Methods and compositions for modulating splicing

Abstract

Described herein are small molecule splicing regulator compounds that regulate the splicing of mRNA, such as pre-mRNA, encoded by a gene, pharmaceutical compositions comprising the same, and methods of using the small molecule splicing regulator compounds to regulate splicing and treat diseases and conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Provisional Application No. 62 / 801,206, filed February 5, 2019, U.S. Provisional Application No. 62 / 801,231, filed February 5, 2019, U.S. Provisional Application No. 62 / 801,208, filed February 5, 2019, U.S. Provisional Application No. 62 / 801,212, filed February 5, 2019, U.S. Provisional Application No. 62 / 801,236, filed February 5, 2019, This application claims the benefit of U.S. Provisional Application No. 62 / 801,387, filed February 5, U.S. Provisional Application No. 62 / 800,691, filed February 4, 2019, U.S. Provisional Application No. 62 / 800,720, filed February 4, 2019, and U.S. Provisional Application No. 62 / 800,779, filed February 4, 2019, the disclosures of which are incorporated herein by reference in their entireties. [Background technology]

[0002] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). Intron sequences are then removed from the pre-mRNA by a process called splicing, resulting in a mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs that code for distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing.

[0003] Current therapeutic approaches to induce and control mRNA expression require methods such as gene therapy, genome editing, or broad oligonucleotide technologies (antisense, RNAi, etc.). Gene therapy and genome editing act upstream of mRNA transcription by affecting the DNA code and thereby altering mRNA expression. Oligonucleotides regulate the action of RNA by standard base / base hybridization. The appeal of this approach lies in the design of the basic pharmacophore of the oligonucleotide, which can be defined in a very simple manner by known base pairing with the target sequence object. Each of these therapeutic approaches suffers from substantial technical, clinical, and regulatory challenges. Some limitations of oligonucleotides (e.g., antisense, RNAi) as therapeutic agents include unfavorable pharmacokinetics, lack of oral bioavailability, and lack of blood-brain barrier penetration, the latter of which prevents delivery to the brain or spinal cord after administration of parenteral agents for the treatment of diseases (e.g., neurological diseases, brain cancer). In addition, oligonucleotides are not effectively taken up into solid tumors without complex delivery systems such as lipid nanoparticles. Furthermore, the majority of oligonucleotides taken up into cells and tissues remain in non-functional compartments (eg, endosomes) and do not gain access to the cytosol and / or nucleus where their targets are located.

[0004] In addition, to anneal to the target, oligonucleotide therapy requires access to the target's complementary base pairs. This approach assumes that pre-mRNA sequences exist as linear RNA in cells. However, pre-mRNA is rarely linear and has complex secondary and tertiary structures. In addition, cis-acting elements (e.g., protein binding elements) and trans-acting factors (e.g., splicing complex components) may generate additional secondary and tertiary complexities (e.g., by binding to pre-mRNA). These characteristics may be limitations of efficacy and effectiveness for oligonucleotide therapy. Summary of the Invention

[0005] The novel small molecule splicing regulators (SMSMs) described herein do not suffer from the above limitations, nor from the structural and steric hindrances that greatly limit oligonucleotide therapy (e.g., by blocking hybridization to pre-mRNA). Small molecules have been essential in elucidating the mechanism, control, and function of many cellular processes, including DNA replication, transcription, and translation. Although several recent reports have described screening of small molecule effectors of splicing, only a few constitutive or alternative splicing regulators have been identified, and many of the small molecule inhibitors lack specificity, lack selectivity, lack potency, exhibit toxicity, or are not orally available. Targeting the RNA transcriptome with small molecule regulators represents an undeveloped therapeutic approach to treat various RNA-mediated diseases. Thus, there remains a need for the development of small molecule RNA regulators useful as therapeutic agents. There is a need in the art for novel regulators of splicing or splicing-dependent processes. Provided herein are small molecule splicing regulators and uses thereof that meet this need.

[0006] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2-C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1-C 4 heteroalkyl; R 15 and R 18 are the same and are selected from hydrogen and deuterium, a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0007] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same, F,-OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0008] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0009] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3- and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0010] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same and are selected from hydrogen and deuterium, a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0011] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2-C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3, substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same, F,-OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0012] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R AHydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0013] In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0014] In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R AHydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 or X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0015] In one embodiment, the compound of formula (I) has the structure of formula (Ia): [ka]

[0016] In one embodiment, the compound of formula (I) has the structure of formula (Ib): [ka]

[0017] In one embodiment, the compound of formula (I) has the structure of formula (Ic): [ka]

[0018] In one embodiment, the compound of formula (I) has the structure of formula (Id): [ka]

[0019] In one embodiment, the compound of formula (I) has the structure of formula (Ie): [ka]

[0020] In one embodiment, the compound of formula (I) has the structure of formula (If): [ka]

[0021] A compound of formula (II), [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same and are selected from hydrogen and deuterium, a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0022] A compound of formula (II), [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1-C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same, F,-OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0023] A compound of formula (II), [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0024] In one aspect, a compound having the structure of formula (II): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0025] In one embodiment, the compound of formula (II) has the structure of formula (IIa): [ka]

[0026] In one embodiment, the compound of formula (II) has the structure of formula (IIb): [ka]

[0027] In one embodiment, the compound of formula (II) has the structure of formula (IIc): [ka]

[0028] In one embodiment, the compound of formula (II) has the structure of formula (IIaa): [ka]

[0029] In one embodiment, the compound of formula (II) has the structure of formula (IIbb): [ka]

[0030] In one embodiment, the compound of formula (II) has the structure of formula (IIcc): [ka]

[0031] In one embodiment, the compound of formula (II) has the structure of formula (IId): [ka]

[0032] In one embodiment, the compound of formula (II) has the structure of formula (IIe): [ka]

[0033] In one embodiment, the compound of formula (II) has the structure of formula (IIf): [ka]

[0034] In one embodiment, the compound of formula (II) has the structure of formula (IIdd): [ka]

[0035] In one embodiment, the compound of formula (II) has the structure of formula (IIee): [ka]

[0036] In one embodiment, the compound of formula (II) has the structure of formula (IIff): [ka]

[0037] In one aspect, a compound having the structure of formula (III): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2or X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0038] In one aspect, a compound having the structure of formula (IV): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0039] Also provided herein is a method of modulating splicing, comprising contacting a cell with a compound described herein, wherein the compound modulates splicing of a splice site sequence of a pre-mRNA encoding an mRNA, the mRNA encoding a target protein or functional RNA.

[0040] Provided herein is a method of treating a disease or condition, the method comprising administering to a subject in need thereof a compound described herein, or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof.

[0041] Provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, and a pharma- ceutically acceptable excipient or carrier.

[0042] Also provided herein is the use of a compound described herein, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a condition or disease.

[0043] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein 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 OF THE PREFERRED EMBODIMENTS

[0044] Certain details of the present specification are described to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the following claims, the term "comprises" and variations thereof, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the disclosure as claimed.

[0045] 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 used in its sense including "and / or" unless the content clearly dictates otherwise.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled 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 this disclosure, suitable methods and materials are described below. definition

[0047] The terms "compound(s) of this disclosure", "compound(s) of the present disclosure", "small molecule stereoregulator(s)", "small molecule splicing modulator(s)", "steric regulator(s)", "splicing modulator(s)", "compound(s) that modify splicing" and "splicing-modifying compound(s)", "SMSM", or "small molecule that binds to target RNA" are used interchangeably herein and refer to the compounds disclosed herein, as well as to stereoisomers, tautomers, solvates, and salts (e.g., pharma- ceutically acceptable salts) thereof. The terms "compound(s) of this disclosure", "compound(s) of the present disclosure", "small molecule stereoregulator(s)", "small molecule splicing regulator(s)", "steric regulator(s)", "splicing regulator(s)", "compound(s) that modify splicing" and "compound(s) that are modifying splicing", "SMSM", or "small molecule that binds to target RNA" refer to a small molecule that binds to a cellular component (e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrate, lipid, cofactor, nutrient, and / or metabolite) and modulates the splicing of a target polynucleotide, e.g., a pre-mRNA. For example, SMSM can directly or indirectly bind to a target polynucleotide, e.g., an RNA (e.g., a pre-mRNA) with mutated, non-mutated, bulged, and / or aberrant splice sites, resulting in the modulation of splicing of the target polynucleotide. For example, SMSM can bind directly or indirectly to proteins, such as spliceosomal proteins or ribonucleoproteins, resulting in conformational regulation of the protein and regulation of splicing of the target RNA. For example, SMSM can bind directly or indirectly to spliceosomal components, such as spliceosomal proteins or snRNAs, resulting in conformational regulation of the spliceosomal and regulation of splicing of the target polynucleotide.These terms specifically exclude compounds that consist of oligonucleotides. These terms include small molecule compounds that can bind to one or more secondary or tertiary structural elements of target RNA. These sites include RNA triplexes, 3WJ, 4WJ, parallel Y junctions, hairpins, bulge loops, pseudoknots, internal loops, and other higher order RNA structural motifs.

[0048] The term "RNA" (ribonucleic acid) as used herein refers to naturally occurring or synthetic oligoribonucleotides, regardless of source (e.g., RNA may be produced by humans, animals, plants, viruses, or bacteria, or may be of synthetic origin), biological context (e.g., RNA may be in the nucleus, circulating in the blood, in vitro, in a cell lysate, or in isolated or pure form), or physical form (e.g., RNA may be in single-stranded, double-stranded, or triple-stranded form (including RNA-DNA hybrids), and may be expressed in any form, including but not limited to DNA, RNA, and / or RNA). The RNA may contain pigenetic, post-transcriptional natural, artificial (e.g., chemical or in vitro) or other modifications, may be bound to, for example, metal ions, small molecules, proteins such as chaperones, or cofactors, or may be in a denatured, partially denatured, or folded state, including any natural or non-natural secondary or tertiary structure, such as a quadruplex, hairpin, triplex, three-way junction (3WJ), four-way junction (4WJ), parallel Y junction, hairpin, bulge loop, pseudoknot, and internal loop, and any transient form or structure adopted by the RNA. In some embodiments, the RNA is 20, 22, 50, 75, or 100 or more nucleotides in length. In some embodiments, the RNA is 250 or more nucleotides in length. In some embodiments, 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 length. In some embodiments, the RNA is 250-1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pre-transcript.In some embodiments, the RNA is non-coding RNA (ncRNA), messenger RNA (mRNA), microRNA (miRNA), ribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudogene, viral RNA, fungal RNA, parasitic RNA, or bacterial RNA.

[0049] As used herein, the term "target polynucleotide" or "target RNA" refers to any type of polynucleotide or RNA, respectively, that has a splice site that can be modulated by the small molecule compounds described herein. For example, a "target polynucleotide" or a "target RNA" can have a secondary or tertiary structure that can bind to the small molecule compounds described herein.

[0050] As used herein, "steric alteration," "steric modification," or "steric adjustment" refers to a change in the spatial orientation of chemical moieties relative to one another. Those skilled in the art will recognize steric mechanisms including, but not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsion, steric inhibition of resonance, and steric inhibition of protonation.

[0051] Any open valency appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0052] The definitions set forth herein apply regardless of whether the terms in question appear alone or in combination. It is contemplated that the definitions set forth herein can be added to form chemically relevant combinations, such as, for example, "heterocycloalkylaryl", "haloalkylheteroaryl", "arylalkylheterocycloalkyl", or "alkoxyalkyl". The last member of the combination is the radical that is bonded to the rest of the molecule. The other members of the combination are bonded to the bonded radical in reverse order relative to the literal sequence, for example, the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl radical substituted by an alkyl substituted by an aryl.

