Methods and compositions for modulating splicing

Abstract

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

Description

cross reference

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 801,729, filed February 6, 2019, and U.S. Provisional Patent Application No. 62 / 801,730, filed February 6, 2019, each of which is incorporated herein by reference in its entirety. [Background technology]

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

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

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

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

[0006] In one embodiment, a compound of formula (I) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -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, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R18 are (i) the same and selected from the group consisting of hydrogen and deuterium, or (ii) the same and 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, b is 0, c is 1, Described herein are compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3 or Table 4.

[0007] In one embodiment, a compound of formula (I) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3.

[0008] In one embodiment, a compound of formula (I) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 4.

[0009] In one embodiment, a compound of formula (II) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are (i) the same and selected from the group consisting of hydrogen and deuterium, or (ii) the same and 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, b is 0, c is 1, Described herein are compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3 or Table 4.

[0010] In one embodiment, a compound of formula (II) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3.

[0011] In one embodiment, a compound of formula (II) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 4.

[0012] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (A): [ka]

[0013] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (B): [ka]

[0014] In some embodiments, the compound of Formula (B) has the structure of Formula (B-1): [ka]

[0015] In some embodiments, the compound of Formula (B) has the structure of Formula (B-2): [ka]

[0016] In some embodiments, the compound of formula (B) has the structure of formula (B-3): [ka]

[0017] In some embodiments, the compound of formula (B) has the structure of formula (B-4): [ka]

[0018] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (C): [ka]

[0019] In some embodiments, the compound of Formula (C) has the structure of Formula (C-1): [ka]

[0020] In some embodiments, the compound of Formula (C) has the structure of Formula (C-2): [ka]

[0021] In some embodiments, the compound of Formula (C) has the structure of Formula (C-3): [ka]

[0022] In some embodiments, the compound of formula (C) has the structure of formula (C-4): [ka]

[0023] For each and every embodiment, substituents may be selected from a subset of the listed alternatives. For example, in some embodiments, R 2 is disclosed to be hydrogen, -CH3, or -OCH3, then R 2 is hydrogen and R2 is -CH3 and R 2 is also disclosed to be -OCH3.

[0024] In some embodiments, R 15 and R 18 In some embodiments, both R 15 and R 18 In some embodiments, both R 15 and R 18 is the same as f, -or 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18 are the same and are selected from F, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18 are the same and are selected from F, —CH, —CHOH, —OCHCN, —OH, —OCH, —OCHCN, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH, —OCH, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH3, and —OCH3. In some embodiments, R 15 and R 18 and R are both F. In some embodiments, R 15 and R 18 Both are -CH3.

[0025] In some embodiments, ring Q is substituted or unsubstituted aryl.

[0026] In some embodiments, ring Q is deuterium, halogen, —OH, —NO 2 , —CN, —SR 2 . 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-hydroxy-phenyl substituted by 1, 2, or 3 substituents independently selected from 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; 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0027] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl.

[0028] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl, where when the aryl is substituted it can be deuterium, halogen, —OH, —NO 2 , —CN, —SR 2 , —S 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 2- C6 alkenyl, substituted or unsubstituted C 2- C6 alkynyl, substituted or unsubstituted C 1- C6 alkoxy, substituted or unsubstituted C 3- C7 cycloalkyl, and substituted or unsubstituted C 2- C heterocycloalkyl; and R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0029] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where when the heteroaryl is substituted, it can be selected from deuterium, halogen, —OH, —NO 2 , —CN, —SR 2 , —S 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 C 1- C6 alkyl, substituted or unsubstituted C 2- C6 alkenyl, substituted or unsubstituted C 2- C6 alkynyl, substituted or unsubstituted C 1- C6 alkoxy, substituted or unsubstituted C 3- C7 cycloalkyl, and substituted or unsubstituted C 2- C heterocycloalkyl; and R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0030] In some embodiments, ring Q is substituted or unsubstituted heteroaryl.

[0031] In some embodiments, ring Q is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

[0032] In some embodiments, ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl.

[0033] In some embodiments, ring Q is [ka] wherein R is a 6-membered monocyclic heteroaryl selected from Q are each independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH), and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0034] In some embodiments, ring Q is [ka] where R Qare each independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH), and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0035] In some embodiments, R Q are each independently selected from hydrogen, —F, —Cl, —CN, —OH, —CH 3 , —CF 3 , and —OCH 3 .

[0036] In some embodiments, ring P is a substituted or unsubstituted heteroaryl.

[0037] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 is selected from cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7In some embodiments, m is selected from cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl, and m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0038] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 is selected from cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 In some embodiments, m is selected from cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl, and m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0039] In some embodiments, R B are each independently selected from deuterium, —F, —Cl, —CN, —CH, —CF, —OH, and —OCH. In some embodiments, R B are each independently selected from hydrogen, deuterium, —F, —Cl, —CN, —CH 3 , —CF 3 , —OH, and —OCH 3 .

[0040] In some embodiments, R B are each independently -F or -OCH. In some embodiments, R B are each independently hydrogen, -F, or -OCH. In some embodiments, R B is hydrogen. In some embodiments, R B is —OCH. In some embodiments, R B is -CH3.

[0041] In some embodiments, R B1 is selected from hydrogen, deuterium, —CH, —CF, and —CD. In some embodiments, R B1 is hydrogen. In some embodiments, R B1 is deuterium. In some embodiments, R B1 is -CH3. In some embodiments, R B1 is -CF3. In some embodiments, R B1 is -CD3.

[0042] In some embodiments, ring Q is deuterium, halogen, —OH, —NO 2 , —CN, —SR 2 . 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1)2, 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from 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 R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0043] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0044] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0045] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0046] In some embodiments, ring Q is [ka] is selected from the group consisting of In the formula, R B1is 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.

[0047] In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is substituted or unsubstituted -CH2CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is substituted or unsubstituted -CH2CH2CH2. In some embodiments, W is -CH2CH2CH2.

[0048] In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene. In some embodiments, W is substituted or unsubstituted cyclopropylene. In some embodiments, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is -CH=CH-.

[0049] In some embodiments, W is a substituted or unsubstituted C1-C2 heteroalkylene. In some embodiments, W is a substituted or unsubstituted -CH2OCH2-. In some embodiments, W is -CH2O-, where O is R 18 is attached to the carbon atom to which the group is attached.

[0050] In some embodiments, R 16 and R 17 One or more of the following may independently be F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl.

[0051] In some embodiments, R 16 and R 17 are independently selected from F, —OH, —OCH, —OCHCH, —OCHCHOH, —OCHCN, —OCF, —CH, —CHCH, —CHOH, —CHCHOH, —CHCN, —CHF, —CHF, —CF, —CHCHF, —CHCHF, and —CHCF.

[0052] In some embodiments, R 16 and R 17 are independently selected from F, —OH, —OCH 3 , —OCF 3 , —CH 3 , —CH 2 OH, —CH 2 F, —CHF 2 , and —CF 3 .

[0053] In some embodiments, R 16 is F. In some embodiments, R 16 is hydrogen. In some embodiments, R 17 is F. In some embodiments, R 17 is hydrogen. In some embodiments, R 16 and R 17 is hydrogen.

[0054] In some embodiments, R 16 is H and R 17 is F. In some embodiments, R 16 is F and R 17 is H.

[0055] In some embodiments, R 2 is hydrogen, -CH3, or -OCH3.

[0056] In some embodiments, R 2 is hydrogen.

[0057] In some embodiments, R Aare each independently hydrogen, F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OH, -OCH3, -OCH2CH3, -OCF3, -CH2F, -CHF2, or -CF3.

[0058] In some embodiments, R A are each independently hydrogen, F, Cl, —CN, —CH3, —OH, —OCH3, —OCF3, —CH2F, —CHF2, or —CF3.

[0059] In some embodiments, R A are each independently hydrogen, F, Cl, —CN, —CH3, or —OCH3.

[0060] In some embodiments, R A are each independently hydrogen, F, Cl, or —CH3.

[0061] In some embodiments, R A is hydrogen.

[0062] In some embodiments, X is -O-. In some embodiments, X is -S-.

[0063] In some embodiments, R 15 and R 18 In some embodiments, both R 15 and R 18 In some embodiments, both R 15 and R 18 is the same as f, -or 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18are the same and are selected from F, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18 are the same and are selected from F, —CH, —CHOH, —OCHCN, —OH, —OCH, —OCHCN, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH, —OCH, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH3, and —OCH3. In some embodiments, R 15 and R 18 and R are both F. In some embodiments, R 15 and R 18 Both are -CH3.

[0064] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , and R 18 At least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of them are F.

[0065] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R16 , R 17 , and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0066] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R18 In some embodiments, one of W comprises fluorine.

[0067] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F.

[0068] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 15 is F, CHF, CHF, CF, or CH. In some embodiments, R15 is F, CF, CHF, or CHF. In some embodiments, R 15 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 18 is F, CHF, CHF, CF, or CH. In some embodiments, R 18 is F, CF, CHF, or CHF. In some embodiments, R 18 is F.

[0069] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R18 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of them are F.

[0070] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0071] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, one of W comprises fluorine.

[0072] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 , and R 16 is hydrogen. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof, R 19 is hydrogen. In some embodiments, R 19 is H, F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 19 is H, F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. In some embodiments, R 19 is F or -OCH3.

[0073] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 20 is hydrogen. In some embodiments, R 20is H, F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 20 is H, F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. In some embodiments, R 20 is F or -OCH3.

[0074] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a 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 (II) or a pharmaceutically acceptable salt or a 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 (II) or a pharmaceutically acceptable salt or a 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 (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 19 and R 20 is H. In some embodiments, R 19 and R 20is D. In some embodiments, R 19 and R 20 is F. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 17 and R 20 is H. In some embodiments, R 17 and R 20 is D. In some embodiments, R 17 and R 20 is F.

[0075] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a 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 R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least two of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17At least one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 At least two of them are F.

[0076] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a 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 R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 At least one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0077] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, W, R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 In some embodiments, one of W comprises fluorine.

[0078] In one aspect, described herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0079] In one aspect, described herein are methods of treating a condition or disease, the methods comprising administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0080] In one aspect, described herein is the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a condition or disease.

[0081] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0082] Certain details herein are described to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the following claims, the term "comprises," and variations thereof, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0083] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0085] definition The terms "compound(s) of this disclosure", "compound(s) of the present disclosure", "small molecule steric regulator(s)", "small molecule splicing regulator(s)", "steric regulator(s)", "splicing regulator(s)", "compound(s) that modify splicing" and "splicing-modifying compound(s)", "SMSM", or "small molecule that binds to target RNA" are used interchangeably herein and refer to the compounds disclosed herein, as well as stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. The terms "compound(s) of this disclosure," "compound(s) of the present disclosure," "small molecule steric regulator(s)," "small molecule splicing regulator(s)," "steric regulator(s)," "splicing regulator(s)," "compound(s) that modify splicing," and "splicing-modifying compound(s)," "SMSM," or "small molecule that binds to target RNA" refer to a small molecule that binds to a cellular component (e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrate, lipid, cofactor, nutrient, and / or metabolite) and modulates the splicing of a target polynucleotide, e.g., a pre-mRNA. For example, an SMSM can bind directly or indirectly to a target polynucleotide, e.g., an RNA (e.g., pre-mRNA) with mutated, non-mutated, bulged, and / or aberrant splice sites, resulting in modulation of the splicing of the target polynucleotide. For example, SMSM can bind directly or indirectly to proteins, such as spliceosomal proteins or ribonucleoproteins, resulting in conformational regulation of the protein and modulation of splicing of target RNAs. For example, SMSM can bind directly or indirectly to spliceosomal components, such as spliceosomal proteins or snRNAs, resulting in conformational regulation of the spliceosomal and modulation of splicing of target polynucleotides.These terms specifically exclude compounds consisting of oligonucleotides. These terms include small molecule compounds that can bind to one or more secondary or tertiary structural elements of target RNA. These sites include RNA triplexes, 3WJs, 4WJs, parallel Y-junctions, hairpins, bulge loops, pseudoknots, internal loops, and other higher-order RNA structural motifs.

[0086] The term "RNA" (ribonucleic acid), as used herein, refers to naturally occurring or synthetic oligoribonucleotides, regardless of source (e.g., RNA may be produced by humans, animals, plants, viruses, or bacteria, or may be of synthetic origin), biological context (e.g., RNA may be in the nucleus, circulating in the blood, in vitro, in a cell lysate, or in isolated or pure form), or physical form (e.g., RNA may be in single-stranded, double-stranded, or triple-stranded form (including RNA-DNA hybrids), and may be in an endogenous form). The RNA may contain pigenetic, post-transcriptional natural, artificial (e.g., chemical or in vitro) or other modifications; may bind, for example, to metal ions, small molecules, proteins such as chaperones, or cofactors; or may be in a denatured, partially denatured, or folded state, including any natural or non-native secondary or tertiary structure, such as a quadruplex, hairpin, triplex, three-way junction (3WJ), four-way junction (4WJ), parallel Y junction, hairpin, bulge loop, pseudoknot, and internal loop, and any transient form or structure adopted by the RNA. In some embodiments, the RNA is 20, 22, 50, 75, or 100 or more nucleotides in length. In some embodiments, the RNA is 250 or more nucleotides in length. In some embodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the RNA is 250-1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pre-transcript.In some embodiments, the RNA is non-coding RNA (ncRNA), messenger RNA (mRNA), microRNA (miRNA), ribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudogene, viral RNA, fungal RNA, parasitic RNA, or bacterial RNA.

[0087] As used herein, the terms "target polynucleotide" and "target RNA" refer to any type of polynucleotide or RNA, respectively, that has a splice site that can be modulated by the small molecule compounds described herein. For example, a "target polynucleotide" or "target RNA" can have a secondary or tertiary structure that can bind to the small molecule compounds described herein.

[0088] As used herein, "steric alteration," "steric modification," or "steric adjustment" refers to a change in the spatial orientation of chemical moieties relative to one another. Those skilled in the art will recognize steric mechanisms, including, but not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsion, steric inhibition of resonance, and steric inhibition of protonation.

