group has 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" means that the alkyl group has 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0374] The term "oxo" refers to a =0 substituent.

[0375] The term "thio" refers to a =S substituent.

[0376] The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0377] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from one to twenty carbon atoms and attached to the rest of the molecule by a single bond. Likewise, an alkyl group containing up to 10 carbon atoms is referred to as a C1-C 10 Alkyl groups, for example, containing up to 6 carbon atoms are C1-C6 alkyl groups. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include, but are not limited to, C1-C6 alkyl groups. 10In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is -CH (CH 3 ) 2 or -C (CH 3 ) 3. Unless otherwise specified in the specification, alkyl can be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0378] The term "alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl group as defined herein. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, the alkoxy group is methoxy. In some embodiments, the alkoxy group is ethoxy.

[0379] The term "alkylamino" refers to a group of the formula -NHR a or -NR a R a A group in which R a is independently an alkyl group as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0380] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR a 2, where R a refers to the rest of the alkenyl group, which may be the same or different. ais H or alkyl. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0381] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group has the formula -C≡CR a , where R a refers to the rest of the alkynyl group. In some embodiments, R a is H or alkyl. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3-C≡CCH2CH3, -CH2C≡CH.

[0382] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatics may be optionally substituted. The term "aromatic" includes both aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0383] The term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl can be optionally substituted. Examples of aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, aryl can be monovalent or divalent (i.e., arylene). Unless otherwise specifically stated in the specification, the term "aryl" or prefix "ar" (e.g., in "aralkyl") is intended to include optionally substituted aryl groups. In some embodiments, aryl is partially reduced to form cycloalkyl as defined herein. In some embodiments, aryl is fully reduced to form cycloalkyl as defined herein.

[0384] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by identical or different halogen atoms, in particular fluorine atoms. Examples of haloalkyl groups include monofluoro, difluoro or trifluoromethyl, ethyl or propyl, such as 3,3,3-trifluoropropyl, 2-fluorotoluene, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms of the alkyl group have been replaced by identical or different halogen atoms.

[0385] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by identical or different halogen atoms, in particular fluorine atoms. Examples of haloalkoxy groups include monofluoro, difluoro or trifluoromethoxy, ethoxy or propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms of the alkoxy group have been replaced by identical or different halogen atoms.

[0386] The term "bicyclic ring system" refers to two rings fused to each other via a common single or double bond (annealed bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system), or via a common single atom (spiro bicyclic ring system). The bicyclic ring system may be saturated, partially unsaturated, unsaturated, or aromatic. The bicyclic ring system may contain heteroatoms selected from N, O, and S.

[0387] The term "carbocycle" or "carbocycle" refers to a ring or ring system in which the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocycle from a "heterocyclic" ring or "heterocycle" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl groups.

[0388] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each atom (i.e., a skeleton atom) forming the ring is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in this case, the cycloalkyl is bonded to a non-aromatic ring carbon atom). The cycloalkyl group includes a group having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrahydronaphthyl, decalinyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise specifically stated in the specification, cycloalkyl groups may be optionally substituted.

[0389] The term "bridged" refers to any ring structure having two or more rings that contains a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the backbone structure of the molecule and is bonded to three or more other backbone atoms. In some embodiments, the bridging atom is C, N, or P. In some embodiments, a bridge is a single atom or chain of atoms connecting two bridgehead atoms. In some embodiments, a bridge is a valence bond connecting two bridgehead atoms. In some embodiments, the bridged ring system is a cycloalkyl group. In some embodiments, the bridged ring system is a heterocycloalkyl group.

[0390] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring can be replaced by one or more N, S, and O atoms. Non-limiting examples of fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycles, 6-6 fused heterocycles, 5-6 fused heterocycles, 5-5 fused heterocycles, 7-5 fused heterocycles, and 5-7 fused heterocycles.

[0391] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless specifically stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0392] The term "haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless specifically stated otherwise in the specification, a haloalkoxy group may be optionally substituted.

[0393] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0394] The term "heteroalkyl" refers to an alkyl group wherein one or more of the skeletal atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-), or a combination thereof. In some embodiments, the heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In some embodiments, the heteroalkyl group is attached to the rest of the molecule at a heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C6 heteroalkyl group. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH2.

[0395] The term "heteroalkylene" refers to an alkyl group as described above, wherein one or more carbon atoms of the alkyl group are replaced by O, N, or S atoms. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain that connects the remainder of the molecule to a radical. Unless otherwise specifically stated in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0396] The term "heterocycloalkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, the heterocycloalkyl group may be a monocyclic or bicyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded via a non-aromatic ring atom) or bridged ring system. The nitrogen, carbon, or sulfur atom in the heterocyclyl group may optionally be oxidized. The nitrogen atom may optionally be quaternized. The heterocycloalkyl group may be partially or fully saturated. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl [1,3] dithianyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of sugars, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the skeleton atoms of the heterocycloalkyl ring). Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted.

[0397] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also referred to as heteroaryl) and heterocycloalkyl rings (also referred to as heteroaliphatic ring groups) that include at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein each heterocyclyl has 3 to 12 atoms in its ring system, and provided that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compound. Non-aromatic heterocyclic groups (also referred to as heterocycloalkyl) include rings with 3 to 12 atoms in their ring system, and aromatic heterocyclic groups include rings with 5 to 12 atoms in their ring system. Heterocyclyl includes benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinedionyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,2,3,6-tetrahydropyridinyl, 3-dioxolanyl, pyrazolyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3h-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and fluoropyridyl. Where possible, the aforementioned groups are C-attached (or C-linked) or N-attached. For example, groups derived from pyrrole include pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).In addition, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (all N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). Heterocyclyl includes benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0398] The term "heteroaryl" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl groups are monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furanyl. In some embodiments, the heteroaryl contains 0-6 nitrogen atoms in the ring. In some embodiments, the heteroaryl contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 4-6 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5-membered or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group. In some embodiments, the heteroaryl group is partially reduced to form a heterocycloalkyl group as defined herein. In some embodiments, the heteroaryl group is fully reduced to form a heterocycloalkyl group as defined herein.

[0399] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is typically a known chemical entity embedded in or attached to a molecule.

[0400] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted by one or more additional groups individually and independently selected from the group consisting of D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -C02H, -C02alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone. In some embodiments, the optional substituents are independently selected from D, halogen, –CN, –NH2, –NH(CH3), –N(CH3)2, –OH, –CO2H, –CO2(C1-C4 alkyl), –C(═O)NH2, –C(═O)NH(C1-C4 alkyl), –C(═O)N(C1-C4 alkyl)2, –S(═O)2NH2, –S(═O)2NH(C1-C4 alkyl), –S(═O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, –SC1-C4 alkyl, –S(═O)C1-C4 alkyl, and –S(═O)2(C1-C4 alkyl). In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0401] The term "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible via the migration of a hydrogen atom, accompanied by a switch in single bonds and adjacent double bonds. In bonded structures where tautomerism is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interchange include:

[0402]

[0403] The term "about" or "approximately" can mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more standard deviations as is customary in the art. Alternatively, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold of a value.

[0404] As used herein, the term "administer" or the like refers to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes (po), intraduodenal routes (id), parenteral injection (including intravenous (iv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravascular or infusion (inf.)), topical (top.) and rectal (pr) administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0405] As used herein, the terms "co-administered," "co-administered," and the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0406] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an agent or compound administered that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated; for example, to reduce and / or alleviate one or more signs, symptoms, or causes of the disease or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic use can be an amount of an agent that clinically significantly reduces one or more symptoms of the disease. In individual cases, techniques such as dose escalation studies can be used to determine an appropriate "effective" amount.

[0407] As used herein, the term "enhance" refers to increasing or prolonging the amount, potency, or duration of a desired effect. For example, with respect to enhancing the splicing of a target, the term "enhance" can refer to the ability to increase or prolong the splicing of a target, whether in amount, potency, or duration.

[0408] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; livestock such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, among others. In one aspect, the mammal is a human. As used herein, the term "animal" includes both humans and non-human animals. In one embodiment, a "non-human animal" is a mammal, for example, a rodent such as a rat or mouse. In one embodiment, the non-human animal is a mouse.

[0409] As used herein, the term "treating," ...

[0410] The term "preventing" or "preventing" a disease state means that clinical symptoms leading to the disease state do not develop in a subject who is exposed to or susceptible to the disease state but does not yet experience or display symptoms of the disease state.

[0411] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients to be administered to a subject (e.g., a human in need thereof).

[0412] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound as described herein and an adjuvant, are administered to a patient simultaneously as a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound as described herein and an adjuvant, are administered to a patient as separate entities simultaneously, concurrently, or sequentially without specific time intervals, wherein such administration provides effective levels of both compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0413] The term "pharmaceutically acceptable" refers to the property of materials useful in preparing pharmaceutical compositions that are generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for veterinary as well as human use. "Pharmaceutically acceptable" may refer to materials (such as carriers or diluents) that do not abrogate the biological activity or properties of a compound and are relatively non-toxic, i.e., materials that can be administered to an individual without causing adverse biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0414] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and mean any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant used to formulate a drug product.

[0415] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. "Pharmaceutically acceptable salts" may refer to compound preparations that do not cause significant irritation to the organism to which they are administered and / or do not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting an SMSM compound of any one of formula (I)-(II) with an acid. A pharmaceutically acceptable salt can also be obtained by reacting a compound of any one of formula (I)-(II) with a base to form a salt. The types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, which are formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.; or an organic acid, e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid; (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions). In some cases, the compounds described herein may be coordinated with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0416] As used herein, the term "nucleic acid" generally refers to one or more nucleobases, nucleosides, or nucleotides, and includes polynucleobases, polynucleosides, and polynucleotides.

[0417] As used herein, the term "polynucleotide" generally refers to a molecule comprising two or more connected nucleic acid subunits (such as nucleotides), and can be used interchangeably with "oligonucleotides". For example, a polynucleotide can include one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T) and uracil (U) or its variants. Nucleotide generally comprises a nucleoside and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphate radicals (PO3) groups. Nucleotide can include a core base, a five-carbon sugar (ribose or deoxyribose) and one or more phosphate radical groups. Ribonucleotides include nucleotides in which sugar is ribose. Deoxyribonucleotides include nucleotides in which sugar is deoxyribose. Nucleotide can be nucleoside monophosphate, nucleoside diphosphate, nucleoside triphosphate or nucleoside polyphosphate. For example, nucleotide can be deoxyribonucleoside polyphosphates, such as deoxyribonucleoside triphosphates (dNTPs), exemplary dNTPs include deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP) and deoxythymidine triphosphate (dTTP). dNTPs can also include detectable labels, such as luminescent labels or markers (e.g., fluorophores). For example, nucleotide can be a purine (i.e., A or G or its variants) or a pyrimidine (i.e., C, T or U or its variants). In some instances, polynucleotides are deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or its derivatives or variants. Exemplary polynucleotides include, but are not limited to, short interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), short hairpin RNA (shRNA), small nuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA), antisense RNA (asRNA) and heteronuclear RNA (hnRNA), and encompass nucleotide sequence and any structural embodiment thereof, such as single-stranded, double-stranded, triple-stranded, spiral, hairpin, stem-loop, protrusion etc. In some cases, polynucleotides are circular. Polynucleotides can have various lengths. For example, the length of polynucleotides can be at least about 7 bases, 8 bases, 9 bases, 10 bases, 20 bases, 30 bases, 40 bases, 50 bases, 100 bases, 200 bases, 300 bases, 400 bases, 500 bases, 1 kilobases (kb), 2kb, 3kb, 4kb, 5kb, 10kb, 50kb or more. The polynucleotides can be isolated from cells or tissues. For example, the polynucleotide sequences can include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules and / or synthetic DNA / RNA analogs.