[0053] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the maximum number of substituents possible, i.e., replacement of one hydrogen to replacement of all hydrogens by substituents.

[0054] The term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur.

[0055] The term "substituent" means an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0056] The term "substituted" means that the specified group has one or more substituents. Any group may have multiple substituents, and when 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 has no substituents. The term "optionally substituted" means that the specified group is not substituted or is substituted with one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the maximum number of substituents possible, i.e., replacement of one hydrogen with a substituent to replacement of all hydrogens.

[0057] The following abbreviations are used throughout this specification: acetic acid (AcOH), ethyl acetate (EtOAc), butyl alcohol (n-BuOH), 1,2-dichloroethane (DCE), dichloromethane (CH 2 Cl 2 , DCM), diisopropylethylamine (Diipea), dimethylformamide (DMF), hydrogen chloride (HCl), methanol (MeOH), methoxymethyl bromide (MOMBr), N-methyl-2-pyrrolidone (NMP), methyl iodide (MeI), n-propanol (n-PrOH), p-methoxybenzyl (PMB), triethylamine (Et 3 N), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (Pd(dppf)Cl 2 ), sodium ethanethiolate (EtSNa), sodium acetate (NaOAc), sodium hydride (NaH), sodium hydroxide (NaOH), tetrahydropyran (THP), and tetrahydrofuran (THF).

[0058] As used herein, C 1 -C x is C 1 -C 2 , C 1 -C 3 ...C 1 -C x As just one example, "C 1 -C4 " indicates that there is a group containing from 1 to 4 carbon atoms within the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C 1 -C 4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0059] The term "oxo" refers to a ═O substituent.

[0060] The term "thioxo" refers to the =S substituent.

[0061] The terms "halo," "halogen," and "halide" are used interchangeably herein and mean fluoro, chloro, bromo, or iodo.

[0062] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the remainder of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C 1 -C 10 Similarly, for example, an alkyl containing up to 6 carbon atoms is referred to as C 1 -C 6 Alkyl. Alkyl (and other moieties defined herein) containing other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 2 -C 8 Alkyl, C 3 -C 8 Alkyl, and C 4 -C 8 Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is -CH(CH 3 ) 2 or -C(CH 3 ) 3 Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group. In some embodiments, an alkyl group is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 In some embodiments, alkyl is -CH 2 In some embodiments, alkyl is -CH 2 CH 2 In some embodiments, alkyl is -CH 2 CH 2 CH 2 -It is.

[0063] The term "alkoxy" refers to a group of the formula -OR a where R ais an alkyl radical as defined. Unless otherwise expressly stated herein, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0064] The term "alkylamino" refers to a group of the formula -NHR a or -NR a R a where R a is each independently an alkyl radical, as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0065] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR a 2 wherein R a refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R a is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH 2 , -C(CH 3 )=CH 2 , -CH=CHCH 3 , -C(CH 3 )=CHCH 3 , and -CH 2 CH=CH 2 Examples include:

[0066] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR awherein R a refers to the remainder of the alkynyl group. In some embodiments, R a is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH 3 , -C≡CCH 2 CH 3 , -CH 2 Examples include C≡CH.

[0067] The term "aromatic" refers to a planar ring having a delocalized electron system containing 4n+2 electrons, where n is an integer. An aromatic may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0068] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise expressly stated herein, the term "aryl" or the prefix "ar-" (e.g., in aralkyl) is intended to include an aryl radical that is optionally substituted. In some embodiments, an aryl group is partially reduced to form a cycloalkyl group, as defined herein. In some embodiments, an aryl group is fully reduced to form a cycloalkyl group, as defined herein.

[0069] The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogen atoms, specifically, fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms.

[0070] The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by the same or different halogen atom, specifically a fluoro atom. Examples of haloalkoxyl include monofluoro-, difluoro-, or trifluoro-methoxy, -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 of the hydrogen atoms of the alkoxy group are replaced by the same or different halogen atoms.

[0071] The term "bicyclic ring system" refers to two rings fused together through a common single or double bond (annealed bicyclic ring system), through an arrangement of three or more common atoms (bridged bicyclic ring system), or through a common single atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated, or aromatic. Bicyclic ring systems can contain heteroatoms selected from N, O, and S.

[0072] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. This term therefore distinguishes carbocyclic rings from "heterocyclic" or "heterocyclic" heterocycles in which the ring backbone contains at least one atom different from 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.

[0073] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) 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 which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3-10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3-10 carbon atoms, 3-8 carbon atoms, 3-6 carbon atoms, or 3-5 carbon atoms. Monocyclic cycloalkyl radicals 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 radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. Unless otherwise expressly stated in the specification, cycloalkyl groups may be optionally substituted.

[0074] The term "bridge" refers to any ring structure having two or more rings that includes a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the skeletal framework of the molecule and is connected to three or more other skeletal atoms. In some embodiments, the bridgehead atom is C, N, or P. In some embodiments, the bridge is a single atom or a chain of atoms connecting two bridgehead atoms. In some embodiments, the bridge is a valence bond connecting two bridgehead atoms. In some embodiments, the bridged ring system is a cycloalkyl. In some embodiments, the bridged ring system is a heterocycloalkyl.

[0075] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. If 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 fused heteroaryl ring may be replaced with 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.

[0076] The term "haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0077] The term "haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0078] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, a fluoroalkyl is 1 -C 6 In some embodiments, fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0079] The term "heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms is an atom 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 combinations thereof. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a C 1 -C 6 Heteroalkyl. Representative heteroalkyl groups include -OCH 2 OMe, -OCH 2 CH 2 OH, -OCH 2 CH 2 OMe, or -OCH 2 CH 2 OCH 2 CH 2 NH 2These include, but are not limited to:

[0080] The term "heteroalkylene" refers to an alkyl radical as described above in which one or more carbon atoms of the alkyl has been replaced with an O, N, or S atom. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain that connects the remainder of the molecule to a radical group. Unless stated otherwise specifically in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include -OCH 2 CH 2 O-, -OCH 2 CH 2 OCH 2 CH 2 O-, or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 Including, but not limited to, O-.

[0081] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise expressly stated in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocycloalkyls have 2-12 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring.In some embodiments, a heterocycloalkyl has 2-12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise expressly stated in this specification, a heterocycloalkyl group may be optionally substituted.

[0082] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (aka heteroaryls) and heterocycloalkyl rings (aka heterocyclic groups) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, with the heterocyclic groups each having 3-12 atoms in their ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, the heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compounds. Non-aromatic heterocyclic groups (aka heterocycloalkyls) contain rings having 3-12 atoms in the ring system, and aromatic heterocyclic groups contain rings having 5-12 atoms in the ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, and cyclohexyl. pyrinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, 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 quinolidinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where possible. For example, pyrrole-derived groups include both pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, imidazole-derived groups include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include 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.

[0083] The term "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryl include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, 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 pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 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 pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, the heteroaryl has 0-6 N atoms in the ring. In some embodiments, the heteroaryl has 1-4 N atoms in the ring. In some embodiments, the heteroaryl has 4-6 N atoms in the ring. In some embodiments, the heteroaryl has 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 has 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl has C 1 -C 9 In some embodiments, the monocyclic heteroaryl is C1 -C 5 In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C 6 -C 9 Heteroaryl. 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.

[0084] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded within or appended to a molecule.

[0085] The term "optionally substituted" or "substituted" means that the referenced group is an alkyl group selected from the group consisting of D, halogen, -CN, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -OH, -CO 2 H, -CO 2 Alkyl, -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH 2 , -NH(CH 3 ), -N(CH 3 )2 , -OH, -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 Alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1 -C 4 Alkyl), -S(=O) 2 N(C 1 -C 4 Alkyl) 2 , C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Fluoroalkyl, C 1 -C 4 Heteroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, -SC 1 -C 4 Alkyl, -S(=O)C 1 -C 4 Alkyl, -S(=O) 2 (C 1 -C 4 In some embodiments, the optional substituents are independently selected from D, halogen, —CN, —NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -NH(cyclopropyl), -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3In some embodiments, a substituent is substituted with one or two of the preceding groups. In some embodiments, any substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0086] The term "tautomer" refers to a proton transfer 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 by the transfer of a hydrogen atom, with a switch of a single bond and an adjacent double bond. In bond configurations where tautomerization 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 tautomer interconversions include the following: [ka]

[0087] The term "about" or "approximately" can mean within an acceptable error range of 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, in accordance with the practice in the art, "about" can mean within one or more standard deviations. Alternatively, "about" can mean within 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.

[0088] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral route (po), intraduodenal route (id), parenteral injection (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.

[0089] As used herein, terms such as "co-administration" are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same time or at different times.

[0090] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an administered agent or compound that will relieve to some extent one or more of the symptoms of the disease or condition being treated, for example, reducing and / or alleviating one or more signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use can be the amount of an agent that causes a clinically significant reduction in one or more disease symptoms. An appropriate "effective" amount can be determined using techniques such as dose escalation studies in individual cases.

[0091] As used herein, the term "enhance" or "enhancing" refers to an increase or prolongation of either the amount, potency, or duration of a desired effect. For example, with respect to enhancing splicing of a target, the term "enhancing" can refer to the ability to increase or prolong splicing of the target in either amount, potency, or duration.

[0092] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, e.g., humans, non-human primates such as chimpanzees, and other ape and monkey species, livestock animals such as cows, horses, sheep, goats, pigs, farm animals such as rabbits, dogs, and cats, laboratory animals such as rodents, e.g., rats, mice, and guinea pigs, and the like. In one aspect, a mammal is a human. The term "animal" as used herein includes humans and non-human animals. In one embodiment, a "non-human animal" is a mammal, e.g., a rodent, such as a rat or a mouse. In one embodiment, a non-human animal is a mouse.

[0093] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating conditions caused by the disease or condition, or prophylactically and / or therapeutically arresting the symptoms of the disease or condition.

[0094] "Preventing" a condition or the term "prevention" means preventing the clinical symptoms of a condition from developing in a subject who may be exposed to or susceptible to the condition, but who has not yet experienced or exhibited symptoms of the condition.

[0095] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or formulation) are used interchangeably and refer to a mixture or solution (to be administered to a subject in need thereof, e.g., a human) containing a therapeutically effective amount of a pharmacologic active ingredient together with one or more pharmacologic acceptable excipients.

[0096] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of two or more active ingredients, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., compounds described herein and auxiliary agents, are administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that active ingredients, e.g., compounds described herein and auxiliary agents, are administered to a patient as separate entities, either simultaneously, concurrently, or sequentially, without any specific intervening time limit, such administration providing effective levels of these two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0097] The term "pharmaceutical acceptable" refers to the attributes of a material that is generally safe, non-toxic, biologically or otherwise undesirable, and useful in the preparation of pharmaceutical compositions that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable" can refer to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0098] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier", and "therapeutically inactive excipient" may be used interchangeably and can mean any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a 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 in formulating a pharmaceutical product.

[0099] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. A "pharmaceutically acceptable salt" can refer to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and / or does not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a SMSM compound of any one of formulas (I)-(II) with an acid. A pharmaceutically acceptable salt can also be obtained by reacting a compound of any one of formulas (I)-(II) with a base to form a salt. Types of pharma- ceutically acceptable salts include (1) salts of the free base derived from the compound with a pharma- ceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like, or with a pharma- ceutically acceptable 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, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2-carboxylic ... and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion.In some cases, the compounds described herein may be coordinated with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0100] As used herein, the term "nucleic acid" generally refers to one or more nucleobases, nucleosides, or nucleotides, and the term includes polynucleobases, polynucleosides, and polynucleotides.

