Methods and compositions for modulating splicing

Abstract

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

Description

[0001] This application is a divisional application of a patent application with an application date of February 6, 2020, application number 202080027261.6, and name “Methods and compositions for regulating splicing”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 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; and U.S. Provisional Application No. 62 / 802,062, filed February 6, 2019. ,065; U.S. Provisional Application No. 62 / 802,068, filed on February 6, 2019; U.S. Provisional Application No. 62 / 802,071, filed on February 6, 2019; U.S. Provisional Application No. 62 / 802,072, filed on February 6, 2019; and U.S. Provisional Application No. 62 / 802,075, filed on February 6, 2019, the disclosures of which are incorporated herein by reference in their entirety. Background Art

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

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

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

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

[0008] In one aspect, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0009]

[0010] in

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

[0012] 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;

[0013] Each R A are 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;

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

[0015] X is –O-, –S-, or –NR 3 -;

[0016] Z is CR 2 ;

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

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

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

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

[0021] R 3 is hydrogen, –CN, substituted or unsubstituted C1–C4 alkyl, –CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, –C1-C4 alkylene-OR 1 , substituted or unsubstituted C3-C4 cycloalkyl or substituted or unsubstituted C2-C3 heterocycloalkyl;

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

[0023] R 15 and R 18 for:

[0024] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0025] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0026] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0027] a is 0 or 1;

[0028] b is 0;

[0029] c is 1; and

[0030] d is 0 or 1.

[0031] In one aspect, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0032]

[0033] in

[0034] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0035] 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;

[0036] Each R A are 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;

[0037] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0038] X is –O-, –S-, or –NR 3 -;

[0039] Z is CR 2 ;

[0040] 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;

[0041] 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;

[0042] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0043] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0044] 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;

[0045] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0046] R 15 and R 18 for:

[0047] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0048] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0049] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0050] a is 0 or 1;

[0051] b is 0;

[0052] c is 1; and

[0053] d is 0 or 1.

[0054] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0055]

[0056] in

[0057] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0058] 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;

[0059] Each R A are 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;

[0060] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0061] X is –O-, –S-, or –NR 3 -;

[0062] Z is CR 2 ;

[0063] 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;

[0064] 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;

[0065] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0066] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0067] 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;

[0068] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0069] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0070] a is 0 or 1;

[0071] b is 0;

[0072] c is 1; and

[0073] d is 0 or 1.

[0074] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0075]

[0076] in

[0077] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0078] 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;

[0079] Each R A are 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;

[0080] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0081] X is –O-, –S-, or –NR 3 -;

[0082] Z is CR 2 ;

[0083] 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;

[0084] 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;

[0085] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0086] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0087] R 3is 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;

[0088] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0089] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0090] a is 0 or 1;

[0091] b is 0;

[0092] c is 1; and

[0093] d is 0 or 1.

[0094] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0095]

[0096] in

[0097] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0098] 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;

[0099] Each R A are independently hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R1 、-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;

[0100] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0101] X is –O-, –S-, or –NR 3 -;

[0102] Z is CR 2 ;

[0103] 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;

[0104] 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;

[0105] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0106] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0107] 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;

[0108] R 11 、R 12 、R 13 、R 14 、R 16 and R 17Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0109] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0110] a is 0 or 1;

[0111] b is 0;

[0112] c is 1; and

[0113] d is 0 or 1.

[0114] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0115]

[0116] in

[0117] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0118] 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;

[0119] Each R A are 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;

[0120] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0121] X is –O-, –S-, or –NR 3 -;

[0122] Z is CR 2 ;

[0123] 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;

[0124] 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;

[0125] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0126] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0127] 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;

[0128] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0129] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0130] a is 0 or 1;

[0131] b is 0;

[0132] c is 1; and

[0133] d is 0 or 1.

[0134] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0135]

[0136] in

[0137] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0138] 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;

[0139] Each R A are 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;

[0140] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0141] X is –O-, –S-, or –NR 3 -;

[0142] Z is CR 2 ;

[0143] 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;

[0144] 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;

[0145] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0146] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0147] 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;

[0148] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0149] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0150] a is 0 or 1;

[0151] b is 0;

[0152] c is 1; and

[0153] d is 0 or 1.

[0154] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0155]

[0156] in

[0157] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0158] 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;

[0159] Each R A are 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;

[0160] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0161] X is –O-, –S-, or –NR 3 -;

[0162] Z is CR 2 ;

[0163] 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;

[0164] 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;

[0165] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0166] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0167] 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;

[0168] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0169] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0170] a is 0 or 1;

[0171] b is 0;

[0172] c is 1; and

[0173] d is 0 or 1.

[0174] In one aspect, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0175]

[0176] in

[0177] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0178] 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;

[0179] Each R A are 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;

[0180] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0181] X is

[0182] Z is CR 2 ;

[0183] 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;

[0184] 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;

[0185] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0186] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0187] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0188] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0189] R 15 and R 18 for:

[0190] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0191] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0192] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0193] a is 0 or 1;

[0194] b is 0;

[0195] c is 1; and

[0196] d is 0 or 1.

[0197] In one aspect, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0198]

[0199] in

[0200] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0201] 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;

[0202] Each R A are 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;

[0203] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0204] X is and Z is N or CR 2 ;or

[0205] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0206] 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;

[0207] 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;

[0208] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0209] R2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0210] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0211] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0212] R 15 and R 18 for:

[0213] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0214] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0215] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0216] a is 0 or 1;

[0217] b is 0;

[0218] c is 1; and

[0219] d is 0 or 1.

[0220] In one aspect, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0221]

[0222] in

[0223] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0224] 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;

[0225] Each R A are 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;

[0226] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0227] X is

[0228] Z is CR 2 ;

[0229] 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;

[0230] 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;

[0231] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0232] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0233] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0234] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0235] R 15 and R 18 for:

[0236] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0237] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0238] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0239] a is 0 or 1;

[0240] b is 0;

[0241] c is 1; and

[0242] d is 0 or 1.

[0243] In one aspect, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0244]

[0245]

[0246] in

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

[0248] 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;

[0249] Each R A are 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;

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

[0251] X is and Z is N or CR 2 ;or

[0252] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0253] 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;

[0254] 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;

[0255] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0256] R2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0257] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0258] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0259] R 15 and R 18 for:

[0260] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0261] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0262] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0263] a is 0 or 1;

[0264] b is 0;

[0265] c is 1; and

[0266] d is 0 or 1.

[0267] In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is and Z is N. In some embodiments, X is And Z is CR 2 .

[0268] In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is -O-, -S-, or -NR 3 -, and Z is CR 2 .

[0269] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0270]

[0271] in

[0272] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0273] 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;

[0274] Each R A are 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;

[0275] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0276] X is

[0277] Z is CR 2 ;

[0278] 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;

[0279] 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;

[0280] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0281] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0282] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0283] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0284] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0285] a is 0 or 1;

[0286] b is 0;

[0287] c is 1; and

[0288] d is 0 or 1.

[0289] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0290]

[0291] in

[0292] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0293] 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;

[0294] Each R A are 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;

[0295] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0296] X is

[0297] Z is CR 2 ;

[0298] 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;

[0299] 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;

[0300] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0301] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0302] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0303] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0304] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0305] a is 0 or 1;

[0306] b is 0;

[0307] c is 1; and

[0308] d is 0 or 1.

[0309] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0310]

[0311] in

[0312] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0313] 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;

[0314] Each R A are 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;

[0315] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0316] X is

[0317] Z is CR 2 ;

[0318] 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;

[0319] 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;

[0320] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0321] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0322] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0323] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0324] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0325] a is 0 or 1;

[0326] b is 0;

[0327] c is 1; and

[0328] d is 0 or 1.

[0329] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0330]

[0331] in

[0332] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0333] 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;

[0334] Each R A are 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;

[0335] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0336] X is

[0337] Z is CR 2 ;

[0338] 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;

[0339] 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;

[0340] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0341] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0342] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0343] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0344] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0345] a is 0 or 1;

[0346] b is 0;

[0347] c is 1; and

[0348] d is 0 or 1.

[0349] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0350]

[0351] in

[0352] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0353] 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;

[0354] Each R A are 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;

[0355] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0356] X is

[0357] Z is CR 2 ;

[0358] 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;

[0359] 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;

[0360] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0361] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0362] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0363] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0364] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0365] a is 0 or 1;

[0366] b is 0;

[0367] c is 1; and

[0368] d is 0 or 1.

[0369] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0370]

[0371] in

[0372] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0373] 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;

[0374] Each R A are 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;

[0375] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0376] X is

[0377] Z is CR 2 ;

[0378] 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;

[0379] 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;

[0380] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0381] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0382] Each R 4are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0383] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0384] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0385] a is 0 or 1;

[0386] b is 0;

[0387] c is 1; and

[0388] d is 0 or 1.

[0389] In one aspect, disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0390]

[0391] in

[0392] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0393] 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;

[0394] Each R A are 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;

[0395] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0396] is a single bond or a double bond;

[0397] X is and Z is C; or

[0398] X is And Z is CR 2 ;

[0399] 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;

[0400] 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;

[0401] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0402] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0403] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0404] R 11 、R 12 、R 13 、R 14 、R 16 and R17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0405] R 15 and R 18 for:

[0406] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0407] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0408] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0409] a is 0 or 1;

[0410] b is 0;

[0411] c is 1; and

[0412] d is 0 or 1.

[0413] In one aspect, disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0414]

[0415] in

[0416] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0417] 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;

[0418] Each R A are 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;

[0419] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0420] is a single bond or a double bond;

[0421] X is and Z is C; or

[0422] X is and Z is N or CR 2 ;

[0423] 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;

[0424] 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;

[0425] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0426] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0427] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0428] R 11 、R 12 、R 13 、R 14 、R 16and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0429] R 15 and R 18 for:

[0430] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0431] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0432] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0433] a is 0 or 1;

[0434] b is 0;

[0435] c is 1; and

[0436] d is 0 or 1.

[0437] In one aspect, disclosed herein is a compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0438]

[0439] in

[0440] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0441] 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;

[0442] Each R A are 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;

[0443] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0444] is a single bond or a double bond;

[0445] X is and Z is C; or

[0446] X is And Z is CR 2 ;

[0447] 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;

[0448] 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;

[0449] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0450] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0451] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0452] Each R 11 、R 12 、R 13 、R 14 、R 16、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0453] R 15 and R 18 for:

[0454] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0455] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0456] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0457] a is 0 or 1;

[0458] b is 0;

[0459] c is 1; and

[0460] d is 0 or 1.

[0461] In one aspect, disclosed herein is a compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0462]

[0463] in

[0464] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0465] 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;

[0466] Each R A are independently hydrogen, deuterium, F, Cl, –CN, –OR1 ,–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;

[0467] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0468] is a single bond or a double bond;

[0469] X is and Z is C; or

[0470] X is and Z is N or CR 2 ;

[0471] 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;

[0472] 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;

[0473] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0474] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0475] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0476] Each R 11 、R 12 、R 13、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0477] R 15 and R 18 for:

[0478] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0479] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0480] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0481] a is 0 or 1;

[0482] b is 0;

[0483] c is 1; and

[0484] d is 0 or 1.