[0418] The polynucleotide may include one or more nucleotide variants, including non-standard nucleotides, non-natural nucleotides, nucleotide analogs and / or modified nucleotides. Examples of modified nucleotides include, but are not limited to, diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, β-D-galactosylinosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylamino Methyluracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosylquenoside, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, quenoside, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, 2,6-diaminopurine, etc. In some cases, the phosphate portion of the nucleotide may include modifications, including modifications to the triphosphate portion. Non-limiting examples of such modifications include longer length phosphate chains (e.g., phosphate chains with 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications of thiol moieties (e.g., α-thiotriphosphate β-thiotriphosphate). Nucleic acid molecules may also be modified at the base moiety (e.g., at one or more atoms that are normally available to form hydrogen bonds with complementary nucleotides and / or at one or more atoms that are normally unable to form hydrogen bonds with complementary nucleotides), the sugar moiety, or the phosphate backbone. Nucleic acid molecules may also include amine-modified groups, such as aminoallyl 1-dUTP (aa-dUTP) and aminohexyl acrylamide-dCTP (aha-dCTP), to covalently attach amine-reactive moieties such as N-hydroxysuccinimide ester (NHS). Substitutes for standard DNA base pairs or RNA base pairs in the oligonucleotides of the present disclosure may provide higher density in bits per cubic mm, higher safety (against accidental or purposeful synthesis of natural toxins), easier recognition in light-programmable polymerases, or lower secondary structure.Such alternative base pairs compatible with native and mutant polymerases for de novo and / or amplification synthesis are described in Betz K, Malyshev DA, Lavergne T, Welte W, Diederichs K, Dwyer TJ, Ordoukhanian P, Romesberg FE, Marx A. Nat. Chem. Biol. 2012 Jul;8(7):612-4, which is incorporated herein by reference for all purposes.

[0419] As used herein, the terms "polypeptide," "protein," and "peptide" are used interchangeably and refer to a polymer of amino acid residues linked via peptide bonds, and which may be composed of two or more polypeptide chains. The terms "polypeptide," "protein," and "peptide" refer to a polymer of at least two amino acid monomers linked together by an amide bond. Amino acids may be L-optical isomers or D-optical isomers. More specifically, the terms "polypeptide," "protein," and "peptide" refer to a molecule composed of two or more amino acids in a specific order; for example, the order is determined by the base sequence of nucleotides in a gene or RNA encoding the protein. Proteins are essential for the structure, function, and regulation of human cells, tissues, and organs, and each protein has a unique function. Examples are hormones, enzymes, antibodies, and any fragments thereof. In some cases, a protein may be a portion of a protein, such as a domain, subdomain, or motif of a protein. In some cases, a protein may be a variant (or mutation) of a protein in which one or more amino acid residues are inserted, deleted, and / or replaced with the naturally occurring (or at least known) amino acid sequence of the protein. A protein or its variant may be naturally occurring or recombinant.

[0420] Methods for detecting and / or measuring polypeptides in biological materials are well known in the art and include, but are not limited to, Western blotting, flow cytometry, ELISA, RIA, and various proteomics techniques. An exemplary method for measuring or detecting polypeptides is an immunoassay, such as ELISA. This type of protein quantification can be based on antibodies capable of capturing specific antigens and a second antibody capable of detecting the captured antigen. Exemplary assays for detecting and / or measuring polypeptides are described in Harlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), Cold Spring Harbor Laboratory Press.

[0421] Methods for detecting and / or measuring RNA in biological material are well known in the art and include, but are not limited to, Northern blotting, RNA protection assays, RT PCR. Suitable methods are described in Molecular Cloning: A Laboratory Manual (4th edition), Michael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN 978-1-936113-42-2.

[0422] As used herein, "small molecular weight compound" can be used interchangeably with "small molecule" or "small organic molecule." Small molecules refer to compounds other than peptides or oligonucleotides; and typically have a molecular weight of less than about 2000 Daltons, such as less than about 900 Daltons.

[0423] Ribonucleoprotein (RNP) refers to a nuclear protein containing RNA. RNP can be a complex of ribonucleic acid and RNA binding protein. This combination can also be referred to as protein-RNA complex. These complexes can play a variety of biological functions, including but not limited to DNA replication, gene expression, RNA metabolism and pre-mRNA splicing. Examples of RNP include ribosomes, telomerase, vault ribonucleoprotein, RNase P, heterogeneous nuclear RNP (hnRNP) and small nuclear RNP (snRNP).

[0424] Nascent RNA transcripts from protein-coding genes and mRNA processing intermediates are collectively referred to as pre-mRNAs, which are typically bound to proteins in the eukaryotic nucleus. From the time when the nascent transcript first appears from RNA polymerase (e.g., RNA polymerase II) until the mature mRNA is transported into the cytoplasm, the RNA molecule is associated with a large number of splicing complex components (e.g., nucleoproteins and snRNAs). These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNAs (hnRNAs) of various sizes (e.g., pre-mRNA and nuclear RNA complexes).

[0425] Splicing complex components play a role in splicing and / or splicing regulation. Splicing complex components may include, but are not limited to, ribonucleoproteins (RNPs), splicing proteins, small nuclear RNAs (snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing complex components include, but are not limited to, those that may be required for splicing, such as constitutive splicing, alternative splicing, regulated splicing, and splicing of specific messages or groups of messages. A group of related proteins, serine-arginine-rich proteins (SR proteins), can play a role in constitutive pre-mRNA splicing and can also regulate alternative splicing site selection in a concentration-dependent manner. SR proteins typically have a modular structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminus (RS domain) rich in arginine and serine residues. Their activity in alternative splicing may be antagonized by members of the hnRNPA / B protein family. Splicing complex components may also include proteins that associate with one or more snRNAs. SR proteins in humans include, but are not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2 / ASF, 9G8, SRp75, SRp30c, SRp20, and P54 / SFRS11. Other splicing complex components that may participate in splice site selection in humans include, but are not limited to, U2 snRNA auxiliary factors (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP 20, SF1, and PTB / hnRNP1. hnRNP proteins in humans include, but are not limited to, A1, A2 / B1, L, M, K, U, F, H, G, R, I, and C1 / C2. Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1. Splicing complex components can be stably or transiently associated with snRNPs or transcripts.

[0426] The term "intron" refers to DNA sequences within a gene and the corresponding sequences in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing shortly after or simultaneously with transcription. Introns are present in the genes of most organisms and many viruses. They can be found in a wide range of genes, including those that produce proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA).

[0427] An "exon" can be any portion of a gene that encodes a portion of the final mature RNA produced from that gene after introns are removed by RNA splicing. The term "exon" refers to a DNA sequence within a gene and the corresponding sequence in the RNA transcript.

[0428] The "spliceosome" can be assembled from snRNA and protein complexes. The spliceosome can remove introns from the transcribed pre-mRNA.

[0429] "Moderate effective dose" (ED 50 ) is the dose at which 50% of the population expresses a specific response. The “median lethal dose” (LD 50 ) is the dose that kills 50% of the population. 50 ) is the dose at which 50% of the population exhibits a specific toxic effect. A particularly useful pharmacological metric is the "therapeutic index," which is traditionally defined as the LD 50 With ED 50 Ratio or TD 50 With ED 50 The therapeutic index provides a simple and useful indicator of the relative benefits of a drug to its adverse effects. Drugs with high therapeutic indices have large therapeutic windows, i.e., the drug can be administered over a wider range of effective doses without causing significant adverse events. In contrast, drugs with small therapeutic indices have small therapeutic windows (small effective dose range without causing significant adverse events).

[0430] As used herein, the term "AUC" refers to the abbreviation of "area under the curve" in a plot of the concentration of a therapeutic agent in some part or tissue (eg, blood or plasma) of a subject to which the therapeutic agent has been administered over time.

[0431] Unless otherwise indicated, the embodiments of compounds of any one of Formulas (I)-(V) may also apply to the corresponding sub-formulas (e.g., Formula (Ia), Formula (IIa), Formula (IIff), etc.). For example, in some embodiments, the sub-formula of Formula (II) is Formula (IIff). For example, in some embodiments, the sub-formula of Formula (IV) is Formula (IIff).

[0432] Small molecule splicing modulators (SMSMs)

[0433] It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effectively used as agents for treating, preventing or ameliorating diseases or conditions associated with target RNA. The present invention provides the unexpected discovery that certain small chemical molecules can modify splicing events in pre-mRNA molecules, referred to herein as small molecule splicing modulators (SMSMs). These SMSMs can modulate specific splicing events in specific pre-mRNA molecules. These SMSMs can operate through a variety of mechanisms to modify splicing events. For example, the SMMSs of the present invention can: 1) interfere with the formation and / or function and / or other properties of the splicing complex, spliceosome and / or its components such as hnRNPs, snRNPs, SR-proteins and other splicing factors or elements, resulting in the prevention or induction of splicing events in pre-mRNA molecules. As another example; 2) prevent and / or modify post-transcriptional regulation (e.g., splicing) of gene products such as hnRNPs, snRNPs, SR-proteins, and other splicing factors, which may subsequently participate in the formation and / or function of spliceosome or splicing complex components; 3) prevent and / or modify phosphorylation, glycosylation, and / or other modifications of gene products, including but not limited to hnRNPs, snRNPs, SR-proteins, and other splicing factors, which may subsequently participate in the formation and / or function of spliceosome or splicing complex components; 4) bind to and / or otherwise affect specific pre-mRNAs, thereby preventing or inducing specific splicing events, for example, by a mechanism that does not involve base pairing with RNA in a sequence-specific manner. The small molecules of the present invention are distinct from and unrelated to antisense or antigene oligonucleotides.

[0434] Compounds that modify the splicing of a gene product are described herein for use in treating, preventing, and / or delaying the progression of a disease or condition (e.g., cancer). Compounds that modify the splicing of a gene product are described herein, wherein the compounds induce a transcriptionally inactive variant or transcript of the gene product. Compounds that modify the splicing of a gene product are described herein, wherein the compounds inhibit a transcriptionally active variant or transcript of the gene product.

[0435] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0436]

[0437] in

[0438] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0439] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0440] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0441] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0442] X is –O-, –S-, or –NR 3 -;

[0443] Z is CR 2 ;

[0444] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0445] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0446] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0447] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0448] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0449] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0450] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0451] a is 0 or 1;

[0452] b is 0;

[0453] c is 1; and

[0454] d is 0 or 1.

[0455] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0456]

[0457]

[0458] in

[0459] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0460] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0461] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0462] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0463] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;or

[0464] X is and Z is N or CR 2 ;

[0465] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0466] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0467] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0468] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0469] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0470] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0471] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0472] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0473] a is 0 or 1;

[0474] b is 0;

[0475] c is 1; and

[0476] d is 0 or 1.

[0477] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is and Z is N or CR 2 In some embodiments, X is -O-, -S-, or -NR 3 -, and Z is CR 2 .

[0478] In one aspect, described herein are compounds having the structure of Formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0479]

[0480] in

[0481] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0482] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0483] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0484] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0485] X is and Z is N or CR 2 ;or

[0486] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0487] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0488] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0489] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0490] R 2is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0491] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0492] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0493] R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0494] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0495] a is 0 or 1;

[0496] b is 0;

[0497] c is 1; and

[0498] d is 0 or 1.

[0499] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is and Z is N or CR 2In some embodiments, X is -O-, -S-, or -NR 3 -, and Z is CR 2 .

[0500] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are identical and are selected from hydrogen and deuterium. In some embodiments, R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

[0501] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0502]

[0503] in

[0504] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0505] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0506] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0507] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0508] X is –O-, –S-, or –NR 3 -;

[0509] Z is CR 2 ;

[0510] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0511] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0512] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0513] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0514] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0515] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0516] R 15 and R 18 are identical and are selected from hydrogen and deuterium;

[0517] a is 0 or 1;

[0518] b is 0;

[0519] c is 1; and

[0520] d is 0 or 1.

[0521] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, R 15 and R 18 All are deuterium.

[0522] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0523]

[0524] in

[0525] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0526] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0527] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0528] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0529] X is –O-, –S-, or –NR 3 -;

[0530] Z is CR 2 ;

[0531] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0532] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0533] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0534] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0535] R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0536] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0537] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0538] a is 0 or 1;

[0539] b is 0;

[0540] c is 1; and

[0541] d is 0 or 1.

[0542] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are identical and are selected from F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In one embodiment, R 15 and R 18 are identical and are selected from the group consisting of F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH2F, –CHF2, and –CF3. In one embodiment, R 15 and R 18 are identical and are selected from the group consisting of F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R 15 and R 18 are the same and are selected from F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3. In one embodiment, R 15 and R 18 are identical and are selected from F, -CH3 and -OCH3. In one embodiment, R 15 and R 18 is F. In one embodiment, R 15 and R 18 In one embodiment, R 15 and R 18 It is -OCH3.