[0089] Any open valency appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0090] The definitions set forth herein apply regardless of whether the terms in question appear alone or in combination. It is contemplated that the definitions set forth herein can be added to form chemically relevant combinations, such as, for example, "heterocycloalkylaryl," "haloalkylheteroaryl," "arylalkylheterocycloalkyl," or "alkoxyalkyl." The last member of the combination is the radical that is bonded to the rest of the molecule. The other members of the combination are bonded to the bonded radical in reverse order relative to the literal sequence; for example, the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl radical substituted by an alkyl substituted by an aryl.

[0091] When referring to the number of substituents, the term "one or more" refers to a range from one substituent to the maximum number of substituents possible, i.e., from the replacement of one hydrogen to the replacement of all hydrogens by substituents.

[0092] The term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0093] The term "substituent" means an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0094] The term "substituted" means that the specified group has one or more substituents. Any group may have multiple substituents, and when a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When referring to the number of substituents, the term "one or more" means from one substituent to the maximum number of substituents possible, i.e., replacement of one hydrogen with a substituent to replacement of all hydrogens with a substituent.

[0095] The following abbreviations are used throughout this specification: acetic acid (AcOH), ethyl acetate (EtOAc), butyl alcohol (n-BuOH), 1,2-dichloroethane (DCE), dichloromethane (CHCl, DCM), diisopropylethylamine (Diipea), dimethylformamide (DMF), hydrogen chloride (HCl), methanol (MeOH), methoxymethyl bromide (MOMBr), N-methyl-2-pyrrolidone (NMP), methyl iodide (MeI), n-propanol (n-PrOH), p-methoxybenzyl (PMB), triethylamine (EtN), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (Pd(dppf)Cl), sodium ethanethiolate (EtSNa), sodium acetate (NaOAc), sodium hydride (NaH), sodium hydroxide (NaOH), tetrahydropyran (THP), tetrahydrofuran (THF).

[0096] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C4" indicates that there are from 1 to 4 carbon atoms present in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms in the group. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms present in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0097] The term "oxo" refers to a ═O substituent.

[0098] The term "thioxo" refers to the ═S substituent.

[0099] The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0100] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C1-C 10 Similarly, when referred to as alkyl, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl containing other numbers of carbon atoms (and other moieties defined herein) are represented similarly. Alkyl groups include C1-C 10Examples of alkyl include, but are not limited to, alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is —CH(CH3)2 or —C(CH3)3. Unless otherwise expressly stated herein, alkyl groups may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkyl is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkyl is -CH2-. In some embodiments, alkyl is -CH2CH2-. In some embodiments, alkyl is -CH2CH2CH2-. In some embodiments, alkyl is -CH2CH2CH2-.

[0101] The term "alkoxy" refers to a group of the formula -OR a where R a is an alkyl radical as defined above. Unless otherwise expressly stated herein, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0102] The term "alkylamino" refers to a group of the formula -NHR a or -NR a R a where R ais each independently an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0103] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R a )=CR a 2, wherein R a refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R a is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0104] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR a wherein R a refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0105] The term "aromatic" refers to a planar ring having a delocalized electron system containing 4n+2 electrons, where n is an integer. A ππ aromatic can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0106] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise expressly stated herein, the term "aryl" or the prefix "ar-" (e.g., in aralkyl) is intended to include aryl radicals that are optionally substituted. In some embodiments, an aryl group is partially reduced to form a cycloalkyl group, as defined herein. In some embodiments, an aryl group is fully reduced to form a cycloalkyl group, as defined herein.

[0107] The term "haloalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by the same or different halogen atoms, specifically, fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group in which all of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms.

[0108] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by the same or different halogen atom, specifically a fluoro atom. Examples of haloalkoxyl include monofluoro-, difluoro-, or trifluoro-methoxy, -ethoxy, or -propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.

[0109] The term "bicyclic ring system" refers to two rings fused together through a common single or double bond (annealed bicyclic ring system), through an arrangement of three or more common atoms (bridged bicyclic ring system), or through a single common atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated, or aromatic. Bicyclic ring systems can contain heteroatoms selected from N, O, and S.

[0110] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes a carbocyclic ring from a "heterocyclic" ring or a "heterocyclic" heterocycle in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0111] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. Unless otherwise expressly stated in the specification, cycloalkyl groups may be optionally substituted.

[0112] The term "bridge" refers to any ring structure having two or more rings that includes a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the skeletal framework of a molecule and is bonded to three or more other skeletal atoms. In some embodiments, the bridgehead atom is C, N, or P. In some embodiments, the bridge is a single atom or a chain of atoms connecting two bridgehead atoms. In some embodiments, the bridge is a valence bond connecting two bridgehead atoms. In some embodiments, the bridged ring system is a cycloalkyl. In some embodiments, the bridged ring system is a heterocycloalkyl.

[0113] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring may be replaced with one or more N, S, and O atoms. Non-limiting examples of fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycles, 6-6 fused heterocycles, 5-6 fused heterocycles, 5-5 fused heterocycles, 7-5 fused heterocycles, and 5-7 fused heterocycles.

[0114] The term "haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0115] The term "haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0116] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0117] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), or combinations thereof. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C-C heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH.

[0118] The term "heteroalkylene" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl have been replaced with an O, N, or S atom. A "heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to the radical group. Unless stated otherwise specifically in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to, -OCH2CHO-, -OCH2CHOCH2CHO-, or -OCH2CHOCH2CHOCH2CHO-.

[0119] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise expressly stated in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially saturated or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2-12 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 1 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms within the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise explicitly in the specification, a heterocycloalkyl group may be optionally substituted.

[0120] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings (also known as heterocyclic groups) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, with heterocyclic groups each having 3 to 12 atoms in their ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 12 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiazole ... oranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3h-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where possible. For example, pyrrole-derived groups include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, imidazole-derived groups include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0121] The term "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls are monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryl has 0 to 6 N atoms in the ring. In some embodiments, the heteroaryl has 1-4 N atoms in the ring. In some embodiments, the heteroaryl has 4-6 N atoms in the ring. In some embodiments, the heteroaryl has 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl has 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl.In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, the heteroaryl group is partially reduced to form a heterocycloalkyl group as defined herein. In some embodiments, the heteroaryl group is fully reduced to form a heterocycloalkyl group as defined herein.

[0122] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded within or appended to a molecule.

[0123] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, —S(═O)(C-C alkyl). In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -NH(cyclopropyl), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituents are substituted with one or two of the preceding groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0124] The term "tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, involving the switching of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomer interconversions include the following: [ka]

[0125] The term "about" or "approximately" can mean within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, in accordance with practice in the art, "about" can mean within one or more standard deviations. Alternatively, "about" can mean within a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within one order of magnitude, within five-fold, or within two-fold of a value.

[0126] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral route (po), intraduodenal route (id), parenteral injection (intravenous (iv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravascular or infusion (inf.), topical (top.), and rectal (pr.) administration. Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0127] As used herein, terms such as "co-administration" are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration, or at the same time or at different times.

[0128] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered drug or compound that will alleviate to some extent one or more of the symptoms of the disease or condition being treated, for example, reducing and / or alleviating one or more signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use can be the amount of drug that results in a clinically significant reduction in one or more disease symptoms. An appropriate "effective" amount can be determined using techniques such as a dose escalation study in each individual case.

[0129] As used herein, the term "enhance" or "enhancing" refers to an increase or prolongation of either the amount, potency, or duration of a desired effect. For example, with respect to enhancing splicing of a target, the term "enhancing" can refer to the ability to increase or prolong splicing of a target in either amount, potency, or duration.

[0130] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, e.g., humans, non-human primates such as chimpanzees, and other ape and monkey species, livestock such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, laboratory animals such as rodents, e.g., rats, mice, and guinea pigs, etc. In one aspect, a mammal is a human. The term "animal" as used herein includes human and non-human animals. In one embodiment, a "non-human animal" is a mammal, e.g., a rodent such as a rat or a mouse. In one embodiment, the non-human animal is a mouse.

[0131] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting symptoms of a disease or condition.

[0132] The term "preventing" a condition or "prevention" means preventing the clinical symptoms of a condition from developing in a subject who may be exposed to or susceptible to the condition, but who has not yet experienced or exhibited symptoms of the condition.

[0133] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or formulation) are used interchangeably and refer to a mixture or solution (to be administered to a subject in need thereof, e.g., a human) containing a therapeutically effective amount of a pharmaceutically active ingredient together with one or more pharmaceutically acceptable excipients.

[0134] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, such as the compounds described herein and auxiliary agents, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds described herein and auxiliary agents, are administered to a patient as separate entities, either simultaneously, concurrently, or sequentially, without any specific intervening time limit, such that administration provides an effective level of these two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0135] The term "pharmaceutically acceptable" refers to the attributes of a material that is generally safe, non-toxic, biologically or otherwise undesirable, and useful in the preparation of pharmaceutical compositions that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable" can refer to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is included.

[0136] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" may be used interchangeably and can refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant used in formulating a pharmaceutical product.

[0137] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. A "pharmaceutically acceptable salt" can refer to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and / or does not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting an SMSM compound of any one of Formulas (I) or (II) with an acid. A pharmaceutically acceptable salt can also be obtained by reacting a compound of any one of Formulas (I) or (II) with a base to form a salt.

[0138] As used herein, the term "nucleic acid" generally refers to one or more nucleobases, nucleosides, or nucleotides, and the term includes polynucleobases, polynucleosides, and polynucleotides.

[0139] As used herein, the term "polynucleotide" generally refers to a molecule containing two or more linked nucleic acid subunits, e.g., nucleotides, and may be used interchangeably with "oligonucleotide." For example, a polynucleotide may contain one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), or variants thereof. A nucleotide generally contains a nucleoside and at least one, two, three, four, five, six, seven, eight, nine, ten, or more phosphate (PO3) groups. A nucleotide may contain a nucleobase, a five-carbon sugar (either ribose or deoxyribose), and one or more phosphate groups. Ribonucleotides include nucleotides in which the sugar is ribose. Deoxyribonucleotides include nucleotides in which the sugar is deoxyribose. A nucleotide can be a nucleoside monophosphate, nucleoside diphosphate, nucleoside triphosphate, or nucleoside polyphosphate. For example, the nucleotide can be a deoxyribonucleoside polyphosphate, such as deoxyribonucleoside triphosphate (dNTP). Exemplary dNTPs include deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP), and deoxythymidine triphosphate (dTTP). The dNTP can also include a detectable tag, such as a luminescent tag or marker (e.g., a fluorophore). For example, the nucleotide can be a purine (i.e., A or G, or a variant thereof) or a pyrimidine (i.e., C, T, or U, or a variant thereof). In some examples, the polynucleotide is deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a derivative or variant thereof.Exemplary polynucleotides include, but are not limited to, short interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), short hairpin RNA (shRNA), small nuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA), antisense RNA (asRNA), and heteronuclear RNA (hnRNA), encompassing both nucleotide sequences and any structural embodiments thereof, such as single-stranded, double-stranded, triple-stranded, helix, hairpin, stem-loop, bulge, etc. In some cases, the polynucleotide is circular. The polynucleotide can have various lengths. For example, a polynucleotide can have a length of at least about 7 bases, 8 bases, 9 bases, 10 bases, 20 bases, 30 bases, 40 bases, 50 bases, 100 bases, 200 bases, 300 bases, 400 bases, 500 bases, 1 kilobase (kb), 2 kb, 3 kb, 4 kb, 5 kb, 10 kb, 50 kb, or more. Polynucleotides can be isolated from cells or tissues. For example, polynucleotide sequences can include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules, and / or synthetic DNA / RNA analogs.

[0140] A polynucleotide may contain one or more nucleotide variants, including non-standard nucleotide(s), unnatural nucleotide(s), nucleotide analog(s), and / or modified nucleotides. Examples of modified nucleotides include diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyl Examples of suitable nucleotides include, but are not limited to, aminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueuosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queuosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, 2,6-diaminopurine, and the like. In some cases, nucleotides may contain modifications of their phosphate moieties, including modifications to the triphosphate moiety. Non-limiting examples of such modifications include longer phosphate chains (e.g., phosphate chains having 4, 5, 6, 7, 8, 9, 10, or more phosphate moieties) and modifications of the thiol moiety (e.g., alpha-thiotriphosphate and beta-thiotriphosphate). Nucleic acid molecules may also be modified at the base moiety (e.g., one or more atoms typically available to form a hydrogen bond with a complementary nucleotide and / or one or more atoms typically unavailable to form a hydrogen bond with a complementary nucleotide), sugar moiety, or phosphate backbone.Nucleic acid molecules may also contain amine-modified groups such as aminoaryl-dUTP (aa-dUTP) and aminohexylacrylamide-dCTP (aha-dCTP) to allow covalent attachment of amine-reactive moieties such as N-hydroxysuccinimide ester (NHS). Substitution of standard DNA or RNA base pairs in the disclosed oligonucleotides can result in higher density in bits per cubic mm, greater safety (resistance to accidental or intentional synthesis of natural toxins), easier discrimination in light-programmed polymerases, or less secondary structure. Such alternative base pairs compatible with native and mutant polymerases for de novo and / or amplification synthesis are described in Betz K, Malyshev DA, Lavergne T, Welte W, Diederichs K, Dwyer TJ, Ordoukhanian P, Romesberg FE, Marx A. Nat. Chem. Biol. 2012 Jul;8(7):612-4, incorporated herein by reference for all purposes.

[0141] As used herein, the terms "polypeptide," "protein," and "peptide" are used interchangeably and refer to a polymer of amino acid residues linked via peptide bonds and may be composed of two or more polypeptide chains. The terms "polypeptide," "protein," and "peptide" refer to a polymer of at least two amino acid monomers linked together via amide bonds. The amino acids may be L or D optical isomers. More specifically, the terms "polypeptide," "protein," and "peptide" refer to a molecule composed of two or more amino acids in a specific order, e.g., an order determined by the base sequence of nucleotides in a gene or RNA encoding the protein. Proteins are essential for the structure, function, and control of cells, tissues, and organs of the body, each with a unique function. Examples include hormones, enzymes, antibodies, and any fragments thereof. In some cases, a protein can be a portion of a protein, e.g., a domain, subdomain, or motif of a protein. In some cases, a protein can be a variant (or mutation) of a protein in which one or more amino acid residues have been inserted into, deleted from, and / or substituted into the naturally occurring (or at least known) amino acid sequence of the protein. The protein or variant thereof can be naturally occurring or recombinant.