[0485] In one aspect, described herein are compounds of formula (III), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0486]

[0487] in

[0488] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0489] 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;

[0490] Each RA are 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;

[0491] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0492] is a single bond or a double bond;

[0493] X is and Z is C; or

[0494] X is And Z is CR 2 ;

[0495] 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;

[0496] 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;

[0497] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0498] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0499] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0500] R 11、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0501] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0502] a is 0 or 1;

[0503] b is 0;

[0504] c is 1; and

[0505] d is 0 or 1.

[0506] In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0507]

[0508] in

[0509] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0510] 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;

[0511] Each R A are 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;

[0512] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0513] is a single bond or a double bond;

[0514] X is and Z is C; or

[0515] X is And Z is CR 2 ;

[0516] 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;

[0517] 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;

[0518] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0519] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0520] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0521] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0522] R 15 and R 18are identical and are selected from the group consisting of: hydrogen and deuterium;

[0523] a is 0 or 1;

[0524] b is 0;

[0525] c is 1; and

[0526] d is 0 or 1.

[0527] In one aspect, described herein are compounds of formula (III), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0528]

[0529] in

[0530] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0531] 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;

[0532] Each R A are 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;

[0533] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0534] is a single bond or a double bond;

[0535] X is and Z is C; or

[0536] X is And Z is CR 2 ;

[0537] 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;

[0538] 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;

[0539] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0540] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0541] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0542] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0543] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0544] a is 0 or 1;

[0545] b is 0;

[0546] c is 1; and

[0547] d is 0 or 1.

[0548] In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0549]

[0550] in

[0551] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0552] 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;

[0553] Each R A are 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;

[0554] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0555] is a single bond or a double bond;

[0556] X is and Z is C; or

[0557] X is And Z is CR 2 ;

[0558] 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;

[0559] 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;

[0560] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0561] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0562] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0563] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0564] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0565] a is 0 or 1;

[0566] b is 0;

[0567] c is 1; and

[0568] d is 0 or 1.

[0569] In one aspect, described herein are compounds of formula (III), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0570]

[0571] in

[0572] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0573] 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;

[0574] Each R A are 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;

[0575] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0576] is a single bond or a double bond;

[0577] X is and Z is C; or

[0578] X is And Z is CR 2 ;

[0579] 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;

[0580] 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;

[0581] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0582] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0583] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0584] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0585] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0586] a is 0 or 1;

[0587] b is 0;

[0588] c is 1; and

[0589] d is 0 or 1.

[0590] In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0591]

[0592] in

[0593] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0594] 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;

[0595] Each R A are 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;

[0596] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0597] is a single bond or a double bond;

[0598] X is and Z is C; or

[0599] X is And Z is CR 2 ;

[0600] 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;

[0601] 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;

[0602] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0603] R 2When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0604] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0605] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0606] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0607] a is 0 or 1;

[0608] b is 0;

[0609] c is 1; and

[0610] d is 0 or 1.

[0611] 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):

[0612]

[0613] 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):

[0614]

[0615] 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):

[0616]

[0617] 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):

[0618]

[0619] 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):

[0620]

[0621] 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):

[0622]

[0623] 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):

[0624]

[0625] 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):

[0626]

[0627] 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):

[0628]

[0629] 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):

[0630]

[0631] 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):

[0632]

[0633] 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):

[0634]

[0635] 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):

[0636]

[0637] 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):

[0638]

[0639] 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):

[0640]

[0641] 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):

[0642]

[0643] 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):

[0644]

[0645] 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):

[0646]

[0647] 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):

[0648]

[0649] 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):

[0650]

[0651] 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):

[0652]

[0653] 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):

[0654]

[0655] 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):

[0656]

[0657] 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):

[0658]

[0659] 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):

[0660]

[0661] 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):

[0662]

[0663] 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):

[0664]

[0665] 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):

[0666]

[0667] 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):

[0668]

[0669] 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):

[0670]

[0671] 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):

[0672]

[0673] 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):

[0674]

[0675] 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):

[0676]

[0677] 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):

[0678]

[0679] 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):

[0680]

[0681] 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):

[0682]

[0683] In some embodiments of the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is substituted or unsubstituted aryl.

[0684] In some embodiments, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of:

[0685] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[0686] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0687] In some embodiments of the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0688] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl group, wherein if the aryl group is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of:

[0689] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[0690] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0691] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, wherein if the heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of:

[0692] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[0693] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0694] In some embodiments of the compounds of Formula (I)-(IV), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, Ring Q is Each R Q independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3 and -OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0695] In some embodiments of the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, Ring Q is a substituted or unsubstituted heteroaryl. In some embodiments, Ring Q is a substituted or unsubstituted 5-membered 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 a 6-membered monocyclic heteroaryl selected from the group consisting of:

[0696] Each R Q is independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3, and -OCH(CH3)2; and Ring P is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In some embodiments, each R Q are independently hydrogen, –F, –Cl, –CN, –OH, –CH 3 , –CF 3 or –OCH 3 .

[0697] 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 a heteroaryl selected from the group consisting of:

[0698] in

[0699] Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0700] R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[0701] m is 0, 1, 2 or 3.

[0702] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[0703] in

[0704] Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0705] R B1Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[0706] m is 0, 1, 2 or 3.

[0707] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R B is independently hydrogen, deuterium, -F, -Cl, -CN, -CH3, -CF3, -OH, or -OCH3. In some embodiments, each R B is independently -F or -OCH3. In some embodiments, R B For H.

[0708] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R B1 is H, deuterium, –CH3, –CF3 or –CD3.

[0709] In some embodiments of the compounds of Formula (I)-(IV), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates 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.

[0710] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from the group consisting of:

[0711] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[0712] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

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

[0714]

[0715] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0716]

[0717] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0718]

[0719]

[0720] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0721]

[0722]

[0723] where R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0724] In some embodiments of the compounds of Formula (I)-(IV), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, W is a substituted or unsubstituted C1-C3 alkylene group. In some embodiments, W is -CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is -CH2CH2CH2-.

[0725] In some embodiments of the compounds of Formula (I)-(IV), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, W is a substituted or unsubstituted C1-C2 heteroalkylene. In some embodiments, W is -CH2OCH2-. In some embodiments, W is -CH2O-, wherein O is attached to a moiety having R 18 The carbon atom of the group.

[0726] In some embodiments of the compounds of Formula (I)-(IV), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, W is a substituted or unsubstituted C3-C8 cycloalkylene or a substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is a substituted or unsubstituted C3-C8 cycloalkylene. In some embodiments, W is a cyclopropylene.

[0727] In some embodiments of the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W is a substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is -CH=CH-.

[0728] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl, or substituted or unsubstituted C2-C4 heterocycloalkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2OH, -CH2CN, -CHF2, -CF3, or cyclopropyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In some embodiments, R is -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is hydrogen.

[0729] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 and R 16 One or more of are independently selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 11 、R12 and R 16 One or more of are independently selected from the group consisting of F, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —CH2CN, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, and —CH2CF3. In some embodiments, R 11 、R 12 and R 16 One or more of are independently selected from the group consisting of: F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R 11 、R 12 and R 16 For hydrogen.

[0730] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 is H, D or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 For F.

[0731] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 12 is H, D or F. In some embodiments, R 12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 For F.

[0732] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 13 is H, D or F. In some embodiments, R 13 is D. In some embodiments, R 13 is H. In some embodiments, R 13 For F.

[0733] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 14 is H, D or F. In some embodiments, R 14 is D. In some embodiments, R 14is H. In some embodiments, R 14 For F.

[0734] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is F, CF3, CHF2 or CH2F. In some embodiments, R 15 For F.

[0735] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 is H, D or F. In some embodiments, R 16 is D. In some embodiments, R 16 is H. In some embodiments, R 16 For F.

[0736] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 is H, D or F. In some embodiments, R 17 is D. In some embodiments, R 17 is H. In some embodiments, R 17 For F.

[0737] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 18 is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is F, CF3, CHF2 or CH2F. In some embodiments, R 18 For F.

[0738] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 and R 17 One or more of are independently selected from the group consisting of: F, –OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 16 and R 17 One or more of are independently selected from the group consisting of F, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH3, —CH2CH3, —CH2OH, —CH2CH2OH, —CH2CN, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, and —CH2CF3. In some embodiments, R 16 and R 17 One or more of are independently selected from the group consisting of: F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R 16 and R 17 For hydrogen.

[0739] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 2 is hydrogen, -CH3 or -OCH3. In some embodiments, R 2 For hydrogen.

[0740] In some embodiments of the compound of Formula (I) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable 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, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl. In some embodiments, R 3 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, cyclopropyl or oxetanyl. In some embodiments, R 3 is hydrogen, -CH3, -CH(CH3)2, cyclopropyl or oxetane. In some embodiments, R 3 It is hydrogen, -CH3 or cyclopropyl.

[0741] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R AR is independently hydrogen, F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OH, -OCH3, -OCH2CH3, -OCF3, -CH2F, -CHF2, or -CF3. In some embodiments, each R A is independently hydrogen, F, Cl, -CN, -CH3, -OH, -OCH3, -OCF3, -CH2F, -CHF2, or -CF3. In some embodiments, each R A is independently hydrogen, F, Cl, -CN, -CH3 or -OCH3. In some embodiments, each R A is independently F, Cl or -CH3. In some embodiments, each R A For hydrogen.

[0742] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In some embodiments, R 15 and R 18 are identical and are selected from the group consisting of: F, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2OH, —CH2CH2OH, —CH2NHCH3, —CH2N(CH3)2, —OH, —OCH3, —OCH2CH3, —OCH2CH2OH, —OCH2CN, —OCF3, —CH2F, —CHF2, and —CF3. In some embodiments, R 15 and R 18 are identical and are selected from the group consisting of: F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In some embodiments, R 15 and R 18 are identical and are selected from the group consisting of: F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2, and -CF3. In some embodiments, R 15 and R 18are identical 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 In some embodiments, R 15 and R 18 It is -OCH3.

[0743] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. In some embodiments, R 15 and R 18 are different and are selected from the group consisting of hydrogen, deuterium, F, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2OH, –CH2CH2OH, –CH2NHCH3, –CH2N(CH3)2, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH2F, –CHF2, and –CF3. In some embodiments, R 15 and R 18 are different and are selected from the group consisting of hydrogen, deuterium, F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In some embodiments, R 15 and R 18 are different and are selected from the group consisting of hydrogen, deuterium, F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2, and -CF3. In some embodiments, R 15 and R 18 are different and are selected from the group consisting of hydrogen, deuterium, F, -CH3 and -OCH3. In some embodiments, R 15 is F and R 18 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 R18 For hydrogen.

[0744] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R 4 R is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl. 4 R is independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -CH2OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R 4 is independently hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R 4 In some embodiments, R 4 is -CH3.

[0745] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them are F.

[0746] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, at least two of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, at least one of R11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them contain fluorine.

[0747] In some embodiments of the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of the fluorine compounds contains fluorine, such as F or C 1-4 Fluoroalkyl groups such as 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, W comprises fluorine.

[0748] In some embodiments of the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R14 、R 15 、R 16 、R 17 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them are F.

[0749] In some embodiments of the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R15 、R 16 、R 17 and R 18 In some embodiments, at least two of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, at least one of R 11 、R 12 、R 13 、R 14 、R 16 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them contain fluorine.

[0750] In some embodiments of the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 At least one of the fluorine compounds contains fluorine, such as F or C 1-4 Fluoroalkyl groups such as 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, W comprises fluorine.

[0751] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 is H, D or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 For F.

[0752] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 12 is H, D or F. In some embodiments, R 12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 For F.