[0543] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0544]

[0545] in

[0546] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0547] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0548] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0549] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0550] X is –O-, –S-, or –NR 3 -;

[0551] Z is CR 2 ;

[0552] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0553] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0554] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0555] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0556] R 3is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ;

[0557] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0558] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0559] a is 0 or 1;

[0560] b is 0;

[0561] c is 1; and

[0562] d is 0 or 1.

[0563] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH2F, –CHF2, and –CF3. In one embodiment, R 15 and R 18are different and are selected from hydrogen, deuterium, F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3 and -OCH3. In one embodiment, R 15 is F and R 18 In one embodiment, R 15 is hydrogen and R 18 is F. In one embodiment, R 15 is hydrogen and R 18 In one embodiment, R 15 is CH3 and R 18 For hydrogen.

[0564] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is -O-.

[0565] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is -S-.

[0566] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is -NR 3 -. In some embodiments, R 3 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, or -CF3. In some embodiments, R 3 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, or -CF3. In some embodiments, R 3 is hydrogen, -CH3 or -CH(CH3)2. In one embodiment, R 3 It is hydrogen or -CH3.

[0567] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0568]

[0569] in

[0570] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0571] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0572] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0573] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0574] X is

[0575] Z is N or CR 2 ;

[0576] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0577] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0578] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0579] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0580] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0581] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0582] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0583] a is 0 or 1;

[0584] b is 0;

[0585] c is 1; and

[0586] d is 0 or 1.

[0587] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are identical and are selected from hydrogen and deuterium. In some embodiments, R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

[0588] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0589]

[0590] in

[0591] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0592] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0593] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0594] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0595] X is

[0596] Z is N or CR 2 ;

[0597] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0598] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0599] Each R1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0600] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0601] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0602] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0603] R 15 and R 18 are identical and are selected from hydrogen and deuterium;

[0604] a is 0 or 1;

[0605] b is 0;

[0606] c is 1; and

[0607] d is 0 or 1.

[0608] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, R 15 and R 18 All are deuterium.

[0609] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0610]

[0611] in

[0612] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0613] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0614] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0615] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0616] X is

[0617] Z is N or CR 2 ;

[0618] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0619] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0620] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0621] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0622] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0623] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0624] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0625] a is 0 or 1;

[0626] b is 0;

[0627] c is 1; and

[0628] d is 0 or 1.

[0629] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are identical and are selected from F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In one embodiment, R 15 and R 18 are identical and are selected from F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –

[0630] In one embodiment, R 15 and R 18are identical and are selected from the group consisting of F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R 15 and R 18 are the same and are selected from F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3. In one embodiment, R 15 and R 18 are identical and are selected from F, -CH3 and -OCH3. In one embodiment, R 15 and R 18 is F. In one embodiment, R 15 and R 18 In one embodiment, R 15 and R 18 It is -OCH3.

[0631] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0632]

[0633] in

[0634] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0635] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0636] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0637] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0638] X is

[0639] Z is N or CR 2 ;

[0640] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0641] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0642] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0643] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0644] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0645] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0646] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0647] a is 0 or 1;

[0648] b is 0;

[0649] c is 1; and

[0650] d is 0 or 1.

[0651] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH2F, –CHF2, and –CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3 and -OCH3. In one embodiment, R 15 is F and R 18 In one embodiment, R 15 is hydrogen and R 18 is F. In one embodiment, R 15 is hydrogen and R 18 In one embodiment, R 15 is CH3 and R 18 For hydrogen.

[0652] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Z is N. In some embodiments, Z is CR 2 .

[0653] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is In some embodiments, X is

[0654] In some embodiments of the compound of formula (I) or formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, E is -NR-. In some embodiments, E is -O-. In some embodiments, E is S(=O). In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in the equatorial position. In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in the axial position. In some embodiments, E is S(=O)(=NR- E In some embodiments, E is S(═O)(═NR E ) and the oxygen atom (=NR E ) is in the flat position, and S(=O)(=NR E ) is in an axial position. In some embodiments, E is S(=O)(=NR E ), and the oxygen atom (=NR E ) is in upright position, and S(=O)(=NR E ) is in the flat position.

[0655] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 In some embodiments, R 16 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 16 The carbon atoms of the groups are in the (R)-configuration.

[0656] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 In some embodiments, R 17 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 17 The carbon atoms of the groups are in the (R)-configuration.

[0657] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 is not hydrogen and R 17 In some embodiments, R 16The carbon atom of the group is in (S)-configuration and has R 17 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 16 The carbon atom of the group is in (S)-configuration and has R 17 In some embodiments, the carbon atoms of the group are in the (R)-configuration. 16 The carbon atoms of the group are in the (R)-configuration and have R 17 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 16 The carbon atoms of the group are in the (R)-configuration and have R 17 The carbon atoms of the groups are in the (R)-configuration.

[0658] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ia):

[0659]

[0660] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ib):

[0661]

[0662] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ib-1):

[0663]

[0664] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ib-2):

[0665]

[0666] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ic):

[0667]

[0668] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ic-1):

[0669]

[0670] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ic-2):

[0671]

[0672] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Id):

[0673]

[0674] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie):

[0675]

[0676] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-1):

[0677]

[0678] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-2):

[0679]

[0680] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-3):

[0681]

[0682] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-4):

[0683]

[0684] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If):

[0685]

[0686] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-1):

[0687]

[0688] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-2):

[0689]

[0690] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-3):

[0691]

[0692] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-4):

[0693]

[0694] In some embodiments of the compound of formula (I) or formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted aryl group. In one embodiment, ring Q is a 2-hydroxy-phenyl group substituted with 1, 2 or 3 substituents independently selected from the following:

[0695] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[0696] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0697] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is a 2-hydroxy-phenyl group substituted with a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. In one embodiment, Ring Q is a 2-hydroxy-phenyl group substituted with a substituted or unsubstituted aryl group, wherein if the aryl group is substituted, it is substituted with 1 or 2 substituents independently selected from the following:

[0698] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1)2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[0699] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0700] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, wherein if the heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from:

[0701] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[0702] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0703] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is

[0704] Each R Q independently selected from hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CF3, –OCH3, –OCH2CH3, –CH2OCH3, –OCH2CH2CH3 and –OCH(CH3)2; Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0705] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is a substituted or unsubstituted heteroaryl. In one embodiment, Ring Q is a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl. In one embodiment, Ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl. In one embodiment, Ring Q is a 6-membered monocyclic heteroaryl selected from the following:

[0706] Ring Q is Each R Q independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3 and -OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0707] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R Q In one embodiment, ring P is a substituted or unsubstituted heteroaryl group. In one embodiment, ring P is a heteroaryl group selected from the group consisting of:

[0708]

[0709] in

[0710] Each R Bindependently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0711] R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[0712] m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0713] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[0714] in

[0715] Each R B independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0716] R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[0717] m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0718] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R B is independently selected from hydrogen, deuterium, -F, -Cl, -CN, -CH3, -CF3, -OH or -OCH3. In one embodiment, each R B are independently H, -F or -OCH3. In one embodiment, R B1 is selected from hydrogen, deuterium, -CH3, -CF3, or -CD3. In one embodiment, m is 0 or 1. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0719] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from:

[0720] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[0721] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0722] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0723] In some embodiments, Ring Q is selected from the group consisting of:

[0724]

[0725] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0726]

[0727]

[0728] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0729]

[0730]

[0731] in

[0732] R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0733] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W is a substituted or unsubstituted C1-C3 alkylene. In one embodiment, W is -CH2-. In one embodiment, W is -CH2CH2-. In one embodiment, W is -CH2CH2CH2-. In one embodiment, W is a substituted or unsubstituted C1-C2 heteroalkylene. In one embodiment, W is -CH2OCH2-. In one embodiment, W is -CH2O-, wherein O is attached to a moiety having R 18In some embodiments, W is a substituted or unsubstituted C3-C8 cycloalkylene or a substituted or unsubstituted C2-C3 alkenylene. In one embodiment, W is a substituted or unsubstituted C3-C8 cycloalkylene. In one embodiment, W is a cyclopropylene. In one embodiment, W is a substituted or unsubstituted C2-C3 alkenylene. In one embodiment, W is -CH=CH-.

[0734] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl, or substituted or unsubstituted C2-C4 heterocycloalkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2OH, -CH2CN, -CHF2, -CF3, or cyclopropyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In one embodiment, R is -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In one embodiment, R is hydrogen.

[0735] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 and R 16 One or more of the following are independently selected from F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In one embodiment, R 11 、R 12 and R 16 One or more of are independently selected from F, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —CH2CN, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, and —CH2CF3. In one embodiment, R 11 、R 12 and R 16 One or more of are independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3. In one embodiment, R 11 、R 12 and R 16 For hydrogen.

[0736] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 and R 17 One or more of the following are independently selected from F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In one embodiment, R 16 and R 17 One or more of are independently selected from F, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —CH2CN, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, and —CH2CF3. In one embodiment, R 16 and R 17 One or more of are independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3. In one embodiment, R16 and R 17 For hydrogen.

[0737] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 2 is hydrogen, -CH3 or -OCH3. In one embodiment, R 2 For hydrogen.

[0738] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R A In one embodiment, R A In one embodiment, R A is hydrogen, F, Cl, -CN, -CH3 or -OCH3. In one embodiment, R A is hydrogen, F, Cl or -CH3. In one embodiment, R A For hydrogen.

[0739] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R 4 are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl. 4 are independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -CH2OCH3, -CH2F, -CHF2, or -CF3. In one embodiment, each R 4 is independently hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2F, -CHF2 or -CF3. In one embodiment, each R 4 In one embodiment, each R 4 is -CH3.

[0740] In some embodiments of the compound of Formula (I) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them are F.

[0741] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 19 、R 20 and R 16 For hydrogen.

[0742] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 In some embodiments, R 19is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 19 In some embodiments, R 19 is F or -OCH3.

[0743] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 In some embodiments, R 20 is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 20 In some embodiments, R 20 is F or -OCH3.

[0744] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 is H, D or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 For F.

[0745] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 12 is H, D or F. In some embodiments, R 12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 For F.

[0746] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R13 is H, D or F. In some embodiments, R 13 is D. In some embodiments, R 13 is H. In some embodiments, R 13 For F.

[0747] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 14 is H, D or F. In some embodiments, R 14 is D. In some embodiments, R 14 is H. In some embodiments, R 14 For F.

[0748] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is H or D. In some embodiments, R15 is H. In some embodiments, R15 is D. In some embodiments, R 15 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is F, CF3, CHF2 or CH2F. In some embodiments, R 15 For F.

[0749] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 is H, D or F. In some embodiments, R 16 is D. In some embodiments, R 16 is H. In some embodiments, R 16 For F.

[0750] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 is H, D or F. In some embodiments, R 17 is D. In some embodiments, R 17 is H. In some embodiments, R 17 For F.

[0751] In some embodiments of the compound of Formula (I) or Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 18is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 In some embodiments, R18 is H or D. In some embodiments, R18 is H. In some embodiments, R18 is D. In some embodiments, R 18 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is F, CF3, CHF2 or CH2F. In some embodiments, R 18 For F.

[0752] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 is H, D or F. In some embodiments, R 20 is D. In some embodiments, R 20 is H. In some embodiments, R 20 For F.

[0753] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 and R 19 is H. In some embodiments, R 16 and R 19 is D. In some embodiments, R 16 and R 19 For F.

[0754] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 and R 20 is H. In some embodiments, R 19 and R 20 is D. In some embodiments, R 19 and R 20 For F.

[0755] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 and R 20 is H. In some embodiments, R 17 and R 20 is D. In some embodiments, R 17 and R 20 For F.

[0756] In some embodiments of the compound of Formula (I) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, at least two of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, at least one of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them contain fluorine.

[0757] In some embodiments of the compound of formula (I) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, W comprises fluorine.

[0758] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 19 、R 20 and R 16 For hydrogen.

[0759] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 In some embodiments, R 19 is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 19 In some embodiments, R 19 is F or -OCH3.

[0760] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 In some embodiments, R 20is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 20 In some embodiments, R 20 is F or -OCH3.

[0761] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R16 、R 19 、R 20 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 At least two of them are F.

[0762] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, at least two of R 11 、R12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, at least one of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them contain fluorine.

[0763] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, W comprises fluorine.