[0101] The term "polynucleotide" as used herein generally refers to a molecule that includes two or more linked nucleic acid subunits, e.g., nucleotides, and may be used interchangeably with "oligonucleotide." For example, a polynucleotide may include one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), or variants thereof. A nucleotide generally includes a nucleoside and at least one, two, three, four, five, six, seven, eight, nine, ten, or more phosphates (POs). 3) group. A nucleotide may include a nucleobase, a pentose sugar (either ribose or deoxyribose), and one or more phosphate groups. Ribonucleotides include nucleotides whose sugar is ribose. Deoxyribonucleotides include nucleotides whose sugar is deoxyribose. A nucleotide may be a nucleoside monophosphate, a nucleoside diphosphate, a nucleoside triphosphate, or a nucleoside polyphosphate. For example, a nucleotide may be a deoxyribonucleoside polyphosphate, such as a deoxyribonucleoside triphosphate (dNTP). Exemplary dNTPs include deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP), and deoxythymidine triphosphate (dTTP). A dNTP may also include a detectable tag, such as a luminescent tag or marker (e.g., a fluorophore). For example, the nucleotides can be purines (i.e., A or G, or variants thereof) or pyrimidines (i.e., C, T, or U, or variants thereof). In some examples, the polynucleotide is deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or derivatives or variants thereof. 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), encompassing both nucleotide sequences and any structural embodiment thereof, such as single-stranded, double-stranded, triple-stranded, helical, hairpin, stem-loop, bulge, etc. In some cases, the polynucleotide is circular. The polynucleotide can have a variety of lengths.For example, the polynucleotide can have a length of 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 kilobase (kb), 2 kb, 3 kb, 4 kb, 5 kb, 10 kb, 50 kb, or more. The polynucleotide can be isolated from a cell or tissue. For example, the polynucleotide sequence can include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules, and / or synthetic DNA / RNA analogs.

[0102] A polynucleotide may include one or more nucleotide variants, including non-standard nucleotide(s), non-natural nucleotide(s), nucleotide analog(s), and / or modified nucleotides. Examples of modified nucleotides include diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methyladen ... Aminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueuosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxocine, pseudouracil, queuosine, 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, nucleotides may contain modifications at their phosphate moieties, including modifications to the triphosphate moiety. Non-limiting examples of such modifications include longer phosphate chains (e.g., phosphate chains having 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications of the thiol moiety (e.g., alpha-thiotriphosphate and beta-thiotriphosphate). Nucleic acid molecules may also be modified at the base moiety (e.g., one or more atoms typically available to form a hydrogen bond with a complementary nucleotide and / or one or more atoms typically not available to form a hydrogen bond with a complementary nucleotide), the sugar moiety, or the phosphate backbone.Nucleic acid molecules may also contain amine-modified groups such as aminoaryl-dUTP (aa-dUTP) and aminohexylacrylamide-dCTP (aha-dCTP) to allow covalent attachment of amine-reactive moieties such as N-hydroxysuccinimide ester (NHS). Substitution of standard DNA or RNA base pairs in the oligonucleotides of the present disclosure may result in higher density in bits per cubic mm, higher safety (resistance to accidental or deliberate synthesis of natural toxins), easier discrimination in light-programmed polymerases, or less 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, incorporated herein by reference for all purposes.

[0103] As used herein, the terms "polypeptide", "protein", and "peptide" are used interchangeably and refer to a polymer of amino acid residues that are linked via peptide bonds and 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 via amide bonds. The amino acids may be L 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, e.g., an order determined by the base sequence of nucleotides in a gene or RNA that encodes the protein. Proteins are essential for the structure, function, and control of cells, tissues, and organs of the body, with each protein having a unique function. Examples include hormones, enzymes, antibodies, and any fragments thereof. In some cases, a protein can be a portion of a protein, e.g., a domain, subdomain, or motif of a protein. In some cases, a protein can be a variant (or mutation) of a protein in which one or more amino acid residues have been inserted into, deleted from, and / or substituted into the naturally occurring (or at least known) amino acid sequence of the protein. The protein or variant thereof can be naturally occurring or recombinant.

[0104] Methods for detecting and / or measuring polypeptides in biological materials are well known in the art, including but not limited to Western blotting, flow cytometry, ELISA, RIA, and various proteomics techniques.An exemplary method for measuring or detecting polypeptides is immunoassays such as ELISA.This type of protein quantification can be based on an antibody that can capture a specific antigen and a second antibody that can detect the captured antigen.An exemplary assay for detecting and / or measuring polypeptides is described in Harlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), Cold Spring Harbor Laboratory Press.

[0105] Methods for detecting and / or measuring RNA in biological materials are well known in the art, including but not limited to Northern blotting, RNA protection assay, RT PCR.Suitable methods are described in Molecular Cloning: A Laboratory Manual (Fourth Edition) By Michael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN 978-1-936113-42-2.

[0106] As used herein, "low molecular weight compound" may be used interchangeably with "small molecule" or "small organic molecule." Small molecule refers to a compound other than a peptide or oligonucleotide, typically having a molecular weight of less than about 2000 daltons, e.g., less than about 900 daltons.

[0107] Ribonucleoprotein (RNP) refers to a nuclear protein that contains RNA. RNP can be a complex of ribonucleic acid and RNA-binding protein. Such a combination can also be called a protein-RNA complex. These complexes can function in several biological functions, including but not limited to DNA replication, gene expression, RNA metabolism, and pre-mRNA splicing. Examples of RNPs include ribosomes, enzyme telomerase, vault ribonucleoprotein, RNase P, heterogeneous nuclear RNPs (hnRNPs), and small nuclear RNPs (snRNPs).

[0108] Nascent RNA transcripts from protein-coding genes and intermediates that process mRNA are collectively referred to as pre-mRNAs and are generally bound by proteins in the nucleus of eukaryotic cells. From the time when the nascent transcript first emerges from RNA polymerase (e.g., RNA polymerase II) until mature mRNA is transported to the cytoplasm, the RNA molecule is associated with a rich set of splicing complex components (e.g., nuclear proteins and snRNAs). These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNAs (hnRNAs) of various sizes (e.g., complexes of pre-mRNAs and nuclear RNAs).

[0109] Splicing complex components function 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, the serine-arginine-rich proteins (SR proteins), can function in constitutive pre-mRNAs and can also control alternative splice 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 rich in arginine and serine residues (RS domain). Their activity in alternative splicing can be antagonized by members of the hnRNP A / B family of proteins. Splicing complex components can also include proteins associated 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 in humans that may be involved in splice site selection include, but are not limited to, U2 snRNA auxiliary factors (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP20, 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 may be stably or transiently associated with snRNPs or transcripts.

[0110] The term "intron" refers to both a DNA sequence within a gene and the corresponding sequence in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing either immediately after transcription or concomitantly with transcription. Introns are found in the genes of most organisms and many viruses. They can be located within a wide variety of genes, including those that produce proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA).

[0111] An "exon" can be any portion of a gene that is produced by the gene that encodes a part of the final mature RNA after introns have been removed by RNA splicing. The term "exon" refers both to DNA sequences within a gene and to the corresponding sequences in the RNA transcript.

[0112] A "spliceosome" may be constructed from a complex of snRNA and proteins. The spliceosome can remove introns from the transcribed pre-mRNA.

[0113] "Intermediate Effective Dose" (ED 50 The "median lethal dose" (LD) is the dose at which 50% of a population develops a particular response. 50 ) is the dose at which 50% of a population is fatal. 50) is the dose at which 50% of a population develops a particular toxic effect. One particularly useful pharmacological endpoint has traditionally been the LD 50 ED 50 Ratio to TD 50 ED 50 The therapeutic index is defined as the ratio of the therapeutic dose to the effective dose. The therapeutic index provides a simple and useful measure of a drug's beneficial versus adverse effects. Drugs with a high therapeutic index have a wide therapeutic window, i.e., they can be administered over a wider effective dose range without suffering from significant adverse events. Conversely, drugs with a small therapeutic index have a narrow therapeutic window (narrow effective dose range without suffering from significant adverse events).

[0114] As used herein, the term "AUC" refers to an abbreviation for "area under the curve" in a graph of therapeutic agent concentration over time in a particular area or tissue, e.g., blood or plasma, of a subject to which the therapeutic agent has been administered.

[0115] Unless otherwise stated, an embodiment of a compound of any one of formulas (I)-(V) may also apply to the corresponding subformula (e.g., formula (Ia), formula (IIa), formula (IIff), etc.). For example, in some embodiments, the subformula of formula (II) is formula (IIff). For example, in some embodiments, the subformula of formula (IV) is formula (IIff). Small molecule splicing regulators (SMSMs)

[0116] It has been found that the compounds of the present invention and their pharma- ceutically acceptable compositions are effective as drugs for use in treating, preventing, or improving 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, herein referred to as small molecule splicing regulators (SMSMs). These SMSMs can regulate specific splicing events in specific pre-mRNA molecules. These SMSMs can operate by various mechanisms to modify splicing events. For example, the SMSMs of the present invention can 1) interfere with the formation and / or function and / or other properties of splicing complexes, spliceosomes, and / or their 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) can prevent and / or modify post-transcriptional regulation (e.g., splicing) of gene products, such as hnRNPs, snRNPs, SR proteins, and other splicing factors, which can then participate in the formation and / or function of spliceosome or splicing complex components, 3) can 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 can then participate in the formation and / or function of spliceosome or splicing complex components, and 4) can bind to and / or otherwise affect specific pre-mRNAs such that specific splicing events are prevented or induced, for example, via mechanisms that do not involve base pairing with the RNA in a sequence-specific manner. Small molecules of the present invention are distinct from and are not related to antisense or antigen oligonucleotides.

[0117] Described herein are compounds that modify the splicing of gene products for use in treating, preventing, and / or slowing the progression of a disease or condition (e.g., cancer). Described herein are compounds that modify the splicing of gene products that induce transcriptionally inactive variants or transcripts of the gene products. Described herein are compounds that modify the splicing of gene products that suppress transcriptionally inactive variants or transcripts of the gene products.

[0118] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0119] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0120] In some embodiments of the compound of Formula (I) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, X is [ka] and Z is N or CR 2 In some embodiments, X is -O-, -S-, or -NR 3- and Z is CR 2 It is.

[0121] In one aspect, a compound having the structure of formula (III): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 or X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0122] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, X is [ka] and Z is N or CR 2 In some embodiments, X is -O-, -S-, or -NR 3 - and Z is CR 2 It is.

[0123] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 are the same and are selected from hydrogen and deuterium. 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C 1 -C 4Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In some embodiments, R is selected from the group consisting of heteroalkyl. 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl.

[0124] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same and are selected from hydrogen and deuterium, a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0125] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, both of R 15 and R 18 Both are deuterium.

[0126] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same, F,-OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0127] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 1 -C 3 Fluoroalkyl, and substituted or unsubstituted C 1 -C 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -CH 2OH, -OCH 2 CN, -OH, -OCH 3 , -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , and -OCH 3 In one embodiment, R 15 and R 18 is F. In one embodiment, R 15 and R 18 -CH 3 In one embodiment, R 15 and R 18 -OCH 3 It is.

[0128] A compound of formula (I) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O-, -S-, or -NR 3 - and Z is CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 3 is hydrogen, -CN, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, or -C 1 -C 4 Alkylene-OR 1 and R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0129] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 1 -C 3 Fluoroalkyl, and substituted or unsubstituted C 1 -C 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , -CH 2 OH, -OCH 2 CN, -OH, -OCH 3 , -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , and -OCH 3 In one embodiment, R 15 is F and R 18 is hydrogen. In one embodiment, R 15 is hydrogen, and R 18 is F. In one embodiment, R 15 is hydrogen, and R 18 CH 3 In one embodiment, R 15 CH 3 and R 18 is hydrogen.