[0753] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 13 is H, D or F. In some embodiments, R 13 is D. In some embodiments, R 13 is H. In some embodiments, R 13 For F.

[0754] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 14 is H, D or F. In some embodiments, R 14 is D. In some embodiments, R 14 is H. In some embodiments, R 14 For F.

[0755] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 15 is F, CF3, CHF2 or CH2F. In some embodiments, R 15 For F.

[0756] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 is H, D or F. In some embodiments, R 16 is D. In some embodiments, R 16 is H. In some embodiments, R 16 For F.

[0757] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17is H, D or F. In some embodiments, R 17 is D. In some embodiments, R 17 is H. In some embodiments, R 17 For F.

[0758] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 18 is H, D, F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CH2F, CHF2, CF3 or CH3. In some embodiments, R 18 is F, CF3, CHF2 or CH2F. In some embodiments, R 18 For F.

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

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

[0761] In some embodiments of the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable 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 pharmaceutically acceptable solvate thereof, R 20 is H, D or F. In some embodiments, R 20 is D. In some embodiments, R 20 is H. In some embodiments, R 20 is F. In some embodiments of the compound of formula (III) or (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 16 and R 19 is H. In some embodiments, R 16 and R 19 is D. In some embodiments, R 16 and R 19 is F. In some embodiments of the compound of formula (III) or (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 and R 20 is H. In some embodiments, R 19 and R 20 is D. In some embodiments, R 19 and R 20 is F. In some embodiments of the compound of formula (III) or (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 and R 20 is H. In some embodiments, R 17 and R 20is D. In some embodiments, R 17 and R 20 For F.

[0762] In some embodiments of the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least two of are F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 At least one of is F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, one of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R17 At least two of them are F.

[0763] In some embodiments of the compound of Formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of contains fluorine, for example F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2 and CH3CH2F. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of is F or C1-C4 fluoroalkyl. In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, at least two of R 11 、R 12 、R 13 、R 14 、R 16 、R 19 、R 20 and R 17 In some embodiments, at least one of R 11 、R 12 、R 13 、R14 、R 16 、R 19 、R 20 and R 17 In some embodiments, R 11 、R 12 、R 13 、R 14 、R 16 and R 17 At least two of them contain fluorine.

[0764] In some embodiments of the compound of formula (III) or (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, W, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 At least one of W, R, or C1-C4 fluoroalkyl groups such as CH2F, CF3, CHF2, and CH3CH2F. 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 19 、R 20 and R 18 In some embodiments, W comprises fluorine.

[0765] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, each R 1 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl. 1 is independently hydrogen, deuterium or C1-C4 alkyl. 1 are independently hydrogen, deuterium or methyl.

[0766] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R E is hydrogen, substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted C3-C6 cycloalkyl. EIn some embodiments, R E It is methyl or ethyl.

[0767] In some embodiments, the compound of formula (I)-(IV) is a single enantiomer. In some embodiments, the compound of formula (I)-(IV) is not racemic. In some embodiments, the compound of formula (I)-(IV) is substantially free of other isomers. In some embodiments, the compound of formula (I)-(IV) is a single isomer that is substantially free of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 25% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 20% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 15% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 10% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 5% or less of other isomers. In some embodiments, the compound of formula (I)-(IV) contains 1% or less of other isomers.

[0768] In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 75%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 80%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 85%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 90%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 95%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 96%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 97%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 98%. In some embodiments, the compounds of Formula (I)-(IV) have a stereochemical purity of at least 98%.

[0769] In some embodiments, the asymmetric carbon atoms of the compounds of formula (I)-(IV) are present in enantiomeric enriched form. In certain embodiments, the asymmetric carbon atoms of the compounds of formula (I)-(IV) have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (S)- or (R)-configuration.

[0770] In one aspect, described herein is a method of modulating splicing comprising contacting a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, with a cell, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA.

[0771] In one aspect, described herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0772] In one aspect, described herein is a method of treating a condition or disease comprising administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0773] In one aspect, described herein is the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the preparation of a medicament for treating a condition or disease.

[0774] Incorporated by Reference

[0775] All publications, patents, and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0776] Certain specific details of this specification are set forth to provide a thorough understanding of the various embodiments. However, it will be understood by those skilled in the art that the present disclosure can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily confusing the description of the embodiments. Unless the context requires otherwise, in the subsequent description and claims, the term "including" and its variants (such as "comprising") should be interpreted in an open, inclusive sense, i.e., "including but not limited to". In addition, the titles provided herein are for convenience only and do not explain the scope or meaning of the disclosure claimed.

[0777] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise.

[0778] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0779] definition

[0780] The terms "disclosed compounds," "compounds of the present disclosure," "small molecule steric modulators," "small molecule splicing modulators," "steric modulators," "splicing modulators," "compounds that modify splicing," and "splicing-modifying compounds," "SMSMs," or "small molecules that bind to target RNAs" are used interchangeably herein and refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. The terms "disclosed compounds," "compounds of the present disclosure," "small molecule steric modulators," "small molecule splicing modulators," "steric modulators," "splicing modulators," "compounds that modify splicing," and "splicing-modifying compounds," "SMSMs," or "small molecules that bind to target RNAs" refer to small molecule compounds that bind to cellular components (e.g., DNA, RNA, pre-mRNA, proteins, RNPs, snRNAs, carbohydrates, lipids, cofactors, nutrients, and / or metabolites) and modulate the splicing of a target polynucleotide (e.g., pre-mRNA). For example, SMSM can be directly or indirectly bound to a target polynucleotide, such as RNA (e.g., pre-mRNA), via a mutated, non-mutated, protruding and / or abnormal splicing site, thereby causing regulation of the splicing of the target polynucleotide. For example, SMSM can be directly or indirectly bound to a protein, such as a spliceosomal protein or a ribonucleoprotein, thereby causing regulation of the spatial regulation of the protein and the splicing of the target RNA. For example, SMSM can be directly or indirectly bound to a spliceosomal component, such as a spliceosomal protein or snRNA, thereby causing regulation of the spatial regulation of the spliceosomal protein or snRNA and the splicing of the target polynucleotide. These terms explicitly exclude compounds consisting of oligonucleotides. These terms include small molecule compounds that can be bound to one or more secondary or tertiary structural elements of the target RNA. These sites include RNA triplexes, 3WJs, 4WJs, parallel Y knots, hairpins, raised loops, pseudoknots, internal loops, and other high-order RNA structural motifs.

[0781] As used herein, the term "RNA" (ribonucleic acid) refers to naturally occurring or synthetic oligoribonucleotides independent of their source (e.g., RNA can be produced by humans, animals, plants, viruses, or bacteria, or can be of synthetic origin), biological context (e.g., RNA can be in the nucleus, circulating in the blood, in vitro, in a cell lysate, or in isolated or purified form), or physical form (e.g., RNA can be single-stranded, double-stranded, or triple-stranded (including RNA-DNA hybrids), can include epigenetic modifications, natural post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, can be bound to, for example, metal ions, small molecules, proteins such as chaperones or cofactors, or can be in a denatured, partially denatured, or folded state, including any natural or non-natural secondary or tertiary structure, such as quadruplexes, hairpins, triplexes, three-way junctions (3WJs), four-way junctions (4WJs), parallel Y-junctions, hairpins, bulged loops, pseudoknots, and internal loops, etc., as well as any transient form or structure adopted by the RNA). In some embodiments, the length of the RNA is 20, 22, 50, 75 or 100 or more nucleotides. In some embodiments, the length of the RNA is 250 or more nucleotides. In some embodiments, the length of the RNA is 350, 450, 500, 600, 750 or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000 or more nucleotides. In some embodiments, the length of the RNA is between 250 and 1,000 nucleotides. In some embodiments, the RNA is pre-RNA, pre-miRNA or pre-transcript. In some embodiments, the RNA is a noncoding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), ribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudogene, viral RNA, fungal RNA, parasitic RNA, or bacterial RNA.

[0782] As used herein, the term "target polynucleotide" or "target RNA" refers to any type of polynucleotide or RNA having a splice site that can be modulated by the small molecule compounds described herein. For example, a "target polynucleotide" or "target RNA" can have a secondary or tertiary structure that can bind to a small molecule compound described herein.

[0783] As used herein, "steric alteration," "steric modification," or "steric modulation" refers to a change in the spatial orientation of chemical moieties relative to one another. One of ordinary skill in the art will recognize that steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsion, steric inhibition of resonance, and steric inhibition of protonation.

[0784] Any open valence appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein represents the presence of hydrogen unless otherwise indicated.

[0785] The definitions described herein apply regardless of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein may be appended to form chemically related combinations, such as "heterocycloalkylaryl," "haloalkylheteroaryl," "arylalkylheterocycloalkyl," or "alkoxyalkyl." The last member of the combination is the group to which the remainder of the molecule is bound. In terms of literal sequence, the other members of the combination are attached to the bound group in reverse order, for example, the combination of arylalkylheterocycloalkyl refers to a heterocycloalkyl group substituted with an alkyl group substituted with an aryl group.

[0786] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitution, ie, replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0787] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0788] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule.

[0789] The term "substituted" means that the specified group bears one or more substituents. Where any group may bear multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the possible substituents. When referring to the number of substituents, the term "one or more" refers to the maximum possible number of substitutions, i.e., replacement of one hydrogen by a substituent up to the replacement of all hydrogens by a substituent.

[0790] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethyl acetate (EtOAc); butanol (n-BuOH); 1,2-dichloroethane (DCE); dichloromethane (CH2Cl2, DCM); 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos); diisopropylethylamine (DIPEA); 4-(dimethylamino)pyridine (DMAP); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); hydrogen chloride (HCl); m-chloroperbenzoic acid (mCPBA); methanol (MeOH); methoxybenzyl alcohol (MPA); Methyl bromide (MOMBr); N-methyl-2-pyrrolidone (NMP); iodomethane (MeI); n-propanol (n-PrOH); p-methoxybenzyl (PMB); triethylamine (Et3N); [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; (Pd(dppf)Cl2); sodium ethanethiolate (EtSNa); sodium acetate (NaOAc); sodium bis(trimethylsilyl)amide (NaHMDS); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF).

[0791] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x By way of example only, a group designated "C1-C4" means that the group has 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" means that the alkyl group has 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0792] The term "oxo" refers to a =0 substituent.

[0793] The term "thio" refers to a =S substituent.

[0794] The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0795] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from one to twenty carbon atoms and attached to the rest of the molecule by a single bond. Likewise, an alkyl group containing up to 10 carbon atoms is referred to as a C1-C 10 Alkyl groups, for example, containing up to 6 carbon atoms are C1-C6 alkyl groups. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include, but are not limited to, C1-C6 alkyl groups. 10In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is -CH (CH 3 ) 2 or -C (CH 3 ) 3. Unless otherwise specified in the specification, alkyl can be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0796] The term "alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl group as defined herein. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, the alkoxy group is methoxy. In some embodiments, the alkoxy group is ethoxy.

[0797] The term "alkylamino" refers to a group of the formula -NHR a or -NR a R a A group in which R a is independently an alkyl group as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0798] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR a 2, where R a refers to the rest of the alkenyl group, which may be the same or different. ais H or alkyl. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0799] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group has the formula -C≡CR a , where R a refers to the rest of the alkynyl group. In some embodiments, R a is H or alkyl. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3-C≡CCH2CH3, -CH2C≡CH.