[0764] In one aspect, described herein are compounds having the structure of Formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0765]

[0766] in

[0767] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0768] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0769] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0770] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0771] is a single bond or a double bond;

[0772] X is and Z is C; or

[0773] X is and Z is N or CR 2 ;

[0774] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0775] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0776] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0777] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0778] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0779] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0780] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0781] a is 0 or 1;

[0782] b is 0;

[0783] c is 1; and

[0784] d is 0 or 1.

[0785] In one aspect, described herein are compounds having the structure of Formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0786]

[0787] in

[0788] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0789] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0790] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0791] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0792] is a single bond or a double bond;

[0793] X is and Z is C; or

[0794] X is and Z is N or CR 2 ;

[0795] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0796] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0797] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0798] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0799] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0800] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0801] R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0802] a is 0 or 1;

[0803] b is 0;

[0804] c is 1; and

[0805] d is 0 or 1.

[0806] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are identical and are selected from hydrogen and deuterium. In some embodiments, R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 15 and R 18are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

[0807] In one aspect, described herein are compounds having the structure of Formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0808]

[0809] in

[0810] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0811] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0812] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0813] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0814] is a single bond or a double bond;

[0815] X is and Z is C; or

[0816] X is and Z is N or CR 2 ;

[0817] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0818] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0819] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0820] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0821] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0822] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0823] R 15 and R 18 are identical and are selected from hydrogen and deuterium;

[0824] a is 0 or 1;

[0825] b is 0;

[0826] c is 1; and

[0827] d is 0 or 1.

[0828] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, R 15 and R 18 All are deuterium.

[0829] In one aspect, described herein are compounds having the structure of Formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0830]

[0831] in

[0832] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0833] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0834] R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0835] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0836] is a single bond or a double bond;

[0837] X is and Z is C; or

[0838] X is and Z is N or CR 2 ;

[0839] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0840] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0841] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0842] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0843] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0844] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0845] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0846] a is 0 or 1;

[0847] b is 0;

[0848] c is 1; and

[0849] d is 0 or 1.

[0850] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are identical and are selected from F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In one embodiment, R 15 and R 18are identical and are selected from the group consisting of F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH2F, –CHF2, and –CF3. In one embodiment, R 15 and R 18 are identical and are selected from the group consisting of F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R 15 and R 18 are the same and are selected from F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3. In one embodiment, R 15 and R 18 are identical and are selected from F, -CH3 and -OCH3. In one embodiment, R 15 and R 18 is F. In one embodiment, R 15 and R 18 In one embodiment, R 15 and R 18 It is -OCH3.

[0851] In one aspect, described herein are compounds having the structure of Formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0852]

[0853] in

[0854] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0855] R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、–S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

[0856] R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl;

[0857] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0858] is a single bond or a double bond;

[0859] X is and Z is C; or

[0860] X is and Z is N or CR 2 ;

[0861] W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene;

[0862] R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl;

[0863] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0864] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0865] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0866] Each R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Independently selected from the group consisting of hydrogen, deuterium, F, –OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0867] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0868] a is 0 or 1;

[0869] b is 0;

[0870] c is 1; and

[0871] d is 0 or 1.

[0872] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH2F, –CHF2, and –CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3. In one embodiment, R 15 and R 18 are different and are selected from hydrogen, deuterium, F, -CH3 and -OCH3. In one embodiment, R 15 is F and R 18In one embodiment, R 15 is hydrogen and R 18 is F. In one embodiment, R 15 is hydrogen and R 18 In one embodiment, R 15 is CH3 and R 18 For hydrogen.

[0873] In some embodiments of the compound of formula (II) or formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, E is -NR-. In some embodiments, E is -O-. In some embodiments, E is S(=O). In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in the equatorial position. In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in the axial position. In some embodiments, E is S(=O)(=NR E In some embodiments, E is S(═O)(═NR E ) and the oxygen atom (=NR E ) is in the flat position, and S(=O)(=NR E ) is in an axial position. In some embodiments, E is S(=O)(=NR E ), and the oxygen atom (=NR E ) is in upright position, and S(=O)(=NR E ) is in the flat position.

[0874] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 In some embodiments, R 16 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 16 In some embodiments, the carbon atoms of the group are in the (R)-configuration. 17 In some embodiments, R 17 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 17 The carbon atoms of the groups are in the (R)-configuration.

[0875] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 is not hydrogen and R 17 In some embodiments, R 16 The carbon atom of the group is in (S)-configuration and has R17 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 16 The carbon atom of the group is in (S)-configuration and has R 17 In some embodiments, the carbon atoms of the group are in the (R)-configuration. 16 The carbon atoms of the group are in the (R)-configuration and have R 17 In some embodiments, the carbon atoms of the group are in the (S)-configuration. 16 The carbon atoms of the group are in the (R)-configuration and have R 17 The carbon atoms of the groups are in the (R)-configuration.

[0876] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIa):

[0877]

[0878] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIb):

[0879]

[0880] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIb-1):

[0881]

[0882] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIb-2):

[0883]

[0884] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIc):

[0885]

[0886] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIc-1):

[0887]

[0888] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIc-2):

[0889]

[0890] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIaa):

[0891]

[0892] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIbb):

[0893]

[0894] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIbb-1):

[0895]

[0896] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIbb-2):

[0897]

[0898] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIcc):

[0899]

[0900] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIcc-1):

[0901]

[0902] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIcc-2):

[0903]

[0904] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IId):

[0905]

[0906] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe):

[0907]

[0908] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-1):

[0909]

[0910] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-2):

[0911]

[0912] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-3):

[0913]

[0914] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-4):

[0915]

[0916] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIf):

[0917]

[0918] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIf-1):

[0919]

[0920] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIf-2):

[0921]

[0922] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIf-3):

[0923]

[0924] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIf-4):

[0925]

[0926] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIdd):

[0927]

[0928] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIee):

[0929]

[0930] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIee-1):

[0931]

[0932] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIee-2):

[0933]

[0934] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIee-3):

[0935]

[0936] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIee-4):

[0937]

[0938] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (III):

[0939]

[0940] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (III-1):

[0941]

[0942] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (III-2):

[0943]

[0944] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (III-3):

[0945]

[0946] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (III-4):

[0947]

[0948] In some embodiments of the compound of formula (II) or formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted aryl group. In one embodiment, ring Q is a 2-hydroxy-phenyl group substituted with 1, 2 or 3 substituents independently selected from the following:

[0949] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[0950] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0951] In some embodiments of the compound of formula (II) or formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In one embodiment, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl, wherein if the aryl group is substituted, it is substituted with 1 or 2 substituents independently selected from the following:

[0952] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[0953] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0954] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, wherein if the heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from:

[0955] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[0956] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0957] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is

[0958] Each R Qindependently selected from hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CF3, –OCH3, –OCH2CH3, –CH2OCH3, –OCH2CH2CH3 and –OCH(CH3)2; Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0959] In some embodiments of the compound of formula (II) or formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted heteroaryl. In one embodiment, ring Q is a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl. In one embodiment, ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl. In one embodiment, ring Q is a 6-membered monocyclic heteroaryl selected from the following:

[0960] Ring Q is Each R Q independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3 and -OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0961] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R Q In one embodiment, ring P is a substituted or unsubstituted heteroaryl group. In one embodiment, ring P is a heteroaryl group selected from the group consisting of:

[0962]

[0963] in

[0964] Each R B independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0965] R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[0966] m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0967] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[0968] in

[0969] Each R B independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0970] R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[0971] m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3.

[0972] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R B is independently selected from hydrogen, deuterium, -F, -Cl, -CN, -CH3, -CF3, -OH or -OCH3. In one embodiment, each R B are independently H, -F or -OCH3. In one embodiment, R B1is selected from hydrogen, deuterium, -CH3, -CF3, or -CD3. In one embodiment, m is 0 or 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0973] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from:

[0974] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[0975] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0976] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0977]

[0978] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0979]

[0980] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0981]

[0982]

[0983] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0984]

[0985]

[0986] in

[0987] R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0988] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W is a substituted or unsubstituted C1-C3 alkylene. In one embodiment, W is -CH2-. In one embodiment, W is -CH2CH2-. In one embodiment, W is -CH2CH2CH2-. In one embodiment, W is a substituted or unsubstituted C1-C2 heteroalkylene. In one embodiment, W is -CH2OCH2-. In one embodiment, W is -CH2O-, wherein O is attached to a moiety having R 18 In some embodiments, W is a substituted or unsubstituted C3-C8 cycloalkylene or a substituted or unsubstituted C2-C3 alkenylene. In one embodiment, W is a substituted or unsubstituted C3-C8 cycloalkylene. In one embodiment, W is a cyclopropylene. In one embodiment, W is a substituted or unsubstituted C2-C3 alkenylene. In one embodiment, W is -CH=CH-.

[0989] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl, or substituted or unsubstituted C2-C4 heterocycloalkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH3, -CH2OH, -CH2CN, -CHF2, -CF3, or cyclopropyl.

[0990] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R is hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In one embodiment, R is -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In one embodiment, R is hydrogen.

[0991] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 and R 16 One or more of the following are independently selected from F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In one embodiment, R 11 、R 12 and R 16 One or more of are independently selected from F, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —CH2CN, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, and —CH2CF3. In one embodiment, R 11 、R 12 and R 16 One or more of are independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3. In one embodiment, R 11 、R 12 and R 16 For hydrogen.

[0992] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 and R 17 One or more of the following are independently selected from F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In one embodiment, R 16 and R 17 One or more of are independently selected from F, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —CH2CN, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, and —CH2CF3. In one embodiment, R 16 and R 17 One or more of are independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3. In one embodiment, R 16 and R 17 For hydrogen.

[0993] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 2When present, it is hydrogen, -CH3 or -OCH3. In one embodiment, R 2 When present, it is hydrogen.

[0994] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R A In one embodiment, R A In one embodiment, R A is hydrogen, F, Cl, -CN, -CH3 or -OCH3. In one embodiment, R A is hydrogen, F, Cl or -CH3. In one embodiment, R A For hydrogen.

[0995] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R 4 are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl. 4 are independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -CH2OCH3, -CH2F, -CHF2, or -CF3. In one embodiment, each R 4 is independently hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2F, -CHF2 or -CF3. In one embodiment, each R 4 In one embodiment, each R 4 is -CH3.

[0996] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them are F.

[0997] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 is H, D or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 For F.

[0998] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 12 is H, D or F. In some embodiments, R 12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 For F.

[0999] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 13 is H, D or F. In some embodiments, R 13 is D. In some embodiments, R 13 is H. In some embodiments, R 13 For F.

[1000] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 14 is H, D or F. In some embodiments, R 14 is D. In some embodiments, R 14 is H. In some embodiments, R 14 For F.

[1001] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is F, CF3, CHF2 or CH2F. In some embodiments, R 15 For F.

[1002] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 is H, D or F. In some embodiments, R 16 is D. In some embodiments, R 16 is H. In some embodiments, R 16 For F.

[1003] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 is H, D or F. In some embodiments, R 17 is D. In some embodiments, R 17 is H. In some embodiments, R 17 For F.

[1004] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 18is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is F, CF3, CHF2 or CH2F. In some embodiments, R 18 For F.

[1005] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, at least two of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, at least one of R 11 、R 12 、R 13 、R 14 、R16 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them contain fluorine.

[1006] In some embodiments of the compound of Formula (II) or Formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, W comprises fluorine.

[1007] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 19 、R 20 and R 16 For hydrogen.

[1008] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 In some embodiments, R 19 is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 19 In some embodiments, R19 is F or -OCH3.

[1009] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 In some embodiments, R 20 is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 20 In some embodiments, R 20 is F or -OCH3.

[1010] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 is H, D or F. In some embodiments, R 20 is D. In some embodiments, R 20 is H. In some embodiments, R 20 For F.

[1011] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 and R 19 is H. In some embodiments, R 16 and R 19 is D. In some embodiments, R 16 and R 19 For F.

[1012] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 and R 20 is H. In some embodiments, R 19 and R 20 is D. In some embodiments, R 19 and R 20 For F.

[1013] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 and R 20 is H. In some embodiments, R17 and R 20 is D. In some embodiments, R 17 and R 20 For F.

[1014] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 19 、R 20 and R 16 For hydrogen.

[1015] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 In some embodiments, R 19 is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 19 In some embodiments, R 19 is F or -OCH3.