[0142] Methods for detecting and / or measuring polypeptides in biological materials are well known in the art, including, but not limited to, Western blotting, flow cytometry, ELISA, RIA, and various proteomics techniques.An exemplary method for measuring or detecting polypeptides is immunoassays such as ELISA.This type of protein quantification can be based on an antibody that can capture a specific antigen and a second antibody that can detect the captured antigen.An exemplary assay for detecting and / or measuring polypeptides is described in Harlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), Cold Spring Harbor Laboratory Press.

[0143] Methods for detecting and / or measuring RNA in biological materials are well known in the art, including but not limited to Northern blotting, RNA protection assay, RT PCR.Suitable methods are described in Molecular Cloning: A Laboratory Manual (Fourth Edition) by Michael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN 978-1-936113-42-2.

[0144] As used herein, "low molecular weight compound" can be used interchangeably with "small molecule" or "small organic molecule." Small molecule refers to a compound other than a peptide or oligonucleotide, and typically has a molecular weight of less than about 2000 daltons, e.g., less than about 900 daltons.

[0145] Ribonucleoprotein (RNP) refers to a nuclear protein containing RNA. RNP can be a complex of ribonucleic acid and RNA-binding protein. Such a combination can also be called a protein-RNA complex. These complexes can function in several biological functions, including, but not limited to, DNA replication, gene expression, RNA metabolism, and pre-mRNA splicing. Examples of RNPs include ribosomes, the enzyme telomerase, vault ribonucleoprotein, RNase P, heterogeneous nuclear RNPs (hnRNPs), and small nuclear RNPs (snRNPs).

[0146] Nascent RNA transcripts from protein-coding genes and mRNA processing intermediates are collectively referred to as pre-mRNA, and are generally bound by proteins in the nucleus of eukaryotic cells.From the time when nascent transcripts first emerge from RNA polymerase (e.g., RNA polymerase II) until mature mRNA is transported to the cytoplasm, RNA molecules associate with a rich set of splicing complex components (e.g., nuclear proteins and snRNAs).These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNAs (hnRNAs) of various sizes (e.g., complexes of pre-mRNA and nuclear RNA).

[0147] Splicing complex components function in splicing and / or splicing regulation. Splicing complex components may include, but are not limited to, ribonucleoproteins (RNPs), splicing proteins, small nuclear RNAs (snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing complex components include, but are not limited to, those required for splicing, such as constitutive splicing, alternative splicing, regulated splicing, and splicing of specific messages or groups of messages. A group of related proteins, serine-arginine-rich proteins (SR proteins), can function on constitutive pre-mRNAs and can also control alternative splice site selection in a concentration-dependent manner. SR proteins typically have a modular structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminus rich in arginine and serine residues (RS domain). Their activity in alternative splicing can be antagonized by members of the hnRNP A / B family of proteins. Splicing complex components can also include proteins associated with one or more snRNAs. SR proteins in humans include, but are not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2 / ASF, 9G8, SRp75, SRp30c, SRp20, and P54 / SFRS11. Other splicing complex components in humans that may be involved in splice site selection include, but are not limited to, U2 snRNA cofactors (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP20, SF1, and PTB / hnRNP1. hnRNP proteins in humans include, but are not limited to, A1, A2 / B1, L, M, K, U, F, H, G, R, I, and C1 / C2.Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1. Splicing complex components may be stably or transiently associated with snRNPs or transcripts.

[0148] The term "intron" refers to both DNA sequences within a gene and the corresponding sequences in unprocessed RNA transcripts. As part of the RNA processing pathway, introns can be removed by RNA splicing either immediately after or co-transcriptionally. Introns are found in the genes of most organisms and many viruses. They can be located within a wide variety of genes, including those that produce proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA).

[0149] An "exon" can be any portion of a gene that is produced by that gene that encodes a part of the final mature RNA after introns have been removed by RNA splicing. The term "exon" refers both to the DNA sequence within a gene and the corresponding sequence in the RNA transcript.

[0150] The "spliceosome" can be constructed from a complex of snRNA and proteins. The spliceosome can remove introns from the transcribed pre-mRNA.

[0151] "Intermediate Effective Dose" (ED 50 The "median lethal dose" (LD) is the dose at which 50% of a population develops a particular response. 50 ) is the dose at which 50% of the population is killed. 50) is the dose at which 50% of a population develops a particular toxic effect. One particularly useful pharmacological endpoint is traditionally known as the LD 50 ED 50 Ratio to TD 50 ED 50 The therapeutic index is defined as the ratio of the therapeutic dose to the effective dose. The therapeutic index provides a simple and useful measure of a drug's beneficial versus adverse effects. Drugs with a high therapeutic index have a wide therapeutic window, i.e., they can be administered over a wider effective dose range without suffering from significant adverse events. Conversely, drugs with a small therapeutic index have a narrow therapeutic window (narrow effective dose range without suffering from significant adverse events).

[0152] As used herein, the term "AUC" refers to the abbreviation for "area under the curve" in a graph of the concentration of a therapeutic agent over time in a particular area or tissue, e.g., blood or plasma, of a subject to which the therapeutic agent has been administered.

[0153] Small molecule splicing regulators (SMSMs) The compounds of the present disclosure and their pharmaceutically acceptable compositions have been found to be effective as drugs for use in the treatment, prevention, or amelioration of diseases or conditions associated with target RNA. The present disclosure provides the unexpected discovery that certain small chemical molecules, referred to herein as small molecule splicing regulators (SMSMs), can modify splicing events in pre-mRNA molecules. These SMSMs can regulate specific splicing events in specific pre-mRNA molecules. These SMSMs can operate by various mechanisms to modify splicing events. For example, the SMSMs of the present disclosure can: 1) interfere with the formation and / or function and / or other properties of splicing complexes, spliceosomes, and / or their components, such as hnRNPs, snRNPs, SR-proteins, and other splicing factors or elements, resulting in the prevention or induction of splicing events in pre-mRNA molecules. As another example, small molecules of the present disclosure can be used to: 2) prevent and / or modify post-transcriptional regulation (e.g., splicing) of gene products, such as hnRNPs, snRNPs, SR proteins, and other splicing factors, which can then participate in the formation and / or function of spliceosome or splicing complex components; 3) prevent and / or modify phosphorylation, glycosylation, and / or other modifications of gene products, including, but not limited to, hnRNPs, snRNPs, SR proteins, and other splicing factors, which can then participate in the formation and / or function of spliceosome or splicing complex components; and 4) bind to and / or otherwise affect specific pre-mRNAs, e.g., to prevent or induce specific splicing events via mechanisms that do not involve base pairing with the RNA in a sequence-specific manner. Small molecules of the present disclosure are distinct from and not related to antisense or antigen oligonucleotides.

[0154] Described herein are compounds that modify the splicing of gene products for use in treating, preventing, and / or slowing the progression of a disease or condition (e.g., cancer). Described herein are compounds that modify the splicing of gene products, which induce transcriptionally inactive variants or transcripts of the gene products. Described herein are compounds that modify the splicing of gene products, which suppress transcriptionally inactive variants or transcripts of the gene products.

[0155] In one embodiment, a compound of formula (I) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are (i) the same and selected from the group consisting of hydrogen and deuterium, or (ii) the same and 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, b is 0, c is 1, Described herein are compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3 or Table 4.

[0156] In one embodiment, a compound of formula (I) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3.

[0157] In one embodiment, a compound of formula (I) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R Eis hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R16 , and R 17 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 4.

[0158] In one embodiment, a compound of formula (II) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18are (i) the same and selected from the group consisting of hydrogen and deuterium, or (ii) the same and 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, b is 0, c is 1, Described herein are compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3 or Table 4.

[0159] In one embodiment, a compound of formula (II) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of hydrogen and deuterium; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 3.

[0160] In one embodiment, a compound of formula (II) [ka] During the ceremony, A is -CR A =CR A - and E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )- and R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted C2-C3 alkynyl; R A are each independently hydrogen, deuterium, F, Cl, -CN, -OR 1 , -SR 1 , -S(=O)R 1 , -S(=O)2R 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, and substituted or unsubstituted C2-C3 heterocycloalkyl; Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is -O- or -S-; Z is CR 2 and W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C2 heteroalkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene; R is hydrogen, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl; R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , and R 20 are each independently hydrogen, deuterium, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same, F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; a is 0, b is 0, c is 1, Described herein are compounds, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein d is 1, with the proviso that the compound is not a compound in Table 4.

[0161] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (A): [ka]

[0162] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (B): [ka]

[0163] In some embodiments, the compound of Formula (B) has the structure of Formula (B-1): [ka]

[0164] In some embodiments, the compound of Formula (B) has the structure of Formula (B-2): [ka]

[0165] In some embodiments, the compound of formula (B) has the structure of formula (B-3): [ka]

[0166] In some embodiments, the compound of formula (B) has the structure of formula (B-4): [ka]

[0167] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (C): [ka]

[0168] In some embodiments, the compound of Formula (C) has the structure of Formula (C-1): [ka]

[0169] In some embodiments, the compound of Formula (C) has the structure of Formula (C-2): [ka]

[0170] In some embodiments, the compound of Formula (C) has the structure of Formula (C-3): [ka]

[0171] In some embodiments, the compound of formula (C) has the structure of formula (C-4): [ka]

[0172] In some embodiments, E is -NR-. In some embodiments, E is -O-. In some embodiments, E is S(=O). In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in the equatorial position. In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in the axial position. In some embodiments, E is S(=O)(=NR E In some embodiments, E is S(=O)(=NR E ) and S(=O)(=NR E The oxygen atom in S(=O)(=NR) is in the equatorial position. E In some embodiments, E is S(=O)(=NR E ) and S(=O)(=NR E The oxygen atom in S(=O)(=NR) is in the axial position. E The nitrogen atom in the ) is in the equatorial position.

[0173] In some embodiments, R 19 is F. In some embodiments, R 20 is F.

[0174] In some embodiments, R 15 and R 18 In some embodiments, both R 15 and R 18 In some embodiments, both R 15 and R 18 is the same as f, -or 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18 are the same and are selected from F, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18 are the same and are selected from F, —CH, —CHOH, —OCHCN, —OH, —OCH, —OCHCN, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH, —OCH, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH3, and —OCH3. In some embodiments, R 15 and R 18 and R are both F. In some embodiments, R 15 and R 18 Both are -CH3.

[0175] In some embodiments, ring Q is substituted or unsubstituted aryl.

[0176] In some embodiments, ring Q is deuterium, halogen, —OH, —NO 2 , —CN, —SR 2 . 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-hydroxy-phenyl substituted with 1, 2, or 3 substituents independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0177] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl.

[0178] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl. In some embodiments, when aryl is substituted, it can be deuterium, halogen, —OH, —NO, —CN, —SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0179] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl. In some embodiments, when the heteroaryl is substituted, it can be deuterium, halogen, —OH, —NO, —CN, —SR 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R 1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments, R 1are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0180] In some embodiments, ring Q is substituted or unsubstituted heteroaryl.

[0181] In some embodiments, ring Q is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

[0182] In some embodiments, ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl.

[0183] In some embodiments, ring Q is [ka] In some embodiments, R is a 6-membered monocyclic heteroaryl selected from Q are each independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH). In some embodiments, ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0184] In some embodiments, ring Q is [ka] In some embodiments, R Qare each independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH, -CHCH, -CHCHCH, -CH(CH), -CF, -OCH, -OCHCH, -CHOCH, -OCHCHCH, and -OCH(CH). In some embodiments, ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0185] In some embodiments, R Q are each independently selected from hydrogen, —F, —Cl, —CN, —OH, —CH, —CF, and —OCH. In some embodiments, R Q is hydrogen. In some embodiments, R Q is -F. In some embodiments, R Q is -Cl. In some embodiments, R Q is -CN. In some embodiments, R Q is —OH. In some embodiments, R Q is -CH3. In some embodiments, R Q is -CF3. In some embodiments, R Q is -OCH3.

[0186] In some embodiments, [ka] teeth, [ka] is.

[0187] In some embodiments, [ka] teeth, [ka] is.

[0188] In some embodiments, ring P is a substituted or unsubstituted heteroaryl.

[0189] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 is selected from the group consisting of cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 In some embodiments, m is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl, and m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0190] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R Bare each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 is selected from the group consisting of cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 In some embodiments, m is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl, and m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0191] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7In some embodiments, m is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0192] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 In some embodiments, R is selected from the group consisting of cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and m is 1, 2, 3, or 4. B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7In some embodiments, m is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0193] In some embodiments, ring P is [ka] is a heteroaryl selected from the group consisting of In the formula, R B are each independently deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 In some embodiments, m is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0194] In some embodiments, RB are each independently hydrogen, deuterium, -F, -Cl, -CN, -CH, -CF, -OH, or -OCH. In some embodiments, R B are each independently deuterium, —F, —Cl, —CN, —CH 3 , —CF 3 , —OH, or —OCH 3 .

[0195] In some embodiments, R B are each independently hydrogen, -F, or -OCH. In some embodiments, R B are each independently -F or -OCH. In some embodiments, R B is hydrogen. In some embodiments, R B is —OCH. In some embodiments, R B is -CH3.

[0196] In some embodiments, R B1 is hydrogen, deuterium, —CH, —CF, or —CD. In some embodiments, R B1 is hydrogen, deuterium, -CH3, -CF3, or -CD3.

[0197] In some embodiments, ring P is [ka] and a heteroaryl selected from the group consisting of:

[0198] In some embodiments, ring P is [ka] and a heteroaryl selected from the group consisting of:

[0199] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] is.

[0200] In some embodiments, ring P is [ka] and a heteroaryl selected from the group consisting of:

[0201] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] In some embodiments, ring P is [ka] is.