[0130] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, X is --O--.

[0131] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, X is --S--.

[0132] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, X is -NR 3 In some embodiments, R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CF 3 In some embodiments, R 3 is hydrogen, -CH 3 , or -CH(CH 3 ) 2 In one embodiment, R 3 is hydrogen or -CH 3 It is.

[0133] In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NRE )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0134] In some embodiments of the compound of Formula (I) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15and R 18 are the same and are selected from hydrogen and deuterium. 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In some embodiments, R is selected from the group consisting of heteroalkyl. 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl.

[0135] In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C4 heteroalkyl; R 15 and R 18 are the same and are selected from hydrogen and deuterium, a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0136] In some embodiments of the compound of Formula (I) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, both of R 15 and R 18 Both are deuterium.

[0137] In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same, F,-OR 1, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0138] In some embodiments of the compound of Formula (I) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 1 -C 3 Fluoroalkyl, and substituted or unsubstituted C 1 -C 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -CH 2 OH, -OCH 2 CN, -OH, -OCH 3 , -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , and -OCH 3 In one embodiment, R 15 and R 18 is F. In one embodiment, R 15 and R 18 is -CH 3 In one embodiment, R 15 and R 18 -OCH 3 It is.

[0139] In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R AHydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0140] In some embodiments of the compound of Formula (I) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 1 -C 3 Fluoroalkyl, and substituted or unsubstituted C 1 -C 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, CH 3, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , -CH 2 OH, -OCH 2 CN, -OH, -OCH 3 , -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , and -OCH 3 In one embodiment, R 15 is F and R 18is hydrogen. In one embodiment, R 15 is hydrogen, and R 18 is F. In one embodiment, R 15 is hydrogen, and R 18 CH 3 In one embodiment, R 15 CH 3 and R 18 is hydrogen.

[0141] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, Z is N. In some embodiments, Z is CR 2 It is.

[0142] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, X is [ka] In some embodiments, X is [ka] It is.

[0143] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or pharma-ceutically 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 S(=O)(=NR E The oxygen atom in S(=O)(=NR) is in the equatorial position. EIn some embodiments, E is S(=O)(=NR E ) and S(=O)(=NR E The oxygen atom in S(=O)(=NR) is in the axial position. E The nitrogen atom in is in the equatorial position.

[0144] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 16 is not hydrogen. In some embodiments, R 16 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (R) configuration.

[0145] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 17 is not hydrogen. In some embodiments, R 17 The carbon atom bearing the group is in the (S) configuration. 17 The carbon atom bearing the group is in the (R) configuration.

[0146] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 16 is not hydrogen, but R 17 is not hydrogen. In some embodiments, R 16 The carbon atom bearing the group is in the (S) configuration and R 17 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (S) configuration and R 17 The carbon atom bearing the group is in the (R) configuration. 16 The carbon atom bearing the group is in the (R) configuration, and R 17 The carbon atom bearing the group is in the (S) configuration. 16The carbon atom bearing the group is in the (R) configuration, and R 17 The carbon atom bearing the group is in the (R) configuration.

[0147] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ia): [ka]

[0148] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ib): [ka]

[0149] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ib-1): [ka]

[0150] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ib-2): [ka]

[0151] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ic): [ka]

[0152] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ic-1): [ka]

[0153] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ic-2): [ka]

[0154] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Id): [ka]

[0155] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie): [ka]

[0156] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-1): [ka]

[0157] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-2): [ka]

[0158] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-3): [ka]

[0159] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (Ie-4): [ka]

[0160] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If): [ka]

[0161] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-1): [ka]

[0162] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-2): [ka]

[0163] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-3): [ka]

[0164] In some embodiments, the compound of Formula (I) or Formula (III) has the structure of Formula (If-4): [ka]

[0165] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted aryl. In one embodiment, ring Q is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1, -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 2-hydroxy-phenyl substituted with 1, 2, or 3 substituents independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0166] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or pharma- ceutically acceptable solvate thereof, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In one embodiment, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl, where when aryl is substituted, it is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 substituted with 1 or 2 substituents independently selected from heterocycloalkyl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2-C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0167] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where when the heteroaryl is substituted, it is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 substituted with 1 or 2 substituents independently selected from heterocycloalkyl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0168] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] where R Q are each independently hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , -OCH 2 CH 2 CH 3 , and -OCH(CH 3 ) 2 and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0169] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or pharma- ceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted heteroaryl. In one embodiment, ring Q is a substituted or unsubstituted 5- 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: Ring Q is [ka] where R Q are each independently hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , -OCH 2 CH 2 CH 3 , and -OCH(CH 3 ) 2 and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0170] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R Q are each independently hydrogen, -F, -Cl, -CN, -OH, -CH 3 , -CF 3 , and -OCH 3 In one embodiment, ring P is selected from: [ka] is a heteroaryl selected from the group consisting of During the ceremony, R B each independently represents hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; 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.

[0171] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B each independently represents hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; 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.

[0172] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R B are each independently hydrogen, deuterium, -F, -Cl, -CN, -CH 3 , -CF 3 , -OH, or -OCH 3 In one embodiment, R B are each independently H, -F, or -OCH 3In one embodiment, R B1 is hydrogen, deuterium, -CH 3 , -CF 3 , or -CD 3 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.

[0173] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0174] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] In some embodiments, ring Q is selected from the group consisting of: [ka] is selected from the group consisting of:

[0175] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of:

[0176] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of In the formula, R B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl.

[0177] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, W is a substituted or unsubstituted C 1 -C 3 In one embodiment, W is -CH 2 In one embodiment, W is -CH 2 CH 2 In one embodiment, W is -CH 2 CH 2 CH 2 In one embodiment, W is a substituted or unsubstituted C 1 -C 2 In one embodiment, W is -CH 2 OCH 2 In one embodiment, W is -CH 2 O-, where O is R 18 In one embodiment, W is attached to a carbon atom bearing a substituted or unsubstituted C 3 -C 8 Cycloalkylene or substituted or unsubstituted C 2 -C 3 In one embodiment, W is substituted or unsubstituted C 3 -C 8 In one embodiment, W is cycloalkylene. In one embodiment, W is cyclopropylene. In one embodiment, W is substituted or unsubstituted C 2 -C 3 In one embodiment, W is -CH=CH-.

[0178] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl, or substituted or unsubstituted C 2 -C 4 In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -C(OH)(CH 3 ) 2 , -CH 2 CN, -CH 2 C(=O)OCH 3 , -CH 2 C(=O)OCH 2 CH 3 , -CH 2 C(=O)NHCH 3 , -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 In one embodiment, R is hydrogen, -CH 3 , -CH 2 OH, -CH 2 CN, -CHF 2 , -CF 3 In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3, cyclopropyl, or oxetanyl. In one embodiment, R is -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R is hydrogen.

[0179] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , and R 16 One or more of the following may be independently selected from the group consisting of F, -OR, 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In one embodiment, R 11 , R 12 , and R 16 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In one embodiment, R 11 , R12 , and R 16 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 11 , R 12 , and R 16 is hydrogen.

[0180] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 16 and R 17 One or more of the following may be independently selected from the group consisting of F, -OR, 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In one embodiment, R 16 and R 17 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2CF 3 In one embodiment, R 16 and R 17 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 16 and R 17 is hydrogen.

[0181] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 2 is hydrogen, -CH 3 , or -OCH 3 In one embodiment, R 2 is hydrogen.

[0182] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R A is hydrogen, F, Cl, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R A is hydrogen, F, Cl, -CN, -CH 3 , -OH, -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , or -CF 3In one embodiment, R A is hydrogen, F, Cl, -CN, -CH 3 , or -OCH 3 In one embodiment, R A is hydrogen, F, Cl, or -CH 3 In one embodiment, R A is hydrogen.

[0183] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 4 each independently represents hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 In one embodiment, R 4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 OCH 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R 4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 F, -CHF 2 , or -CF3 In one embodiment, R 4 Each is hydrogen. In one embodiment, R 4 are -CH 3 It is.

[0184] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R 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 R are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R 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.

[0185] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 , and R 16 is hydrogen.

[0186] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 19 is hydrogen. In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 19 F or -OCH 3 It is.

[0187] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 20 is hydrogen. In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 20 F or -OCH 3 It is.

[0188] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0189] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0190] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0191] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0192] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 15 are H, D, F, and CH 2 F, CHF 2 , C.F. 3 , or C.H. 3 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 , F, C.H. 2 F, CHF 2 , C.F.3 , or C.H. 3 In some embodiments, R 15 , F, CF 3 , CHF 2 , or C.H. 2 F. In some embodiments, R 15 is F.

[0193] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0194] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0195] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 18 are H, D, F, and CH 2 F, CHF 2 , C.F. 3 , or C.H. 3 In some embodiments, R 18 is H or D. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R 18 , F, C.H. 2 F, CHF 2 , C.F. 3 , or C.H. 3In some embodiments, R 18 , F, CF 3 , CHF 2 , or C.H. 2 F. In some embodiments, R 18 is F.

[0196] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0197] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0198] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0199] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 17 and R 20 is H. In some embodiments, R 17 and R 20is D. In some embodiments, R 17 and R 20 is F.

[0200] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H. 3 CH 2 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of the following is F or C: 1 -C 4 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 R 11 , R 12 , R 13 , R 14, R 16 , and R 17 At least one of 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 the groups contain fluorine.

[0201] In some embodiments of the compound of Formula (I) or Formula (III) or a pharma- ceutically acceptable salt or pharma-ceutically 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 the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H. 3 CH 2 In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, W comprises fluorine.

[0202] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20, and R 16 is hydrogen.

[0203] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 19 is hydrogen. In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 19 F or -OCH 3 It is.

[0204] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 20 is hydrogen. In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCH 2 CH 3, -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 20 F or -OCH 3 It is.

[0205] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 R 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 18In 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 R 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 R 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.

[0206] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF2 , and C.H. 3 CH 2 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 the following is F or C: 1 -C 4 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 R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 At least one of 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 , R14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0207] In some embodiments of the compound of Formula (III) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H. 3 CH 2 In some embodiments, 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.

[0208] In one aspect, a compound having the structure of formula (II): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0209] In one aspect, a compound having the structure of formula (IV): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are (i) the same and selected from hydrogen and deuterium, or (ii) the same and F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, -OR1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0210] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 15 and R 18 are the same and are selected from hydrogen and deuterium. 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In some embodiments, R is selected from the group consisting of heteroalkyl. 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl.

[0211] In one aspect, a compound having the structure of formula (II): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same and are selected from hydrogen and deuterium, a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0212] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, both of R 15 and R 18 Both are deuterium.

[0213] In one aspect, a compound having the structure of formula (II): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are the same, F,-OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0214] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 1 -C 3 Fluoroalkyl, and substituted or unsubstituted C 1 -C 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -CH 2 OH, -OCH 2 CN, -OH, -OCH 3 , -OCH2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are the same, F, -CH 3 , and -OCH 3 In one embodiment, R 15 and R 18 is F. In one embodiment, R 15 and R 18 is -CH 3 In one embodiment, R 15 and R 18 -OCH 3 It is.