[1016] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 In some embodiments, R 20 is H, F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and –CH2CF3. In some embodiments, R 20 In some embodiments, R 20 is F or -OCH3.

[1017] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 At least two of them are F.

[1018] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, at least two of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, at least one of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16and R 17 At least two of them contain fluorine.

[1019] In some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, W comprises fluorine.

[1020] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R E is hydrogen, substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted C3-C6 cycloalkyl. E In some embodiments, R E It is methyl or ethyl.

[1021] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R 1 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl. 1 is independently hydrogen, deuterium, or C1-C4 alkyl. 1 are independently hydrogen, deuterium or methyl.

[1022] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[1023] Each R B independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[1024] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[1025] Each R B independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and m is 1, 2, 3, or 4. In some embodiments, R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[1026] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[1027] Each RB independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[1028] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1029] wherein each of the ring Q groups may be optionally replaced by 1-3 R B Substitute, where each R B independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1030] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1031] wherein each of the ring Q groups may be optionally replaced by 1-3 R B Substitute, where each R B independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1032] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1033] wherein each of the ring Q groups may be optionally substituted with 1, 2, 3, 4 or 5 R B Substitute, where each R B independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1034] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1035] where R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl, and wherein each of the ring Q groups may be optionally substituted by 1, 2, 3, 4 or 5 R B Substitute, where each R B independently selected from deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7In some embodiments, R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

[1036] In some embodiments, provided herein are compounds of Table 1A or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 1A.

[1037] Table 1A: Exemplary SMSM compounds

[1038]

[1039]

[1040]

[1041]

[1042] In some embodiments, provided herein are compounds of Table IB or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table IB.

[1043] Table 1B: Exemplary SMSM compounds

[1044]

[1045]

[1046]

[1047]

[1048] In some embodiments, provided herein are compounds of Table 1C or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 1C.

[1049] Table 1C: Exemplary SMSM compounds

[1050]

[1051]

[1052]

[1053]

[1054] In some embodiments, provided herein are compounds of Table ID or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table ID.

[1055] Table ID: Exemplary SMSM compounds

[1056]

[1057]

[1058]

[1059] In some embodiments, provided herein are compounds of Table IE or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table IE.

[1060] Table 1E: Exemplary SMSM compounds

[1061]

[1062]

[1063]

[1064]

[1065] In some embodiments, provided herein are compounds of Table IF or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table IF.

[1066] Table 1F: Exemplary SMSM compounds

[1067]

[1068]

[1069]

[1070] In some embodiments, provided herein are compounds of Table 1G or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 1G.

[1071] Table 1G: Exemplary SMSM compounds

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078] In some embodiments, provided herein are compounds of Table 1H or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 1H.

[1079] Table 1H: Exemplary SMSM compounds

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087] In some embodiments, provided herein are compounds of Table II or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table II.

[1088] Table II: Exemplary SMSM compounds

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095] In some embodiments, provided herein are compounds of Table 1J or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 1J.

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122] In some embodiments, provided herein are compounds of Table 6 or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 6.

[1123] In some embodiments, provided herein are compounds of Table 7 or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 7.

[1124] In some embodiments, provided herein are compounds of Table 8 or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 8.

[1125] In some embodiments, provided herein are compounds of Table 9 or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of compounds of Table 9.

[1126] In some cases, a SMSM provided herein may be designated by more than one SMSM# in different sections of the application; for example, the same compound may appear more than once in Tables 1A-1J, Table 4, and Tables 6-9, in the Examples, and in the Schemes.

[1127] In some embodiments, the compounds of Formula (I)-(IV) are racemic. In some embodiments, the compounds of Formula (I)-(IV) are diastereomers.

[1128] In some embodiments, the compound of formula (I)-(IV) is a single enantiomer. In some embodiments, the compound of formula (I)-(IV) is not racemic. In some embodiments, the compound of formula (I)-(IV) is substantially free of other isomers. In some embodiments, the compound of formula (I)-(IV) is a single isomer that is substantially free of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 25% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 20% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 15% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 10% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 5% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 1% or less of other isomers.

[1129] In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 75%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 80%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 85%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 90%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 95%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 96%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 97%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 98%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 99%.

[1130] In some embodiments, the asymmetric carbon atoms of the compounds of Formula (I)-(IV) are present in enantiomeric enriched form. In certain embodiments, the asymmetric carbon atoms of the compounds of Formula (I)-(IV) have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (S)- or (R)-configuration.

[1131] In some embodiments, compounds of formula (I)-(IV) are prepared from racemic starting materials (and / or intermediates) and separated into each enantiomer as an intermediate or final product by chiral chromatography. Unless otherwise indicated, it is understood that the absolute configuration of the isolated intermediate and final compound is not to be determined. In some embodiments, the absolute stereochemistry of the drawn enantiomers is arbitrarily specified. In some embodiments, two enantiomers are synthesized.

[1132] In some embodiments, the SMSM described herein has one or more stereocenters, and each stereocenter exists independently in the R or S configuration. The compounds proposed herein include all diastereoisomers, enantiomers and epimer forms and their appropriate mixtures. The compounds and methods provided herein include all cis (cis), trans (trans), syn (syn), anti (anti), entgegen (E) and zusammen (Z) isomers, and their appropriate mixtures. In certain embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereoisomers and recovering optically pure enantiomers. In some embodiments, the resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereoisomers are separated by separation / resolving techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography or by forming diastereomeric salts and separation by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[1133] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are generally useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug cannot. The solubility of the prodrug in the pharmaceutical composition may also be higher than that of the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. An example of a prodrug is, but is not limited to, a compound described herein, which is administered in the form of an ester ("prodrug") to facilitate delivery across cell membranes where water solubility is not conducive to migration, but once inside the cell where water solubility is beneficial, it is subsequently metabolically hydrolyzed to a carboxylic acid active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acidic group, wherein the peptide is metabolized to reveal the active portion. In certain embodiments, when administered in vivo, the prodrug is chemically converted into the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[1134] In one aspect, prodrugs are designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug, or to alter other characteristics or properties of a drug. Once a pharmaceutically active compound is known, prodrugs of that compound can be designed using knowledge of in vivo pharmacokinetic, pharmacodynamic processes, and drug metabolism (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401, Rooseboom et al., Pharmacological Reviews, 56: 53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14).

[1135] In certain instances, certain compounds described herein may be a derivative or prodrug of another active compound.

[1136] In some embodiments, sites on the aromatic ring portion of the compounds described herein are susceptible to various metabolic reactions, and therefore, the introduction of appropriate substituents on the aromatic ring structure will reduce, minimize, or eliminate the metabolic pathway. In certain embodiments, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are halogen or alkyl groups (by way of example only).

[1137] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioactive isotope) or labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[1138] The compounds described herein include isotopically labeled compounds which are identical to those depicted in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, e.g. 2 H. 3 h. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F. 36 In one aspect, an isotopically labeled compound as described herein, for example one in which a radioactive isotope such as 3 H and 14 C, which may be useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[1139] In additional or further embodiments, the compounds described herein are metabolized when administered to an organism in need thereof to produce a metabolite, which is then used to produce a desired effect, including a desired therapeutic effect.

[1140] The compounds described herein can be formed into and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, benzoic acid, benzoyl benzoate ... (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions). In some cases, the compounds described herein may be coordinated with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[1141] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates. Solvates comprise stoichiometric or non-stoichiometric solvents and can be formed during crystallization using pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of compounds described herein can be conveniently prepared or formed during the methods described herein. In addition, provided herein are compounds that can exist in the form of unsolvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to unsolvated forms.

[1142] In some embodiments, the SMSM has a molecular weight of at most about 2000 Daltons, 1500 Daltons, 1000 Daltons, or 900 Daltons. In some embodiments, the SMSM has a molecular weight of at least 100 Daltons, 200 Daltons, 300 Daltons, 400 Daltons, or 500 Daltons. In some embodiments, the SMSM does not contain a phosphodiester bond.

[1143] Methods for preparing compounds

[1144] The compounds described herein can be synthesized using standard synthetic techniques or using a combination of methods known in the art and methods described herein. Unless otherwise indicated, conventional mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacological methods can be used. Standard organic chemistry techniques can be used to prepare compounds, for example, those described in March's Advanced Organic Chemistry, 6th edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein can be employed, such as varying solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. Starting materials can be obtained from commercial sources or can be readily prepared. As an example only, a scheme for preparing SMSM is provided.

[1145] Suitable reference books and treatises that detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th ed., Wiley Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd Revised and Supplemented Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia"(1999)John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[1146] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio or carboxyl groups, where they are desired in the final product, to avoid their unwanted participation in the reactions. Detailed descriptions of suitable techniques for creating protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference).

[1147] SMSMs can be prepared using known techniques and further chemically modified, in some embodiments, to facilitate intranuclear transfer to, for example, splicing complex components, spliceosomes, or pre-mRNA molecules. One of ordinary skill in the art will understand standard medicinal chemistry methods for chemical modification for intranuclear transfer (e.g., to reduce charge, optimize size, and / or alter lipophilicity).

[1148] Pharmaceutical composition

[1149] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the selected route of administration. For example, a summary of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[1150] The pharmaceutical composition can be a mixture of the SMSM described herein and one or more other chemical components (i.e., pharmaceutically acceptable ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[1151] The compositions described herein can be administered to a subject in a variety of ways, including parenteral, intravenous, intradermal, intramuscular, colonic, rectal, or intraperitoneal. In some embodiments, the small molecule splicing regulator or a pharmaceutically acceptable salt thereof is administered by intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection of the subject. In some embodiments, the pharmaceutical composition can be administered parenterally, intravenously, intramuscularly, or orally. The oral dosage form comprising the small molecule splicing regulator can be in any form suitable for oral administration, such as a liquid, tablet, capsule, or the like. The oral formulation can be further coated or treated to prevent or reduce its dissolution in the stomach. The compositions of the present invention can be administered to a subject using any appropriate method known in the art. Suitable formulations and delivery methods for the present invention are generally well known in the art. For example, the small molecule splicing regulators described herein can be formulated into a pharmaceutical composition with a pharmaceutically acceptable diluent, carrier, or excipient. The composition may contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, including pH adjusters and buffers, tonicity adjusters, wetting agents, etc., such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.

[1152] The pharmaceutical preparations described herein can be administered to a subject in a variety of ways by a variety of routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, oral, topical or transdermal routes of administration. The pharmaceutical preparations described herein include but are not limited to aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and immediate release and controlled release mixed formulations.

[1153] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation comprising the SMSM described herein is in the form of a capsule. In one aspect, the liquid dosage form for oral administration is in the form of an aqueous suspension or solution selected from, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[1154] For administration by inhalation, the SMSM described herein can be formulated as an aerosol, mist, or powder. For buccal or sublingual administration, the composition can take the form of tablets, lozenges, or gels formulated in a conventional manner. In some embodiments, the SMSM described herein can be prepared as a transdermal dosage form. In some embodiments, the SMSM described herein can be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In some embodiments, the SMSM described herein can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. In some embodiments, the SMSM described herein can be formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, colloid suppositories, or retention enemas.

[1155] Editing

[1156] Extensive post-transcriptional processing occurs prior to eukaryotic pre-mRNA maturation and export from the nucleus to the cytoplasm, including the addition of a 7-methylguanosine cap at the 5' end, cleavage and addition of a poly-A tail at the 3' end, and removal of intervening sequences or introns by the spliceosome. The vast majority of higher eukaryotic genes contain multiple introns, which are spliced ​​with high accuracy and fidelity to maintain the reading frame of the exons. Pre-mRNA splicing utilizes recognition of intron and exon boundaries and short internal consensus sequences by a series of small nuclear ribonucleoprotein (snRNP) complexes (e.g., snRNP U1, U2, U4, U5, U6, U11, U12m U4atc, and U6atc) and a large number of proteins, including spliceosomal proteins and positively and negatively acting splicing regulators.