[0202] In some embodiments, ring P is [ka] and a heteroaryl selected from the group consisting of:

[0203] In some embodiments, ring P is [ka] and a heteroaryl selected from the group consisting of:

[0204] In some embodiments, ring Q is deuterium, halogen, —OH, —NO 2 , —CN, —SR 2 . 1 , -S(=O)R 1 , -S(=O)2R 1 , -N(R 1 )2, -C(=O)R1 , -OC(=O)R 1 , -C(=O)OR 1 , -C(=O)N(R 1 )2, 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from 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 R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0205] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0206] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0207] In some embodiments, ring Q is [ka] is selected from the group consisting of:

[0208] In some embodiments, ring Q is [ka] is selected from the group consisting of In the formula, R B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0209] In some embodiments, ring Q is [ka] is selected from the group consisting of wherein each ring Q group is selected from 1 to 3 R B and R B are each independently deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 It is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0210] In some embodiments, ring Q is [ka] is selected from the group consisting of wherein each ring Q group is selected from 1 to 3 R B and R Bare each independently deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 It is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0211] In some embodiments, ring Q is [ka] is selected from the group consisting of wherein each ring Q group is selected from 1, 2, 3, 4, or 5 R B and R B are each independently deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 It is selected from the group consisting of cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0212] In some embodiments, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, ring Q is [ka] is selected from the group consisting of In the formula, R B1is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 is selected from the group consisting of cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl; Each ring Q group may contain 1, 2, 3, 4, or 5 R B and R B are each independently deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, deuterium-substituted C1-C6 alkoxy, -OCD3, substituted or unsubstituted C 3-7 In some embodiments, R is selected from the group consisting of cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. B1 is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl.

[0213] In some embodiments, W is substituted or unsubstituted C1-C2 alkylene.

[0214] In some embodiments, W is C1-C2 alkylene substituted with 1, 2, 3, or 4 substituents each independently selected from F, -OH, -OCH3, and CH3.

[0215] In some embodiments, W is -CH2-, -CHF-, -CH(CH3)-, -CH(OH)-, -CH(OCH3)-, -CF2-, -CH2CH2-, -CHFCH2-, -CH2CHF-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(OCH3)CH2-, -CH2CH(OCH3)-, -CF2CH2-, or -CH2CF2-.

[0216] In some embodiments, W is -CHFCH2-, -CH2CHF-, -CF2CH2-, or -CH2CF2-. In some embodiments, W is -CHFCH2-. In some embodiments, W is -CH2CHF-. In some embodiments, W is -CF2CH2-. In some embodiments, W is -CH2CF2-.

[0217] In some embodiments, W is a substituted or unsubstituted C3-C4 alkylene.

[0218] In some embodiments, W is a C3-C4 alkylene substituted with 1, 2, 3, or 4 substituents each independently selected from F, -OH, -OCH3, and -CH3.

[0219] In some embodiments, W is -CH2CH2CH2-, -CHFCH2CH2-, -CH2CHFCH2-, -CH2CH2CHF-, -CF2CH2CH2-, -CH2CF2CH2-, -CH2CH2CF2-, -CH(OH)CH2CH2-, -CH2CH(OH)CH2-, -CH2CH2CH(OH)-, -CH(OCH3)CH2CH2-, -CH2CH(OCH3)CH2-, -CH2CH2CH(OCH3)-, --CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, or -CH2CH2CH(CH3)-.

[0220] In some embodiments, W is —CH 2 CHFCH 2 — or —CH 2 CF 2 CH 2 —. In some embodiments, W is —CH 2 CHFCH 2 —. In some embodiments, W is —CH 2 CF 2 CH 2 —.

[0221] In some embodiments, W is -CHFCH2CH2- or -CF2CH2CH2-. In some embodiments, W is -CHFCH2CH2-. In some embodiments, W is -CF2CH2CH2-.

[0222] In some embodiments, W is —CH 2 CH 2 CHF— or —CH 2 CH 2 CF 2 —. In some embodiments, W is —CH 2 CH 2 CHF—. In some embodiments, W is —CH 2 CH 2 CF 2 —.

[0223] In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is substituted or unsubstituted -CH2CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is substituted or unsubstituted -CH2CH2CH2. In some embodiments, W is -CH2CH2CH2.

[0224] In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene or substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3-C8 cycloalkylene. In some embodiments, W is substituted or unsubstituted cyclopropylene. In some embodiments, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is -CH=CH-.

[0225] In some embodiments, W is a substituted or unsubstituted C1-C2 heteroalkylene. In some embodiments, W is a substituted or unsubstituted -CH2OCH2-. In some embodiments, W is -CH2O-, where O is R18 is attached to the carbon atom to which the group is attached.

[0226] In some embodiments, R 16 and R 17 One or more of the following may independently be F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl.

[0227] In some embodiments, R 16 and R 17 are independently selected from F, —OH, —OCH, —OCHCH, —OCHCHOH, —OCHCN, —OCF, —CH, —CHCH, —CHOH, —CHCHOH, —CHCN, —CHF, —CHF, —CF, —CHCHF, —CHCHF, and —CHCF.

[0228] In some embodiments, R 16 and R 17 are independently selected from F, —OH, —OCH 3 , —OCF 3 , —CH 3 , —CH 2 OH, —CH 2 F, —CHF 2 , and —CF 3 .

[0229] In some embodiments, R 16 is F. In some embodiments, R 16 is hydrogen. In some embodiments, R 17 is F. In some embodiments, R 17 is hydrogen. In some embodiments, R 16 and R 17 is hydrogen.

[0230] In some embodiments, R 16 is H and R 17 is F. In some embodiments, R 16 is F and R 17 is H.

[0231] In some embodiments, R 16 is not hydrogen. In some embodiments, R 16 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (R) configuration.

[0232] In some embodiments, R 17 is not hydrogen. In some embodiments, R 17 The carbon atom bearing the group is in the (S) configuration. 17 The carbon atom bearing the group is in the (R) configuration.

[0233] In some embodiments, R 16 is not hydrogen, but R 17 is not hydrogen. In some embodiments, R 16 The carbon atom bearing the group is in the (S) configuration and the R 17 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (S) configuration and the R 17 The carbon atom bearing the group is in the (R) configuration. In some embodiments, R 16 The carbon atom bearing the group is in the (R) configuration, and R 17 The carbon atom bearing the group is in the (S) configuration. 16 The carbon atom bearing the group is in the (R) configuration, and R 17 The carbon atom bearing the group is in the (R) configuration.

[0234] In some embodiments, R 2 is hydrogen, -CH3, or -OCH3.

[0235] In some embodiments, R 2 is hydrogen.

[0236] In some embodiments, R Aare each independently hydrogen, F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OH, -OCH3, -OCH2CH3, -OCF3, -CH2F, -CHF2, or -CF3.

[0237] In some embodiments, R A are each independently hydrogen, F, Cl, —CN, —CH3, —OH, —OCH3, —OCF3, —CH2F, —CHF2, or —CF3.

[0238] In some embodiments, R A are each independently hydrogen, F, Cl, —CN, —CH3, or —OCH3.

[0239] In some embodiments, R A are each independently hydrogen, F, Cl, or —CH3.

[0240] In some embodiments, R A is hydrogen.

[0241] In some embodiments, X is -O-. In some embodiments, X is -S-.

[0242] In some embodiments, R 15 and R 18 In some embodiments, both R 15 and R 18 In some embodiments, both R 15 and R 18 is the same as f, -or 1 , substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 fluoroalkyl, and substituted or unsubstituted C1-C3 heteroalkyl. 15 and R 18are the same and are selected from F, -CH, -CHCH, -CHCHCH, -CH(CH), -CHOH, -CHCHOH, -CHNHCH, -CHN(CH), -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CHF, -CHF, and -CF. 15 and R 18 are the same and are selected from F, —CH, —CHOH, —OCHCN, —OH, —OCH, —OCHCN, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH, —OCH, —OCF, —CHF, —CHF, and —CF. In some embodiments, R 15 and R 18 are the same and are selected from F, —CH3, and —OCH3. In some embodiments, R 15 and R 18 and R are both F. In some embodiments, R 15 and R 18 Both are -CH3.

[0243] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , and R 18 At least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of them are F.

[0244] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R16 , R 17 , and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0245] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R18 In some embodiments, one of W comprises fluorine.

[0246] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F.

[0247] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 15 is F, CHF, CHF, CF, or CH. In some embodiments, R15 is F, CF, CHF, or CHF. In some embodiments, R 15 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 is F. In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 18 is F, CHF, CHF, CF, or CH. In some embodiments, R 18 is F, CF, CHF, or CHF. In some embodiments, R 18 is F.

[0248] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R18 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 At least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of them are F.

[0249] In some embodiments of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or a 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 R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0250] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 In some embodiments, one of W comprises fluorine.

[0251] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 , and R 16 is hydrogen. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof, R 19 is hydrogen. In some embodiments, R 19 is H, F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 19 is H, F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. In some embodiments, R 19 is F or -OCH3.

[0252] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 20 is hydrogen. In some embodiments, R 20is H, F, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -CHF, -CHF, -CF, -CHCHF, -CHCHF, and -CHCF. 20 is H, F, —OH, —OCH, —OCF, —CH, —CHOH, —CHF, —CHF, and —CF. In some embodiments, R 20 is F or -OCH3.

[0253] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a 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 (II) or a pharmaceutically acceptable salt or a 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 (II) or a pharmaceutically acceptable salt or a 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 (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 19 and R 20 is H. In some embodiments, R 19 and R 20is D. In some embodiments, R 19 and R 20 is F. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 17 and R 20 is H. In some embodiments, R 17 and R 20 is D. In some embodiments, R 17 and R 20 is F.

[0254] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a 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 R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least two of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17At least one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 and one of R is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 At least two of them are F.

[0255] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or a 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 R comprises fluorine, e.g., F, or C-C fluoroalkyl, e.g., CHF, CF, CHF, and CHCHF. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least one of R is F or C-C fluoroalkyl. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 At least one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 At least two of the groups contain fluorine.

[0256] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 At least one of W, R comprises fluorine, e.g., F, or C1-C4 fluoroalkyl, e.g., CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, W, R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 In some embodiments, one of W comprises fluorine.

[0257] In some embodiments of the compounds of Formula (I)-(II) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R E is hydrogen. In some embodiments, R E is methyl or ethyl. In some embodiments, R E is methyl. In some embodiments, R E is ethyl.

[0258] In some embodiments of the compounds of Formula (I)-(II) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, R 1 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, or substituted or unsubstituted C1-C4 haloalkyl. 1 are each independently hydrogen, deuterium, or C1-C4 alkyl. In some embodiments, R 1 are each independently hydrogen, deuterium, or methyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is methyl.

[0259] In some embodiments, compounds of Formula (I) or Formula (II) are prepared from racemic starting materials (and / or intermediates) and separated into individual enantiomers as intermediates or final products by chiral chromatography. It is understood that the absolute configuration of the separated intermediates and final compounds is not determined unless otherwise stated. In some embodiments, the absolute stereochemistry of the depicted enantiomers is arbitrarily assigned. In some embodiments, both enantiomers are synthesized.

[0260] In one aspect, provided herein is a compound selected from Table 1, Table 2, and Table 5, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0261] In some embodiments, the compounds made in the following examples are made from racemic starting materials (and / or intermediates) and separated into individual enantiomers by chiral chromatography as final products or intermediates. It is understood that unless otherwise stated, the absolute configurations of intermediates and final compounds separated as depicted are assigned arbitrarily and not determined.

[0262] In some embodiments, the compound of Formula (I) or Formula (II) is a single enantiomer. In some embodiments, the compound of Formula (I) or Formula (II) is not racemic. In some embodiments, the compound of Formula (I) or Formula (II) is substantially free of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) is a single isomer substantially free of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) contains 25% or less of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) contains 20% or less of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) contains 15% or less of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) contains 10% or less of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) contains 5% or less of other isomers. In some embodiments, the compound of Formula (I) or Formula (II) contains 1% or less of other isomers.

[0263] In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 75%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 80%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 85%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 90%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 95%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 96%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 97%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 98%. In some embodiments, the compound of Formula (I) or Formula (II) has a stereochemical purity of at least 99%.

[0264] In some embodiments, the asymmetric carbon atom of a compound of Formula (I) or Formula (II) is present in enantiomerically enriched form. In certain embodiments, the asymmetric carbon atom of a compound of Formula (I) or Formula (II) is in the (S) or (R) configuration in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0265] In some embodiments, the compound is [ka] [ka] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0266] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0267] In some embodiments, the compound is 4-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 4-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 4-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 4-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 6-(4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one, 6-(4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one, 6-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one, 6-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide, 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide, 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide, 6-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide, 6-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-3-methylquinazolin-4(3H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-3-methylquinazolin-4(3H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-3-methylquinazolin-4(3H)-one, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-3-methylquinazolin-4(3H)-one, 7-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-1-methylquinolin-4(1H)-one, 7-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-1-methylquinolin-4(1H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-1-methylquinolin-4(1H)-one, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-1-methylquinolin-4(1H)-one, 7-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one, 7-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one, 7-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one, 7-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one, 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one, 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol, 2-(6-(((1R,5R,6R,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,5S,6S,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,5R,6R,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,5S,6S,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2S,3R,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2R,3S,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3R,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3S,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 4-chloro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 4-chloro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-fluoro-6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)phenol, 2-fluoro-6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)phenol, 3-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 3-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol, 5-(3-fluoro-1H-pyrazol-1-yl)-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 5-(3-fluoro-1H-pyrazol-1-yl)-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-indazol-1-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-indazol-1-yl)phenol, 2-(6-(((1R,3r,5S,7s)-7-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile, 5-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol, 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol, 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyrimidin-2(1H)-one, 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyrimidin-2(1H)-one, 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one, 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one, 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinolin-6-ol, 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinolin-6-ol, 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinoxalin-6-ol, 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinoxalin-6-ol, 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinolin-7-ol, 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinolin-7-ol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyrazin-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyrazin-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthiophen-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthiophen-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthiophen-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthiophen-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-3-yl)phenol, 5-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methyloxazol-2(3H)-one, 5-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methyloxazol-2(3H)-one, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-5-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-5-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyridin-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyridin-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylpyridin-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylpyridin-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyridazin-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyridazin-4-yl)phenol, 5-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol, 5-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 5-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)phenol, 4-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)thio)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 4-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)thio)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamide, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one, 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamide, 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one, 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one, 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(3-methylisoxazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,5-a]pyridin-6-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,5-a]pyridin-6-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-7-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-7-yl)phenol, 4-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 4-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)isoquinolin-6-ol, 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)isoquinolin-7-ol, 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)isoquinolin-6-ol, 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)isoquinolin-7-ol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyrazin-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyrazin-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyrazin-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyrazin-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyridin-2-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol, 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxy-3-methylbenzo[d]oxazol-2(3H)-one, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridin-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(pyridin-2-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol, 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxy-3-methylbenzo[d]oxazol-2(3H)-one, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridin-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(3-methylisoxazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(3-methyl-1H-1,2,4-triazol-1-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-3-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(3-methyl-1H-1,2,4-triazol-1-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-3-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-3-yl)phenol, 5-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol, 5-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol, 4-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 4-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 4-(2-fluoro-4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one, 4-(2-fluoro-4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)pyridin-2(1H)-one, 4-fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 4-(2-fluoro-4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one, 4-(2-fluoro-4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)pyridin-2(1H)-one, 4-fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one, 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one, 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one, 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one, 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,3S,5S)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol, 2-(6-(((1S,3R,5R)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2S,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol, 2-(6-(((1S,3R,5R)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,3S,5S)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2R,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2S,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2S,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol, 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazol-1-yl)phenol, 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol, or 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0268] In some embodiments, exemplary SMSM compounds are summarized in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0269] In some embodiments, pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds of Table 1 are disclosed herein.

