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 / 802,054, filed February 6, 2019, U.S. Provisional Application No. 62 / 802,057, filed February 6, 2019, U.S. Provisional Application No. 62 / 802,059, filed February 6, 2019, U.S. Provisional Application No. 62 / 802,061, filed February 6, 2019, U.S. Provisional Application No. 62 / 802,065, filed February 6, 2019, This application claims the benefit of U.S. Provisional Application No. 62 / 802,068, filed February 6, 2019, U.S. Provisional Application No. 62 / 802,071, filed February 6, 2019, U.S. Provisional Application No. 62 / 802,072, filed February 6, 2019, and U.S. Provisional Application No. 62 / 802,075, filed February 6, 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 produces a single precursor messenger RNA (pre-mRNA). Intron sequences are then removed from the pre-mRNA by a process called splicing, resulting in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing generates multiple mRNAs that encode 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 involve methods such as gene therapy, genome editing, or broad oligonucleotide technologies (e.g., antisense, RNAi). Gene therapy and genome editing act upstream of mRNA transcription by affecting the DNA code and thereby altering mRNA expression. Oligonucleotides modulate RNA action through standard base / base hybridization. The appeal of this approach lies in the design of the oligonucleotide's basic pharmacophore, which can be defined in a straightforward manner by known base pairing with the target sequence. Each of these therapies faces 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, which prevents delivery to the brain or spinal cord after parenteral administration for the treatment of diseases (e.g., neurological disorders, brain cancer). In addition, oligonucleotides are not effectively taken up by solid tumors without complex delivery systems such as lipid nanoparticles. Furthermore, the majority of oligonucleotides taken up by 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. Furthermore, cis-acting elements (e.g., protein binding elements) and trans-acting factors (e.g., splicing complex components) may create additional secondary and tertiary complexities (e.g., by binding to pre-mRNA). These characteristics may limit the efficacy and effectiveness of 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 severely limit oligonucleotide therapy (e.g., by blocking hybridization to pre-mRNA). Small molecules have been essential in elucidating the mechanisms, regulation, and function of many cellular processes, including DNA replication, transcription, and translation. Although several recent reports have described screening for small molecule effectors of splicing, only a few constitutive or alternative splicing regulators have been identified, and many small molecule inhibitors lack specificity, selectivity, efficacy, toxicity, or are not orally available. Targeting the RNA transcriptome with small molecule regulators represents an untapped therapeutic approach for treating various RNA-mediated diseases. Therefore, 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] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0007] In one embodiment, 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 Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0008] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0009] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0010] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0011] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0012] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0013] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0014] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0015] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0016] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0017] In one embodiment, 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 Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0018] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, X is [ka] and Z is N. In some embodiments, X is [ka] and Z is CR 2 is.

[0019] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof, X is —O—, —S—, or —NR 3 - and Z is CR 2 is.

[0020] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1, -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; R11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0021] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0022] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0023] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0024] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0025] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0026] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0027] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0028] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0029] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0030] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0031] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0032] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0033] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0034] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0035] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0036] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ia): [ka]

[0037] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ib): [ka]

[0038] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ib1). [ka]

[0039] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ib2). [ka]

[0040] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ic): [ka]

[0041] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ic1). [ka]

[0042] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ic2): [ka]

[0043] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Id): [ka]

[0044] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie): [ka]

[0045] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie1). [ka]

[0046] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie2). [ka]

[0047] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie3): [ka]

[0048] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie4): [ka]

[0049] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If): [ka]

[0050] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If1). [ka]

[0051] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If2). [ka]

[0052] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If3). [ka]

[0053] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If4). [ka]

[0054] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIa): [ka]

[0055] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIb): [ka]

[0056] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIb1): [ka]

[0057] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIb2): [ka]

[0058] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIc): [ka]

[0059] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIc1): [ka]

[0060] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIc2): [ka]

[0061] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIId): [ka]

[0062] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe): [ka]

[0063] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe1): [ka]

[0064] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe2): [ka]

[0065] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe3): [ka]

[0066] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe4): [ka]

[0067] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf): [ka]

[0068] In some embodiments, the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (IIIf1): [ka]

[0069] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf2): [ka]

[0070] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf3): [ka]

[0071] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf4): [ka]

[0072] In some embodiments of the compounds of Formulae (I)-(IV) or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, ring Q is substituted or unsubstituted aryl.

[0073] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1, -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-hydroxy-phenyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0074] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0075] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl, where when aryl is substituted it is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; In the formula, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0076] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where when heteroaryl is substituted it is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; In the formula, R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0077] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is [ka] where R Q are each independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH), and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0078] In some embodiments of the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, ring Q is a substituted or unsubstituted heteroaryl. In some embodiments, ring Q is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl. In some embodiments, ring Q is [ka] wherein R is a 6-membered monocyclic heteroaryl selected from the group consisting of Qare each independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH), and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Q are each independently hydrogen, —F, —Cl, —CN, —OH, —CH 3 , —CF 3 , or —OCH 3 .