[0215] In one aspect, a compound having the structure of formula (II): [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR E )-and R A Hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O) 2 R 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C4 Heteroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 is heterocycloalkyl, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl, or substituted or unsubstituted C 2 -C 3 is alkynyl, Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X, [ka] and Z is C; or X, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 1 -C 2 Heteroalkylene, substituted or unsubstituted C 3 -C 8 Cycloalkylene, or substituted or unsubstituted C 2 -C 7 is heterocycloalkylene, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 2 -C 5 is heterocycloalkyl, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 When present, hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 is haloalkyl, R 4 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 is heteroalkyl, R 11 , R 12 , R 13 , R 14 , R16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, wherein d is 0 or 1.

[0216] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 1 -C 3 Fluoroalkyl, and substituted or unsubstituted C 1 -C 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, CH 3 , -CH 2 CH 3 , -CH2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , -CH 2 OH, -OCH 2 CN, -OH, -OCH 3 , -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 15 and R 18 are not the same as hydrogen, deuterium, F, -CH 3 , and -OCH 3 In one embodiment, R 15 is F and R 18 is hydrogen. In one embodiment, R 15 is hydrogen, and R 18is F. In one embodiment, R 15 is hydrogen, and R 18 CH 3 In one embodiment, R 15 CH 3 and R 18 is hydrogen.

[0217] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 S(=O)(=NR E The oxygen atom in S(=O)(=NR) is in the equatorial position. E In some embodiments, E is S(=O)(=NR E ) and S(=O)(=NR E The oxygen atom in S(=O)(=NR) is in the axial position. E The nitrogen atom in is in the equatorial position.

[0218] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 16 is not hydrogen. In some embodiments, R 16 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (R) configuration. 17 is not hydrogen. In some embodiments, R 17 The carbon atom bearing the group is in the (S) configuration.17 The carbon atom bearing the group is in the (R) configuration.

[0219] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 16 is not hydrogen, but R 17 is not hydrogen. In some embodiments, R 16 The carbon atom bearing the group is in the (S) configuration and R 17 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (S) configuration and R 17 The carbon atom bearing the group is in the (R) configuration. 16 The carbon atom bearing the group is in the (R) configuration, and R 17 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (R) configuration, and R 17 The carbon atom bearing the group is in the (R) configuration.

[0220] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIa): [ka]

[0221] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIb): [ka]

[0222] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIb-1): [ka]

[0223] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIb-2): [ka]

[0224] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIc): [ka]

[0225] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIc-1): [ka]

[0226] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIc-2): [ka]

[0227] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIaa): [ka]

[0228] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIbb): [ka]

[0229] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIbb-1): [ka]

[0230] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIbb-2): [ka]

[0231] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIcc): [ka]

[0232] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIcc-1): [ka]

[0233] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIcc-2): [ka]

[0234] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IId): [ka]

[0235] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIe): [ka]

[0236] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIe-1): [ka]

[0237] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-2): [ka]

[0238] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-3): [ka]

[0239] In one embodiment, the compound of Formula (II) or Formula (IV) has the structure of Formula (IIe-4): [ka]

[0240] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIf): [ka]

[0241] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIf-1): [ka]

[0242] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIf-2): [ka]

[0243] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIf-3): [ka]

[0244] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIf-4): [ka]

[0245] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIdd): [ka]

[0246] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIee): [ka]

[0247] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIee-1): [ka]

[0248] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIee-2): [ka]

[0249] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIee-3): [ka]

[0250] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIee-4): [ka]

[0251] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIff): [ka]

[0252] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIff-1): [ka]

[0253] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIff-2): [ka]

[0254] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIff-3): [ka]

[0255] In one embodiment, the compound of formula (II) or formula (IV) has the structure of formula (IIff-4): [ka]

[0256] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted aryl. In one embodiment, ring Q is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 2-hydroxy-phenyl substituted with 1, 2, or 3 substituents independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0257] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma- ceutically acceptable solvate thereof, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In one embodiment, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl, where when aryl is substituted, it is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 substituted with 1 or 2 substituents independently selected from heterocycloalkyl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0258] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where when the heteroaryl is substituted, it is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 substituted with 1 or 2 substituents independently selected from heterocycloalkyl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0259] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] where R Q are each independently hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , -OCH 2 CH 2 CH 3 , and -OCH(CH 3 ) 2 and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0260] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma- ceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted heteroaryl. In one embodiment, ring Q is a substituted or unsubstituted 5- 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: Ring Q is [ka] where R Q are each independently hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , -OCH 2 CH 2 CH 3 , and -OCH(CH 3 ) 2 and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0261] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R Q are each independently hydrogen, -F, -Cl, -CN, -OH, -CH 3 , -CF 3 , and -OCH 3 In one embodiment, ring P is selected from: [ka] is a heteroaryl selected from the group consisting of During the ceremony, In the formula, R B each independently represents hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; 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.

[0262] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B each independently represents hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3.

[0263] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R B are each independently hydrogen, deuterium, -F, -Cl, -CN, -CH 3 , -CF 3 , -OH, or -OCH 3 In one embodiment, R B are each independently H, -F, or -OCH 3 In one embodiment, R B1 is hydrogen, deuterium, -CH 3 , -CF 3 , or -CD 3 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.

[0264] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is Deuterium, halogens, -OH, -NO 2 , -CN, -SR 1 , -S(=O)R 1 , -S(=O) 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C2 -C 7 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 Haloalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 It is a heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0265] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of:

[0266] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of:

[0267] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of:

[0268] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of In the formula, R B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl.

[0269] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, W is a substituted or unsubstituted C 1 -C 3 In one embodiment, W is -CH 2 In one embodiment, W is -CH 2 CH 2 In one embodiment, W is -CH 2 CH 2 CH 2 In one embodiment, W is a substituted or unsubstituted C 1 -C 2 In one embodiment, W is -CH 2 OCH 2 In one embodiment, W is -CH 2 O-, where O is R 18 In one embodiment, W is attached to a carbon atom bearing a substituted or unsubstituted C 3 -C 8Cycloalkylene or substituted or unsubstituted C 2 -C 3 In one embodiment, W is substituted or unsubstituted C 3 -C 8 In one embodiment, W is cycloalkylene. In one embodiment, W is cyclopropylene. In one embodiment, W is substituted or unsubstituted C 2 -C 3 In one embodiment, W is -CH=CH-.

[0270] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, substituted or unsubstituted C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl, or substituted or unsubstituted C 2 -C 4 In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -C(OH)(CH 3 ) 2 , -CH 2 CN, -CH 2 C(=O)OCH 3 , -CH 2 C(=O)OCH 2 CH 3 , -CH 2 C(=O)NHCH 3, -CH 2 C(=O)N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl. In one embodiment, R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 In one embodiment, R is hydrogen, -CH 3 , -CH2 OH, -CH 2 CN, -CHF 2 , -CF 3 or cyclopropyl.

[0271] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R is hydrogen, —CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl. In one embodiment, R is -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R is hydrogen.

[0272] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 11 , R 12 , and R 16 One or more of the following may be independently selected from the group consisting of F, -OR, 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In one embodiment, R 11 , R 12 , and R 16 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In one embodiment, R 11 , R 12 , and R 16 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 11 , R 12 , and R 16 is hydrogen.

[0273] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 16 and R 17 One or more of the following may be independently selected from the group consisting of F, -OR, 1 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Fluoroalkyl, and substituted or unsubstituted C 1 -C 4 In one embodiment, R 16 and R 17 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In one embodiment, R 16 and R 17 One or more of the groups are independently selected from F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In one embodiment, R 16 and R 17 is hydrogen.

[0274] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 2 If present, -CH 3 , or -OCH 3 In one embodiment, R 2 When present, it is hydrogen.

[0275] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R A is hydrogen, F, Cl, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R A is hydrogen, F, Cl, -CN, -CH 3 , -OH, -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R A is hydrogen, F, Cl, -CN, -CH 3 , or -OCH 3 In one embodiment, R A is hydrogen, F, Cl, or -CH 3 In one embodiment, R A is hydrogen.

[0276] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 4 each independently represents hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Haloalkyl, or substituted or unsubstituted C 1 -C 4 In one embodiment, R 4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH2 N(CH 3 ) 2 , -CH 2 OCH 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R 4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 F, -CHF 2 , or -CF 3 In one embodiment, R 4 Each is hydrogen. In one embodiment, R 4 are -CH 3 It is.

[0277] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R 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 R are F. In some embodiments, R 11 , R 12 , R 13, R 14 , R 16 , and R 17 At least one of R 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.

[0278] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 is F.

[0279] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 is F.

[0280] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 is F.

[0281] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 is F.

[0282] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 15 are H, D, F, and CH 2 F, CHF 2 , C.F. 3 , or C.H. 3 In some embodiments, R 15 is H or D. In some embodiments, R 15 , F, C.H. 2 F, CHF 2 , C.F. 3 , or C.H. 3 In some embodiments, R 15 , F, CF 3 , CHF 2 , or C.H. 2 F. In some embodiments, R 15 is F.

[0283] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 is F.

[0284] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically 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 is F.

[0285] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 18 are H, D, F, and CH 2 F, CHF 2 , C.F. 3 , or C.H. 3 In some embodiments, R 18 is H or D. In some embodiments, R 18 , F, C.H. 2 F, CHF 2 , C.F. 3 , or C.H. 3 In some embodiments, R 18 , F, CF 3 , CHF 2 , or C.H. 2 F. In some embodiments, R 18 is F.

[0286] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H.3 CH 2 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of the following is F or C: 1 -C 4 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 R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of 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 the groups contain fluorine.

[0287] In some embodiments of the compound of Formula (II) or Formula (IV) or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate thereof, W, R11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H. 3 CH 2 In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, one of W comprises fluorine.

[0288] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 , and R 16 is hydrogen.

[0289] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 19 is hydrogen. In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 19 F or -OCH 3 It is.

[0290] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 20 is hydrogen. In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 20 are H, F, -OH, -OCH3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 20 F or -OCH 3 It is.

[0291] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0292] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0293] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 is F.

[0294] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 17 and R 20is H. In some embodiments, R 17 and R 20 is D. In some embodiments, R 17 and R 20 is F.

[0295] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 , and R 16 is hydrogen.

[0296] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 19 is hydrogen. In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 19 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3In some embodiments, R 19 F or -OCH 3 It is.

[0297] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 20 is hydrogen. In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 In some embodiments, R 20 are H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 In some embodiments, R 20 F or -OCH 3 It is.

[0298] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R16 , R 17 , R 19 , R 20 , and R 18 At least one of R 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 R 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 R 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.

[0299] In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H. 3 CH 2 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 the following is F or C: 1 -C 4 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 R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R17 At least one of 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 , and R 17 At least two of the groups contain fluorine. In some embodiments of the compound of formula (IV) or a pharma- ceutically acceptable salt or a pharma-ceutically 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 the groups is fluorine, e.g., F, or C. 1 -C 4 Fluoroalkyl, e.g., CH 2 F, C.F. 3 , CHF 2 , and C.H. 3 CH 2 In some embodiments, 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, one of W comprises fluorine.

[0300] In some embodiments of the compounds of Formula (I)-(IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R Eis hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R E is hydrogen. In some embodiments, R E is methyl or ethyl.

[0301] In some embodiments of the compounds of Formula (I)-(IV) or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof, R 1 each independently represents hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 Alkyl, -CD 3 , or substituted or unsubstituted C 1 -C 4 In some embodiments, R 1 are each independently hydrogen, deuterium, or C 1 -C 4 In some embodiments, R 1 are each independently hydrogen, deuterium, or methyl.

[0302] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring P is [ka] wherein R is a heteroaryl selected from the group consisting of B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1- C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 In some embodiments, m is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0303] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring P is [ka] wherein R is a heteroaryl selected from the group consisting of B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 In some embodiments, R is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and m is 1, 2, 3, or 4.B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 In some embodiments, m is selected from heterocycloalkyl. 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.