[0800] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatics may be optionally substituted. The term "aromatic" includes both aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0801] The term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl can be optionally substituted. Examples of aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, aryl can be monovalent or divalent (i.e., arylene). Unless otherwise specifically stated in the specification, the term "aryl" or prefix "ar" (e.g., in "aralkyl") is intended to include optionally substituted aryl groups. In some embodiments, aryl is partially reduced to form cycloalkyl as defined herein. In some embodiments, aryl is fully reduced to form cycloalkyl as defined herein.

[0802] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by identical or different halogen atoms, in particular fluorine atoms. Examples of haloalkyl groups include monofluoro, difluoro or trifluoromethyl, ethyl or propyl, such as 3,3,3-trifluoropropyl, 2-fluorotoluene, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms of the alkyl group have been replaced by identical or different halogen atoms.

[0803] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by identical or different halogen atoms, in particular fluorine atoms. Examples of haloalkoxy groups include monofluoro, difluoro or trifluoromethoxy, ethoxy or propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms of the alkoxy group have been replaced by identical or different halogen atoms.

[0804] The term "bicyclic ring system" refers to two rings fused to each other via a common single or double bond (annealed bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system), or via a common single atom (spiro bicyclic ring system). The bicyclic ring system may be saturated, partially unsaturated, unsaturated, or aromatic. The bicyclic ring system may contain heteroatoms selected from N, O, and S.

[0805] The term "carbocycle" or "carbocycle" refers to a ring or ring system in which the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocycle from a "heterocyclic" ring or "heterocycle" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl groups.

[0806] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each atom (i.e., a skeleton atom) forming the ring is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in this case, the cycloalkyl is bonded to a non-aromatic ring carbon atom). The cycloalkyl group includes a group having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrahydronaphthyl, decalinyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise specifically stated in the specification, cycloalkyl groups may be optionally substituted.

[0807] The term "bridged" refers to any ring structure having two or more rings that contains a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the backbone structure of the molecule and is bonded to three or more other backbone atoms. In some embodiments, the bridging atom is C, N, or P. In some embodiments, a bridge is a single atom or chain of atoms connecting two bridgehead atoms. In some embodiments, a bridge is a valence bond connecting two bridgehead atoms. In some embodiments, the bridged ring system is a cycloalkyl group. In some embodiments, the bridged ring system is a heterocycloalkyl group.

[0808] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring can be replaced by one or more N, S, and O atoms. Non-limiting examples of fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycles, 6-6 fused heterocycles, 5-6 fused heterocycles, 5-5 fused heterocycles, 7-5 fused heterocycles, and 5-7 fused heterocycles.

[0809] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless specifically stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0810] The term "haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless specifically stated otherwise in the specification, a haloalkoxy group may be optionally substituted.

[0811] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0812] The term "heteroalkyl" refers to an alkyl group wherein one or more of the skeletal atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-), or a combination thereof. In some embodiments, the heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In some embodiments, the heteroalkyl group is attached to the rest of the molecule at a heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C6 heteroalkyl group. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH2.

[0813] The term "heteroalkylene" refers to an alkyl group as described above, wherein one or more carbon atoms of the alkyl group are replaced by O, N, or S atoms. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain that connects the remainder of the molecule to a radical. Unless otherwise specifically stated in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0814] The term "heterocycloalkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, the heterocycloalkyl group may be a monocyclic or bicyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded via a non-aromatic ring atom) or bridged ring system. The nitrogen, carbon, or sulfur atom in the heterocyclyl group may optionally be oxidized. The nitrogen atom may optionally be quaternized. The heterocycloalkyl group may be partially or fully saturated. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl [1,3] dithianyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of sugars, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the skeleton atoms of the heterocycloalkyl ring). Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted.

[0815] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also referred to as heteroaryl) and heterocycloalkyl rings (also referred to as heteroaliphatic ring groups) that include at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein each heterocyclyl has 3 to 12 atoms in its ring system, and provided that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compound. Non-aromatic heterocyclic groups (also referred to as heterocycloalkyl) include rings with 3 to 12 atoms in their ring system, and aromatic heterocyclic groups include rings with 5 to 12 atoms in their ring system. Heterocyclyl includes benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinedionyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,2,3,6-tetrahydropyridinyl, 3-dioxolanyl, pyrazolyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3h-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and fluoropyridyl. Where possible, the aforementioned groups are C-attached (or C-linked) or N-attached. For example, groups derived from pyrrole include pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).In addition, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (all N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). Heterocyclyl includes benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0816] The term "heteroaryl" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl groups are monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furanyl. In some embodiments, the heteroaryl contains 0-6 nitrogen atoms in the ring. In some embodiments, the heteroaryl contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 4-6 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5-membered or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group. In some embodiments, the heteroaryl group is partially reduced to form a heterocycloalkyl group as defined herein. In some embodiments, the heteroaryl group is fully reduced to form a heterocycloalkyl group as defined herein.

[0817] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is typically a known chemical entity embedded in or attached to a molecule.

[0818] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted by one or more additional groups individually and independently selected from the group consisting of D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -C02H, -C02alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone. In some embodiments, the optional substituents are independently selected from D, halogen, –CN, –NH2, –NH(CH3), –N(CH3)2, –OH, –CO2H, –CO2(C1-C4 alkyl), –C(═O)NH2, –C(═O)NH(C1-C4 alkyl), –C(═O)N(C1-C4 alkyl)2, –S(═O)2NH2, –S(═O)2NH(C1-C4 alkyl), –S(═O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, –SC1-C4 alkyl, –S(═O)C1-C4 alkyl, and –S(═O)2(C1-C4 alkyl). In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0819] The term "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible via the migration of a hydrogen atom, accompanied by a switch in single bonds and adjacent double bonds. In bonded structures where tautomerism is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interchange include:

[0820]

[0821] The term "about" or "approximately" can mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more standard deviations as is customary in the art. Alternatively, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold of a value.

[0822] As used herein, the term "administer" or the like refers to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes (po), intraduodenal routes (id), parenteral injection (including intravenous (iv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravascular or infusion (inf.)), topical (top.) and rectal (pr) administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0823] As used herein, the terms "co-administered," "co-administered," and the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0824] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an agent or compound administered that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated; for example, to reduce and / or alleviate one or more signs, symptoms, or causes of the disease or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic use can be an amount of an agent that clinically significantly reduces one or more symptoms of the disease. In individual cases, techniques such as dose escalation studies can be used to determine an appropriate "effective" amount.

[0825] As used herein, the term "enhance" refers to increasing or prolonging the amount, potency, or duration of a desired effect. For example, with respect to enhancing the splicing of a target, the term "enhance" can refer to the ability to increase or prolong the splicing of a target, whether in amount, potency, or duration.

[0826] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; livestock such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, among others. In one aspect, the mammal is a human. As used herein, the term "animal" includes both humans and non-human animals. In one embodiment, a "non-human animal" is a mammal, for example, a rodent such as a rat or mouse. In one embodiment, the non-human animal is a mouse.

[0827] As used herein, the term "treating," ...

[0828] The term "preventing" or "preventing" a disease state means that clinical symptoms leading to the disease state do not develop in a subject who is exposed to or susceptible to the disease state but does not yet experience or display symptoms of the disease state.

[0829] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients to be administered to a subject (e.g., a human in need thereof).

[0830] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound as described herein and an adjuvant, are administered to a patient simultaneously as a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound as described herein and an adjuvant, are administered to a patient as separate entities simultaneously, concurrently, or sequentially without specific time intervals, wherein such administration provides effective levels of both compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0831] The term "pharmaceutically acceptable" refers to the property of materials useful in preparing pharmaceutical compositions that are generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for veterinary as well as human use. "Pharmaceutically acceptable" may refer to materials (such as carriers or diluents) that do not abrogate the biological activity or properties of a compound and are relatively non-toxic, i.e., materials that can be administered to an individual without causing adverse biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0832] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and mean any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant used to formulate a drug product.

[0833] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. "Pharmaceutically acceptable salts" may refer to compound formulations that do not cause significant irritation to the organism to which they are administered and / or do not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting an SMSM compound of any one of 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.

[0834] The types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, which are formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.; or an organic acid, e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid; (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions). In some cases, the compounds described herein may be coordinated with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0835] As used herein, the term "nucleic acid" generally refers to one or more nucleobases, nucleosides, or nucleotides, and includes polynucleobases, polynucleosides, and polynucleotides.

[0836] As used herein, the term "polynucleotide" generally refers to a molecule comprising two or more connected nucleic acid subunits (such as nucleotides), and can be used interchangeably with "oligonucleotides". For example, a polynucleotide can include one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T) and uracil (U) or its variants. Nucleotide generally comprises a nucleoside and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphate radicals (PO3) groups. Nucleotide can include a core base, a five-carbon sugar (ribose or deoxyribose) and one or more phosphate radical groups. Ribonucleotides include nucleotides in which sugar is ribose. Deoxyribonucleotides include nucleotides in which sugar is deoxyribose. Nucleotide can be nucleoside monophosphate, nucleoside diphosphate, nucleoside triphosphate or nucleoside polyphosphate. For example, nucleotide can be deoxyribonucleoside polyphosphates, such as deoxyribonucleoside triphosphates (dNTPs), exemplary dNTPs include deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP) and deoxythymidine triphosphate (dTTP). dNTPs can also include detectable labels, such as luminescent labels or markers (e.g., fluorophores). For example, nucleotide can be a purine (i.e., A or G or its variants) or a pyrimidine (i.e., C, T or U or its variants). In some instances, polynucleotides are deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or its derivatives or variants. Exemplary polynucleotides include, but are not limited to, short interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), short hairpin RNA (shRNA), small nuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA), antisense RNA (asRNA) and heteronuclear RNA (hnRNA), and encompass nucleotide sequence and any structural embodiment thereof, such as single-stranded, double-stranded, triple-stranded, spiral, hairpin, stem-loop, protrusion etc. In some cases, polynucleotides are circular. Polynucleotides can have various lengths. For example, the length of polynucleotides can be at least about 7 bases, 8 bases, 9 bases, 10 bases, 20 bases, 30 bases, 40 bases, 50 bases, 100 bases, 200 bases, 300 bases, 400 bases, 500 bases, 1 kilobases (kb), 2kb, 3kb, 4kb, 5kb, 10kb, 50kb or more. The polynucleotides can be isolated from cells or tissues. For example, the polynucleotide sequences can include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules and / or synthetic DNA / RNA analogs.

[0837] The polynucleotide may include one or more nucleotide variants, including non-standard nucleotides, non-natural nucleotides, nucleotide analogs and / or modified nucleotides. Examples of modified nucleotides include, but are not limited to, diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, β-D-galactosylinosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylamino Methyluracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosylquenoside, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, quenoside, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, 2,6-diaminopurine, etc. In some cases, the phosphate portion of the nucleotide may include modifications, including modifications to the triphosphate portion. Non-limiting examples of such modifications include longer length phosphate chains (e.g., phosphate chains with 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications of thiol moieties (e.g., α-thiotriphosphate β-thiotriphosphate). Nucleic acid molecules may also be modified at the base moiety (e.g., at one or more atoms that are normally available to form hydrogen bonds with complementary nucleotides and / or at one or more atoms that are normally unable to form hydrogen bonds with complementary nucleotides), the sugar moiety, or the phosphate backbone. Nucleic acid molecules may also include amine-modified groups, such as aminoallyl 1-dUTP (aa-dUTP) and aminohexyl acrylamide-dCTP (aha-dCTP), to covalently attach amine-reactive moieties such as N-hydroxysuccinimide ester (NHS). Substitutes for standard DNA base pairs or RNA base pairs in the oligonucleotides of the present disclosure may provide higher density in bits per cubic mm, higher safety (against accidental or purposeful synthesis of natural toxins), easier recognition in light-programmable polymerases, or lower secondary structure.Such alternative base pairs compatible with native and mutant polymerases for de novo and / or amplification synthesis are described in Betz K, Malyshev DA, Lavergne T, Welte W, Diederichs K, Dwyer TJ, Ordoukhanian P, Romesberg FE, Marx A. Nat. Chem. Biol. 2012 Jul;8(7):612-4, which is incorporated herein by reference for all purposes.