[0079] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring P is a substituted or unsubstituted heteroaryl. In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; m is 0, 1, 2, or 3.

[0080] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; m is 0, 1, 2, or 3.

[0081] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R B are each independently hydrogen, deuterium, -F, -Cl, -CN, -CH, -CF, -OH, or -OCH. In some embodiments, R B are each independently -F or -OCH. In some embodiments, R B is H.

[0082] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, RB1 is hydrogen, deuterium, -CH3, -CF3, or -CD3.

[0083] In some embodiments of a compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, 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.

[0084] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0085] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is [ka] is selected from the group consisting of:

[0086] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is [ka] is selected from the group consisting of:

[0087] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is [ka] is selected from the group consisting of:

[0088] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is [ka] wherein R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0089] In some embodiments of a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is -CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is -CH2CH2CH2-.

[0090] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, W is substituted or unsubstituted C1-C2 heteroalkylene. In some embodiments, W is -CH2OCH2-. In some embodiments, W is -CH2O-, where O is R 18 The carbon atom bearing the group is bonded to the carbon atom.

[0091] In some embodiments of a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, W is substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene. In some embodiments, W is cyclopropylene.

[0092] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is -CH=CH-.

[0093] In some embodiments of the compound of Formulae (I)-(IV) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl, or substituted or unsubstituted C2-C4 heterocycloalkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHCHCHOH, -CHCN, -CHF, -CHF, -CF, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHOH, -CHCN, -CHF, -CF, or cyclopropyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHF, -CHF, -CF, cyclopropyl, or oxetanyl. In some embodiments, R is -CH, -CHCH, -CHF, -CHF, or -CF. In some embodiments, R is hydrogen.

[0094] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 11 , R 12 , and R 16 One or more of the following may independently be F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 11 , R 12 , and R 16 are independently selected from the group consisting of F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 11 , R 12 , and R 16 is independently selected from the group consisting of F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. 11 , R 12 , and R 16 is hydrogen.

[0095] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0096] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 12 is H, D, or F. In some embodiments, R12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 is F.

[0097] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0098] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0099] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 15 is H, D, F, CHF, CHF, CF, or CH. In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CHF, CHF, CF, or CH. In some embodiments, R 15 is F, CF, CHF, or CHF. In some embodiments, R 15 is F.

[0100] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 16 is H, D, or F. In some embodiments, R 16is D. In some embodiments, R 16 is H. In some embodiments, R 16 is F.

[0101] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0102] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 18 is H, D, F, CHF, CHF, CF, or CH. In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CHF, CHF, CF, or CH. In some embodiments, R 18 is F, CF, CHF, or CHF. In some embodiments, R 18 is F.

[0103] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 16 and R 17 One or more of the following may independently be F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. 16 and R 17are independently selected from the group consisting of F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 16 and R 17 is independently selected from the group consisting of F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. 16 and R 17 is hydrogen.

[0104] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 2 is hydrogen, —CH, or —OCH. In some embodiments, R 2 is hydrogen.

[0105] In some embodiments of the compound of Formula (I) or (III), or a pharmaceutically acceptable salt or solvate thereof, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -NR 3 In some embodiments, R 3 is hydrogen, —CH, —CHCH, —CH(CH), —CHF, —CHF, —CF, cyclopropyl, or oxetanyl. 3 is hydrogen, —CH, —CHCH, —CH(CH), —CF, cyclopropyl, or oxetanyl. 3 is hydrogen, —CH, —CH(CH), cyclopropyl, or oxetanyl. In some embodiments, R 3 is hydrogen, —CH3, or cyclopropyl.

[0106] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R A are each independently hydrogen, F, Cl, -CN, -CH, -CHCH, -CHCHCH, -CH(CH), -OH, -OCH, -OCHCH, -OCF, -CHF, -CHF, or -CF. A are each independently hydrogen, F, Cl, —CN, —CH, —OH, —OCH, —OCF, —CHF, —CHF, or —CF. In some embodiments, R A are each independently hydrogen, F, Cl, —CN, —CH, or —OCH. In some embodiments, R A are each independently hydrogen, F, Cl, or —CH. In some embodiments, R A are each hydrogen.

[0107] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 15 and R 18 In some embodiments, both R 15 and R 18 In some embodiments, both R 15 and R 18 is the same as f, -or 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18 are the same and are selected from the group consisting of F, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18are the same and are selected from the group consisting of F, —CH, —CHOH, —OCHCN, —OH, —OCH, —OCHCN, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from the group consisting of F, —CH, —OCH, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from the group consisting of F, —CH3, and —OCH3. In some embodiments, R 15 and R 18 is F. In some embodiments, R 15 and R 18 is -CH3. In some embodiments, R 15 and R 18 is -OCH3.