[0304] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring P is [ka] wherein R is a heteroaryl selected from the group consisting of B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7In some embodiments, m is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0305] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] wherein each ring Q group is selected from the group consisting of 1 to 3 R B and R B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 It is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0306] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] wherein each ring Q group is selected from the group consisting of 1 to 3 R B and R B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 It is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0307] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] wherein each ring Q group is selected from the group consisting of 1, 2, 3, 4, or 5 R B and R B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6Alkynyl, substituted or unsubstituted C 1- C 6 Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 It is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0308] In some embodiments of the compound of Formula (I)-(IV) or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, ring Q is [ka] wherein R B1 is hydrogen, deuterium, substituted or unsubstituted C 1- C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1- C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl, each ring Q group is selected from the group consisting of 1, 2, 3, 4, or 5 R B and R B each independently represents deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6Alkoxy, Deuterium-substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 In some embodiments, R is selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. B1 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, -CD 3 , substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl.

[0309] In some embodiments, provided herein is a compound of Table 1A, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1A. [Table 1-1] [Table 1-2] [Table 1-3]

[0310] In some embodiments, provided herein is a compound of Table 1B, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1B. [Table 2-1] [Table 2-2] [Table 2-3]

[0311] In some embodiments, provided herein is a compound of Table 1C, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1C. [Table 3-1] [Table 3-2] [Table 3-3]

[0312] In some embodiments, provided herein is a compound of Table 1D, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1D. [Table 4-1] [Table 4-2] [Table 4-3]

[0313] In some embodiments, provided herein is a compound of Table 1E, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1E. [Table 5-1] [Table 5-2] [Table 5-3]

[0314] In some embodiments, provided herein is a compound of Table 1F, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1F. [Table 6-1] [Table 6-2] [Table 6-3]

[0315] In some embodiments, provided herein is a compound of Table 1G, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1G. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0316] In some embodiments, provided herein is a compound of Table 1H, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1H. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0317] In some embodiments, provided herein is a compound of Table 1I, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1I. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0318] In some embodiments, provided herein is a compound of Table 1J, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate of a compound of Table 1J. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7]

Table 10-8

Table 10-9

Table 10-10

Table 10-11

Table 10-12

Table 10-13

Table 10-14

Table 10-15

Table 10-16

Table 10-17

Table 10-18

Table 10-19

Table 10-20

Table 10-21

Table 10-22

Table 10-23

[0319] In some embodiments, provided herein is a compound of Table 6, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate of a compound of Table 6.

[0320] In some embodiments, provided herein is a compound of Table 7, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate of a compound of Table 7.

[0321] In some embodiments, provided herein is a compound of Table 8, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate of a compound of Table 8.

[0322] In some embodiments, provided herein is a compound of Table 9, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate of a compound of Table 9.

[0323] In some cases, the SMSMs provided herein may be designated by more than one SMSM number in different parts of the application, e.g., the same compound may appear more than once herein, e.g., in Tables 1A-1J, Tables 4 and Tables 6-9, the Examples, and the Schemes.

[0324] In some embodiments, the compounds of Formulae (I)-(IV) are racemic. In some embodiments, the compounds of Formulae (I)-(IV) are diastereomers.

[0325] In some embodiments, the compounds of Formulae (I)-(IV) are single enantiomers. In some embodiments, the compounds of Formulae (I)-(IV) are not racemic. In some embodiments, the compounds of Formulae (I)-(IV) are substantially free of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) are single isomers substantially free of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) contain 25% or less of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) contain 20% or less of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) contain 15% or less of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) contain 10% or less of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) contain 5% or less of other isomers. In some embodiments, the compounds of Formulae (I)-(IV) contain 1% or less of other isomers.

[0326] In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 75%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 80%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 85%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 90%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 95%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 96%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 97%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 98%. In some embodiments, the compounds of Formulae (I)-(IV) have a stereochemical purity of at least 99%.

[0327] In some embodiments, the asymmetric carbon atom of the compound of formula (I)-(IV) is present in an enantiomerically enriched form. In certain embodiments, the asymmetric carbon atom of the compound of formula (I)-(IV) has an enantiomeric excess of at least 50% in the (S) or (R) configuration, at least 60% in the enantiomeric excess, at least 70% in the enantiomeric excess, at least 80% in the enantiomeric excess, at least 90% in the enantiomeric excess, at least 95% in the enantiomeric excess, or at least 99% in the enantiomeric excess.

[0328] In some embodiments, the compounds of formulae (I)-(IV) are prepared from racemic starting materials (and / or intermediates) and separated into individual enantiomers by chiral chromatography as intermediates or final products. It is understood that the absolute configuration of the separated intermediates and final compounds is not determined unless otherwise stated. In some embodiments, the absolute stereochemistry of the depicted enantiomers is arbitrarily assigned. In some embodiments, both enantiomers are synthesized.

[0329] In some embodiments, the SMSM described herein has one or more stereocenters, each of which exists independently in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, and appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound / salt pair, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, the resolution of the enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by chromatography, or by 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.

[0330] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because in some situations they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active entity, a carboxylic acid, once inside the cell where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical, or therapeutically active form of the compound.

[0331] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other characteristics or properties of a drug.Knowledge of a pharmacokinetic, pharmacodynamic process, and in vivo drug metabolism allows for the design of prodrugs of this compound. (See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 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, Vol. 14 of the ACS Symposium Series).

[0332] In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0333] In some embodiments, sites on the aromatic ring moieties of the compounds described herein are susceptible to a variety of metabolic reactions, and the incorporation of appropriate substituents on the aromatic ring structure will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens or alkyl groups.

[0334] In another embodiment, the compounds described herein are isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0335] The compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures presented herein, but that are owing to 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 normally found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 The isotopes include hydrogen isotopes, such as Cl, carbon isotopes, nitrogen isotopes, oxygen isotopes, sulfur isotopes, fluorine isotopes, and chlorine isotopes. In one embodiment, the isotopically labeled compounds described herein, e.g., 3 H and 14 Incorporation of a radioactive isotope such as C is useful for drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0336] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need of producing a metabolite, which is then used to provide a desired effect, including a desired therapeutic effect.

[0337] The compounds described herein may be formed as and / or used as pharma- ceutically acceptable salts. Types of pharma-ceutically acceptable salts include: (1) salts of a free base derived from the compound with a pharma- ceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or with a pharma- ceutically acceptable 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, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2-carboxylic acid, 1,2-dimethylphenylsulfonic ... (1) acid addition salts formed by reacting the acid protons present in the parent compound with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein may be coordinated with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and the like. In other cases, the compounds described herein may form salts with amino acids, including, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0338] It should be understood that the reference to pharmaceutically acceptable salt includes solvent addition forms, specifically solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the crystallization process with pharmaceutically acceptable solvents such as 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 the compounds described herein are easily prepared or formed during the process described herein. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0339] In some embodiments, SMSM has a molecular weight of up to about 2000, 1500, 1000, or 900 daltons. In some embodiments, SMSM has a molecular weight of at least 100, 200, 300, 400, or 500 daltons. In some embodiments, SMSM does not contain a phosphodiester bond.

[0340] Methods for making compounds The compounds described herein can be synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology can be used unless otherwise indicated. The compounds can be prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. The starting materials may be available from commercial sources or can be easily prepared. By way of example only, a scheme for preparing an exemplary SMSM is provided.

[0341] Suitable references and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. 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 references and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein or provide references to articles that describe the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged 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 1992 Guide 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 in total), “Organic Reactions” (1942-2000) John Wiley&Sons (over 55 volumes in total), and “Chemistry of Functional Groups” John Wiley&Sons (73 volumes in total).

[0342] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, if desired in the final product, to avoid undesired participation in the reaction.Detailed descriptions of the techniques applicable to the creation of protective 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, which are incorporated herein by reference for such disclosure.

[0343] SMSMs can be made using known techniques and, in some embodiments, can be further chemically modified to facilitate nuclear import, for example, into splicing complex components, spliceosomes, or pre-mRNA molecules. Those of skill in the art will understand standard medicinal chemistry approaches for chemical modification for nuclear import (e.g., charge reduction, size optimization, and / or lipophilicity modification).

[0344] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharma- ceutically usable preparations. Appropriate formulations depend on the route of administration selected. Summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams&Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0345] A pharmaceutical composition can be a mixture of the SMSM described herein with one or more other chemical components (i.e., pharma- ceutically acceptable components), such as a carrier, excipient, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, permeation enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. A pharmaceutical composition facilitates administration of a compound to an organism.

[0346] The compositions described herein can be administered to a subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, intracolonically, rectally, or intraperitoneally. In some embodiments, the small molecule splicing regulator or a pharma- ceutically acceptable salt thereof is administered to the subject by intraperitoneal, intramuscular, subcutaneous, or intravenous injection. In some embodiments, the pharmaceutical composition can be administered parenterally, intravenously, intramuscularly, or orally. The oral agent 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 dissolution in the stomach. The compositions of the present invention can be administered to a subject using any suitable method known in the art. Formulations and delivery methods suitable for use in the present invention are generally well known in the art. For example, the small molecule splicing regulator described herein can be formulated as a pharmaceutical composition together with a pharma- ceutical acceptable diluent, carrier, or excipient. The compositions may contain pharma- ceutically acceptable auxiliary substances necessary to approximate physiological conditions, including pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, and the like.

[0347] The pharmaceutical formulations described herein may be administered to a subject in a variety of ways by multiple 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, buccal, topical, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixtures of immediate release and controlled release formulations.

[0348] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation comprising SMSM described herein is in the form of a capsule. In one aspect, the liquid formulation for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersion, emulsion, solution, elixir, gel, and syrup.

[0349] For administration by inhalation, the SMSM described herein can be formulated for use as an aerosol, mist, or powder. For buccal or sublingual administration, the compositions 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, jelly suppositories, or retention enemas.

[0350] Splicing Extensive post-transcriptional processing occurs before eukaryotic pre-mRNA matures and exits the nucleus into the cytoplasm, including the addition of a 7-methylguanosine cap at the 5' end, the cleavage and addition of a polyA tail at the 3' end, and the removal of intervening sequences or introns by the spliceosome. The majority of genes in higher eukaryotes contain multiple introns that are spliced ​​with high accuracy and fidelity to maintain the reading frame of the exons. Splicing of pre-mRNA can utilize the recognition of short consensus sequences at the boundaries and within introns and exons by a large number of proteins, including small nuclear ribonucleoprotein (snRNP) complexes (e.g., snRNPs U1, U2, U4, U5, U6, U11, U12m U4atc, and U6atc) and spliceosomal proteins, as well as an array of splicing regulators that act both positively and negatively.

[0351] Serine-arginine rich (SR) domain-containing proteins generally play a role in promoting 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, can also control splicing by binding to intronic or exonic splicing suppressor (ISS or ESS) sequences, acting as general splicing regulators. The SR protein family is a class of at least 10 proteins that have characteristic serine / arginine rich domains in addition to RNA binding. SR proteins are generally believed to simultaneously bind U170K, a core component of U1 snRNP at the 5' splice site, and U2AF35 at the 3' splice site, and thus enhance splicing by bridging these two ends of the intron. Although this particular function of SR proteins appears to be redundant, as any individual SR protein can engage pre-mRNAs in constitutive splicing, the roles of various SR proteins in alternative splicing of specific pre-mRNAs are distinct, in part due to their ability to recognize and bind unique consensus sequences. Phosphorylation of the RS domain of SR proteins may lead to the control 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 kinase (SRPK), Cdc2-like kinase (Clk), pre-mRNA processing variant 4 (PRP4), and topoisomerase I. Optimal phosphorylation of SR proteins may be required for proper function, as both hypophosphorylation and hyperphosphorylation of the RS domain may be detrimental to their role in constitutive and alternative splicing.