[0838] As used herein, the terms "polypeptide," "protein," and "peptide" are used interchangeably and refer to a polymer of amino acid residues linked via peptide bonds, and which may be composed of two or more polypeptide chains. The terms "polypeptide," "protein," and "peptide" refer to a polymer of at least two amino acid monomers linked together by an amide bond. Amino acids may be L-optical isomers or D-optical isomers. More specifically, the terms "polypeptide," "protein," and "peptide" refer to a molecule composed of two or more amino acids in a specific order; for example, the order is determined by the base sequence of nucleotides in a gene or RNA encoding the protein. Proteins are essential for the structure, function, and regulation of human cells, tissues, and organs, and each protein has a unique function. Examples are hormones, enzymes, antibodies, and any fragments thereof. In some cases, a protein may be a portion of a protein, such as a domain, subdomain, or motif of a protein. In some cases, a protein may be a variant (or mutation) of a protein in which one or more amino acid residues are inserted, deleted, and / or replaced with the naturally occurring (or at least known) amino acid sequence of the protein. A protein or its variant may be naturally occurring or recombinant.

[0839] Methods for detecting and / or measuring polypeptides in biological materials are well known in the art and include, but are not limited to, Western blotting, flow cytometry, ELISA, RIA, and various proteomics techniques. An exemplary method for measuring or detecting polypeptides is an immunoassay, such as ELISA. This type of protein quantification can be based on antibodies capable of capturing specific antigens and a second antibody capable of detecting the captured antigen. Exemplary assays for detecting and / or measuring polypeptides are described in Harlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), Cold Spring Harbor Laboratory Press.

[0840] Methods for detecting and / or measuring RNA in biological material are well known in the art and include, but are not limited to, Northern blotting, RNA protection assays, RT PCR. Suitable methods are described in Molecular Cloning: A Laboratory Manual (4th edition), Michael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN 978-1-936113-42-2.

[0841] As used herein, "small molecular weight compound" can be used interchangeably with "small molecule" or "small organic molecule." Small molecules refer to compounds other than peptides or oligonucleotides; and typically have a molecular weight of less than about 2000 Daltons, such as less than about 900 Daltons.

[0842] Ribonucleoprotein (RNP) refers to a nuclear protein containing RNA. RNP can be a complex of ribonucleic acid and RNA binding protein. This combination can also be referred to as protein-RNA complex. These complexes can play a variety of biological functions, including but not limited to DNA replication, gene expression, RNA metabolism and pre-mRNA splicing. Examples of RNP include ribosomes, telomerase, vault ribonucleoprotein, RNase P, heterogeneous nuclear RNP (hnRNP) and small nuclear RNP (snRNP).

[0843] Nascent RNA transcripts from protein-coding genes and mRNA processing intermediates are collectively referred to as pre-mRNAs, which are typically bound to proteins in the eukaryotic nucleus. From the time when the nascent transcript first appears from RNA polymerase (e.g., RNA polymerase II) until the mature mRNA is transported into the cytoplasm, the RNA molecule is associated with a large number of splicing complex components (e.g., nucleoproteins and snRNAs). These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNAs (hnRNAs) of various sizes (e.g., pre-mRNA and nuclear RNA complexes).

[0844] Splicing complex components play a role in splicing and / or splicing regulation. Splicing complex components may include, but are not limited to, ribonucleoproteins (RNPs), splicing proteins, small nuclear RNAs (snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing complex components include, but are not limited to, those that may be required for splicing, such as constitutive splicing, alternative splicing, regulated splicing, and splicing of specific messages or groups of messages. A group of related proteins, serine-arginine-rich proteins (SR proteins), can play a role in constitutive pre-mRNA splicing and can also regulate alternative splicing site selection in a concentration-dependent manner. SR proteins typically have a modular structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminus (RS domain) rich in arginine and serine residues. Their activity in alternative splicing may be antagonized by members of the hnRNPA / B protein family. Splicing complex components may also include proteins that associate with one or more snRNAs. SR proteins in humans include, but are not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2 / ASF, 9G8, SRp75, SRp30c, SRp20, and P54 / SFRS11. Other splicing complex components that may participate in splice site selection in humans include, but are not limited to, U2 snRNA auxiliary factors (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP 20, SF1, and PTB / hnRNP1. hnRNP proteins in humans include, but are not limited to, A1, A2 / B1, L, M, K, U, F, H, G, R, I, and C1 / C2. Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1. Splicing complex components can be stably or transiently associated with snRNPs or transcripts.

[0845] The term "intron" refers to DNA sequences within a gene and the corresponding sequences in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing shortly after or simultaneously with transcription. Introns are present in the genes of most organisms and many viruses. They can be found in a wide range of genes, including those that produce proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA).

[0846] An "exon" can be any portion of a gene that encodes a portion of the final mature RNA produced from that gene after introns are removed by RNA splicing. The term "exon" refers to a DNA sequence within a gene and the corresponding sequence in the RNA transcript.

[0847] The "spliceosome" can be assembled from snRNA and protein complexes. The spliceosome can remove introns from the transcribed pre-mRNA.

[0848] "Moderate effective dose" (ED 50 ) is the dose at which 50% of the population expresses a specific response. The “median lethal dose” (LD 50 ) is the dose that kills 50% of the population. 50 ) is the dose at which 50% of the population exhibits a specific toxic effect. A particularly useful pharmacological metric is the "therapeutic index," which is traditionally defined as the LD 50 With ED 50 Ratio or TD 50 With ED 50 The therapeutic index provides a simple and useful indicator of the relative benefits of a drug to its adverse effects. Drugs with high therapeutic indices have large therapeutic windows, i.e., the drug can be administered over a wider range of effective doses without causing significant adverse events. In contrast, drugs with small therapeutic indices have small therapeutic windows (small effective dose range without causing significant adverse events).

[0849] As used herein, the term "AUC" refers to the abbreviation of "area under the curve" in a plot of the concentration of a therapeutic agent in some part or tissue (eg, blood or plasma) of a subject to which the therapeutic agent has been administered over time.

[0850] Small molecule splicing modulators (SMSMs)

[0851] It has now been found that the compounds of the present disclosure and pharmaceutically acceptable compositions thereof are effectively used as agents for treating, preventing or ameliorating diseases or conditions associated with target RNA. The present disclosure provides the unexpected discovery that certain small chemical molecules can modify splicing events in pre-mRNA molecules, referred to herein as small molecule splicing modulators (SMSMs). These SMSMs can regulate specific splicing events in specific pre-mRNA molecules. These SMSMs can operate through a variety of mechanisms to modify splicing events. For example, the SMMSs of the present 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; 2) prevent and / or modify post-transcriptional regulation (e.g., splicing) of gene products such as hnRNPs, snRNPs, SR-proteins, and other splicing factors, which may subsequently participate in the formation and / or function of spliceosome or splicing complex components; 3) prevent and / or modify phosphorylation, glycosylation, and / or other modifications of gene products, including but not limited to hnRNPs, snRNPs, SR-proteins, and other splicing factors, which may subsequently participate in the formation and / or function of spliceosome or splicing complex components; 4) bind to and / or otherwise affect specific pre-mRNAs, thereby preventing or inducing specific splicing events, for example, by a mechanism that does not involve base pairing with RNA in a sequence-specific manner. The small molecules of the present disclosure are distinct from and unrelated to antisense or antigene oligonucleotides.

[0852] Compounds that modify the splicing of a gene product are described herein for use in treating, preventing, and / or delaying the progression of a disease or condition (e.g., cancer). Compounds that modify the splicing of a gene product are described herein, wherein the compounds induce a transcriptionally inactive variant or transcript of the gene product. Compounds that modify the splicing of a gene product are described herein, wherein the compounds inhibit a transcriptionally active variant or transcript of the gene product.

[0853] In some embodiments, compounds of formula (I)-(IV) are prepared from racemic starting materials (and / or intermediates) and separated into each enantiomer as an intermediate or final product by chiral chromatography. Unless otherwise indicated, it is understood that the absolute configuration of the isolated intermediate and final compound is not to be determined. In some embodiments, the absolute stereochemistry of the drawn enantiomers is arbitrarily specified. In some embodiments, two enantiomers are synthesized.

[0854] In one aspect, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0855]

[0856] in

[0857] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0858] 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;

[0859] Each R A are 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;

[0860] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0861] X is –O-, –S-, or –NR 3 -;

[0862] Z is CR 2 ;

[0863] 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;

[0864] 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;

[0865] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0866] R 2is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0867] 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;

[0868] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0869] R 15 and R 18 for:

[0870] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0871] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0872] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0873] a is 0 or 1;

[0874] b is 0;

[0875] c is 1; and

[0876] d is 0 or 1.

[0877] In one aspect, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0878]

[0879] in

[0880] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0881] 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;

[0882] Each R A are 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;

[0883] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0884] X is and Z is N or CR 2 ;or

[0885] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0886] 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;

[0887] 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;

[0888] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0889] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0890] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0891] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0892] R 15 and R 18 for:

[0893] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0894] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0895] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0896] a is 0 or 1;

[0897] b is 0;

[0898] c is 1; and

[0899] d is 0 or 1.

[0900] In one aspect, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0901]

[0902] in

[0903] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0904] 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;

[0905] Each R A are 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;

[0906] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0907] X is and Z is N or CR 2 ;or

[0908] X is –O-, –S-, or –NR 3 -, and Z is CR 2 ;

[0909] 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;

[0910] 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;

[0911] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0912] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0913] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0914] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0915] R 15 and R 18 for:

[0916] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0917] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0918] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0919] a is 0 or 1;

[0920] b is 0;

[0921] c is 1; and

[0922] d is 0 or 1.

[0923] In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is and Z is N. In some embodiments, X is And Z is CR 2 .

[0924] In some embodiments of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, X is -O-, -S-, or -NR 3 -, and Z is CR 2 .

[0925] In one aspect, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0926]

[0927] in

[0928] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0929] 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;

[0930] Each R A are 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;

[0931] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0932] X is –O-, –S-, or –NR 3 -;

[0933] Z is CR 2 ;

[0934] 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;

[0935] 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;

[0936] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0937] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0938] 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;

[0939] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0940] R 15 and R 18 for:

[0941] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[0942] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[0943] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0944] a is 0 or 1;

[0945] b is 0;

[0946] c is 1; and

[0947] d is 0 or 1.

[0948] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0949]

[0950] in

[0951] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0952] 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;

[0953] Each R A are 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;

[0954] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0955] X is –O-, –S-, or –NR 3 -;

[0956] Z is CR 2 ;

[0957] 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;

[0958] 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;

[0959] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0960] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0961] 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;

[0962] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[0963] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0964] a is 0 or 1;

[0965] b is 0;

[0966] c is 1; and

[0967] d is 0 or 1.