[0108] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18 are the same and are selected from the group consisting of hydrogen, deuterium, F, CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18are not the same and are selected from the group consisting of hydrogen, deuterium, F, -CH, -CHOH, -OCHCN, -OH, -OCH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18 are not the same and are selected from the group consisting of hydrogen, deuterium, F, —CH, —OCH, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are not the same and are selected from the group consisting of hydrogen, deuterium, F, —CH3, and —OCH3. In some embodiments, R 15 is F and R 18 is hydrogen. In some embodiments, R 15 is hydrogen and R 18 is F. In some embodiments, R 15 is hydrogen and R 18 is CH3. In some embodiments, R 15 is CH3 and R 18 is hydrogen.

[0109] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 4 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl. 4 are each independently hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -CHOCH, -CHF, -CHF, or -CF. 4 are each independently hydrogen, —CH, —CHCH, —CHOH, —CHOCH, —CHF, —CHF, or —CF. 4 Each is hydrogen. In some embodiments, R 4 is -CH3.

[0110] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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 and 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 At least two of 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 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of them are F.

[0111] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 11, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R is F or C-C fluoroalkyl. 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 In some embodiments, 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 17At least two of the groups contain fluorine.

[0112] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. 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.

[0113] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or 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 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R18 At least two of 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 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of them are F.

[0114] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 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.

[0115] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. 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.

[0116] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0117] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0118] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0119] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0120] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R15 is H, D, F, CHF, CHF, CF, or CH. In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CHF, CHF, CF, or CH. In some embodiments, R 15 is F, CF, CHF, or CHF. In some embodiments, R 15 is F.

[0121] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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. In some embodiments of the compounds of Formulas (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0122] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 18 is H, D, F, CHF, CHF, CF, or CH. In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CHF, CHF, CF, or CH. In some embodiments, R 18 is F, CF, CHF, or CHF. In some embodiments, R 18 is F.

[0123] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, R 11 , R 12 , R 19 , R 20 , and R 16 In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, R 19 is hydrogen. In some embodiments, R 19 is H, F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 19 is H, F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. In some embodiments, R 19 is F or -OCH3.

[0124] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, R 20 is hydrogen. In some embodiments, R 20 is H, F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 20 is H, F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. In some embodiments, R 20 is F or -OCH3.

[0125] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, R 19 is H, D, or F. In some embodiments, R 19 is D. In some embodiments, R 19 is H. In some embodiments, R 19 is F. In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or 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. In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or 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. In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or 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. In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, R 17 and R 20 is H. In some embodiments, R 17 and R 20 is D. In some embodiments, R 17 and R 20 is F.

[0126] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or 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 18 and 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 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 is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R19 , R 20 , and R 17 At least two of them are F.

[0127] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or 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 comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. 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 R is F or C-C fluoroalkyl. 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 In some embodiments, 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 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0128] In some embodiments of the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. 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.

[0129] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl. 1 are each independently hydrogen, deuterium, or C1-C4 alkyl. In some embodiments, R 1 are each independently hydrogen, deuterium, or methyl.

[0130] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R E is hydrogen. In some embodiments, R E is methyl or ethyl.

[0131] In some embodiments, the compounds of Formulas (I)-(IV) are single enantiomers. In some embodiments, the compounds of Formulas (I)-(IV) are not racemic. In some embodiments, the compounds of Formulas (I)-(IV) are substantially free of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) are single isomers substantially free of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) contain 25% or less of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) contain 20% or less of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) contain 15% or less of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) contain 10% or less of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) contain 5% or less of other isomers. In some embodiments, the compounds of Formulas (I)-(IV) contain 1% or less of other isomers.

[0132] In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 75%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 80%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 85%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 90%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 95%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 96%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 97%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 98%. In some embodiments, the compounds of Formulas (I)-(IV) have a stereochemical purity of at least 98%.

[0133] In some embodiments, the asymmetric carbon atom of a compound of Formulas (I)-(IV) is present in enantiomerically enriched form. In certain embodiments, the asymmetric carbon atom of a compound of Formulas (I)-(IV) is in the (S) or (R) configuration in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0134] In one aspect, described herein is a method of modulating splicing, comprising contacting a cell with a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound modulates splicing of a splice site sequence in a pre-mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or functional RNA.

[0135] In one aspect, described herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0136] In one aspect, described herein are methods of treating a condition or disease, the methods comprising administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0137] In one aspect, described herein is the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a condition or disease.

[0138] 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 INVENTION

[0139] Certain details herein are described to provide a thorough understanding of 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 claimed disclosure.

[0140] 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.