[0352] In higher eukaryotes, the majority of genes contain one or more introns, creating a situation where exons are spliced ​​together to generate mature mRNA and microRNA (miRNA). In the host nucleus, pre-mRNA splicing is the mechanism by which introns are removed from pre-mRNA and exons are ligated together to generate mature mRNA, which is then transported to the cytoplasm and translated into a polypeptide gene product. Splicing of pre-mRNA can occur in cis, where two exons originate from two adjacent co-transcriptional sequences, or in trans, where two exons originate from different pre-mRNA transcripts. The ratio of different protein products (isoforms) can be due to the frequency of alternative splicing events in pre-mRNA, which results in different amounts of distinct splice variants. In some embodiments, alternative splicing of pre-mRNA can result in the expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 protein isoforms.

[0353] Abnormal splicing is believed to be responsible for approximately half of all genetic diseases. Abnormal splicing due to mutations in consensus sequences involved in exon-intron boundary recognition accounts for up to 15% of genetic diseases. In addition, defects in the splicing mechanism itself due to loss or gain of function of splicing factors and regulators are the cause of a wide range of human diseases, ranging from cancer to neurodegenerative diseases. Both constitutive and alternative splicing are subject to control by upstream signaling pathways. This control can be essential during development, upon tissue-specific expression of certain isoforms, during the cell cycle, and in response to exogenous signaling molecules.

[0354] Alternative splicing allows a single gene to express different isoforms of mRNA, and therefore plays an important role in contributing to cellular complexity in higher eukaryotes without the need to expand genomes.Splicing can also be controlled by upstream signaling pathways.For example, upstream signaling pathways can regulate alternative splicing and increase or decrease the expression level of different isoforms of mRNA.

[0355] Alternative splicing events are highly controlled by multiple splicing factors in a tissue type, developmental stage, and signal-dependent manner. In addition, non-mutation-based causes of splicing defects and defects in the splicing machinery itself, for example due to loss / gain of function of splicing factors or their relative stoichiometry, are the cause of a wide range of human diseases, from cancer to neurodegenerative diseases. In many diseases, pathology is caused by a change in the ratio of different isoforms of two or more proteins expressed from a gene. In some embodiments, the change in the ratio of protein products is due to a change in the frequency of alternative splicing events in the pre-mRNA, leading to a change in the ratio of splice variants produced. In some embodiments, alternative splicing of the pre-mRNA can result in the expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 protein isoforms. In some embodiments, the change in splice variant ratio is caused by a genetic mutation.

[0356] In eukaryotes, the majority of splicing processes occur in unique steps and are catalyzed by the spliceosome, an RNA-protein complex that may contain a subset of hundreds of different proteins in addition to the five spliceosomal snRNAs. These factors are responsible for the precise positioning of the spliceosome on the 5' and 3' splice site sequences. The reason so many factors are required reflects the observation that exon recognition can be influenced by many pre-mRNA features, such as exon length, sequence recognition, the presence of enhancer and silencer elements, the strength of upstream splicing signals, promoter architecture, and RNA processing rate, secondary and tertiary RNA structures, etc.

[0357] All mammalian diseases are ultimately mediated by the transcriptome. Insofar as messenger mRNA (mRNA) is part of the transcriptome and all protein expression originates from mRNA, there exists the possibility of intervening in protein-mediated diseases by regulating the expression of the associated protein and then regulating the translation of the corresponding upstream mRNA. However, mRNA is only a small part of the transcriptome, and other transcriptional RNAs, including (but not limited to) microRNAs (miRNAs), long non-coding RNAs (lncRNAs), long intergenic non-coding RNAs (lincRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), small Cajal body-specific RNAs (scaRNAs), piwi-interacting RNAs (piRNAs), competitive endogenous RNAs (ceRNAs), and pseudogenes, also directly control cell biology through the structure and function of RNA structures (e.g., ribonucleoproteins) and also through protein expression and action. Drugs that intervene at this level have the potential to regulate any cellular process. Existing therapeutics, such as antisense RNA or siRNA, have in most cases yet to overcome significant challenges, such as drug delivery, absorption, distribution to target organs, pharmacokinetics, and cell penetration. In contrast, small molecules have a long history of successfully overcoming these barriers, making them suitable as drugs and easily optimized by a series of analogues to overcome such challenges. In sharp contrast, the application of small molecules as ligands of RNA to provide therapeutic benefits has received little or no attention from the drug discovery community.

[0358] DNA sequences in chromosomes are transcribed into pre-mRNA, which contains coding regions (exons) and generally contains intervening non-coding regions (introns). Introns are removed from the pre-mRNA by splicing. The pre-mRNA proceeds in a two-step mechanism. In the first step, the 5' splice site is cleaved, resulting in a "free" 5' exon and a lariat intermediate. In the second step, the 5' exon is ligated to the 3' exon with release of the intron as the lariat product. These steps are catalyzed in a complex of small nuclear ribonucleoproteins and proteins called the spliceosome.

[0359] 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.

[0360] Introns are portions of eukaryotic DNA that lie between coding portions or "exons" of that DNA. Introns and exons are transcribed into an RNA called the "primary transcript, pre-mRNA" (or "pre-mRNA"). Introns can be removed from the pre-mRNA, allowing the native protein encoded by the exons to be produced (the term "native protein" as used herein refers to a naturally occurring, wild-type, or functional protein). The removal of introns from the pre-mRNA and the subsequent joining of exons occurs in the process of splicing.

[0361] The splicing process is a series of reactions that take place on RNA after transcription but before translation and are mediated by splicing factors. Thus, an RNA that contains both exons and intron(s) can be referred to as a "pre-mRNA," and an RNA from which the intron(s) are removed and the exons are spliced ​​together sequentially, thereby allowing a protein to be translated from it by the ribosome, can be referred to as a mature mRNA ("mRNA").

[0362] Introns can be defined by a set of "splice elements", which are relatively short conserved RNA segments that are part of the splicing mechanism and may be required for splicing and bind to various splicing factors that perform splicing reactions.Thus, introns are each defined by a 5' splice site, a 3' splice site, and a branch point located between them.Splice elements also include exon splicing enhancers and silencers located within exons, and intron splicing enhancers and silencers located within introns away from splice sites and branch points.In addition to splice sites and branch points, these elements control aberrant alternative splicing and constitutive splicing.

[0363] The initial RNA transcripts (pre-mRNAs) of most eukaryotic genes are retained in the nucleus until non-coding intronic sequences are removed by the spliceosome to produce mature messenger RNA (mRNA). Because the resulting splicing can be different, the synthesis of alternative protein products from the same primary transcript can be influenced by tissue-specific or developmental signals. A significant proportion of human genetic diseases, including some cancers, are thought to result from deviations from the normal pattern of pre-mRNA splicing. The spliceosome is a complex that contains small nuclear RNAs and ribonucleoprotein (snRNP) particles composed of proteins. The snRNA components of the spliceosome can facilitate two transesterification reactions of splicing.

[0364] Two unique 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 in only a subset of eukaryotes and splices the rare U12-type class of introns. The U2-dependent spliceosome is assembled from U1, U2, U5, and U4 / U6 snRNPs, as well as a number of non-snRNP proteins. The U2 snRNP is recruited with two weakly associated protein subunits, SF3a and SF3b, during the first ATP-dependent step in spliceosome assembly. SF3b is composed of seven conserved proteins, including PHF5α, SF3b155, SF3b145, SF3b130, SF3b49, SF3b14a, and SF3b10.

[0365] Splicing or RNA splicing typically 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 and the subsequent ligation of exons. Sequential transesterification reactions begin with nucleophilic attack of the 5' splice site (5'ss) by a branched adenosine (branch point, BP) in the downstream intron, resulting 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), resulting in the removal of the intron lariat and the formation of a spliced ​​RNA product.

[0366] Splicing can be controlled by various cis-acting elements and trans-acting factors. Cis-acting elements are sequences of mRNA and can include core consensus sequences and other control elements. Core consensus sequences can typically refer to conserved RNA sequence motifs including 5'ss, 3'ss, polypyrimidine tracts, and BP regions that can function for spliceosome recruitment. BP refers to a partially conserved sequence of pre-mRNA, generally less than 50 nucleotides upstream of the 3'ss. BP reacts with 5'ss during the first step of the splicing reaction. Other cis-acting control elements can include exon splicing enhancers (ESEs), exon splicing silencers (ESSs), intron splicing enhancers (ISEs), and intron splicing silencers (ISSs). Trans-acting factors can be proteins or ribonucleoproteins that bind to cis-acting elements.

[0367] Splice site specification and regulated splicing can be achieved primarily by two dynamic macromolecular mechanisms, the major spliceosome (U2-dependent) and the minor spliceosome (U12-dependent). Each spliceosome contains five snRNPs: U1, U2, U4, U5, and U6 snRNPs (processing approximately 95.5% of all introns) for the major spliceosome, and U11, U12, U4atac, U5, and U6 snRNPs (processing approximately 95.5% of all introns) for the minor spliceosome. 6 atac snRNP. Spliceosomal recognition of consensus sequence elements at 5'ss, 3'ss, and BP sites is one of the steps in the splicing pathway and can be regulated by ESE, ISE, ESS, and ISS, which can be recognized by auxiliary splicing factors including SR proteins and hnRNPs. Polypyrimidine tract binding protein (PTBP) can bind to polypyrimidine tracts of introns and promote RNA looping.

[0368] Alternative splicing is a mechanism by which a single gene can ultimately produce several different proteins. Alternative splicing is achieved by the concerted action of a variety of different proteins called "alternative splicing control proteins" that associate with the pre-mRNA, allowing distinct alternative exons to be included in the mature mRNA. These alternative forms of the transcript of this gene can give rise to distinct isoforms of a particular protein. Sequences in the pre-mRNA molecule that can bind to alternative splicing control proteins can be found in introns or exons, including but not limited to ISS, ISE, ESS, ESE, and polypyrimidine tracts. Many mutations can alter the splicing pattern. For example, mutations can be cis-acting elements and can be located in core consensus sequences (e.g., 5'ss, 3'ss, and BP) or in control elements that regulate spliceosome recruitment, including ESE, ESS, ISE, and ISS.

[0369] Cryptic splice sites, such as cryptic 5'ss and cryptic 3'ss, can refer to splice sites that are not normally recognized by the spliceosome and are therefore dormant. Cryptic splice sites can be recognized or activated, for example, by mutations in cis-acting elements or trans-acting factors, or by structural features such as bulges.

[0370] Splicing Regulation The present invention contemplates the use of small molecules with favorable drug properties that modulate the splicing activity of a target RNA. Provided herein are small molecule splicing regulators (SMSMs) that modulate the splicing of a target polynucleotide. In some embodiments, the SMSMs bind to and modulate a target RNA. In some embodiments, provided herein are libraries of SMSMs that bind to and modulate one or more target RNAs. In some embodiments, the target RNA is an mRNA. In some embodiments, the target RNA is an mRNA 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 molecules modulate the splicing of a target RNA. In some embodiments, the small molecules provided herein modulate the splicing of a sequence of a target RNA. In some embodiments, the small molecules provided herein modulate the splicing of a cryptic splice site sequence of a target RNA. In some embodiments, the small molecules provided herein bind to a target RNA. In some embodiments, the small molecules provided herein bind to a splicing complex component. In some embodiments, the small molecules provided herein bind to a target RNA and a splicing complex component.