[0968] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0969]

[0970] in

[0971] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[0972] 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;

[0973] Each R A are 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;

[0974] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0975] X is –O-, –S-, or –NR 3 -;

[0976] Z is CR 2 ;

[0977] 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;

[0978] 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;

[0979] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0980] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[0981] 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;

[0982] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[0983] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0984] a is 0 or 1;

[0985] b is 0;

[0986] c is 1; and

[0987] d is 0 or 1.

[0988] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0989]

[0990] in

[0991] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NRE )-;

[0992] 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;

[0993] Each R A are 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;

[0994] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0995] X is –O-, –S-, or –NR 3 -;

[0996] Z is CR 2 ;

[0997] 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;

[0998] 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;

[0999] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1000] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1001] R 3is 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;

[1002] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1003] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1004] a is 0 or 1;

[1005] b is 0;

[1006] c is 1; and

[1007] d is 0 or 1.

[1008] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1009]

[1010] in

[1011] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1012] 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;

[1013] Each R A are independently hydrogen, deuterium, F, Cl, –CN, –OR1 ,–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;

[1014] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1015] X is –O-, –S-, or –NR 3 -;

[1016] Z is CR 2 ;

[1017] 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;

[1018] 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;

[1019] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1020] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1021] 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;

[1022] Each R 11 、R 12 、R 13 、R14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1023] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1024] a is 0 or 1;

[1025] b is 0;

[1026] c is 1; and

[1027] d is 0 or 1.

[1028] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1029]

[1030] in

[1031] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1032] 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;

[1033] Each R A are 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;

[1034] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1035] X is –O-, –S-, or –NR 3 -;

[1036] Z is CR 2 ;

[1037] 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;

[1038] 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;

[1039] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1040] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1041] 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;

[1042] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1043] R 15and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1044] a is 0 or 1;

[1045] b is 0;

[1046] c is 1; and

[1047] d is 0 or 1.

[1048] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1049]

[1050] in

[1051] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1052] 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;

[1053] Each R A are 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;

[1054] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1055] X is –O-, –S-, or –NR 3 -;

[1056] Z is CR 2 ;

[1057] 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;

[1058] 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;

[1059] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1060] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1061] 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;

[1062] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1063] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1064] a is 0 or 1;

[1065] b is 0;

[1066] c is 1; and

[1067] d is 0 or 1.

[1068] In one aspect, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1069]

[1070] in

[1071] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1072] 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;

[1073] Each R A are 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;

[1074] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1075] X is

[1076] Z is CR 2 ;

[1077] 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;

[1078] 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;

[1079] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1080] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1081] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1082] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1083] R 15 and R 18 for:

[1084] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[1085] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[1086] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1087] a is 0 or 1;

[1088] b is 0;

[1089] c is 1; and

[1090] d is 0 or 1.

[1091] In one aspect, disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1092]

[1093] in

[1094] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1095] 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;

[1096] Each R A are 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;

[1097] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1098] X is

[1099] Z is CR 2 ;

[1100] 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;

[1101] 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;

[1102] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1103] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1104] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1105] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1106] R 15 and R 18 for:

[1107] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[1108] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[1109] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1110] a is 0 or 1;

[1111] b is 0;

[1112] c is 1; and

[1113] d is 0 or 1.

[1114] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1115]

[1116] in

[1117] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1118] 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;

[1119] Each R A are 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;

[1120] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1121] X is

[1122] Z is CR 2 ;

[1123] 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;

[1124] 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;

[1125] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1126] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1127] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1128] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1129] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[1130] a is 0 or 1;

[1131] b is 0;

[1132] c is 1; and

[1133] d is 0 or 1.

[1134] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1135]

[1136] in

[1137] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1138] 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;

[1139] Each R A are 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;

[1140] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1141] X is

[1142] Z is CR 2 ;

[1143] 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;

[1144] 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;

[1145] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1146] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1147] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1148] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1149] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[1150] a is 0 or 1;

[1151] b is 0;

[1152] c is 1; and

[1153] d is 0 or 1.

[1154] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1155]

[1156] in

[1157] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1158] 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;

[1159] Each R A are 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;

[1160] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1161] X is

[1162] Z is CR 2 ;

[1163] 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;

[1164] 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;

[1165] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1166] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1167] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1168] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1169] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1170] a is 0 or 1;

[1171] b is 0;

[1172] c is 1; and

[1173] d is 0 or 1.

[1174] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1175]

[1176] in

[1177] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1178] 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;

[1179] Each R A are 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;

[1180] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1181] X is

[1182] Z is CR 2 ;

[1183] 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;

[1184] 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;

[1185] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1186] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1187] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1188] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1189] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1190] a is 0 or 1;

[1191] b is 0;

[1192] c is 1; and

[1193] d is 0 or 1.

[1194] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1195]

[1196] in

[1197] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1198] 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;

[1199] Each R A are 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;

[1200] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1201] X is

[1202] Z is CR 2 ;

[1203] 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;

[1204] 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;

[1205] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1206] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1207] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1208] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1209] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1210] a is 0 or 1;

[1211] b is 0;

[1212] c is 1; and

[1213] d is 0 or 1.

[1214] In one aspect, described herein are compounds of formula (II), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1215]

[1216] in

[1217] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1218] 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;

[1219] Each R A are 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;

[1220] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1221] X is

[1222] Z is CR 2 ;

[1223] 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;

[1224] 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;

[1225] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1226] R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1227] Each R 4are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1228] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1229] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1230] a is 0 or 1;

[1231] b is 0;

[1232] c is 1; and

[1233] d is 0 or 1.

[1234] In one aspect, disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1235]

[1236] in

[1237] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1238] 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;

[1239] Each R A are 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;

[1240] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1241] is a single bond or a double bond;

[1242] X is and Z is C; or

[1243] X is And Z is CR 2 ;

[1244] 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;

[1245] 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;

[1246] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1247] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1248] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1249] R 11 、R 12 、R 13 、R 14 、R 16 and R17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1250] R 15 and R 18 for:

[1251] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[1252] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[1253] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1254] a is 0 or 1;

[1255] b is 0;

[1256] c is 1; and

[1257] d is 0 or 1.

[1258] In one aspect, disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1259]

[1260] in

[1261] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1262] 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;

[1263] Each R A are 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;

[1264] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1265] is a single bond or a double bond;

[1266] X is and Z is C; or

[1267] X is and Z is N or CR 2 ;

[1268] 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;

[1269] 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;

[1270] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1271] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1272] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1273] R 11 、R 12 、R 13 、R 14 、R 16and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1274] R 15 and R 18 for:

[1275] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[1276] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[1277] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1278] a is 0 or 1;

[1279] b is 0;

[1280] c is 1; and

[1281] d is 0 or 1.

[1282] In one aspect, disclosed herein is a compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1283]

[1284] in

[1285] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1286] 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;

[1287] Each R A are 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;

[1288] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1289] is a single bond or a double bond;

[1290] X is and Z is C; or

[1291] X is And Z is CR 2 ;

[1292] 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;

[1293] 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;

[1294] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1295] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1296] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1297] Each R 11 、R 12 、R 13 、R 14 、R 16、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1298] R 15 and R 18 for:

[1299] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[1300] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[1301] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1302] a is 0 or 1;

[1303] b is 0;

[1304] c is 1; and

[1305] d is 0 or 1.

[1306] In one aspect, disclosed herein is a compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1307]

[1308] in

[1309] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1310] 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;

[1311] Each R A are independently hydrogen, deuterium, F, Cl, –CN, –OR1 ,–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;

[1312] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1313] is a single bond or a double bond;

[1314] X is and Z is C; or

[1315] X is and Z is N or CR 2 ;

[1316] 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;

[1317] 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;

[1318] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1319] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1320] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1321] Each R 11 、R 12 、R 13、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1322] R 15 and R 18 for:

[1323] 1) are identical and selected from the group consisting of: hydrogen and deuterium;

[1324] 2) are identical and selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; or

[1325] 3) are different and selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1326] a is 0 or 1;

[1327] b is 0;

[1328] c is 1; and

[1329] d is 0 or 1.

[1330] In one aspect, described herein are compounds of formula (III), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1331]

[1332] in

[1333] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1334] 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;

[1335] Each RA are 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;

[1336] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1337] is a single bond or a double bond;

[1338] X is and Z is C; or

[1339] X is And Z is CR 2 ;

[1340] 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;

[1341] 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;

[1342] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1343] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1344] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1345] R 11、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1346] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[1347] a is 0 or 1;

[1348] b is 0;

[1349] c is 1; and

[1350] d is 0 or 1.

[1351] In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1352]

[1353] in

[1354] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1355] 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;

[1356] Each R A are 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;

[1357] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1358] is a single bond or a double bond;

[1359] X is and Z is C; or

[1360] X is And Z is CR 2 ;

[1361] 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;

[1362] 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;

[1363] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1364] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1365] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1366] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1367] R 15 and R 18are identical and are selected from the group consisting of: hydrogen and deuterium;

[1368] a is 0 or 1;

[1369] b is 0;

[1370] c is 1; and

[1371] d is 0 or 1.

[1372] In one aspect, described herein are compounds of formula (III), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1373]

[1374] in

[1375] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1376] 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;

[1377] Each R A are 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;

[1378] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1379] is a single bond or a double bond;

[1380] X is and Z is C; or

[1381] X is And Z is CR 2 ;

[1382] 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;

[1383] 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;

[1384] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1385] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1386] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1387] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1388] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1389] a is 0 or 1;

[1390] b is 0;

[1391] c is 1; and

[1392] d is 0 or 1.

[1393] In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1394]

[1395] in

[1396] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1397] 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;

[1398] Each R A are 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;

[1399] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1400] is a single bond or a double bond;

[1401] X is and Z is C; or

[1402] X is And Z is CR 2 ;

[1403] 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;

[1404] 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;

[1405] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1406] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1407] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1408] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1409] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1410] a is 0 or 1;

[1411] b is 0;

[1412] c is 1; and

[1413] d is 0 or 1.

[1414] In one aspect, described herein are compounds of formula (III), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[1415]

[1416] in

[1417] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1418] 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;

[1419] Each R A are 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;

[1420] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1421] is a single bond or a double bond;

[1422] X is and Z is C; or

[1423] X is And Z is CR 2 ;

[1424] 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;

[1425] 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;

[1426] Each R 1are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1427] R 2 When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1428] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1429] R 11 、R 12 、R 13 、R 14 、R 16 and R 17 Each of which is independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1430] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1431] a is 0 or 1;

[1432] b is 0;

[1433] c is 1; and

[1434] d is 0 or 1.

[1435] In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[1436]

[1437] in

[1438] E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-;

[1439] 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;

[1440] Each R A are 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;

[1441] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1442] is a single bond or a double bond;

[1443] X is and Z is C; or

[1444] X is And Z is CR 2 ;

[1445] 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;

[1446] 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;

[1447] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[1448] R 2When present, hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, –CD3 or substituted or unsubstituted C1-C4 haloalkyl;

[1449] Each R 4 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl;

[1450] Each R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 19 and R 20 Independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1451] R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl;

[1452] a is 0 or 1;

[1453] b is 0;

[1454] c is 1; and

[1455] d is 0 or 1.