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0142] definition The terms "compound(s) of this disclosure", "compound(s) of the present disclosure", "small molecule steric regulator(s)", "small molecule splicing regulator(s)", "steric regulator(s)", "splicing regulator(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 stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. The terms "compound(s) of this disclosure," "compound(s) of the present disclosure," "small molecule steric regulator(s)," "small molecule splicing regulator(s)," "steric regulator(s)," "splicing regulator(s)," "compound(s) that modify splicing," and "splicing-modifying compound(s)," "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, an SMSM can bind directly or indirectly to a target polynucleotide, e.g., an RNA (e.g., pre-mRNA) with mutated, non-mutated, bulged, and / or aberrant splice sites, resulting in modulation of the 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 modulation of splicing of target RNAs. 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 modulation of splicing of target polynucleotides.These terms specifically exclude compounds consisting 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, 3WJs, 4WJs, parallel Y junctions, hairpins, bulge loops, pseudoknots, internal loops, and other higher-order RNA structural motifs.

[0143] 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 in an endogenous form). The RNA may contain pigenetic, post-transcriptional natural, artificial (e.g., chemical or in vitro) or other modifications; may bind, for example, to 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-native 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.

[0144] As used herein, the terms "target polynucleotide" and "target RNA" refer 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 "target RNA" can have a secondary or tertiary structure that can bind to the small molecule compounds described herein.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] When referring to 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., from the replacement of one hydrogen to the replacement of all hydrogens by substituents.

[0149] 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 it does not occur.

[0150] The term "substituent" means an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0151] 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 unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When referring to 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 with a substituent.

[0152] The following abbreviations are used throughout this specification: acetic acid (AcOH), ethyl acetate (EtOAc), butyl alcohol (n-BuOH), 1,2-dichloroethane (DCE), dichloromethane (CHCl, DCM), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), diisopropylethylamine (DIPEA), 4-(dimethylamino)pyridine (DMAP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hydrogen chloride (HCl), meta-chloroperbenzoic acid (mCPBA), methanol (MeOH), methoxymethyl bromide (mCPBA), methylparaben (MPAR ... Methyl (MOMBr), N-methyl-2-pyrrolidone (NMP), methyl iodide (MeI), n-propanol (n-PrOH), p-methoxybenzyl (PMB), triethylamine (EtN), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (Pd(dppf)Cl), sodium ethanethiolate (EtSNa), sodium acetate (NaOAc), sodium bis(trimethylsilyl)amide (NaHMDS), sodium hydride (NaH), sodium hydroxide (NaOH), tetrahydropyran (THP), tetrahydrofuran (THF).

[0153] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C4" indicates that there are from 1 to 4 carbon atoms present in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms in the group. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms present 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.

[0154] The term "oxo" refers to a ═O substituent.

[0155] The term "thioxo" refers to the ═S substituent.

[0156] The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0157] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C1-C 10 Similarly, when referred to as alkyl, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl containing other numbers of carbon atoms (and other moieties defined herein) are represented similarly. Alkyl groups include C1-C 10Examples of alkyl include, but are not limited to, alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. 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, alkyl is methyl or ethyl. In some embodiments, alkyl is —CH(CH3)2 or —C(CH3)3. Unless otherwise expressly stated herein, alkyl groups may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkyl is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkyl is -CH2-. In some embodiments, alkyl is -CH2CH2-. In some embodiments, alkyl is -CH2CH2CH2-. In some embodiments, alkyl is -CH2CH2CH2-.

[0158] The term "alkoxy" refers to a group of the formula -OR a where R a is an alkyl radical as defined above. 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, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0159] The term "alkylamino" refers to a group of the formula -NHR a or -NR a R a where R ais 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.

[0160] 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=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0161] 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 a wherein 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≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0162] The term "aromatic" refers to a planar ring having a delocalized electron system containing 4n+2 electrons, where n is an integer. A ππ aromatic can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0163] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can 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 can 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 aryl radicals that are 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.

[0164] The term "haloalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been 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 of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms.

[0165] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been 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 hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.

[0166] 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 single common 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.

[0167] 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. Thus, this term distinguishes a carbocyclic ring from a "heterocyclic" ring or a "heterocyclic" heterocycle in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0168] 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 through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl 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.

[0169] 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 a molecule and is bonded 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.

[0170] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or 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.

[0171] The term "haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0172] The term "haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0173] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0174] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), or combinations thereof. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C-C heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH.

[0175] The term "heteroalkylene" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl have been replaced with an O, N, or S atom. A "heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to the 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, but are not limited to, -OCH2CHO-, -OCH2CHOCH2CHO-, or -OCH2CHOCH2CHOCH2CHO-.

[0176] 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 saturated 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 specified, 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 to 12 carbons, 1 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms within 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) comprising the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise explicitly in the specification, a heterocycloalkyl group may be optionally substituted.

[0177] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings (also known as heterocyclic groups) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, with heterocyclic groups each having 3 to 12 atoms in their ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 12 atoms in their 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, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiazole ... oranyl, 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) and 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 a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0178] The term "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls are monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls 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, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryl has 0 to 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 is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl.In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 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.

[0179] 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.

[0180] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, —S(═O)(C-C alkyl). In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -NH(cyclopropyl), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituents are substituted with one or two of the preceding groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0181] The term "tautomer" refers to a proton migration 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 migration of a hydrogen atom, involving the switching of a single bond and an adjacent double bond. In bonding 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]

[0182] 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 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 one order of magnitude, within five-fold, or within two-fold of a value.