[0270] In some embodiments, exemplary SMSM compounds are summarized in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0271] In some embodiments, pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds of Table 2 are disclosed herein.

[0272] In some embodiments, the SMSM described herein is not a compound in Table 3. [Table 3-1] [Table 3-2]

[0273] In some embodiments, W is not -CH2CH2-, CH2CH2CH2-, or -CH2OCH2-.

[0274] In some embodiments, A is not -CH=CH-.

[0275] In some embodiments, R 15 , R 16 , R 17 , and R18 and are not simultaneously hydrogen. 15 and R 18 and are not simultaneously hydrogen. 16 and R 17 is not hydrogen at the same time.

[0276] In some embodiments, (i) W is —CHCH—, CHCHCH—, or —CHOCH—, (ii) A is —CH═CH—, and (ii) R 16 and R 17 If both R and R are hydrogen, 15 and R 18 is not hydrogen at the same time.

[0277] In some embodiments, when W is —CH2CH2—, CH2CH2CH2—, or —CH2OCH2—, R 15 , R 16 , R 17 , and R 18 and R are not simultaneously hydrogen. In some embodiments, when A is -CH=CH-, R 15 , R 16 , R 17 , and R 18 and R are not simultaneously hydrogen. In some embodiments, when A is -CH=CH-, R 16 and R 17 is not hydrogen at the same time.

[0278] In some embodiments, ring Q is [ka] isn't it.

[0279] In some embodiments, the compound is not a compound in Table 3.

[0280] In some embodiments, the SMSM described herein is not a compound in Table 4. [Table 4]

[0281] In some embodiments, W is not —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —.

[0282] In some embodiments, A is not -CH=CH-.

[0283] In some embodiments, X is not —O—.

[0284] In some embodiments, R 16 and R 17 and are not simultaneously hydrogen. 15 and R 18 is not -CH. In some embodiments, R 16 and R 17 is also hydrogen, R 15 and R 18 is not -CH. In some embodiments, R 15 and R 18 is -CH3, R 16 and R 17 is not hydrogen at the same time.

[0285] In some embodiments, (i) W is CH2CH2- or CH2CH2CH2-, (ii) A is -CH=CH-, and (iii) R 16および R 17 are hydrogen, and (iv) R 15 and R 18 is -CH3, and (v) X is -O-, then ring Q is not a substituted monocyclic aryl.

[0286] In some embodiments, (i) W is CH2CH2- or CH2CH2CH2-, (ii) A is -CH=CH-, and (iii) R 15 and R 18 is -CH3, and (v) X is -O-, then R 16 and R 17 is not hydrogen at the same time.

[0287] In some embodiments, ring Q is [ka] isn't it.

[0288] In some embodiments, the compound is not a compound in Table 4.

[0289] In some cases, the SMSMs provided herein may be designated by more than one number in different parts of this application, for example, the same compound may appear more than once in the tables, examples, and schemes.

[0290] In some embodiments, the SMSM compounds described herein are prepared from racemic starting materials (and / or intermediates) and separated into individual enantiomers as intermediates or final products by chiral chromatography. It is understood that the absolute configuration of the separated intermediates and final compounds is not determined unless otherwise stated. In some embodiments, the absolute stereochemistry of the depicted enantiomers is arbitrarily assigned. In some embodiments, both enantiomers are synthesized.

[0291] In some embodiments, the SMSM described herein is a single enantiomer. In some embodiments, the SMSM described herein is not racemic. In some embodiments, the SMSM described herein is substantially free of other isomers. In some embodiments, the SMSM described herein is a single isomer substantially free of other isomers. In some embodiments, the SMSM described herein contains 25% or less of other isomers. In some embodiments, the SMSM described herein contains 20% or less of other isomers. In some embodiments, the SMSM described herein contains 15% or less of other isomers. In some embodiments, the SMSM described herein contains 10% or less of other isomers. In some embodiments, the SMSM described herein contains 5% or less of other isomers. In some embodiments, the SMSM described herein contains 1% or less of other isomers.

[0292] In some embodiments, the SMSM described herein has at least 75% stereochemical purity. In some embodiments, the SMSM described herein has at least 80% stereochemical purity. In some embodiments, the SMSM described herein has at least 85% stereochemical purity. In some embodiments, the SMSM described herein has at least 90% stereochemical purity. In some embodiments, the SMSM described herein has at least 95% stereochemical purity. In some embodiments, the SMSM described herein has at least 96% stereochemical purity. In some embodiments, the SMSM described herein has at least 97% stereochemical purity. In some embodiments, the SMSM described herein has at least 98% stereochemical purity. In some embodiments, the SMSM described herein has at least 99% stereochemical purity.

[0293] In some embodiments, the SMSMs described herein have one or more stereocenters, each of which independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form diastereomeric compound / salt pairs, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of the enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0294] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may be, for example, bioavailable by oral administration, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of the prodrug increases its effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside cells, where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) linked to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0295] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other characteristics or properties of a drug. Once a pharmaceutically active compound is known, through knowledge of the pharmacokinetics, pharmacodynamic processes, and in vivo drug metabolism, prodrugs of this compound can be designed. (See, for example, Nogrady (1985) Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992) The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401; Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series).

[0296] In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0297] In some embodiments, sites on the aromatic ring moiety of the compounds described herein are susceptible to various metabolic reactions, and incorporation of appropriate substituents on the aromatic ring structure will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens or alkyl groups.

[0298] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0299] The compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures presented herein, but that are substituted with one or more atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds include, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 In one embodiment, the isotopes of the isotopes described herein, e.g., hydrogen isotopes such as Cl, carbon isotopes, nitrogen isotopes, oxygen isotopes, sulfur isotopes, fluorine isotopes, and chlorine isotopes, are included. 3 H and 14 Incorporation of radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0300] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite, which is then used to bring about a desired effect, including a desired therapeutic effect.

[0301] The compounds described herein may be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) salts of a free base derived from the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or a pharmaceutically acceptable organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2 (1) Acid addition salts formed by reacting the parent compound with 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein may coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0302] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and can be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.In some embodiments, the solvates of the compounds described herein are easily prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated and solvated forms.In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0303] In some embodiments, SMSM has a molecular weight of up to about 2000, 1500, 1000, or 900 daltons. In some embodiments, SMSM has a molecular weight of at least 100, 200, 300, 400, or 500 daltons. In some embodiments, SMSM does not contain phosphodiester bonds.

[0304] Methods for making compounds The compounds described herein can be synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology can be used. The compounds can be prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions, can be used. Starting materials can be available from commercial sources or can be readily prepared. By way of example only, a scheme for preparing an exemplary SMSM is provided.

[0305] In some embodiments, the scheme for preparing SMSM described herein is Scheme 1. [ka]

[0306] In some embodiments, the scheme for preparing SMSM described herein is Scheme 2. [ka]

[0307] In some embodiments, the scheme for preparing SMSM described herein is Scheme 3. [ka]

[0308] In some embodiments, the scheme for preparing SMSM described herein is Scheme 4. [ka]

[0309] In some embodiments, the scheme for preparing SMSM described herein is Scheme 5. [ka]

[0310] In some embodiments, the scheme for preparing SMSM described herein is Scheme 6. [ka]

[0311] In some embodiments, the scheme for preparing SMSM described herein is Scheme 7. [ka]

[0312] In some embodiments, the scheme for preparing SMSM described herein is Scheme 8. [ka]

[0313] In some embodiments, the scheme for preparing SMSM described herein is Scheme 9. [ka]

[0314] In some embodiments, the scheme for preparing SMSM described herein is Scheme 10. [ka]

[0315] In some embodiments, the scheme for preparing SMSM described herein is Scheme 11. [ka]

[0316] In some embodiments, the scheme for preparing SMSM described herein is Scheme 12. [ka]

[0317] Suitable references and papers detailing the synthesis of, or providing references to articles describing the preparation of, reactants useful in preparing the compounds described herein include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers that detail the synthesis of, or provide references to articles describing the preparation of, reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC“Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN:0-471-19031-4, March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley&Sons, ISBN:0-471-60180-2, Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN:3-527-29871-1, Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN:0-471-93022-9, Solomons,TWG “Organic Chemistry” 7th Edition(2000)John Wiley & Sons, ISBN: 0-471-19095-0, Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X (8 volumes), "Organic Reactions" (1942-2000) John Wiley & Sons (over 55 volumes), and "Chemistry of Functional Groups" John Wiley & Sons (73 volumes).

[0318] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, if desired in the final product, to avoid their undesired participation in the reaction. Detailed descriptions of techniques applicable to the creation of protecting groups and their removal are found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosures.

[0319] SMSMs can be made using known techniques and, in some embodiments, can be further chemically modified to facilitate nuclear import, for example, into splicing complex components, spliceosomes, or pre-mRNA molecules. Those skilled in the art will understand standard medicinal chemistry approaches for chemical modification (e.g., charge reduction, size optimization, and / or lipophilicity modification) for nuclear import.

[0320] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutically usable preparations. Appropriate formulations depend on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0321] A pharmaceutical composition can be a mixture of the SMSM described herein with one or more other chemical components (i.e., pharmaceutically acceptable components), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[0322] The compositions described herein can be administered to a subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, intracolonically, rectally, or intraperitoneally. In some embodiments, the small molecule splicing regulator or a pharmaceutically acceptable salt thereof is administered to the subject by intraperitoneal, intramuscular, subcutaneous, or intravenous injection. In some embodiments, the pharmaceutical composition can be administered parenterally, intravenously, intramuscularly, or orally. Oral formulations containing small molecule splicing regulators can be in any form suitable for oral administration, such as liquids, tablets, or capsules. Oral formulations can be further coated or treated to prevent or reduce dissolution in the stomach. The compositions of the present disclosure can be administered to a subject using any suitable method known in the art. Formulations and delivery methods suitable for use in the present disclosure are generally known in the art. For example, the small molecule splicing regulators described herein can be formulated into pharmaceutical compositions with pharmaceutically acceptable diluents, carriers, or excipients. The compositions may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, including pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, and the like.

[0323] The pharmaceutical formulations described herein may be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixtures of immediate release and controlled release formulations.

[0324] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulations comprising SMSM described herein are in the form of a capsule. In one aspect, the liquid pharmaceutical dosage form for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0325] For administration by inhalation, the SMSM described herein can be formulated for use as an aerosol, mist, or powder. For buccal or sublingual administration, the compositions can take the form of tablets, lozenges, or gels formulated in conventional manner. In some embodiments, the SMSM described herein can be prepared as a transdermal dosage form. In some embodiments, the SMSM described herein can be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In some embodiments, the SMSM described herein can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. In some embodiments, the SMSM described herein can be formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0326] Splicing Extensive post-transcriptional processing occurs before eukaryotic pre-mRNA matures and exits the nucleus into the cytoplasm, including the addition of a 7-methylguanosine cap at the 5' end, the cleavage and addition of a poly(A) tail at the 3' end, and the removal of intervening sequences or introns by the spliceosome. The majority of genes in higher eukaryotes contain multiple introns that are spliced ​​with high precision and fidelity to maintain the reading frame of the exons. Splicing of pre-mRNA can utilize the recognition of short consensus sequences at the boundaries and within introns and exons by a number of proteins, including small nuclear ribonucleoprotein (snRNP) complexes (e.g., snRNPs U1, U2, U4, U5, U6, U11, U12m U4atc, and U6atc) and spliceosomal proteins, as well as an array of splicing regulators that act both positively and negatively.

[0327] Serine-arginine-rich (SR) domain-containing proteins generally promote constitutive splicing. They can also regulate alternative splicing by binding to intronic or exonic splicing enhancer (ISE) or ESE sequences, respectively. Other pre-mRNA binding proteins, such as hnRNPs, can control splicing by binding to intronic or exonic splicing suppressor (ISS or ESS) sequences, acting as general splicing regulators. The SR protein family is a class of at least 10 proteins that possess a characteristic serine / arginine-rich domain in addition to RNA binding. SR proteins are generally thought to simultaneously bind to U170K, a core component of the U1 snRNP at the 5' splice site, and U2AF35 at the 3' splice site, thereby enhancing splicing by bridging these two ends of the intron. Although this specific function of SR proteins appears redundant, because any individual SR protein can participate in constitutive splicing of pre-mRNAs, the roles of various SR proteins in the alternative splicing of specific pre-mRNAs are distinct, in part due to their ability to recognize and bind unique consensus sequences. Phosphorylation of the RS domain of SR proteins may regulate their protein interactions, RNA binding, localization, transport, and role in alternative splicing. Several cellular kinases have been identified that phosphorylate SR proteins, including SR protein kinase (SRPK), Cdc2-like kinase (Clk), pre-mRNA processing variant 4 (PRP4), and topoisomerase I. Optimal phosphorylation of SR proteins may be required for their proper function, as both hypophosphorylation and hyperphosphorylation of the RS domain can be detrimental to their role in constitutive and alternative splicing.