[1456] 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):

[1457]

[1458] 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):

[1459]

[1460] 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):

[1461]

[1462] 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):

[1463]

[1464] 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):

[1465]

[1466] 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):

[1467]

[1468] 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):

[1469]

[1470] 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):

[1471]

[1472] 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):

[1473]

[1474] 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):

[1475]

[1476] 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):

[1477]

[1478] 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):

[1479]

[1480] 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):

[1481]

[1482] 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):

[1483]

[1484] 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):

[1485]

[1486] 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):

[1487]

[1488] 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):

[1489]

[1490] 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):

[1491]

[1492] 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):

[1493]

[1494] 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):

[1495]

[1496] 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):

[1497]

[1498] 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):

[1499]

[1500] 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):

[1501]

[1502] 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):

[1503]

[1504] 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):

[1505]

[1506] 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):

[1507]

[1508] 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):

[1509]

[1510] 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):

[1511]

[1512] 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):

[1513]

[1514] 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):

[1515]

[1516] 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):

[1517]

[1518] 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):

[1519]

[1520] 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):

[1521]

[1522] 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):

[1523]

[1524] 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):

[1525]

[1526] 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):

[1527]

[1528] In some embodiments, Ring Q is substituted or unsubstituted aryl.

[1529] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[1530] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[1531] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[1532] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[1533] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl group, wherein if the aryl group is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of:

[1534] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1)2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[1535] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[1536] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, wherein if the heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of:

[1537] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein

[1538] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[1539] In some embodiments, Ring Q is Each R Qindependently selected from the group consisting of hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CF3, –OCH3, –OCH2CH3, –CH2OCH3, –OCH2CH2CH3 and –OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[1540] In some embodiments, ring Q is a substituted or unsubstituted heteroaryl. In some embodiments, ring Q is a substituted or unsubstituted 5-membered 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 a 6-membered monocyclic heteroaryl selected from the group consisting of:

[1541] Each R Q is independently selected from the group consisting of hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3, and -OCH(CH3)2; and Ring P is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In some embodiments, each R Q are independently hydrogen, –F, –Cl, –CN, –OH, –CH 3 , –CF 3 or –OCH 3 .

[1542] In some embodiments, ring P is a substituted or unsubstituted heteroaryl. In some embodiments, ring P is a heteroaryl selected from the group consisting of:

[1543] in

[1544] Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[1545] R B1Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[1546] m is 0, 1, 2 or 3.

[1547] In some embodiments, Ring P is a heteroaryl group selected from the group consisting of:

[1548] in

[1549] Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[1550] R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and

[1551] m is 0, 1, 2 or 3.

[1552] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of: Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3-7In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[1553] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of: Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and m is 1, 2, 3, or 4. In some embodiments, R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 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.

[1554] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring P is a heteroaryl group selected from the group consisting of:

[1555] Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3-7In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[1556] In some embodiments, each R B independently hydrogen, deuterium, –F, –Cl, –CN, –CH3, –CF 3、– OH or -OCH3. In some embodiments, each R B is independently -F or -OCH3.

[1557] In some embodiments, R B1 Hydrogen, deuterium, –CH3, –CF 3或 –CD3.

[1558] 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.

[1559] In some embodiments, Ring Q is 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from the group consisting of:

[1560] Deuterium, halogen, –OH, –NO2, –CN, –SR 1 、–S(=O)R 1 、–S(=O)2R 1 ,–N(R 1 )2, –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 、–C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein

[1561] Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[1562] In some embodiments, Ring Q is selected from the group consisting of:

[1563]

[1564] In some embodiments, Ring Q is selected from the group consisting of:

[1565]

[1566] In some embodiments, Ring Q is selected from the group consisting of:

[1567]

[1568] In some embodiments, Ring Q is selected from the group consisting of:

[1569] where R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

[1570] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1571] wherein each of the ring Q groups may be optionally replaced by 1-3 R B Substitute, where each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1572] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1573] wherein each of the ring Q groups may be optionally replaced by 1-3 R B Substitute, where each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1574] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1575] wherein each of the ring Q groups may be optionally substituted with 1, 2, 3, 4 or 5 R B Substitute, where each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1576] In some embodiments of the compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[1577] where R B1 Selected from the group c...

Claims

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

2. The compound according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: hydrogen and deuterium.

3. The compound according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

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

6. The compound according to claim 5 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: hydrogen and deuterium.

7. The compound according to claim 5 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

8. The compound according to claim 5 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

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

10. The compound according to claim 9 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: hydrogen and deuterium.

11. The compound according to claim 9 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

12. The compound according to claim 9 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (Ia):

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (Ib):

15. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (Ic):

16. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (Id):

17. A compound according to any one of claims 1 to 12 or 16, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (Ie):

18. A compound according to any one of claims 1 to 12 or 16, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (If):

19. The compound according to claim 9 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (III) has the structure of formula (IIIa):

20. The compound according to claim 9 or 19, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (III) has the structure of formula (IIIb):

21. The compound according to claim 9 or 19, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (III) has a structure of formula (IIIc):

22. The compound according to claim 9 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (III) has the structure of formula (IIId):

23. The compound according to claim 9 or 23, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (III) has the structure of formula (IIIe):

24. The compound according to claim 9 or 23, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (III) has the structure of formula (IIIf): 25 . The compound according to claim 1 , or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted aryl group.

26. The compound according to claim 25, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 , –C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

27. The compound according to claim 25, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

28. The compound according to claim 27, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted aryl group, wherein if the aryl group is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 , –C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

29. The compound according to claim 27, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, wherein if the heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 , –C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

30. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein: Ring Q is Each R Q independently selected from the group consisting of hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CF3, –OCH3, –OCH2CH3, –CH2OCH3, –OCH2CH2CH3 and –OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

31. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted heteroaryl group.

32. The compound according to claim 31 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl group.

33. The compound according to claim 32 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl group.

34. The compound according to claim 33, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is a 6-membered monocyclic heteroaryl selected from the group consisting of: Each R Q independently selected from the group consisting of hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CF3, –OCH3, –OCH2CH3, –CH2OCH3, –OCH2CH2CH3 and –OCH(CH3)2; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

35. The compound according to claim 30 or 34, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R Q are independently hydrogen, –F, –Cl, –CN, –OH, –CH3, –CF3 or –OCH3.

36. The compound according to claim 30 or 34, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring P is a substituted or unsubstituted heteroaryl group.

37. The compound according to claim 36 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring P is a heteroaryl group selected from the group consisting of: in Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and m is 1, 2 or 3.

38. The compound according to claim 36 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring P is a heteroaryl group selected from the group consisting of: in Each R B independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, –CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, –OCD3, substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl; and m is 1, 2 or 3.

39. The compound according to claim 37 or 38, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R B are independently hydrogen, deuterium, –F, –Cl, –CN, –CH3, –CF3, –OH or –OCH3.

40. The compound according to claim 37-39, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R B is independently -F or -OCH3.

41. A compound according to any one of claims 37 to 39, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R B1 is H, deuterium, –CH3, –CF3 or –CD3.

42. The compound according to claim 37 or 38, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein m is 1.

43. A compound according to any one of claims 1 to 24 or 31, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is 2-naphthyl substituted at position 3 with 0, 1 and 2 substituents independently selected from the group consisting of: Deuterium, halogen, –OH, –NO2, –CN, –SR 1 , –S(=O)R 1 、–S(=O)2R 1 , –N(R 1 )2. –C(=O)R 1 、–OC(=O)R 1 、–C(=O)OR 1 , –C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein Each R 1 and -C3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

44. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of:

45. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of:

46. ​​The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of:

47. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein ring Q is selected from the group consisting of: in R B1 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C2-C7 heterocycloalkyl.

48. The compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C1-C3 alkylene group.

49. The compound according to claim 48, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2-.

50. The compound according to claim 48, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2CH2-.

51. The compound according to claim 48, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2CH2CH2-.

52. A compound according to any one of claims 1-47, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C1-C2 heteroalkylene.

53. The compound according to claim 52, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2OCH2-.

54. A compound according to any one of claims 13-15, 19-21 or 25-47, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH2O-, wherein O is attached to a moiety having R 18 The carbon atom of the group.

55. The compound according to any one of claims 1-47, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C3-C8 cycloalkylene or a substituted or unsubstituted C2-C3 alkenylene.

56. The compound according to claim 55, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C3-C8 cycloalkylene group.

57. The compound according to claim 56, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is cyclopropylene.

58. The compound according to claim 55, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is a substituted or unsubstituted C2-C3 alkenylene.

59. The compound according to claim 58, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein W is -CH=CH-.

60. A compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C5 cycloalkyl, or substituted or unsubstituted C2-C4 heterocycloalkyl.

61. A compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, - CH2C(=O)N(CH3)2, –CH2NH2, –CH2NHCH3, –CH2N(CH3)2, –CH2F, –CHF2, –CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl or azetidinyl.

62. A compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, - CHF2, –CF3, cyclopropyl, or oxetane.

63. A compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl.

64. A compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl or oxetanyl.

65. The compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2OH, -CH2CN, -CHF2, -CF3 or cyclopropyl.

66. The compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl.

67. The compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is -CH3, -CH2CH3, -CH2F, -CHF2 or -CF3.

68. The compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R is hydrogen.

69. A compound according to any one of claims 1-15, 19-21 or 25-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 One or more of are independently selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

70. A compound according to any one of claims 1-15, 19-21 or 25-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 One or more of are independently selected from the group consisting of: F, –OH, –OCH3, –OCH2CH3, –OCH2CH2OH, –OCH2CN, –OCF3, –CH3, –CH2CH3, –CH2OH, –CH2CH2OH, –CH2CN, – CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, and -CH2CF3.

71. A compound according to any one of claims 1-15, 19-21 or 25-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 One or more of are independently selected from the group consisting of F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3.

72. A compound according to any one of claims 1-15, 19-21 or 25-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 and R 16 For hydrogen.

73. A compound according to any one of claims 1-12, 16-18 or 22-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 One or more of are independently selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl.

74. A compound according to any one of claims 1-12, 16-18 or 22-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 One or more of are independently selected from the group consisting of F, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2 and -CH2CF3.

75. A compound according to any one of claims 1-12, 16-18 or 22-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 One or more of are independently selected from the group consisting of F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2 and -CF3.

76. A compound according to any one of claims 1-12, 16-18 or 22-68, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 16 and R 17 For hydrogen.

77. A compound according to any one of claims 1 to 76, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 2 It is hydrogen, –CH3 or –OCH3.

78. The compound according to claim 77, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 2 For hydrogen.

79. The compound according to any one of claims 1-4 or 13-78, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein X is -O-.

80. The compound according to any one of claims 1-4 or 13-78, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein X is -S-.

81. A compound according to any one of claims 1-4 or 13-78, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein X is -NR 3 -.

82. The compound according to claim 81 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 3 It is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl or oxetanyl.

83. The compound according to claim 81 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 3 It is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, cyclopropyl or oxetanyl.

84. The compound according to claim 81 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 3 It is hydrogen, -CH3, -CH(CH3)2, cyclopropyl or oxetanyl.

85. The compound according to claim 81 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 3 It is hydrogen, -CH3 or cyclopropyl.

86. A compound according to any one of claims 1 to 85, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R A are independently hydrogen, F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OH, -OCH3, -OCH2CH3, -OCF3, -CH2F, -CHF2 or -CF3.