[0183] 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 of skill 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.

[0184] 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.

[0185] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered drug or compound that will alleviate 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 drug that results in a clinically significant reduction in one or more disease symptoms. An appropriate "effective" amount can be determined using techniques such as a dose escalation study in each individual case.

[0186] 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 a target in either amount, potency, or duration.

[0187] 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 such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, laboratory animals such as rodents, e.g., rats, mice, and guinea pigs, etc. In one aspect, a mammal is a human. The term "animal" as used herein includes human 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, the non-human animal is a mouse.

[0188] 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 a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting symptoms of a disease or condition.

[0189] The term "preventing" a condition or "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.

[0190] 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 pharmaceutically active ingredient together with one or more pharmaceutically acceptable excipients.

[0191] As used herein, the term "pharmaceutical combination" refers to 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, such as the compounds described herein and auxiliary agents, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the 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 that administration provides an effective level of these two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0192] The term "pharmaceutically 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 included.

[0193] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" may be used interchangeably and can refer to 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.

[0194] 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 the 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 an SMSM compound of any one of Formulas (I)-(IV) with an acid. A pharmaceutically acceptable salt can also be obtained by reacting a compound of any one of Formulas (I)-(IV) with a base to form a salt.

[0195] Types of pharmaceutically acceptable salts include (1) salts of the free base derived from the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or the like, or with a pharmaceutically 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 (1) Acid addition salts formed by reacting the parent compound with 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (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 coordinate 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, and the like.

[0196] 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.

[0197] As used herein, the term "polynucleotide" generally refers to a molecule containing two or more linked nucleic acid subunits, e.g., nucleotides, and may be used interchangeably with "oligonucleotide." For example, a polynucleotide may contain one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), or variants thereof. A nucleotide generally contains a nucleoside and at least one, two, three, four, five, six, seven, eight, nine, ten, or more phosphate (PO3) groups. A nucleotide may contain a nucleobase, a five-carbon sugar (either ribose or deoxyribose), and one or more phosphate groups. Ribonucleotides include nucleotides in which the sugar is ribose. Deoxyribonucleotides include nucleotides in which the sugar is deoxyribose. A nucleotide can be a nucleoside monophosphate, nucleoside diphosphate, nucleoside triphosphate, or nucleoside polyphosphate. For example, the nucleotide can be a deoxyribonucleoside polyphosphate, such as deoxyribonucleoside triphosphate (dNTP). Exemplary dNTPs include deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP), and deoxythymidine triphosphate (dTTP). The dNTP can also include a detectable tag, such as a luminescent tag or marker (e.g., a fluorophore). For example, the nucleotide can be a purine (i.e., A or G, or a variant thereof) or a pyrimidine (i.e., C, T, or U, or a variant thereof). In some examples, the polynucleotide is deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a derivative or variant 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 embodiments thereof, such as single-stranded, double-stranded, triple-stranded, helix, hairpin, stem-loop, bulge, etc. In some cases, the polynucleotide is circular. The polynucleotide can have various lengths. For example, a 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. Polynucleotides can be isolated from cells or tissues. For example, polynucleotide sequences can include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules, and / or synthetic DNA / RNA analogs.

[0198] A polynucleotide may contain one or more nucleotide variants, including non-standard nucleotide(s), unnatural 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-methylaminomethyl Examples of suitable nucleotides include, but are not limited to, aminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueuosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, 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, and the like. In some cases, nucleotides may contain modifications of 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 unavailable to form a hydrogen bond with a complementary nucleotide), sugar moiety, or 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 disclosed oligonucleotides can result in higher density in bits per cubic mm, greater safety (resistance to accidental or intentional 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.

[0199] As used herein, the terms "polypeptide," "protein," and "peptide" are used interchangeably and refer to a polymer of amino acid residues linked via peptide bonds and 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 encoding the protein. Proteins are essential for the structure, function, and control of cells, tissues, and organs of the body, each with 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.

[0200] 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.

[0201] 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.

[0202] As used herein, "low molecular weight compound" can be used interchangeably with "small molecule" or "small organic molecule." Small molecule refers to a compound other than a peptide or oligonucleotide, and typically has a molecular weight of less than about 2000 daltons, e.g., less than about 900 daltons.

[0203] Ribonucleoprotein (RNP) refers to a nuclear protein containing 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, the enzyme telomerase, vault ribonucleoprotein, RNase P, heterogeneous nuclear RNPs (hnRNPs), and small nuclear RNPs (snRNPs).

[0204] Nascent RNA transcripts from protein-coding genes and mRNA processing intermediates are collectively referred to as pre-mRNA, and are generally bound by proteins in the nucleus of eukaryotic cells.From the time when nascent transcripts first emerge from RNA polymerase (e.g., RNA polymerase II) until mature mRNA is transported to the cytoplasm, RNA molecules associate 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-mRNA and nuclear RNA).