[0328] In higher eukaryotes, the majority of genes contain one or more introns, creating a situation in which exons are spliced ​​together to produce mature mRNA and microRNA (miRNA). In the host nucleus, pre-mRNA splicing is a mechanism in which introns are removed from pre-mRNA and exons are ligated together to produce mature mRNA, which is then transported to the cytoplasm and translated into polypeptide gene products. Pre-mRNA splicing can occur in cis, where two exons are derived from two adjacent co-transcriptional sequences, or in trans, where two exons are derived from different pre-mRNA transcripts. The ratio of different protein products (isoforms) can be due to the frequency of alternative splicing events within pre-mRNA, which result in different amounts of distinct splice variants. In some embodiments, alternative splicing of pre-mRNA can result in the expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 protein isoforms.

[0329] Abnormal splicing is thought to be responsible for approximately half of all genetic disorders. Abnormal splicing due to mutations in consensus sequences involved in exon-intron boundary recognition accounts for up to 15% of genetic disorders. In addition, defects in the splicing mechanism, resulting from loss or gain of function of splicing factors and regulatory factors, are responsible for a wide range of human diseases, from cancer to neurodegenerative disorders. Both constitutive and alternative splicing are subject to control by upstream signaling pathways. This control can be essential during development, tissue-specific expression of certain isoforms, during the cell cycle, and in response to exogenous signaling molecules.

[0330] Alternative splicing allows a single gene to express different isoforms of mRNA, and therefore plays an important role in contributing to the cellular complexity of higher eukaryotes without the need to expand the genome.Splicing can also be controlled by upstream signaling pathways.For example, upstream signaling pathways can regulate alternative splicing, increasing or decreasing the expression level of different isoforms of mRNA.

[0331] Alternative splicing events are highly regulated by numerous splicing factors in tissue-specific, developmental, and signal-dependent manners. Furthermore, non-mutation-based causes of splicing defects and defects in the splicing machinery itself, for example, due to loss / gain of function of splicing factors or their relative stoichiometry, are the cause of a wide range of human diseases, from cancer to neurodegenerative diseases. In many diseases, pathology is caused by a change in the ratio of different isoforms of two or more proteins expressed from a gene. In some embodiments, the change in the ratio of protein products is due to a change in the frequency of alternative splicing events within pre-mRNA, leading to a change in the ratio of splice variants produced. In some embodiments, alternative splicing of pre-mRNA can result in the expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 protein isoforms. In some embodiments, the change in splice variant ratio is caused by a genetic mutation.

[0332] In eukaryotes, the vast majority of splicing processes occur in distinct steps and are catalyzed by the spliceosome, an RNA-protein complex that can contain hundreds of different protein subsets in addition to the five spliceosomal snRNAs. These factors are responsible for the precise positioning of the spliceosome at the 5' and 3' splice site sequences. The need for so many factors reflects the observation that exon recognition can be influenced by many pre-mRNA features, such as exon length, sequence recognition, the presence of enhancer and silencer elements, the strength of upstream splicing signals, promoter architecture, and RNA processing rate, secondary and tertiary RNA structure, etc.

[0333] All mammalian diseases are ultimately mediated by the transcriptome. To the extent that messenger mRNA (mRNA) is part of the transcriptome and all protein expression is derived from mRNA, there is potential for intervention in protein-mediated diseases by regulating the expression of associated proteins and then regulating the translation of corresponding upstream mRNAs. However, mRNAs are only a small portion of the transcriptome; other transcriptional RNAs, including (but not limited to) microRNAs (miRNAs), long noncoding RNAs (lncRNAs), long intergenic noncoding RNAs (lincRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), small Cajal body-specific RNAs (scaRNAs), piwi-interacting RNAs (piRNAs), competitive endogenous RNAs (ceRNAs), and pseudogenes, also directly regulate cell biology through the structure and function of RNA structures (e.g., ribonucleoproteins) and through protein expression and action. Drugs intervening at this level have the potential to modulate any cellular process. Existing therapeutics, such as antisense RNA or siRNA, often have yet to overcome significant challenges, such as drug delivery, absorption, distribution to target organs, pharmacokinetics, and cell penetration. In contrast, small molecules have a long history of successfully overcoming these barriers, making them suitable as drugs and easily optimized by a series of analogs to overcome such challenges. In stark contrast, the application of small molecules as ligands of RNA to provide therapeutic benefit has received little or no attention from the drug discovery community.

[0334] DNA sequences in chromosomes are transcribed into pre-mRNA, which contains coding regions (exons) and generally contains intervening non-coding regions (introns). Introns are removed from the pre-mRNA by splicing. The pre-mRNA proceeds in a two-step mechanism. In the first step, the 5' splice site is cleaved, resulting in a "free" 5' exon and a lariat intermediate. In the second step, the 5' exon is ligated to the 3' exon with release of the intron as the lariat product. These steps are catalyzed in a small nuclear ribonucleoprotein-protein complex called the spliceosome.

[0335] In most cases, the splicing reaction occurs within the same pre-mRNA molecule, which is called cis-splicing. Splicing between two independently transcribed pre-mRNAs is called trans-splicing.

[0336] Introns are portions of eukaryotic DNA that lie between coding portions or "exons" of that DNA. Introns and exons are transcribed into RNA called the "primary transcript, pre-mRNA" (or "pre-mRNA"). Introns can be removed from the pre-mRNA, allowing the native protein encoded by the exons to be produced (the term "native protein" as used herein refers to a naturally occurring, wild-type, or functional protein). The removal of introns from the pre-mRNA and the subsequent joining of exons occurs through the process of splicing.

[0337] The splicing process is a series of reactions that take place on RNA after transcription but before translation and are mediated by splicing factors. Thus, RNA that contains both exons and intron(s) can be referred to as a "pre-mRNA," and RNA from which the intron(s) have been removed and the exons have been sequentially spliced ​​together, thereby allowing a protein to be translated from it by ribosomes, can be referred to as a mature mRNA ("mRNA").

[0338] Introns can be defined by a set of "splice elements," which are relatively short, conserved RNA segments that are part of the splicing mechanism and may be required for splicing and bind to various splicing factors that perform the splicing reaction. Thus, each intron is defined by a 5' splice site, a 3' splice site, and a branch point located between them. Splice elements also include exon splicing enhancers and silencers located within exons, and intron splicing enhancers and silencers located within introns away from splice sites and branch points. In addition to splice sites and branch points, these elements control aberrant alternative splicing and constitutive splicing.

[0339] The initial RNA transcripts (pre-mRNAs) of most eukaryotic genes are retained in the nucleus until non-coding intronic sequences are removed by the spliceosome to produce mature messenger RNA (mRNA). Because different splicing events can occur, the synthesis of alternative protein products from the same primary transcript can be influenced by tissue-specific or developmental signals. A significant proportion of human genetic diseases, including some cancers, are thought to result from deviations from the normal pattern of pre-mRNA splicing. The spliceosome is a complex containing small nuclear RNAs and ribonucleoprotein (snRNP) particles composed of proteins. The snRNA component of the spliceosome can facilitate two transesterification reactions of splicing.

[0340] Two unique spliceosomes coexist in most eukaryotes: the U2-dependent spliceosome, which catalyzes the removal of U2-type introns, and the less abundant U12-dependent spliceosome, which is present in only a subset of eukaryotes and splices the rare U12-type class of introns. The U2-dependent spliceosome is assembled from the U1, U2, U5, and U4 / U6 snRNPs and numerous non-snRNP proteins. During the first ATP-dependent step in spliceosome assembly, the U2 snRNP is recruited with two weakly associated protein subunits, SF3a and SF3b. ​​SF3b is composed of seven conserved proteins, including PHF5α, SF3b155, SF3b145, SF3b130, SF3b49, SF3b14a, and SF3b10.

[0341] Splicing, or RNA splicing, typically refers to the editing of nascent precursor messenger RNA (pre-mRNA) transcripts into mature messenger RNA (mRNA). Splicing is a biochemical process involving the removal of introns and the subsequent ligation of exons. Sequential transesterification reactions begin with nucleophilic attack of the 5' splice site (5'ss) by a branched adenosine (branch point, BP) in the downstream intron, resulting in the formation of an intron lariat intermediate with a 2'-5'-phosphodiester bond. This is followed by a 5'ss-mediated attack on the 3' splice site (3'ss), resulting in the removal of the intron lariat and the formation of the spliced ​​RNA product.

[0342] Splicing can be controlled by various cis-acting elements and trans-acting factors. Cis-acting elements are sequences in mRNA and can include core consensus sequences and other regulatory elements. Core consensus sequences typically refer to conserved RNA sequence motifs, including the 5'ss, 3'ss, polypyrimidine tract, and BP region, which can function for spliceosome recruitment. BP refers to a partially conserved sequence in pre-mRNA, generally less than 50 nucleotides upstream of the 3'ss. BP interacts with the 5'ss during the first step of the splicing reaction. Other cis-acting regulatory elements can include exon splicing enhancers (ESEs), exon splicing silencers (ESSs), intron splicing enhancers (ISEs), and intron splicing silencers (ISSs). Trans-acting factors can be proteins or ribonucleoproteins that bind to cis-acting elements.

[0343] Splice site identification and regulated splicing are primarily achieved by two dynamic macromolecular mechanisms: the major spliceosome (U2-dependent) and the minor spliceosome (U12-dependent). Each spliceosome contains five snRNPs: U1, U2, U4, U5, and U6 snRNPs (which process approximately 95.5% of all introns) in the major spliceosome, and U11, U12, U4atac, U5, and U6atac snRNPs in the minor spliceosome. Spliceosomal recognition of consensus sequence elements at the 5'ss, 3'ss, and BP sites is one of the steps in the splicing pathway and can be regulated by ESEs, ISEs, ESSs, and ISSs, which can be recognized by auxiliary splicing factors, including SR proteins and hnRNPs. Polypyrimidine tract binding proteins (PTBPs) can bind to polypyrimidine tracts in introns and promote RNA looping.

[0344] Alternative splicing is a mechanism by which a single gene can ultimately produce several different proteins. Alternative splicing is achieved through the coordinated action of a variety of different proteins called "alternative splicing control proteins" that associate with the pre-mRNA, allowing distinct alternative exons to be included in the mature mRNA. These alternative forms of the gene's transcript can give rise to distinct isoforms of a particular protein. Sequences in pre-mRNA molecules that can be bound by alternative splicing control proteins can be found in introns or exons, including, but not limited to, ISSs, ISEs, ESSs, ESEs, and polypyrimidine tracts. Many mutations can alter splicing patterns. For example, mutations can be in cis-acting elements and can be located in core consensus sequences (e.g., 5'ss, 3'ss, and BPs) or in regulatory elements that regulate spliceosome recruitment, including ESEs, ESSs, ISEs, and ISSs.

[0345] Cryptic splice sites, such as cryptic 5'ss and cryptic 3'ss, can refer to splice sites that are not normally recognized by the spliceosome and are therefore dormant. Cryptic splice sites can be recognized or activated, for example, by mutations in cis-acting elements or trans-acting factors, or by structural features such as bulges.

[0346] Splicing regulation The present disclosure contemplates the use of small molecules with favorable drug properties that modulate the splicing activity of a target RNA. Provided herein are small molecule splicing modulators (SMSMs) that modulate the splicing of a target polynucleotide. In some embodiments, the SMSMs bind to and modulate the target RNA. In some embodiments, provided herein are libraries of SMSMs that bind to and modulate one or more target RNAs. In some embodiments, the target RNA is an mRNA. In some embodiments, the target RNA is a non-coding mRNA. In some embodiments, the target RNA is a pre-mRNA. In some embodiments, the target RNA is an hnRNA. In some embodiments, the small molecule modulates the splicing of a target RNA. In some embodiments, the small molecule provided herein modulates the splicing of a sequence in the target RNA. In some embodiments, the small molecule provided herein modulates the splicing of a cryptic splice site sequence in the target RNA. In some embodiments, the small molecule provided herein binds to the target RNA. In some embodiments, the small molecule provided herein binds to a splicing complex component. In some embodiments, the small molecules provided herein bind to target RNA and splicing complex components.

[0347] Thus, provided herein are methods for preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting the pre-mRNA molecule and / or other elements of the splicing machinery (e.g., in a cell) with a compound provided herein to prevent or induce a splicing event in the pre-mRNA molecule. The prevented or induced splicing event can be, for example, an aberrant splicing event, a constitutive splicing event, or an alternative splicing event.

[0348] Further provided herein is a method for identifying a compound capable of preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting the compound with splicing elements and / or factors involved in alternative splicing, aberrant splicing, and / or constitutive splicing as described herein (e.g., in a cell) under conditions where a positive effect (prevention or induction of splicing) or a negative effect (no prevention or induction of splicing) is produced and detected, and identifying a compound that produces a positive effect as a compound that can prevent or induce a splicing event.

[0349] In some embodiments, the small molecule compounds described herein in a pharmaceutically acceptable carrier prevent or induce alternative or aberrant splicing events in pre-mRNA molecules.As mentioned above, the small molecule compounds provided herein are not antisense oligonucleotides or antigen oligonucleotides.Table 1, Table 2, and Table 5 show the chemical structures and names of exemplary compounds and are not intended to be comprehensive.