87. A compound according to any one of claims 1 to 85, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R A are independently hydrogen, F, Cl, -CN, -CH3, -OH, -OCH3, -OCF3, -CH2F, -CHF2 or -CF3.

88. A compound according to any one of claims 1 to 85, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R A are independently hydrogen, F, Cl, -CN, -CH3 or -OCH3.

89. A compound according to any one of claims 1 to 85, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R A are independently hydrogen, F, Cl or -CH3.

90. A compound according to any one of claims 1 to 85, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R A For hydrogen.

91. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 All are deuterium.

92. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 All are deuterium.

93. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl and substituted or unsubstituted C1-C3 heteroalkyl.

94. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of F, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CH2F, -CHF2 and -CF3.

95. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2 and -CF3.

96. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3.

97. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are the same and are selected from the group consisting of: F, -CH3 and -OCH3.

98. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 For F.

99. A compound according to any one of claims 1 to 90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 It is -CH3.

100. A compound according to any one of claims 1 to 90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 It is -OCH3.

101. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of: hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl and substituted or unsubstituted C1-C3 heteroalkyl.

102. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of hydrogen, deuterium, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CH2F, -CHF2 and -CF3.

103. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of hydrogen, deuterium, F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, -OCF3, -CH2F, -CHF2 and -CF3.

104. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of hydrogen, deuterium, F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2 and -CF3.

105. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 and R 18 are different and selected from the group consisting of hydrogen, deuterium, F, -CH3 and -OCH3.

106. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 is F and R 18 For hydrogen.

107. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 is hydrogen and R 18 For F.

108. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 is hydrogen and R 18 For CH3.

109. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 15 is CH3 and R 18 For hydrogen.

110. A compound according to any one of claims 5 to 109, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl.

111. A compound according to any one of claims 5-109 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 are independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -CH2OCH3, -CH2F, -CHF2 or -CF3.

112. A compound according to any one of claims 5-109 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 are independently hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2F, -CHF2 or -CF3.

113. A compound according to any one of claims 5-109 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 For hydrogen.

114. A compound according to any one of claims 5-109 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein each R 4 It is -CH3.

115. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is F.

116. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the above comprises fluorine.

117. The compound according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 2-(5-(((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol; 2-(5-(((1S,2R,3R,5S,6R)-2,6-difluoro-8-azabicyclo[ 3.2.1] oct-3-yl-1,5-d2)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,3R,5R)-6,6-difluoro-8-azabicyclo[ 3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5S,7R)-2-fluoro-7-methyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 6-(5-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1S,3R,5R)-6,6-difluoro-8-azabicyclo[ 3.2.1] oct-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 6-(5-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 2-(5-(((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5S,6S)-2,6-difluoro-8-azabicyclo[ 3.2.1] oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5S,7R)-2-fluoro-7-methyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 6-(5-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,2S,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 6-(5-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 2-(5-(((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)thio)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)thio)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)thio)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)thio)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-(((1S,2R,3R,5R)-2-Fluoro-9-azabicyclo[3.3.1]non-3-yl)thio)pyrazin-2-yl)isoquinolin-7-ol.

118. The compound according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 2-(5-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol; 2-(5-(((1S,2S,3R,5S,6R)-2,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,3R,5R)-6,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2R,3S,5S,7R)-2-fluoro-1,5,7-trimethyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 6-(5-(((1R,2S,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1S,3R,5R)-6,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,3S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 6-(5-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 2-(5-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5S,6S)-2,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5S,7R)-2-fluoro-1,5,7-trimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 6-(5-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,2S,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,2S,3S,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 6-(5-(((1S,2R,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 2-(5-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)thio)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,2S,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)thio)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)thio)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)thio)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-(((1S,2R,3R,5R)-2-Fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)thio)pyrazin-2-yl)isoquinolin-7-ol.

119. The compound according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 5-(1H-imidazol-1-yl)-2-(5-(methyl((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino)pyrazin-2-yl)phenol; 2-(5-(((1S,3S,4R,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol; 2-(5-(((1S,2S,3R,5S,6R)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl-5-d)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1R,3R,5S)-7,7-difluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,3S,4S,5R,7S)-4-fluoro-1,7-dimethyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5S)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 6-(5-(((1S,3S,4R,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,3R,5S)-7,7-difluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,3S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(((1S,2S,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)(methyl)amino)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 6-(5-(((1S,2S,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyrazin-2-yl)isoquinolin-7-ol; 5-(1H-imidazol-1-yl)-2-(5-(((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2R,3R,5S,6S)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,3S,4S,5R,7S)-4-fluoro-1,7-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 6-(5-(((1S,3S,4R,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1S,3S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(((1R,3S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 6-(5-(((1S,2R,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyrazin-2-yl)isoquinolin-7-ol; 5-(1H-imidazol-1-yl)-2-(5-(((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio)pyrazin-2-yl)phenol; 2-(5-(((1S,3S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(((1S,2S,3R,5S)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)thio)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 5-(5-(((1S,2R,3R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)thio)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-(((1S,2R,3R,5R)-2-Fluoro-1-methyl-9-azabicyclo[3.3.1]nonan-3-yl)thio)pyrazin-2-yl)isoquinolin-7-ol.

120. The compound according to claim 5, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 2-(5-(1-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-4-fluoro-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,2S,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2S,3S,5S,6R)-2,6-difluoro-8-azabicyclo[ 3.2.1] oct-3-yl-1,5-d2)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,2R,3R,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2S,3S,5S,6S)-2,6-difluoro-8-azabicyclo[ 3.2.1] oct-3-yl) vinyl) pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,2R,3R,5S,7R)-2-fluoro-7-methyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 5-(4-Fluoro-1H-pyrazol-1-yl)-2-(5-(1-((1R,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)phenol; 6-(5-(1-((1R,2R,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(1-((1R,2R,3R,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(1-((1R,2R,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(1-((1S,2S,3S,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-(1-((1S,2S,3S,5R)-2-Fluoro-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol.

121. The compound according to claim 5, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 2-(5-(1-((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-4-fluoro-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,2S,3R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2S,3S,5S,6R)-2,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,2R,3R,5R)-6,6-difluoro-2-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2S,3S,5S,6S)-2,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,2R,3R,5S,7R)-2-fluoro-1,5,7-trimethyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 2-(5-(1-((1R,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)-5-(4-fluoro-1H-pyrazol-1-yl)phenol; 6-(5-(1-((1R,2R,3R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(1-((1R,2R,3R,5R)-6,6-difluoro-2-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(1-((1R,2R,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(1-((1S,2S,3S,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-(1-((1S,2S,3S,5R)-2-Fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol.

122. The compound according to claim 5, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 5-(1H-imidazol-1-yl)-2-(5-(1-((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)phenol; 4-Fluoro-5-(1H-imidazol-1-yl)-2-(5-(1-((1S,3R,5R)-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)phenol; 2-(5-(1-((1S,3R,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5R)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2S,3S,5S,6R)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl-5-d)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1R,3R,4R,5R)-7,7-difluoro-4-methoxy-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2S,3S,5S,6S)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]oct-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,3R,4R,5R,7S)-4-fluoro-1,7-dimethyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-(1-((1S,2R,3S,5S)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 2-(5-(1-((1R,3R,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)-5-(4-fluoro-1H-pyrazol-1-yl)phenol; 6-(5-(1-((1S,3R,4R,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(1-((1R,3R,4R,5R)-7,7-difluoro-4-methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-(1-((1R,3R,4R,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-(1-((1S,2S,3S,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-(1-((1S,2S,3S,5R)-2-Fluoro-1-methyl-9-azabicyclo[3.3.1]non-3-yl)vinyl)pyrazin-2-yl)isoquinolin-7-ol.

123. The compound according to claim 9, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 2-(5-((Z)-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 5-(5-((Z)-((1R,5S)-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 5-(5-((E)-((1R,5S)-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 2-(5-((Z)-((1R,2S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol; 2-(5-((E)-((1S,2S,5S,6R)-2-fluoro-6-methoxy-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5S,6R)-2,6-difluoro-8-azabicyclo[ 3.2.1] oct-3-ylidene-1,5-d2)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((Z)-((1R,2R,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]oct-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5S,6S)-2,6-difluoro-8-azabicyclo[ 3.2.1] octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((Z)-((1R,2R,5S)-2-fluoro-7-methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2R,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-6-en-3-ylidene)methyl)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 6-(5-((Z)-((1R,2S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-((Z)-((1R,2R,5R)-6,6-difluoro-2-methoxy-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-((E)-((1S,2S,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-((E)-((1S,2S,5R)-2-Fluoro-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol.

124. The compound according to claim 9, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 2-(5-((Z)-((1R,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1R,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 5-(5-((Z)-((1R,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 5-(5-((E)-((1R,5S)-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; 2-(5-((Z)-((1R,2S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol; 2-(5-((E)-((1S,2S,5S,6R)-2-fluoro-6-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5S,6R)-2,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((Z)-((1R,2R,5R)-6,6-difluoro-2-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5S,6S)-2,6-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((Z)-((1R,2R,5S,7R)-2-fluoro-1,5,7-trimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2R,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-6-en-3-ylidene)methyl)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 6-(5-((Z)-((1R,2S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-((Z)-((1R,2R,5R)-6,6-difluoro-2-methoxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-((E)-((1S,2S,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-((E)-((1S,2S,5R)-2-Fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol.

125. The compound according to claim 9, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is: 5-(1H-imidazol-1-yl)-2-(5-((E)-((1S,5R)-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)phenol; 5-(1H-imidazol-1-yl)-2-(5-((E)-((1R,5S)-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)phenol; 2-(1H-imidazol-1-yl)-5-(5-((E)-((1S,5R)-1-methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)pyridin-4-ol; 2-(1H-imidazol-1-yl)-5-(5-((E)-((1R,5S)-1-methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)pyridin-4-ol; 2-(5-((Z)-((1S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5R)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(5-methyl-2H-tetrazol-2-yl)phenol; 2-(5-((E)-((1S,2S,5S,6R)-2-fluoro-6-methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5S,6R)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene-5-d)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((Z)-((1R,4R,5R)-7,7-difluoro-4-methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2S,5S,6S)-2,6-difluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2R,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((Z)-((1S,4R,5R)-4-fluoro-1,7-dimethyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-5-(1H-imidazol-1-yl)phenol; 2-(5-((E)-((1S,2R,5S)-2-fluoro-1-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ylidene)methyl)pyrazin-2-yl)-5-(2-methoxypyridin-4-yl)phenol; 6-(5-((Z)-((1S,4S,5R)-4-fluoro-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol; 6-(5-((Z)-((1R,4R,5R)-7,7-difluoro-4-methoxy-1-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol; 5-(5-((E)-((1S,2S,5R)-2-fluoro-1-methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)-2-(1H-imidazol-1-yl)pyridin-4-ol; or 6-(5-((E)-((1S,2S,5R)-2-Fluoro-1-methyl-9-azabicyclo[3.3.1]nonan-3-ylidene)methyl)pyrazin-2-yl)isoquinolin-7-ol.

126. A method of regulating splicing, comprising contacting a compound described in any one of claims 1-125, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, with a cell, wherein the compound regulates splicing at a splice site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA.

127. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 125 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

128. A method of treating a condition or disease comprising administering to a subject in need thereof a compound as described in any one of claims 1-125, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

129. Use of a compound according to any one of claims 1 to 125 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating a disorder or disease.

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