[0205] 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 required for splicing, such as constitutive splicing, alternative splicing, regulated splicing, and splicing of specific messages or groups of messages. A group of related proteins, serine-arginine-rich proteins (SR proteins), can function on 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 cofactors (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.

[0206] The term "intron" refers to both DNA sequences within a gene and the corresponding sequences in unprocessed RNA transcripts. As part of the RNA processing pathway, introns can be removed by RNA splicing either immediately after or co-transcriptionally. 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).

[0207] An "exon" can be any portion of a gene that is produced by that gene that encodes a part of the final mature RNA after introns have been removed by RNA splicing. The term "exon" refers both to the DNA sequence within a gene and the corresponding sequence in the RNA transcript.

[0208] The "spliceosome" can be constructed from a complex of snRNA and proteins. The spliceosome can remove introns from the transcribed pre-mRNA.

[0209] "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 the population is killed. 50) is the dose at which 50% of a population develops a particular toxic effect. One particularly useful pharmacological endpoint is traditionally known as 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).

[0210] As used herein, the term "AUC" refers to the abbreviation for "area under the curve" in a graph of the concentration of a therapeutic agent over time in a particular area or tissue, e.g., blood or plasma, of a subject to which the therapeutic agent has been administered.

[0211] Small molecule splicing regulators (SMSMs) The compounds of the present disclosure and their pharmaceutically acceptable compositions have been found to be effective as drugs for use in the treatment, prevention, or amelioration of diseases or conditions associated with target RNA. The present disclosure provides the unexpected discovery that certain small chemical molecules, referred to herein as small molecule splicing regulators (SMSMs), can modify splicing events in pre-mRNA molecules. 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 disclosure 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, small molecules of the present disclosure can be used to: 2) prevent and / or modify post-transcriptional regulation (e.g., splicing) of gene products, such as hnRNPs, snRNPs, SR proteins, and other splicing factors, which can then participate in the formation and / or function of spliceosome or splicing complex components; 3) prevent and / or modify phosphorylation, glycosylation, and / or other modifications of gene products, including, but not limited to, hnRNPs, snRNPs, SR proteins, and other splicing factors, which can then participate in the formation and / or function of spliceosome or splicing complex components; and 4) bind to and / or otherwise affect specific pre-mRNAs, e.g., to prevent or induce specific splicing events via mechanisms that do not involve base pairing with the RNA in a sequence-specific manner. Small molecules of the present disclosure are distinct from and not related to antisense or antigen oligonucleotides.

[0212] 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, which induce transcriptionally inactive variants or transcripts of the gene products. Described herein are compounds that modify the splicing of gene products, which suppress transcriptionally inactive variants or transcripts of the gene products.

[0213] In some embodiments, compounds of Formulas (I)-(IV) are prepared from racemic starting materials (and / or intermediates) and separated into individual enantiomers as intermediates or final products by chiral chromatography. 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.

[0214] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0215] In one embodiment, 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 Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0216] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0217] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, X is [ka] and Z is N. In some embodiments, X is [ka] and Z is CR 2 is.

[0218] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof, X is —O—, —S—, or —NR 3 - and Z is CR 2 is.

[0219] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0220] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0221] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0222] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0223] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0224] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0225] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 3 is hydrogen, -CN, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0226] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0227] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0228] In one embodiment, 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 Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0229] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; RA are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0230] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1, -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; R11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0231] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0232] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0233] In one embodiment, 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 E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0234] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0235] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0236] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0237] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is N or CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; or 3) Not the same as hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Disclosed herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0238] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0239] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18are the same and are selected from the group consisting of hydrogen and deuterium; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0240] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0241] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0242] In one embodiment, a compound of formula (III) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0243] In one embodiment, a compound of formula (IV) [ka] During the ceremony, E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; [ka] is a single bond or a double bond, X is, [ka] and Z is C, or X is, [ka] and Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, or substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C5 heterocycloalkyl; R1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 when present, is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 4 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 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 C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are not the same, hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 0 or 1.

[0244] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ia): [ka]

[0245] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ib): [ka]

[0246] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ib1). [ka]

[0247] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ib2). [ka]

[0248] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ic): [ka]

[0249] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ic1). [ka]

[0250] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ic2): [ka]

[0251] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Id): [ka]

[0252] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie): [ka]

[0253] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie1). [ka]

[0254] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie2). [ka]

[0255] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie3): [ka]

[0256] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (Ie4): [ka]

[0257] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If): [ka]

[0258] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If1). [ka]

[0259] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If2). [ka]

[0260] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If3). [ka]

[0261] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof has the structure of Formula (If4). [ka]

[0262] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIa): [ka]

[0263] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIb): [ka]

[0264] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIb1): [ka]

[0265] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIb2): [ka]

[0266] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIc): [ka]

[0267] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIc1): [ka]

[0268] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIc2): [ka]

[0269] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIId): [ka]

[0270] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe): [ka]

[0271] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe1): [ka]

[0272] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe2): [ka]

[0273] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe3): [ka]

[0274] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIe4): [ka]

[0275] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf): [ka]

[0276] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf1): [ka]

[0277] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf2): [ka]

[0278] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf3): [ka]

[0279] In some embodiments, the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, has the structure of Formula (IIIf4): [ka]

[0280] In some embodiments, ring Q is substituted or unsubstituted aryl.