[0350] In some embodiments, a composition comprises a small molecule splicing regulator compound (SMSM), wherein the SMSM interacts with a bulge-forming unpaired nucleobase of an RNA duplex, and the RNA duplex comprises a splice site. Provided herein is a composition comprising a complex comprising a small molecule splicing regulator compound (SMSM) bound to an RNA duplex, wherein the SMSM interacts with a bulge-forming unpaired nucleobase of the RNA duplex, and the RNA duplex comprises a splice site. In some embodiments, the double-stranded RNA comprises an alpha helix. In some embodiments, the bulge-forming unpaired nucleobase is located on the outer portion of the helix of the double-stranded RNA. In some embodiments, the bulge-forming unpaired nucleobase is located within the inner portion of the helix of the double-stranded RNA. In some embodiments, the SMSM forms one or more intermolecular interactions with the double-stranded RNA. In some embodiments, the SMSM forms one or more intermolecular interactions with the bulge-forming unpaired nucleobase. In some embodiments, the intermolecular interaction is selected from the group consisting of ionic interactions, hydrogen bonds, dipole-dipole interactions, or van der Waals interactions. In some embodiments, a first portion of SMSM interacts with a bulge-forming unpaired nucleobase on a first RNA strand of an RNA duplex. In some embodiments, a second portion of SMSM interacts with one or more nucleobases of a second RNA strand of an RNA duplex, wherein the first RNA strand is not the second RNA strand. In some embodiments, the exchange rate of a bulge-forming unpaired nucleobase from the interior of the helix of the double-stranded RNA to the exterior of the helix is ​​reduced. In some embodiments, SMSM reduces the rotation rate of the bulge-forming unpaired nucleobase. In some embodiments, SMSM reduces the rotation rate of the bulge-forming unpaired nucleobase around the phosphate backbone of an RNA strand of the RNA duplex. In some embodiments, SMSM modulates the distance of the bulge-forming unpaired nucleobase from the second nucleobase of the double-stranded RNA. In some embodiments, SMSM reduces the distance of a bulge-forming unpaired nucleobase from a second nucleobase of the double-stranded RNA. In some embodiments, the bulge-forming unpaired nucleobase is located within a helix of the double-stranded RNA of the complex.In some embodiments, SMSM reduces the size of a bulge in an RNA duplex. In some embodiments, SMSM eliminates a bulge in an RNA duplex. In some embodiments, SMSM stabilizes a bulge in an RNA duplex. In some embodiments, SMSM modulates splicing at a splice site in an RNA duplex. In some embodiments, SMSM increases splicing at a splice site in an RNA duplex. In some embodiments, SMSM decreases splicing at a splice site in an RNA duplex. In some embodiments, a bulge-forming unpaired nucleobase has adjusted base stacking within the RNA strand of the RNA duplex. In some embodiments, a bulge-forming unpaired nucleobase has increased base stacking within the RNA strand of the RNA duplex. In some embodiments, a bulge-forming unpaired nucleobase has decreased base stacking within the RNA strand of the RNA duplex. In some embodiments, SMSM is not an aptamer. In some embodiments, the RNA duplex comprises a pre-mRNA. In some embodiments, the bulge-forming unpaired nucleobase is free to rotate around the phosphate backbone of the RNA strand of the RNA duplex in the absence of SMSM.

[0351] In some embodiments, the method of modulating splicing comprises contacting a cell with a small molecule splicing modulator compound (SMSM), wherein the SMSM has an IC50 of less than 50 nM. 50and killing the cells. In some embodiments, a method of modulating splicing comprises contacting a cell with a small molecule splicing regulator compound (SMSM), wherein the SMSM modulates splicing of a splice site sequence in a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or functional RNA, and the total amount of mRNA is increased by at least about 10% compared to the total amount of mRNA encoding the target protein or functional RNA produced in a control cell. In some embodiments, a method of modulating splicing comprises contacting a cell with a small molecule splicing regulator compound (SMSM), wherein the SMSM modulates splicing of a splice site sequence in a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or functional RNA, and the total amount of mRNA, target protein, and / or functional RNA is at least 10% less than the total amount of mRNA, target protein, and / or functional RNA in the control cell.

[0352] In some embodiments, a method of modulating splicing comprises contacting a cell with a small molecule splicing modulator compound (SMSM), wherein the SMSM modulates splicing of a splice site sequence of a pre-mRNA encoding a first mRNA isoform associated with a disease or condition and a second mRNA isoform, such that the total amount of the first mRNA isoform is reduced by at least about 10% compared to the total amount of the first mRNA isoform in a control cell, and / or the total amount of the second mRNA isoform is increased by at least about 10% compared to the total amount of the first mRNA isoform in a control cell. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, the cell comprising an amount of a first mRNA isoform and an amount of a second mRNA isoform present in the cell, wherein the ratio of the first mRNA isoform to the second mRNA isoform is decreased by at least 1.2-fold, the first mRNA and the second mRNA are encoded by pre-mRNAs comprising splice site sequences, and the first mRNA isoform is associated with a disease or condition and the second mRNA isoform is associated with a disease or condition.

[0353] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the SMSM modulates exon inclusion, exon exclusion, pseudoexon inclusion, intron retention, or splicing at a cryptic splice site of the polynucleotide, and wherein the SMSM modulates splicing of the splice site sequence. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, wherein the splice site sequence comprises a splice site sequence selected from the group consisting of the splice site sequences in Table 2A, Table 2B, Table 2C, and Table 2D. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises a sequence selected from GGAguaag and AGAguaag. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises at least one bulge-forming nucleotide at position -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises a mutant nucleotide at position -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence.

[0354] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell containing a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of NGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk, where N or n is A, U, G, or C, B is C, G, or U, H or h is A, C, or U, d is a, g, or u, m is a or c, r is a or g, v is a, c, or g, and k is g or u. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell containing a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of NNBgunnnn, NNBhunnnn, and NNBgvnnnn, where N or n is A, U, G, or C, B is C, G, or U, H or h is A, C, or U, d is a, g, or u, m is a or c, r is a or g, v is a, c, or g, and k is g or u. In some embodiments, the splice site sequence comprises a sequence selected from the group consisting of NNBgurrrn, NNBguwwdn, NNBguvmvn, NNBguvbbn, NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, and NNBgvdnvn, where N or n is A, U, G, or C, B is C, G, or U, H or h is A, C, or U, d is a, g, or u, m is a or c, r is a or g, v is a, c, or g, and k is g or u. In some embodiments, the nucleotide at position −3, −2, −1, +1, +2, +3, +4, +5, or +6 of the splice site sequence is a bulge-forming nucleotide.In some embodiments, the nucleotide at position -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence is a variant nucleotide. In some embodiments, the splice site sequence comprises a sequence selected from the group consisting of the splice site sequences of Table 2A, Table 2B, Table 2C, and Table 2D.

[0355] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell containing a polynucleotide having a splice site sequence, thereby modulating splicing of the polynucleotide, wherein the polynucleotide is encoded by a gene selected from the group consisting of the genes in Table 2A, Table 2B, Table 2C, and Table 2D. In some embodiments, the gene is HTT. In some embodiments, modulating splicing of the polynucleotide comprises inhibiting skipping of exon 7. In some embodiments, the gene is DMD. In some embodiments, modulating splicing of the polynucleotide comprises promoting skipping of exon 51.

[0356] In some embodiments, a method for modulating splicing comprises contacting a small molecule splicing regulator compound (SMSM) with a cell, wherein SMSM interacts with a bulge-forming unpaired nucleobase of an RNA duplex in the cell, wherein the double-stranded RNA comprises a splice site sequence, and wherein SMSM modulates splicing of the RNA duplex. In some embodiments, the method comprises adjusting the relative position of a first nucleobase with a second nucleobase, wherein the first nucleobase and the second nucleobase are within the double-stranded RNA, and the method comprises contacting a small molecule splicing regulator compound (SMSM) or a pharmaceutically acceptable salt thereof with the double-stranded RNA, wherein the first nucleobase is a bulge-forming unpaired nucleobase of the RNA duplex, and wherein the double-stranded RNA comprises a splice site sequence.

[0357] In some embodiments, the double-stranded RNA comprises a helix. In some embodiments, the bulge-forming unpaired nucleobase is located on the outer portion of the helix of the double-stranded RNA before contact with SMSM. In some embodiments, SMSM forms one or more intermolecular interactions with the double-stranded RNA. In some embodiments, SMSM forms one or more intermolecular interactions with the bulge-forming unpaired nucleobase. In some embodiments, the intermolecular interactions are selected from the group including ionic interactions, hydrogen bonds, dipole-dipole interactions, or van der Waals interactions. In some embodiments, the exchange rate of the bulge-forming unpaired nucleobase from the inner portion of the helix of the double-stranded RNA to the outer portion of the helix is ​​reduced. In some embodiments, the rotation rate of the bulge-forming unpaired nucleobase is reduced. In some embodiments, the rotation rate of the bulge-forming unpaired nucleobase around the phosphate backbone of an RNA strand of the RNA duplex is reduced. In some embodiments, the distance of the bulge-forming unpaired nucleobase from a second nucleobase of the double-stranded RNA is adjusted after contact with SMSM. In some embodiments, the distance of the bulge-forming unpaired nucleobase from a second nucleobase of the double-stranded RNA is reduced. In some embodiments, the bulge-forming unpaired nucleobase is located inside the helix of the double-stranded RNA. In some embodiments, the size of the bulge in the RNA duplex is reduced. In some embodiments, the bulge in the RNA duplex is removed or maintained. In some embodiments, splicing at a splice site of the RNA duplex is promoted. In some embodiments, base stacking of the bulge-forming unpaired nucleobase within the RNA strand of the RNA duplex is increased after contact with SMSM. In some embodiments, the distance of the bulge-forming unpaired nucleobase from a second nucleobase of the double-stranded RNA is increased or maintained. In some embodiments, the bulge in the RNA duplex is stabilized after contact with SMSM. In some embodiments, the bulge-forming unpaired nucleobase is located on the outer portion of the helix of the double-stranded RNA. In some embodiments, the size of the bulge in the RNA duplex is increased. In some embodiments, splicing at a splice site of the RNA duplex is inhibited. In some embodiments, splicing is inhibited at the splice junction.In some embodiments, base stacking of bulge-forming unpaired nucleobases within an RNA strand of an RNA duplex is reduced after contact with SMSM. In some embodiments, the RNA duplex comprises a pre-mRNA.

[0358] In some embodiments, a method of treating a subject having a tumor comprises administering a small molecule splicing regulator compound (SMSM) to the subject, wherein the size of the tumor is reduced. In some embodiments, a method of treating a subject having a tumor comprises administering a small molecule splicing regulator compound (SMSM) to the subject, wherein tumor growth is inhibited by at least 20%. In some embodiments, a method of treating, preventing, and / or delaying the progression of a condition or disease comprises administering a small molecule splicing regulator compound (SMSM) to the subject, wherein the SMSM regulates splicing of a polynucleotide in the subject's cells, and the condition or disease is associated with splicing of a splice site. In some embodiments, the subject has a disease or condition. In some embodiments, a method of treating a subject having a disease or condition comprises administering a small molecule splicing regulator compound (SMSM) to a subject having a disease or condition selected from the group consisting of diseases in Table 2A, Table 2B, Table 2C, and Table 2D. In some embodiments, a method of treating a subject having a disease or condition comprises administering to the subject having the disease or condition a small molecule splicing regulator compound (SMSM), wherein the SMSM is selected from the group consisting of the SMSMs in Table 1, Table 2, and Table 5. In some embodiments, a method of treating a subject having a disease or condition comprises administering to the subject having the disease or condition a small molecule splicing regulator compound (SMSM), wherein the SMSM binds to a pre-mRNA comprising a splice site sequence selected from the group consisting of the splice site sequences in Table 2A, Table 2B, Table 2C, and Table 2D. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the polynucleotide is a pre-mRNA. In some embodiments, the disease or condition is spinal muscular atrophy. In some embodiments, the disease or condition is Duchenne muscular dystrophy. In some embodiments, the method further comprises administering to the subject an additional therapeutic molecule. In some embodiments, the SMSM is a compound described herein.In some embodiments, the SMSM is selected from the group consisting of the SMSMs in Table 1, Table 2, and Table 5.

[0359] In some embodiments, modulating splicing comprises preventing, inhibiting, or reducing splicing of a splice site sequence of a polynucleotide. In some embodiments, modulating splicing comprises enhancing, promoting, or increasing splicing of a splice site sequence of a polynucleotide. In some embodiments, the splice site sequence is a 5' splice site sequence, a 3' splice site sequence, a branch point splice site sequence, or a cryptic splice site sequence. In some embodiments, the splice site comprises a mutation, the splice site comprises a bulge, the splice site comprises a mutation and a bulge, the splice site does not comprise a mutation, the splice site does not comprise a bulge, or the splice site does not comprise a mutation and does not comprise a bulge. In some embodiments, the bulge is a bulge caused by a mutation. In some embodiments, the bulge-forming nucleotide is a mutated nucleotide. In some embodiments, the bulge-forming nucleotide is not a mutated nucleotide. In some embodiments, SMSM modulates the K of a splicing complex component for a polynucleotide. D In some embodiments, SMSM reduces the K of a splicing complex component for a polynucleotide. DIn some embodiments, SMSM inhibits binding of splicing complex components to polynucleotides at, upstream of, or downstream of splice site sequences. In some embodiments, SMSM promotes binding of splicing complex components to polynucleotides at, upstream of, or downstream of splice site sequences. In some embodiments, the polynucleotide is RNA. In some embodiments, the RNA is pre-mRNA. In some embodiments, the RNA is heterogeneous nuclear RNA. In some embodiments, the splice site sequence is a 5' splice site sequence, a 3' splice site sequence, a branch point (BP) splice site sequence, an exon splicing enhancer (ESE) sequence, an exon splicing silencer (ESS) sequence, an intron splicing enhancer (ISE) sequence, an intron splicing silencer (ISS) sequence, a polypyrimidine tract sequence, or any combination thereof. In some embodiments, the polynucleotide is at least 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 250, 500, 750, 1,000, 2,000, 5,000, 10,000, 50,000, 100,000, 500,000, or 1,000,000 nucleotides in length. In some embodiments, SMSM binds to a splice site sequence of the polynucleotide. In some embodiments, SMSM interacts with a bulge in a splice site sequence of the polynucleotide. In some embodiments, the polynucleotide comprises a cis-acting element sequence. In some embodiments, the cis-acting element sequence does not comprise a bulge. In some embodiments, the cis-acting element sequence does not comprise a mutation. In some embodiments, the cis-acting element sequence comprises a mutation, a bulge, or a combination thereof, in the cis-acting element sequence, 1-1000 nucleobases upstream of the cis-acting element sequence, or 1-1000 nucleobases downstream of the cis-acting element sequence. In some embodiments, the cis-acting element sequence comprises a control element sequence that regulates the recruitment of a splicing complex component to the polynucleotide.In some embodiments, the cis-acting element sequence comprises a control element sequence that regulates the recruitment of spliceosomes to the polynucleotide. In some embodiments, the control element sequence comprises an exon splicing enhancer (ESE) sequence, an exon splicing silencer (ESS) sequence, an intron splicing enhancer (ISE) sequence, an intron splicing silencer (ISS) sequence, and combinations thereof. In some embodiments, SMSM binds to a splicing complex component. In some embodiments, the splicing complex component is 9G8, A1 hnRNP, A2 hnRNP, ASD-1, ASD-2b, ASF, B1 hnRNP, C1 hnRNP, C2 hnRNP, CBP20, CBP80, CELF, F hnRNP, FBP11, Fox-1, Fox-2, G hnRNP, H hnRNP, hnRNP 1, hnRNP 3, hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulator protein (KSRP), L hnRNP, M hnRNP, mBBP, muscle blind-like (MBNL), NF45, NFAR, Nova-1, Nova-2, nPTB, P54 / SFRS11, polypyrimidine tract binding protein (PTB), PRP19 complex protein, R hnRNP, RNPC1, SAM68, SC35, SF, SF1 / BBP, SF2, SF3a, SF3B, SFRS10, Sm protein, SR protein, SRm300, SRp20, SRp30c, SRP35C, SRP36, SRP38, SRp40, SRp55, SRp75, SRSF, STAR, GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR, TRA2, TRA2a / b, U hnRNP, U1 snRNP, U11 snRNP, U12 snRNP, U1-C, U2 snRNP, U2AF1-RS2, U2AF35, U2AF65, U4 snRNP, U5 snRNP, U6 snRNP, Urp, YB1, or any combination thereof. In some embodiments, the splicing complex component comprises RNA.In some embodiments, the splicing complex component is a small nuclear RNA (snRNA). In some embodiments, the snRNA comprises U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, U6 snRNA, U11 snRNA, U12 snRNA, U4atac snRNA, U5 snRNA, U6atac snRNA, or any combination thereof. In some embodiments, the splicing complex component comprises a protein. In some embodiments, the splicing complex component comprises a small nuclear ribonucleoprotein (snRNP). In some embodiments, the snRNP comprises U1 snRNP, U2 snRNP, U4 snRNP, U5 snRNP, U6 snRNP, U11 snRNP, U12 snRNP, U4atac snRNP, U5 snRNP, U6atac snRNP, or any combination thereof. In some embodiments, the protein is a serine / arginine-rich (SR) protein. In some embodiments, the splice site sequence contains bases that are mismatched to bases in the snRNA sequence. In some embodiments, the bulge is due to a base-pairing mismatch between the splice site sequence and the snRNA sequence.