[0371] Thus, provided herein are methods of preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting a pre-mRNA molecule and / or other elements of the splicing machinery (e.g., in a cell) with a compound provided herein to prevent or induce a splicing event in the pre-mRNA molecule. The prevented or induced splicing event can be, for example, an aberrant splicing event, a constitutive splicing event, or an alternative splicing event.

[0372] 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 with splicing elements and / or factors involved in alternative splicing, aberrant splicing, and / or constitutive splicing as described herein (e.g., in a cell) under conditions where a positive effect (prevention or induction of splicing) or a negative effect (no prevention or induction of splicing) is produced and detected, and identifying the compound that produces a positive effect as a compound that can prevent or induce a splicing event.

[0373] In some embodiments, the small molecule compounds described herein in a pharma- ceutically acceptable carrier prevent or induce alternative or aberrant splicing events in pre-mRNA molecules. As mentioned above, the small molecule compounds provided herein are not antisense oligonucleotides or antigen oligonucleotides. Tables 1A-1J and Tables 6-9 show the chemical structures and names of exemplary compounds and are not intended to be comprehensive.

[0374] In some embodiments, the composition comprises a small molecule splicing regulator compound (SMSM), where the SMSM interacts with a bulge-forming unpaired nucleobase of an RNA duplex, and 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, where the SMSM interacts with a bulge-forming unpaired nucleobase of an RNA duplex, and the RNA duplex comprises a splice site. In some embodiments, the double-stranded RNA comprises an alpha helix. In some embodiments, the bulge-forming unpaired nucleobase is located on the outer portion of the helix of the double-stranded RNA. In some embodiments, the bulge-forming unpaired nucleobase is located within the inner portion of the helix of the double-stranded RNA. In some embodiments, the SMSM forms one or more intermolecular interactions with the double-stranded RNA. In some embodiments, the SMSM forms one or more intermolecular interactions with the bulge-forming unpaired nucleobase. In some embodiments, the intermolecular interaction is selected from the group including ionic interactions, hydrogen bonds, dipole-dipole interactions, or van der Waals interactions. In some embodiments, a first portion of SMSM interacts with a bulge-forming unpaired nucleobase on a first RNA strand of an RNA duplex. In some embodiments, a second portion of SMSM interacts with one or more nucleobases of a second RNA strand of an RNA duplex, where the first RNA strand is not the second RNA strand. In some embodiments, the exchange rate of a bulge-forming unpaired nucleobase from an interior portion of a helix of a double-stranded RNA to an exterior portion of the helix is ​​reduced. In some embodiments, SMSM reduces the rotation rate of a bulge-forming unpaired nucleobase. In some embodiments, SMSM reduces the rotation rate of a bulge-forming unpaired nucleobase around the phosphate backbone of an RNA strand of an RNA duplex. In some embodiments, SMSM modulates the distance of a bulge-forming unpaired nucleobase from a second nucleobase of a double-stranded RNA. In some embodiments, the SMSM reduces the distance of a bulge-forming unpaired nucleobase from a second nucleobase of the double-stranded RNA. In some embodiments, the bulge-forming unpaired nucleobase is located within a helix of the double-stranded RNA of the complex.In some embodiments, SMSM reduces the size of a bulge in an RNA duplex. In some embodiments, SMSM eliminates a bulge in an RNA duplex. In some embodiments, SMSM stabilizes a bulge in an RNA duplex. In some embodiments, SMSM modulates splicing at a splice site in an RNA duplex. In some embodiments, SMSM increases splicing at a splice site in an RNA duplex. In some embodiments, SMSM decreases splicing at a splice site in an RNA duplex. In some embodiments, a bulge-forming unpaired nucleobase has adjusted base stacking within an RNA strand of an RNA duplex. In some embodiments, a bulge-forming unpaired nucleobase has increased base stacking within an RNA strand of an RNA duplex. In some embodiments, a bulge-forming unpaired nucleobase has decreased base stacking within an RNA strand of an RNA duplex. In some embodiments, SMSM is not an aptamer. In some embodiments, the RNA duplex comprises a pre-mRNA. In some embodiments, the bulge-forming unpaired nucleobase is free to rotate about the phosphate backbone of the RNA strand of the RNA duplex in the absence of SMSM.

[0375] In some embodiments, a method of modulating splicing comprises contacting a cell with a small molecule splicing regulator compound (SMSM), wherein the SMSM has an IC of less than 50 nM. 50and killing the cell with . In some embodiments, the method of modulating splicing comprises contacting a cell with a small molecule splicing regulator compound (SMSM), where the SMSM modulates splicing of a splice site sequence of a pre-mRNA encoding an mRNA, where the mRNA encodes a target protein or functional RNA, and the total amount of 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, the method of modulating splicing comprises contacting a cell with a small molecule splicing regulator compound (SMSM), where the SMSM modulates splicing of a splice site sequence of a pre-mRNA encoding an mRNA, where the mRNA encodes a target protein or functional RNA, and the total amount of mRNA, target protein, and / or functional RNA is at least 10% less than the total amount of mRNA, target protein, and / or functional RNA in a control cell.

[0376] In some embodiments, a method of modulating splicing comprises contacting a cell with a small molecule splicing regulator compound (SMSM), wherein the SMSM modulates splicing of a splice site sequence of a pre-mRNA encoding a first mRNA isoform associated with a disease or condition and a second mRNA isoform, such that the total amount of the first mRNA isoform is decreased 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 includes contacting a small molecule splicing regulator 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, where a ratio of the first mRNA isoform to the second mRNA isoform is decreased by at least 1.2-fold, the first mRNA and the second mRNA are encoded by pre-mRNAs comprising splice site sequences, the first mRNA isoform is associated with the disease or condition and the second mRNA isoform is associated with the disease or condition.

[0377] In some embodiments, the method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, where the SMSM modulates exon inclusion, exon exclusion, pseudoexon inclusion, intron retention, or splicing at a cryptic splice site of the polynucleotide, and the SMSM modulates splicing of the splice site sequence. In some embodiments, the method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, where the splice site sequence comprises a splice site sequence selected from the group consisting of splice site sequences in Table 2A, Table 2B, Table 2C, or Table 2D. In some embodiments, the method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, where the splice site sequence comprises a sequence selected from GGAguaag and AGAguaag. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, where the splice site sequence comprises at least one bulge-forming nucleotide at position -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, where the splice site sequence comprises a mutant nucleotide at position -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence.

[0378] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of NGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk, where 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, and k is g or u. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, wherein th...

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony, X is -NR ３ - and Z is CR ２ and R ２ is hydrogen or deuterium, R ３ is hydrogen, C １ -C ４ Alkyl, -CD ３ , or C １ -C ４ is haloalkyl, E is -NR-, R Ａ is hydrogen or deuterium, Ring Q is 【Chemistry 2】 wherein R Ｑ are each independently hydrogen, deuterium, —F, —Cl, —CN, —OH, or —CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ , -OCH ３ , -OCH ２ CH ３ , -CH ２ OCH ３ , -OCH ２ CH ２ CH ３ , and -OCH(CH ３ ) ２ and Ring P is a substituted or unsubstituted heteroaryl, or Ring Q is a substituted or unsubstituted 6-5 fused heteroaryl, 6-6 fused heteroaryl, or 5-6 fused heteroaryl; W is C １ -C ３ Alkylene or C １ -C ２ is heteroalkylene, R is hydrogen; R １１ , R １２ , R １３ and R １４ , each independently represents hydrogen, deuterium, F, C １ -C ４ Alkyl, and C １ -C ４ fluoroalkyl; R １６ is H and R １７ is F or R １６ is F and R １７ is H, R １５ and R １８ are (i) the same and selected from hydrogen and deuterium, or (ii) the same and selected from F, and C １ -C ４ alkyl, or (iii) are not the same and are selected from the group consisting of hydrogen, deuterium, F, and C. １ -C ４ is selected from the group consisting of alkyl, a is 0, b is 0, c is 1, and A compound, or a pharma- ceutically acceptable salt thereof, wherein d is 1.

2. the compound of formula (I) has the structure of formula (Ie); or 【Chemistry 3】 The compound of formula (I) has the structure of formula (If): 【Chemistry 4】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. Ring Q 【Chemistry 5】 Wherein R Ｑ are each independently selected from hydrogen and deuterium; and The compound according to claim 1 or 2, wherein ring P is a substituted or unsubstituted heteroaryl. or a pharma- ceutically acceptable salt thereof.

4. Ring P is 【Chemistry 6】 is a heteroaryl selected from the group consisting of In the formula, R Ｂ are each independently hydrogen, deuterium, halogen, hydroxy, cyano, C １ -C ６ Alkyl, -CD ３ , C １ -C ６ Fluoroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, deuterium-substituted C １ -C ６ Alkoxy and -OCD ３ is selected from R Ｂ１ But hydrogen, deuterium, C １ -C ６ Alkyl, -CD ３ , C １ -C ６ Fluoroalkyl, and C １ -C ６ heteroalkyl, and 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is 1, 2, or 3.

5. Ring P is 【Chemistry 7】 is a heteroaryl selected from the group consisting of In the formula, R Ｂ are each independently hydrogen, deuterium, halogen, hydroxy, cyano, C １ -C ６ Alkyl, -CD ３ , C １ -C ６ Fluoroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, deuterium-substituted C １ -C ６ Alkoxy and -OCD ３ is selected from R Ｂ１ But hydrogen, deuterium, C １ -C ６ Alkyl, -CD ３ , C １ -C ６ Fluoroalkyl, and C １ -C ６ heteroalkyl, and 5. The compound of claim 4, wherein m is 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

6. R Ｂ are each independently hydrogen, deuterium, -F, -Cl, -CN, or -CH ３ , -CF ３ , —OH, or —OCH ３ 6. The compound of claim 4 or 5, selected from:

7. R Ｂ１ is hydrogen, deuterium, -CH ３ , -CF ３ , or -CD ３ 6. The compound of claim 4 or 5, selected from:

8. When ring Q is a substituted or unsubstituted 6-5 fused heteroaryl, a substituted or unsubstituted 6-6 fused heteroaryl, or a substituted or unsubstituted 5-6 fused heteroaryl, the heterocycle is substituted with D, halogen, -CN, -NH ２ , -OH, -NH(CH ３ ), -N(CH ３ ) ２ , -NH(cyclopropyl), -C(=O)NH ２ , -C(=O)NH(CH ３ ), -C(=O)N(CH ３ ) ２ , -CH ３ , -CH ２ CH ３ , -CF ３ , -OCH ３ , and -OCF ３ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, substituted by one or more substituents each independently selected from:

9. Ring Q is 【Chemistry 8】 or Ring Q is 【Chemistry 9】 is selected from the group consisting of In the formula, R Ｂ１ But hydrogen, deuterium, C １ -C ６ Alkyl, -CD ３ , C １ -C ６ Fluoroalkyl, and C １ -C ６ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from: heteroalkyl.

10. W is C ２ -C ３ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, which is alkylene.

11. W is -CH ２ CH ２ --, --CH ２ CH ２ CH ２ - or -CH ２ OCH ２ 10. The compound according to any one of claims 1 to 9, wherein: -, or a pharma- ceutically acceptable salt thereof.

12. R Ａ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

13. R １５ and R １８ are both hydrogen, or R １５ and R １８ 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein both of are deuterium.

14. R １６ is H and R １７ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein:

15. R １６ is F and R １７ The compound according to any one of claims 1 to 13, wherein is H, or a pharma- ceutically acceptable salt thereof.

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