[0281] In some embodiments, ring Q is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1, -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-hydroxy-phenyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0282] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0283] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl, where if the aryl is substituted it is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; In the formula, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0284] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where when the heteroaryl is substituted it is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; In the formula, R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0285] In some embodiments, ring Q is [ka] where R Q are each independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH), and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0286] In some embodiments, ring Q is a substituted or unsubstituted heteroaryl. In some embodiments, ring Q is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl. In some embodiments, ring Q is [ka] wherein R is a 6-membered monocyclic heteroaryl selected from the group consisting of Q are each independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH), and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Qare each independently hydrogen, —F, —Cl, —CN, —OH, —CH 3 , —CF 3 , or —OCH 3 .

[0287] In some embodiments, ring P is substituted or unsubstituted heteroaryl. In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; m is 0, 1, 2, or 3.

[0288] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R Bare each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; m is 0, 1, 2, or 3.

[0289] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring P is [ka] wherein R is a heteroaryl selected from the group consisting of B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1- C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7In some embodiments, m is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 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.

[0290] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring P is [ka] wherein R is a heteroaryl selected from the group consisting of B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1- C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 2- C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 In some embodiments, R is selected from the group consisting of cycloalkyl, substituted or unsubstituted C-C 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 C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 In some embodiments, m is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 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.

[0291] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring P is [ka] wherein R is a heteroaryl selected from the group consisting of B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 In some embodiments, m is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 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.

[0292] In some embodiments, R B are each independently hydrogen, deuterium, -F, -Cl, -CN, -CH, -CF, -OH, or -OCH. In some embodiments, R B are each independently -F or -OCH3.

[0293] In some embodiments, R B1 is hydrogen, deuterium, -CH3, -CF3, or -CD3.

[0294] In some embodiments, 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.

[0295] In some embodiments, ring Q is Deuterium, halogens, -OH, -NO2, -CN, -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; In the formula, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0296] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0297] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0298] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0299] In some embodiments, ring Q is [ka] wherein R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0300] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 It is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0301] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 It is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0302] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C 1- C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 It is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0303] In some embodiments of the compounds of Formulae (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, ring Q is [ka] wherein R B1 is hydrogen, deuterium, substituted or unsubstituted C 1- C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C 1- C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C-C heterocycloalkyl, wherein each ring Q group is selected from the group consisting of 1, 2, 3, 4, or 5 R B and R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 In some embodiments, R is selected from the group consisting of cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0304] In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is -CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is -CH2CH2CH2-.

[0305] In some embodiments, W is substituted or unsubstituted C1-C2 heteroalkylene. In some embodiments, W is -CH2OCH2-. In some embodiments, W is -CH2O-, where O is R 18 The carbon atom bearing the group is bonded to the carbon atom.

[0306] In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene. In some embodiments, W is cyclopropylene.

[0307] In some embodiments, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is -CH=CH-.

[0308] In some embodiments, R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl, or substituted or unsubstituted C2-C4 heterocycloalkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHCHCHOH, -CHCN, -CHF, -CHF, -CF, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH, -CHOH, -CHCN, -CHF, -CF, or cyclopropyl. In some embodiments, R is hydrogen, -CH, -CHCH, -CHF, -CHF, -CF, cyclopropyl, or oxetanyl. In some embodiments, R is -CH, -CHCH, -CHF, -CHF, or -CF. In some embodiments, R is hydrogen.

[0309] In some embodiments, R 11 , R 12 , and R 16One or more of the following may independently be F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 11 , R 12 , and R 16 are independently selected from the group consisting of F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 11 , R 12 , and R 16 is independently selected from the group consisting of F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. 11 , R 12 , and R 16 is hydrogen.

[0310] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0311] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0312] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0313] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0314] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 15 is H, D, F, CHF, CHF, CF, or CH. In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CHF, CHF, CF, or CH. In some embodiments, R 15 is F, CF, CHF, or CHF. In some embodiments, R 15 is F.

[0315] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0316] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0317] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 18 is H, D, F, CHF, CHF, CF, or CH. In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CHF, CHF, CF, or CH. In some embodiments, R 18 is F, CF, CHF, or CHF. In some embodiments, R 18 is F.

[0318] In some embodiments, R 16 and R 17 One or more of the following may independently be F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 16 and R 17 are independently selected from the group consisting of F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 16 and R 17is independently selected from the group consisting of F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. 16 and R 17 is hydrogen.