[1157] Proteins containing serine-arginine (SR)-rich domains generally function to promote constitutive splicing. They can also regulate alternative splicing by binding to intronic or exonic splicing enhancer (ISE) or ESE sequences, respectively. Other pre-mRNA-binding proteins, such as hnRNPs, regulate splicing by binding to intronic or exonic splicing suppressor (ISS or ESS) sequences and can also act as general splicing regulators. The SR protein family is a class of at least 10 proteins that, in addition to RNA binding, also possess characteristic serine / arginine-rich domains. SR proteins are generally believed to enhance splicing by simultaneously binding to U170K, a core component of the U1 snRNP, at the 5' splice site and U2AF35 at the 3' splice site, thereby bridging the two ends of the intron. Although this specialized function of SR proteins may seem redundant, since any single SR protein can ensure constitutive splicing of a pre-mRNA, the roles of various SR proteins in the alternative splicing of specific pre-mRNAs are distinct, in part due to their ability to recognize and bind to unique consensus sequences. Phosphorylation of the RS domain of SR proteins can lead to regulation of their protein interactions, RNA binding, localization, trafficking, and role in alternative splicing. Several cellular kinases have been identified that phosphorylate SR proteins, including SR protein kinases (SRPKs), Cdc2-like kinases (Clks), pre-mRNA processing mutant 4 (PRP4), and topoisomerase I. Proper function of SR proteins may require optimal phosphorylation, as both hypophosphorylation and hyperphosphorylation of the RS domain may be detrimental to their role in constitutive and alternative splicing.

[1158] In higher eukaryotes, most genes include one or more introns, which result in exon splicing together to generate mature mRNA and microRNA (miRNA). In the host cell nucleus, pre-mRNA splicing is to remove introns from pre-mRNA and exons are linked together to generate mature mRNA and pre-miRNA, which are then exported to cytoplasm to translate into the mechanism of polypeptide gene products. The splicing of pre-mRNA can occur in cis, where two exons are from two adjacent co-transcribed sequences, or trans, when two exons are from different pre-mRNA transcripts. The ratio of different protein products (isoforms) may be due to the frequency of alternative splicing events in pre-mRNA, which results in different numbers of different splice variants. In some embodiments, the alternative splicing of pre-mRNA may result in 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 protein isoforms being expressed.

[1159] Abnormalities in splicing are thought to contribute to approximately half of all genetic diseases. Aberrant splicing due to mutations in consensus sequences involved in exon-intron boundary recognition contributes to up to 15% of genetic disorders. Furthermore, defects in the splicing system itself, caused by loss or gain of function of splicing factors and regulators, contribute to a wide range of human diseases, from cancer to neurodegeneration. Both constitutive and alternative splicing are regulated by upstream signaling pathways. This regulation can be essential during development, in the tissue-specific expression of certain isoforms, during the cell cycle, and in response to external signaling molecules.

[1160] Alternative splicing allows a single gene to express different mRNA isoforms, thus playing a major role in promoting cellular complexity in higher eukaryotes without the need for genome expansion. Splicing can also be regulated by upstream signaling pathways. For example, upstream signaling pathways can regulate alternative splicing and increase or decrease the expression levels of different mRNA isoforms.

[1161] Alternative splicing events are highly regulated by a variety of splicing factors in a tissue type, developmental stage, and signal transduction dependent manner. In addition, the non-mutational causes of splicing defects and the defects of the splicing system itself, such as due to the loss / acquisition of splicing factor functions or their relative stoichiometry, have led to a variety of human diseases from cancer to neurodegenerative diseases. In many diseases, the disease state is caused by the change in the ratio of different isoforms of two or more proteins expressed by a gene. In some embodiments, the change in the protein product ratio is due to the change in the frequency of the alternative splicing events in the pre-mRNA, causing the ratio of the splice variants produced to change. In some embodiments, the alternative splicing of the pre-mRNA may result in 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 kinds of protein isoforms being expressed. In some embodiments, the change in the splice variant ratio is caused by a genetic mutation.

[1162] In eukaryotes, the vast majority of splicing processes are catalyzed by the spliceosome, an RNA-protein complex that emerges at a distinct step and, in addition to the five spliceosomal snRNAs, may contain a subset of hundreds of different proteins. These factors determine the precise positioning of the spliceosome relative to the 5' and 3' splice site sequences. The need for so many factors reflects the observation that exon recognition can be influenced by many pre-mRNA features, such as exon length, sequence identity, the presence of enhancer and silencer elements, the strength of upstream splicing signaling, promoter structure, as well as RNA synthesis rate, secondary and tertiary RNA structure.

[1163] All mammalian diseases are ultimately mediated by the transcriptome. As long as messenger mRNA (mRNA) is part of the transcriptome and all protein expression is derived from mRNA, it is possible to intervene in protein-mediated diseases by modulating the expression of related proteins and, in turn, by regulating the translation of corresponding upstream mRNAs. However, mRNA is only a small part of the transcriptome: other transcribed RNAs also directly regulate cell biology through the structure and function of RNA structures (e.g., ribonucleoproteins) and through protein expression and action (including but not limited to microRNAs (miRNAs), long noncoding RNAs (lncRNAs), long intergenic noncoding RNAs (lincRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), small Cajal body-specific RNAs (scaRNAs), piwi-interacting RNAs (piRNAs), competing endogenous RNAs (ceRNAs), and pseudogenes). Drugs that intervene at this level have the potential to modulate any and all cellular processes. In most cases, existing therapeutic approaches (such as antisense RNA or siRNA) have not yet overcome significant challenges such as drug delivery, absorption, target organ distribution, pharmacokinetics, and cellular penetration. In contrast, small molecules have a long history of successfully overcoming these obstacles, and these properties make them suitable for use as drugs, which can be easily optimized through a series of analogs to overcome these challenges. In stark contrast, the use of small molecules as RNA ligands for therapeutic benefit has received little attention from the drug discovery community.

[1164] The DNA sequence in the chromosome is transcribed into pre-mRNA, which contains coding regions (exons) and usually also contains intervening non-coding regions (introns). Introns are removed from the pre-mRNA by splicing. Pre-mRNA splicing is carried out by a two-step mechanism. In the first step, the 5' splice site is cut to obtain a "free" 5' exon and a lariat intermediate. In the second step, the 5' exon is connected to the 3' exon and the intron is released as a lariat product. These steps are catalyzed in a complex of small nuclear ribonucleoproteins and proteins called spliceosomes.

[1165] In most cases, the splicing reaction occurs within the same pre-mRNA molecule, which is called cis-splicing. Splicing between two independently transcribed pre-mRNAs is called trans-splicing.

[1166] Introns are parts of eukaryotic DNA that are inserted between the coding portions of the DNA, or "exons." Introns and exons are transcribed into RNA, which is called a "primary transcript, precursor to mRNA" (or "pre-mRNA"). Introns can be removed from pre-mRNA so that the native protein encoded by the exons can be produced (as used herein, the term "native protein" refers to a naturally occurring, wild-type or functional protein). The removal of introns from pre-mRNA and the subsequent joining of exons occurs during the splicing process.

[1167] The splicing process is a series of reactions that occur on RNA after transcription but before translation and is mediated by splicing factors. Thus, "pre-mRNA" may be an RNA that contains both exons and introns, and mature mRNA ("mRNA") may be an RNA that has had introns removed and exons linked together in sequence so that a protein can be translated from it by the ribosome.

[1168] Introns can be defined by a set of "splicing elements", which are part of the splicing system, may be required for splicing, and are relatively short, conserved RNA segments that bind various splicing factors that carry out the splicing reaction. Thus, each intron is defined by a 5' splice site, a 3' splice site, and a branch point located between them. Splicing elements also include exonic splicing enhancers and silencers located in exons, and intronic splicing enhancers and silencers located in introns at a certain distance from the splice sites and branch points. In addition to splice sites and branch points, these elements also control optional abnormal and constitutive splicing.

[1169] The initial RNA transcript (pre-mRNA) of most eukaryotic genes is retained in the cell nucleus until non-coding intron sequences are removed by the spliceosome to produce mature messenger RNA (mRNA). The splicing that occurs varies, so the synthesis of alternative protein products from the same primary transcript may be influenced by tissue-specific or developmental signaling. It is believed that a large proportion of human genetic diseases, including many cancers, are caused by deviations from the normal pattern of pre-mRNA splicing. The spliceosome is a complex that contains ribonucleoprotein (snRNP) particles composed of small nuclear RNAs and proteins. The snRNA component of the spliceosome can promote two transesterification reactions of splicing.

[1170] Two distinct spliceosomes coexist in most eukaryotes: the U2-dependent spliceosome, which catalyzes the removal of U2-type introns, and the less abundant U12-dependent spliceosome, which is present only in a subset of eukaryotes and splices the rare U12-type introns. The U2-dependent spliceosome is assembled from the U1, U2, U5, and U4 / U6 snRNPs, as well as numerous non-snRNP proteins. The U2 snRNP is recruited by two weakly binding protein subunits, SF3a and SF3b, during the first ATP-dependent step of spliceosome assembly. SF3b is composed of seven conserved proteins: PHF5α, SF3b155, SF3b145, SF3b130, SF3b49, SF3b14a, and SF3b10.

[1171] Splicing or RNA splicing generally refers to the editing of nascent precursor messenger RNA (pre-mRNA) transcripts into mature messenger RNA (mRNA). Splicing is a biochemical process that involves the removal of introns followed by exon ligation. A sequential transesterification reaction is initiated by a nucleophilic attack of a branched adenosine (branch point; BP) in a downstream intron on the 5' splice site (5'ss), which results in the formation of an intron lariat intermediate with a 2',5'-phosphodiester bond. This is followed by a 5'ss-mediated attack on the 3' splice site (3'ss), which results in the removal of the intron lariat and the formation of a spliced ​​RNA product.

[1172] Splicing can be regulated by various cis-acting elements and trans-acting factors. Cis-acting elements are sequences of mRNA and may include core consensus sequences and other regulatory elements. Core consensus sequences generally refer to conserved RNA sequence motifs, including 5'ss, 3'ss, polypyrimidine tracts and BP regions, which can play a role in recruiting the spliceosome. BP refers to a partially conserved sequence of pre-mRNA, usually less than 50 nucleotides upstream of the 3'ss. During the first step of the splicing reaction, BP reacts with the 5'ss. Other regulatory cis-acting elements may include exon splicing enhancers (ESEs), exon splicing silencers (ESSs), intron splicing enhancers (ISEs) and intron splicing silencers (ISSs). Trans-acting factors may be proteins or ribonucleoproteins that bind to cis-acting elements.

[1173] Splice site recognition and regulated splicing are primarily accomplished by two dynamic macromolecular machinery: the major (U2-dependent) and minor (U12-dependent) spliceosomes. Each spliceosome contains five snRNPs: the major spliceosome is comprised of the U1, U2, U4, U5, and U6 snRNPs (which process approximately 95.5% of all introns); and the minor spliceosome is comprised of the U11, U12, U4atac, U5, and U6atac snRNPs. Spliceosomal recognition of consensus sequence elements at the 5'ss, 3'ss, and BP sites is a step in the splicing pathway and can be regulated by the ESEs, ISEs, ESSs, and ISSs, which can be recognized by auxiliary splicing factors, including SR proteins and hnRNPs. Polypyrimidine tract binding protein (PTBP) can bind to the polypyrimidine tracts of introns and may promote RNA circularization.

[1174] Alternative splicing is a mechanism by which a single gene can ultimately produce several different proteins. Alternative splicing can be achieved through the coordinated action of a variety of different proteins associated with pre-mRNA (called "alternative splicing regulatory proteins") and results in the inclusion of unique alternative exons in mature mRNA. These alternative forms of gene transcripts can produce different isoforms of specific proteins. The pre-mRNA molecule sequence that can be bound to the alternative splicing regulatory protein can be found in introns or exons, including but not limited to ISS, ISE, ESS, ESE and polypyrimidine tracts. Many mutations can change splicing patterns. For example, mutations can be cis-acting elements and can be located at core consensus sequences (e.g., 5'ss, 3'ss and BP) or regulatory elements that regulate spliceosome recruitment, including ESE, ESS, ISE and ISS.

[1175] Cryptic splice sites, such as cryptic 5'ss and cryptic 3'ss, may refer to splice sites that are not normally recognized by the spliceosome and are therefore dormant. Cryptic splice sites may be recognized or activated, for example, by mutations in cis-acting elements or trans-acting factors, or structural configurations (e.g., bulges).