[0319] In some embodiments, R 2 is hydrogen, —CH, or —OCH. In some embodiments, R 2 is hydrogen.

[0320] In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -NR 3 -It is.

[0321] In some embodiments, R 3 is hydrogen, —CH, —CHCH, —CH(CH), —CHF, —CHF, —CF, cyclopropyl, or oxetanyl. 3 is hydrogen, —CH, —CHCH, —CH(CH), —CF, cyclopropyl, or oxetanyl. 3 is hydrogen, —CH, —CH(CH), cyclopropyl, or oxetanyl. In some embodiments, R 3 is hydrogen, —CH3, or cyclopropyl.

[0322] In some embodiments, R A are each independently hydrogen, F, Cl, -CN, -CH, -CHCH, -CHCHCH, -CH(CH), -OH, -OCH, -OCHCH, -OCF, -CHF, -CHF, or -CF. A are each independently hydrogen, F, Cl, —CN, —CH, —OH, —OCH, —OCF, —CHF, —CHF, or —CF. In some embodiments, R Aare each independently hydrogen, F, Cl, —CN, —CH, or —OCH. In some embodiments, R A are each independently hydrogen, F, Cl, or —CH. In some embodiments, R A are each hydrogen.

[0323] In some embodiments, R 15 and R 18 In some embodiments, both R 15 and R 18 In some embodiments, both R 15 and R 18 is the same as f, -or 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18 are the same and are selected from the group consisting of F, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, ...

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony, X is -O- or -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 , C 1 -C 4 haloalkyl, or C 3 -C 4 cycloalkyl; E is -NR-, R Ａ are each independently hydrogen or deuterium; Ring Q is a substituted or unsubstituted 2-hydroxy-phenyl, or a substituted or unsubstituted 6-6, 6-5, or 5-6 fused heteroaryl; W is C 1 -C 3 alkylene, or C 1 -C 2 heteroalkylene; R is hydrogen; R １１ , R １２ , R １３ , and R １４ are each independently selected from the group consisting of hydrogen, deuterium, F, and C 1 -C 4 alkyl; R 16 is H and R 17 is F, or R 16 is F and R 17 is H; R １５ and R １８ but, 1) are the same and are selected from the group consisting of hydrogen and deuterium; 2) are the same and are selected from the group consisting of F, and C 1 -C 4 alkyl; or 3) are not the same and are selected from the group consisting of hydrogen, deuterium, F, and C 1 -C 4 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 formula (Id): 【Chemistry 2】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

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

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

5. 5. The compound of any one of claims 1 to 4, wherein ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a pharma- ceutically acceptable salt thereof.

6. Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where the heteroaryl is substituted, Deuterium, halogen, -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 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkoxy; In the formula, R １ are each independently hydrogen, deuterium, C 1 -C 4 alkyl, -CD ３ 6. The compound of claim 5, wherein R is C 1 -C 4 haloalkyl, or C 1 -C 4 heteroalkyl, or a pharma- ceutically acceptable salt thereof.

7. Ring Q is 【Chemistry 5】 Wherein R Ｑ are each independently selected from the group consisting of hydrogen or deuterium; Ring P is 【Chemistry 6】 is a heteroaryl selected from the group consisting of In the formula, R Ｂ each independently represents 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 the group consisting of R Ｂ１ is hydrogen, deuterium, C 1 -C 6 alkyl, -CD ３ , C 1 -C 6 fluoroalkyl, and C 1 -C 6 heteroalkyl; 6. The compound according to any one of claims 1 to 5, wherein m is 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

8. Ring P is 【Chemistry 7】 is a heteroaryl selected from the group consisting of wherein each R B is independently selected from the group consisting of 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 ; R B1 is selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, -CD 3 , C 1 -C 6 fluoroalkyl, and C 1 -C 6 heteroalkyl; 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein m is 1, 2, or 3.

9. A compound according to claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein ring Q is a substituted or unsubstituted 6-6, 6-5 or 5-6 fused heteroaryl, which if substituted is substituted by one or more substituents independently selected from oxo, D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -C(=O)(1-azetidinyl), -CH3, -CH2CH3, -CH2CF3, -CF3, -OCH3, -OCH2F, and -OCF3.

10. Ring Q is 【Chemistry 8】 or Ring Q is 【Chemistry 9】 selected from the group consisting of: The compound of claims 1 to 4, wherein R B1 is selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, -CD 3 , C 1 -C 6 fluoroalkyl, and C 1 -C 6 heteroalkyl, or a pharma- ceutically acceptable salt thereof.

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

12. R ２ is hydrogen, R Ａ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein each is hydrogen.

13. X is -NR ３ - and R ３ is hydrogen, -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ F, -CHF ２ 13. The compound of any one of claims 1 to 12, wherein:

14. R １５ and R １８ are hydrogen, R １５ and R １８ Both are -CH ３ That is, R １５ is hydrogen, R １８ CH ３ is, or R １５ CH ３ and R １８ is hydrogen, 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier.

Images