[1176] Splicing regulation

[1177] The present invention contemplates the use of small molecules with favorable pharmaceutical properties that regulate the splicing activity of a target RNA. Provided herein are small molecule splicing regulators (SMSMs) that regulate the splicing of a target polynucleotide. In some embodiments, a SMSM binds to and regulates a target RNA. In some embodiments, a library of SMSMs is provided herein that binds to and regulates one or more target RNAs. In some embodiments, the target RNA is an mRNA. In some embodiments, the target RNA is an mRNA of a non-coding RNA. In some embodiments, the target RNA is a pre-mRNA. In some embodiments, the target RNA is an hnRNA. In some embodiments, the small molecule regulates the splicing of a target RNA. In some embodiments, the small molecule provided herein regulates splicing at the sequence of the target RNA. In some embodiments, the small molecule provided herein regulates splicing at a hidden splice site sequence of the target RNA. In some embodiments, the small molecule provided herein binds to a target RNA. In some embodiments, the small molecule provided herein binds to a splicing complex component. In some embodiments, the small molecule provided herein binds to a target RNA and a splicing complex component.

[1178] Therefore, provided herein is a method for preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting a pre-mRNA molecule and / or other elements of a splicing system (e.g., in a cell) with a compound provided herein to prevent or induce a splicing event in a pre-mRNA molecule. The splicing event prevented or induced can be, for example, an abnormal splicing event, a constitutive splicing event, or an alternative splicing event.

[1179] Further provided herein is a method for identifying a compound capable of preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting the compound (e.g., within a cell) with splicing elements and / or factors involved in alternative, aberrant and / or constitutive splicing as described herein under conditions whereby a positive (prevention or induction of splicing) or negative (no prevention or induction of splicing) effect occurs and detecting the compound that produces a positive effect, and identifying the compound capable of preventing or inducing the splicing event.

[1180] In some embodiments, the small molecule compounds described herein in a pharmaceutically acceptable carrier prevent or induce alternative or abnormal splicing events in pre-mRNA molecules. As described above, the small molecule compounds provided herein are not antisense or antigene oligonucleotides. Tables 1A-1J and Tables 6-9 show the chemical structures and names of exemplary compounds and are not intended to be all-inclusive.

[1181] In some embodiments, a composition comprises a composition of a small molecule splicing regulator compound (SMSM); wherein the SMSM interacts with an unpaired protruding nucleobase of an RNA duplex, and wherein the RNA duplex comprises a splice site. Provided herein is a composition comprising a complex comprising a small molecule splicing regulator compound (SMSM) bound to an RNA duplex, wherein the SMSM interacts with an unpaired protruding nucleobase of an RNA duplex, and wherein the RNA duplex comprises a splice site. In some embodiments, the duplex RNA comprises an α-helix. In some embodiments, the unpaired protruding nucleobase is located on the outer portion of the helix of the duplex RNA. In some embodiments, the unpaired protruding nucleobase is located within the inner portion of the helix of the duplex RNA. In some embodiments, the SMSM forms one or more intermolecular interactions with the duplex RNA. In some embodiments, the SMSM forms one or more intermolecular interactions with the unpaired protruding nucleobase. In some embodiments, the intermolecular interaction is selected from the group comprising: ionic interaction, hydrogen bond, dipole-dipole interaction, or van der Waals interaction. In some embodiments, the first portion of the SMSM interacts with an unpaired protruding nucleobase of the first RNA strand of the RNA duplex. In some embodiments, the second portion of the SMSM interacts with one or more nucleobases of the second RNA strand of the RNA duplex, wherein the first RNA strand is not the second RNA strand. In some embodiments, the exchange rate of the unpaired protruding nucleobase from the interior of the helix of the duplex RNA to the exterior of the helix is ​​reduced. In some embodiments, the SMSM reduces the rotation rate of the unpaired protruding nucleobase. In some embodiments, the SMSM reduces the rotation rate of the unpaired protruding nucleobase around the phosphate backbone of the RNA strand of the RNA duplex. In some embodiments, the SMSM regulates the distance between the unpaired protruding nucleobase and the second nucleobase of the duplex RNA. In some embodiments, the SMSM reduces the distance between the unpaired protruding nucleobase and the second nucleobase of the duplex RNA. In some embodiments, the unpaired protruding nucleobase is located within the interior of the helix of the duplex RNA of the complex. In some embodiments, the SMSM reduces the size of the protrusion of the RNA duplex. In some embodiments, SMSM removes bulges from an RNA duplex. In some embodiments, SMSM stabilizes bulges from an RNA duplex. In some embodiments, SMSM modulates splicing at a splice site of an RNA duplex. In some embodiments, SMSM increases splicing at a splice site of an RNA duplex. In some embodiments, SMSM reduces splicing at a splice site of an RNA duplex. In some embodiments, unpaired bulge nucleobases have modulated base stacking within the RNA strand of an RNA duplex.In some embodiments, the unpaired bulge nucleobase has increased base stacking within the RNA strand of the RNA duplex. In some embodiments, the unpaired bulge nucleobase has reduced base stacking within the RNA strand of the RNA duplex. In some embodiments, SMSM is not an aptamer. In some embodiments, the RNA duplex comprises pre-mRNA. In some embodiments, in the absence of SMSM, the unpaired bulge nucleobase is free to rotate around the phosphate backbone of the RNA strand of the RNA duplex.

[1182] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM modulates splicing at an IC of less than 50 nM. 50 Killing the cell. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM regulates splicing at a splicing site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA, and wherein the total amount of the mRNA is increased by at least about 10% compared to the total amount of mRNA encoding the target protein or functional RNA produced in a control cell. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM regulates splicing at a splicing site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA, and wherein the total amount of the mRNA, the target protein, and / or the functional RNA is at least 10% less than the total amount of the mRNA, the target protein, and / or the functional RNA in a control cell.

[1183] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM modulates splicing at a splice site sequence of a pre-mRNA encoding a first mRNA isoform and a second mRNA isoform associated with a disease or condition, wherein the total amount of the first mRNA isoform is reduced by at least about 10% compared to the total amount of the first mRNA isoform in a control cell, and / or the total amount of the second mRNA isoform is increased by at least about 10% compared to the total amount of the first mRNA isoform in a control cell. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, the cell comprising an amount of a first mRNA isoform and an amount of a second mRNA isoform present in the cell; wherein the ratio of the first mRNA isoform to the second mRNA isoform is reduced by at least 1.2-fold; wherein the first mRNA and the second mRNA are encoded by a pre-mRNA comprising a splice site sequence, and wherein the first mRNA isoform is associated with the disease or condition and the second mRNA isoform.

[1184] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the SMSM modulates exon inclusion, exon exclusion, pseudoexon inclusion, intron retention, or splicing at a cryptic splice site of the polynucleotide, and wherein the SMSM modulates splicing of the splice site sequence. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the splice site sequence comprises a splice site sequence selected from the group consisting of splice site sequences of Table 2A, Table 2B, Table 2C, or Table 2D. A method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises a sequence selected from the group consisting of GGAguaag and AGAguaag. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises at least one bulge nucleotide at the -3, -2, -1, +1, +2, +3, +4, +5, or +6 position of the splice site sequence. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises a mutant nucleotide at the -3, -2, -1, +1, +2, +3, +4, +5, or +6 position of the splice site sequence.

[1185] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of: NGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U, G, or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c, or g; k is g or u. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of: NNBgunnnn, NNBhunnnn, or NNBgvnnnn; wherein N or n is A, U, G, or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c, or g; k is g or u. In some embodiments, the splice site sequence comprises a sequence selected from the group consisting of: NNBgurrrn, NNBguwwdn, NNBguvmvn, NNBguvbbn, NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, or NNBgvdnvn; wherein N or n is A, U, G, or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c, or g; k is g or u. In some embodiments, the nucleotides at positions -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence are bulge nucleotides. In some embodiments, the nucleotides at positions -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence are mutant nucleotides. In some embodiments, the splice site sequence comprises a sequence selected from the group consisting of a splice site sequence of Table 2A, Table 2B, Table 2C, or Table 2D.

[1186] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the polynucleotide encodes a gene selected from the group consisting of Table 2A, Table 2B, Table 2C, or Table 2D. In some embodiments, the gene is SMN2. In some embodiments, regulating splicing of the polynucleotide comprises inhibiting skipping of exon 7. In some embodiments, the gene is DMD. In some embodiments, regulating splicing of the polynucleotide comprises promoting skipping of exon 51.

[1187] In addition, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell; wherein the SMSM interacts with an unpaired bulge nucleobase of an RNA duplex in the cell; wherein the duplex RNA comprises a splice site sequence; and wherein the SMSM regulates splicing of the RNA duplex. In some embodiments, a method of regulating the relative position of a first nucleobase relative to a second nucleobase, wherein the first nucleobase and the second nucleobase are within a duplex RNA, the method comprising contacting a small molecule splicing modulator compound (SMSM) with the duplex RNA or a pharmaceutically acceptable salt thereof, wherein the first nucleobase is an unpaired bulge nucleobase of the RNA duplex; wherein the duplex RNA comprises a splice site sequence.

[1188] In some embodiments, the duplex RNA comprises a spiral. In some embodiments, prior to contact with SMSM, the protruding nucleobase is located on the outer portion of the spiral of the duplex RNA. In some embodiments, SMSM forms one or more intermolecular interactions with the duplex RNA. In some embodiments, SMSM forms one or more intermolecular interactions with the unpaired protruding nucleobase. In some embodiments, the intermolecular interaction is selected from the group comprising: ionic interaction, hydrogen bonding, dipole-dipole interaction, or van der Waals interaction. In some embodiments, the exchange rate of the unpaired protruding nucleobase from the interior of the spiral of the duplex RNA to the outer portion of the spiral is reduced. In some embodiments, the rotation rate of the unpaired protruding nucleobase is reduced. In some embodiments, the rotation rate of the unpaired protruding nucleobase around the phosphate backbone of the RNA chain of the RNA duplex is reduced. In some embodiments, after contact with SMSM, the distance between the unpaired protruding nucleobase and the second nucleobase of the duplex RNA is modulated. In some embodiments, the distance between the unpaired protruding nucleobase and the second nucleobase of the duplex RNA is reduced. In some embodiments, the unpaired bulge nucleobase is located within the inner portion of the helix of the duplex RNA. In some embodiments, the size of the bulge of the RNA duplex is reduced. In some embodiments, the bulge of the RNA duplex is removed or maintained. In some embodiments, splicing at the splice site of the RNA duplex is promoted. In some embodiments, after exposure to SMSM, the base stacking of the unpaired bulge nucleobase within the RNA strand of the RNA duplex is increased. In some embodiments, the distance between the unpaired bulge nucleobase and the second nucleobase of the duplex RNA is increased or maintained. In some embodiments, after exposure to SMSM, the bulge of the RNA duplex is stabilized. In some embodiments, the unpaired bulge nucleobase is located on the outer portion of the helix of the duplex RNA. In some embodiments, the size of the bulge of the RNA duplex is increased. In some embodiments, splicing at the splice site of the RNA duplex is inhibited. In some embodiments, splicing is inhibited at the splice site. In some embodiments, after exposure to SMSM, the base stacking of the unpaired bulge nucleotides within the RNA strand of the RNA duplex is reduced. In some embodiments, the RNA duplex comprises pre-mRNA.

[1189] In some embodiments, a method of treating a subject having a tumor, comprising administering a small molecule splicing modulator compound (SMSM) to the subject, wherein the size of the tumor is reduced. In some embodiments, a method of treating a subject having a tumor, comprising administering a small molecule splicing modulator compound (SMSM) to the subject, wherein the growth of the tumor is inhibited by at least 20. In some embodiments, a method of treating, preventing, and / or delaying the progression of a condition or disease, comprising administering a small molecule splicing modulator compound (SMSM) to a subject, wherein the SMSM modulates the splicing of a splice site of a polynucleotide in a cell of the subject, wherein the condition or disease is associated with the splicing of the splice site. In some embodiments, the subject has a disease or condition. In some embodiments, a method of treating a subject having a disease or condition, comprising administering a small molecule splicing modulator compound (SMSM) to a subject having a disease or condition selected from the group consisting of: a disease of Table 2A, Table 2B, Table 2C, or Table 2D. In some embodiments, a method of treating a subject having a disease or condition comprises administering a small molecule splicing modulator compound (SMSM) to the subject having the disease or condition, wherein the SMSM is selected from the group consisting of: the SMSM of Tables 1A-1J and Tables 6-9. In some embodiments, a method of treating a subject having a disease or condition comprises administering a small molecule splicing modulator compound (SMSM) to the subject having the disease or condition, wherein the SMSM binds to a pre-mRNA comprising a splice site sequence selected from the group consisting of: the splice site sequences of Table 2A, Table 2B, Table 2C, or Table 2D. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the polynucleotide is a pre-mRNA. In some embodiments, the disease or condition is spinal muscular atrophy. In some embodiments, the disease or condition is Duchenne muscular dystrophy. In some embodiments, the method further comprises administering an additional therapeutic molecule to the subject. In some embodiments, the SMSM is a compound described herein. In some embodiments, the SMSM is selected from the group consisting of the SMSMs of Tables 1A-1J and Tables 6-9.

[1190] In some embodiments, regulating splicing comprises preventing, inhibiting or reducing splicing at a splice site sequence of the polynucleotide. In some embodiments, regulating splicing comprises enhancing, promoting or increasing splicing at a splice site sequence of the polynucleotide. In some embodiments, the splice site sequence is a 5' splice site sequence, a 3' splice site sequence, a branch point splice site sequence or a cryptic splice site sequence. In some embodiments, the splice site comprises a mutation, the splice site comprises a bulge, the splice site comprises a mutation and a bulge, the splice site does not comprise a mutation, the splice site does not comprise a bulge or the splice site does not comprise a mutation and does not comprise a bulge. In some embodiments, the bulge is a bulge caused by a mutation. In some embodiments, the bulge nucleotide is a mutant nucleotide. In some embodiments, the bulge nucleotide is not a mutant nucleotide. In some embodiments, SMSM reduces the K of a splicing complex component to a polynucleotide. D In some embodiments, SMSM increases the K of splicing complex components to polynucleotides. D. In some embodiments, SMSM inhibits the binding of splicing complex components to polynucleotides at a splice site sequence, upstream of a splice site sequence, or downstream of a splice site sequence. In some embodiments, SMSM promotes the binding of splicing complex components to polynucleotides at a splice site sequence, upstream of a splice site sequence, or downstream of a splice site sequence. In some embodiments, the polynucleotide is RNA. In some embodiments, the RNA is pre-mRNA. In some embodiments, the RNA is a heterogeneous nuclear RNA. In some embodiments, the splice site sequence is a 5' splice site sequence, a 3' splice site sequence, a branch point (BP) splice site sequence, an exon splicing enhancer (ESE) sequence, an exon splicing silencer (ESS) sequence, an intron splicing enhancer (ISE) sequence, an intron splicing silencer (ISS) sequence, a polypyrimidine tract sequence, or any combination thereof. In some embodiments, the length of the polynucleotide is at least 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 250, 500, 750, 1,000, 2,000, 5,000, 10,000, 50,000, 100,000, 500,000, or 1,000,000 nucleotides. In some embodiments, the SMSM binds to the splice site sequence of the polynucleotide. In some embodiments, the SMSM interacts with the protrusion of the splice site sequence of the polynucleotide. In some embodiments, the polynucleotide comprises a cis-acting element sequence. In some embodiments, the cis-acting element sequence does not comprise a protrusion. In some embodiments, the cis-acting element sequence does not comprise a mutation. In some embodiments, the cis-acting element sequence includes a mutation, a protrusion, or a combination thereof 1-1000 nucleobases upstream or 1-1000 nucleobases downstream of the cis-acting element sequence. In some embodiments, the cis-acting element sequence comprises a regulatory element sequence, and the regulatory element sequence regulates the recruitment of splicing complex components to the polynucleotide. In some embodiments, the cis-acting element sequence comprises a regulatory element sequence, and the regulatory element sequence regulates the recruitment of spliceosomes to the polynucleotide. In some embodiments, the regulatory element sequence comprises an exon splicing enhancer (ESE) sequence, an exon splicing silencer (ESS) sequence, an intron splicing enhancer (ISE) sequence, an intron splicing silencer (ISS) sequence, and combinations thereof. In some embodiments, SMSM binds to the splicing complex components.In some embodiments, the splicing complex components are 9G8, A1 hnRNP, A2 hnRNP, ASD-1, ASD-2b, ASF, B1 hnRNP, C1 hnRNP, C2 hnRNP, CBP20, CBP80, CELF, F hnRNP, FBP11, Fox-1, Fox-2, GhnRNP, H hnRNP, hnRNP 1, hnRNP 3, hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulatory protein (KSRP), L hnRNP, M hnRNP, mBBP, muscle-blind protein (MBP), like)(MBNL), NF45, NFAR, Nova-1, Nova-2, nPTB, P54 / SFRS11, polypyrimidine tract binding protein (PTB), PRP19 complex protein, R hnRNP, RNPC1, SAM68, SC35, SF, SF1 / BBP, SF2, SF3 a, SF3B, SFRS10, Sm protein, SR protein, SRm300, SRp20, SRp30c, SRP35C, SRP36, SRP38, SRp40, SRp55, SRp75, SRSF, STAR, GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR, TRA2, TRA2a / b, U hnRNP, U1snRNP, U11 snRNP, U12 In some embodiments, the splicing complex components include RNA. In some embodiments, the splicing com...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is –O-, –S- or –NR 3 -; Z is CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and is selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

2. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is –O-, –S- or –NR 3 -; Z is CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are identical and are selected from hydrogen and deuterium; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

3. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is –O-, –S- or –NR 3 -; Z is CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

4. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is –O-, –S- or –NR 3 -; Z is CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, –CN, substituted or unsubstituted C1-C4 alkyl, –CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, or -C1-C4 alkylene-OR 1 ; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

5. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and is selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

6. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

7. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

8. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; is a single bond or a double bond; X is and Z is C; or X is and Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 (i) are the same and are selected from hydrogen and deuterium, (ii) are the same and are selected from the group consisting of: F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl, or (iii) is different and is selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

9. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; is a single bond or a double bond; X is and Z is C; or X is and Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are identical and are selected from hydrogen and deuterium; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

10. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; is a single bond or a double bond; X is and Z is C; or X is and Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

11. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; is a single bond or a double bond; X is and Z is C; or X is and Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

12. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R A For hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 , –S(=O)R 1 、–S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is Z is N or CR 2 ; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C2-C5 heterocycloalkyl; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are identical and are selected from hydrogen and deuterium; a is 0 or 1; b is 0; c is 1; and d is 0 or 1.

13. The compound according to claim 12 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (Ia):

14. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (Ib):

15. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (Ic):

16. The compound according to claim 12 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (Id):

17. The compound according to claim 12 or 16, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (Ie):

18. The compound according to claim 12 or 16, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (If):

19. The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted aryl group.

20. The compound according to claim 19 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted by 1, 2 or 3 substituents independently selected from the following: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 21 . The compound according to claim 20 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

22. The compound according to claim 21 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl group, wherein if the aryl group is substituted, it is substituted with 1 or 2 substituents independently selected from the following: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

23. The compound according to claim 21 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, wherein if the heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from the following: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

24. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: Ring Q is Each R Q independently selected from hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CF 3、 –OCH3, –OCH2CH3, –CH2OCH3, –OCH2CH2CH3 and –OCH(CH3)2; Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 25 . The compound according to claim 1 , or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted heteroaryl group. 26 . The compound according to claim 25 , or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl group. 27 . The compound according to claim 26 , or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl group.

28. The compound according to claim 27 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a 6-membered monocyclic heteroaryl selected from the following: Ring Q is Each R Q independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3 and -OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

29. The compound according to claim 24 or 28, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R Q are independently selected from hydrogen, -F, -Cl, -CN, -OH, -CH3, -CF3 or -OCH3.

30. The compound according to claim 24 or 28, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring P is a substituted or unsubstituted heteroaryl group.

31. The compound according to claim 30, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring P is a heteroaryl group selected from the group consisting of: in Each R B independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and m is 1, 2 or 3.

32. The compound according to claim 30, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring P is a heteroaryl group selected from the group consisting of: in Each R B independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and m is 1, 2 or 3.

33. The compound according to claim 31 or 32, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R B are independently selected from hydrogen, deuterium, -F, -Cl, -CN, -CH3, -CF3, -OH or -OCH3.

34. The compound according to claim 33, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R B is independently -F or -OCH3.

35. The compound according to claim 31 or 32, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R B1 Selected from hydrogen, deuterium, –CH3, –CF3 or –CD3.

36. The compound according to claim 31 or 32, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein m is 0 or 1.

37. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-naphthyl substituted at position 3 by 0, 1 and 2 substituents independently selected from the following: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

38. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of:

39. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of:

40. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of:

41. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of: in R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C1-C3 alkylene group.

43. The compound according to claim 42, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2-.

44. The compound according to claim 42, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2CH2-.

45. The compound according to claim 42, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2CH2CH2-.

46. ​​The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C1-C2 heteroalkylene.

47. The compound according to claim 46, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2OCH2-.

48. A compound according to any one of claims 13-15 and 19-41, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2O-, wherein O is attached to a moiety having R 18 The carbon atom of the group.

49. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C3-C8 cycloalkylene or a substituted or unsubstituted C2-C3 alkenylene. 50 . The compound according to claim 49 , or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C 3 -C 8 cycloalkylene group.

51. The compound according to claim 50, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is cyclopropylene.

52. The compound according to claim 49, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C2-C3 alkenylene.

53. The compound according to claim 52, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH=CH-.

54. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl or substituted or unsubstituted C2-C4 heterocycloalkyl.

55. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl or azetidinyl.

56. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl.

57. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl.

58. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl or oxetanyl.

59. The compound according to any one of claims 1-53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2OH, -CH2CN, -CHF2, -CF3 or cyclopropyl.

60. The compound according to any one of claims 1-53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl.

61. The compound according to any one of claims 1-53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is -CH3, -CH2CH3, -CH2F, -CHF2 or -CF3.

62. A compound according to any one of claims 1-53, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen.

63. A compound according to any one of claims 1-15 or 19-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 One or more of the following are independently selected from F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

64. A compound according to any one of claims 1-15 or 19-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 One or more of are independently selected from F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2 and –CH2CF3.

65. A compound according to any one of claims 1-15 or 19-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 One or more of are independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3.

66. A compound according to any one of claims 1-15 or 19-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 For hydrogen.

67. A compound according to any one of claims 1-12 or 16-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 One or more of the following are independently selected from F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

68. A compound according to any one of claims 1-12 or 16-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 One or more of are independently selected from F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2 and –CH2CF3.

69. A compound according to any one of claims 1-12 or 16-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 One or more of are independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3.

70. A compound according to any one of claims 1-12 or 16-62, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 For hydrogen.

71. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 2 It is hydrogen, –CH3 or –OCH3.

72. The compound according to claim 71 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 2 For hydrogen.

73. A compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R A is hydrogen, F, Cl, –CN, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –OH, –OCH3, –OCH2CH3, –OCF3, –CH2F, –CHF2, or –CF3.

74. A compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R A is hydrogen, F, Cl, –CN, –CH3, –OH, –OCH3, –OCF3, –CH2F, –CHF2 or -CF3.

75. A compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R A is hydrogen, F, Cl, –CN, –CH3 or –OCH3.

76. A compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R A It is hydrogen, F, Cl or -CH3.

77. A compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R A For hydrogen.

78. A compound according to any one of claims 12 to 77, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 All are hydrogen.

79. A compound according to any one of claims 12-77, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 All are deuterium.

80. A compound according to any one of claims 12-79, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl.

81. A compound according to any one of claims 12-79, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 are independently hydrogen, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –CH2OCH3, –CH2F, –CHF2 or –CF3.

82. A compound according to any one of claims 12-79, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 are independently hydrogen, –CH3, –CH2CH3, –CH2OH, –CH2OCH3, –CH2F, –CHF2 or –CF3.

83. A compound according to any one of claims 12-79, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 For hydrogen.

84. A compound according to any one of claims 12-79, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 It is -CH3.

85. A compound or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound is selected from Tables 1A-1J and Tables 6-9.

86. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is F.

87. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the above comprises fluorine.

88. A pharmaceutical composition comprising a compound according to any one of claims 1 to 87 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

89. A method of treating a condition or disease comprising administering to a subject in need thereof a compound as described in any one of claims 1-87, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

90. Use of a compound according to any one of claims 1 to 87 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating a disorder or disease.

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