[0360] In some embodiments, the method includes upregulating the expression of a native protein in a cell containing DNA encoding the native protein, wherein the DNA contains or does not contain a mutation that causes its downregulation by aberrant and / or alternative splicing of the native protein. For example, the DNA can encode a pre-mRNA with a mutation or abnormal secondary or tertiary structure that causes the downregulation of one or more isoforms of the protein. The method can include introducing into the cell a small molecule provided herein that prevents the aberrant splicing event, thereby allowing the native intron to be removed by correct splicing and the native protein to be produced by the cell. In some embodiments, the method includes introducing into the cell a small molecule provided herein that modulates alternative splicing events to produce a protein with a different function than the protein that would be produced without the modulation of alternative splicing.

[0361] In some embodiments, a method includes downregulating expression of a native protein in a cell containing DNA encoding the native protein, wherein the DNA contains a mutation that causes its upregulation by aberrant and / or alternative splicing of the native protein, or does not contain a mutation. For example, the DNA can encode a pre-mRNA with a mutation or an abnormal secondary or tertiary structure that causes the upregulation of one or more isoforms of the protein. The method can include introducing into a cell a small molecule provided herein that prevents aberrant splicing events, thereby allowing the native intron to be removed by correct splicing and the native protein to be produced by the cell. In some embodiments, the method includes introducing into a cell a small molecule provided herein that modulates alternative splicing events to produce a protein with a different function than the protein that would be produced without modulation of alternative splicing. For example, the method can include preventing aberrant splicing and / or preventing alternative splicing events in a pre-mRNA containing a mutation or an abnormal secondary or tertiary structure. When present in a pre-mRNA, a mutation or aberrant secondary or tertiary structure can cause the pre-mRNA to be incorrectly spliced, producing an aberrant mRNA or mRNA fragment that differs from the mRNA that would normally result from a pre-mRNA that does not contain the mutation or aberrant secondary or tertiary structure. For example, a pre-mRNA molecule can contain (i) a first set of splice elements that define naturally occurring introns that can be removed by splicing in the absence of the mutation or aberrant secondary or tertiary structure to produce a first mRNA molecule that encodes a natural protein, and (ii) a second set of splice elements induced by the mutation or aberrant secondary or tertiary structure that define an aberrant intron that differs from the naturally occurring introns and that can be removed by splicing in the presence of the mutation or aberrant secondary or tertiary structure to produce an aberrant second mRNA molecule that differs from the first mRNA molecule.The method can include contacting a pre-mRNA molecule and / or other factors and / or elements of the splicing machinery described herein (e.g., in a cell) with a compound described herein to prevent or promote aberrant splicing events in the pre-mRNA molecule, thereby removing a native intron by correct splicing and increasing production of the native protein in the cell.

[0362] In some embodiments, the method includes upregulating expression of an RNA that would otherwise be downregulated by modulating alternative splicing events in the RNA. The method can include contacting a pre-mRNA molecule and / or other elements and / or factors of the splicing machinery with a compound described herein to modulate the alternative splicing event, thereby inhibiting natural splicing events and promoting alternative splicing events, thereby upregulating expression of an RNA that would otherwise be downregulated under the control of natural splicing events.

[0363] In some embodiments, the method involves downregulating expression of an RNA that would otherwise be upregulated by modulating alternative splicing events in the RNA. The method can include contacting a pre-mRNA molecule and / or other elements and / or factors of the splicing machinery with a compound described herein to modulate the alternative splicing event, thereby inhibiting natural splicing events and promoting alternative splicing events, thereby downregulating expression of an RNA that would otherwise be upregulated under the control of natural splicing events.

[0364] The methods, compounds, and compositions described herein have a variety of uses. For example, they are useful in any process where it is desirable to have a means for downregulating the expression of an expressed RNA until a certain time and then upregulating RNA expression. For such uses, the expressed RNA can be any RNA that encodes a protein to be produced, as long as the gene contains a natural intron. The RNA can be mutated by any suitable means, such as site-directed mutagenesis to intentionally create an abnormal second set of splice elements that define an abnormal intron that substantially downregulates the expression of the gene (see T. Kunkel, U.S. Pat. No. 4,873,192). The sequence encoding the RNA can be inserted into a suitable expression vector, and this expression vector can be inserted into a host cell (e.g., a eukaryotic cell such as yeast, insect, or mammalian cell (e.g., human, rat)) by standard recombinant techniques. The host cell can then be grown in culture by standard techniques. If it is desired to upregulate expression of a mutant gene, a suitable compound of the present disclosure in a suitable formulation may be added to the culture medium, thereby causing expression of that gene to be upregulated.

[0365] Also provided herein is a method for changing the ratio of splice variants produced from a gene. The method can include contacting pre-mRNA molecules and / or other elements and / or factors of the splicing machinery with a compound(s) described herein to regulate alternative splicing events. The compound(s) of the present disclosure can be used to affect 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 alternative splicing events that may occur within the pre-mRNA. In some embodiments, a first splice variant can be downregulated or inhibited, and / or a second splice variant can be upregulated, resulting in a change in the ratio of two or more splice variants of RNA. In some embodiments, a first splice variant can be upregulated, while a second splice variant may not be affected, thereby changing the ratio of RNA. In some embodiments, the first splice variant may be downregulated while the second splicing event may be unaffected, thereby altering the ratio of RNAs.

[0366] The methods, compounds, and formulations described herein are also useful as in vitro or in vivo tools for examining and modulating splicing events (e.g., alternative splicing events) in human or animal RNAs encoded by genes, e.g., developmentally regulated and / or tissue regulated.

[0367] The compounds and formulations described herein are also useful as therapeutic agents for treating diseases associated with abnormal and / or alternative splicing.Thus, in some embodiments, a method for treating a subject with a condition or disorder associated with alternative or aberrant splicing events in pre-mRNA molecules comprises administering a therapeutically effective amount of a compound described herein to the subject to regulate alternative splicing events or prevent aberrant splicing events, thereby treating the subject.This method can, for example, restore correct splicing events in pre-mRNA molecules.This method can, for example, utilize the small molecule compounds described herein in a pharmaceutically acceptable carrier.

[0368] The formulations containing the small molecules described herein can contain physiologically or pharmaceutically acceptable carriers, such as aqueous carriers.Therefore, the formulations for use in the methods described herein include, but are not limited to, oral administration, parenteral administration, such as subcutaneous, intradermal, intramuscular, intravenous, and intraarterial administration, and topical administration (for example, administration of an aerosolized formulation with respirable particles to the lungs of patients with cystic fibrosis or lung cancer, or administration of a cream or lotion formulation for transdermal administration to patients with psoriasis).These formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art.The most suitable administration route in any given case can depend on the subject being treated, the nature and severity of the condition, and the specific active compound being used, which can be easily determined by those skilled in the art.

[0369] As discussed above, methods are also provided herein for using the compounds described herein having the properties described above to prepare a medicament for upregulating or downregulating RNA expression in patients with disorders associated with aberrant or alternative splicing of pre-mRNA molecules. In some embodiments, the medicament upregulates gene expression. In other embodiments, the medicament downregulates gene expression. In producing a medicament according to the present disclosure, the compound may be mixed with, inter alia, a pharmaceutically acceptable carrier. The carrier may be solid or liquid. One or more compounds may be incorporated into the formulations described herein in any combination, which may be prepared by any of the well-known pharmaceutical techniques, such as mixing components and / or including one or more auxiliary therapeutic ingredients.

[0370] The present inventors have identified low molecular weight compounds (sometimes referred to herein as small molecules) that block and / or enhance (promote, increase) mRNA splicing. Splicing that can be controlled by the methods described herein includes alternative splicing, such as exon skipping, intron retention, pseudoexon skipping, exon exclusion, partial intron exclusion, and others. Depending on factors such as the splicing sequence and RNA (or gene encoding the RNA) or the exons involved, splicing modulation can be achieved in the presence or absence of antisense oligonucleotides (AOs) specific to the splicing sequence of interest. In some embodiments, the small molecule and the AO act synergistically.

[0371] In some embodiments, the method includes contacting a splice-modulating compound (e.g., SMSM) with a pre-mRNA that modulates splicing of the pre-mRNA to support expression of a transcript that promotes cell proliferation. For example, the SMSM described herein can increase one or more isoforms of a transcript that promotes cell proliferation. For example, the SMSM described herein can decrease expression of one or more isoforms of a transcript that prevents or inhibits cell proliferation.

[0372] In some embodiments, the method includes contacting a splice-modulating compound (e.g., SMSM) with a pre-mRNA that modulates the splicing of the pre-mRNA to support the expression of a transcript that prevents or inhibits cell proliferation. For example, the SMSM described herein can increase one or more isoforms of a transcript that prevents or inhibits cell proliferation. For example, the SMSM described herein can decrease the expression of one or more isoforms of a transcript that promotes cell proliferation.

[0373] In some embodiments, a method for modulating pre-mRNA splicing includes using SMSM to reduce the expression or functionality of one or more isoforms of a transcript in a subject. The method can include administering SMSM or a composition comprising SMSM to the subject, wherein SMSM binds to the pre-mRNA or a splicing complex component and modulates splicing of the pre-mRNA to support the expression of one or more isoforms of the transcript. The method can include administering SMSM or a composition comprising SMSM to the subject, wherein SMSM binds to the pre-mRNA or a splicing complex component and modulates splicing of the pre-mRNA to favor the expression of one or more isoforms of the transcript.

[0374] In some embodiments, the present disclosure provides a method for treating a subject suffering from a disease or condition associated with abnormal splicing of pre-mRNA. The method can include administering SMSM or a composition comprising SMSM to the subject, wherein SMSM binds to the pre-mRNA or a splicing complex component and regulates pre-mRNA splicing, inhibiting the expression of one or more isoforms of the transcript. The method can include administering SMSM or a composition comprising SMSM to the subject, wherein SMSM binds to the pre-mRNA or a splicing complex component and regulates pre-mRNA splicing, increasing the expression of one or more isoforms of the transcript.

[0375] Some diseases are associated with the expression of abnormal gene products (e.g., RNA transcripts or proteins) of genes. For example, abnormal amounts of RNA transcripts can cause disease due to changes in corresponding protein expression. Changes in the amount of a specific RNA transcript can be the result of several factors. First, changes in the amount of RNA transcripts, such as due to disruption of transcription factors or parts of the transcription process, can result in abnormal transcription levels of a specific gene, resulting in changes in the expression level of a specific RNA transcript. Second, changes in the splicing of a specific RNA transcript, such as due to disruption of a specific splicing process or a genetic mutation that results in modified splicing, can change the level of a specific RNA transcript. Changes in the stability of a specific RNA transcript or changes in components that maintain the stability of an RNA transcript, such as changes in the poly(A) tail incorporation process or changes in the effect on certain factors or proteins that bind to and stabilize the RNA transcript, can lead to changes in the level of a specific RNA transcript. The translation level of a specific RNA transcript can also affect the amount of those transcripts, potentially affecting or upregulating the decay process of the RNA transcript. Finally, aberrant RNA transport or RNA sequestration can also lead to altered functional levels of RNA transcripts, affecting their stability, further processing, or translation.

[0376] In some embodiments, provided herein are methods for modulating the amount of one, two, three, or more RNA transcripts encoded by a pre-mRNA, comprising contacting a cell with an SMSM compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is contacted with the SMSM compound or a pharmaceutically acceptable salt thereof in cell culture. In other embodiments, the cell is contacted with the SMSM compound or a pharmaceutically acceptable salt thereof in a subject (e.g., a non-human animal subject or a human subject).

[0377] In some embodiments, provided herein are methods for treating, preventing, and / or delaying the progression of a disease or condition, comprising administering to a subject, particularly a mammal, an effective amount of a small molecule splicing regulator described herein.

[0378] In some embodiments, provided herein are compositions and methods for treating a disease or condition, comprising a stereoregulator compound or a pharmaceutically acceptable salt thereof that promotes the prevention or correction of exon skipping in pre-mRNA. The present disclosure further provides compositions and methods for increasing mature mRNA, and thus protein, production in a subject's cells, where the subject is in need thereof, e.g., a subject that can benefit from increased protein production. The present disclosure further provides compositions and methods for decreasing mature mRNA, and thus protein, production in a subject's cells, where the subject is in need thereof, e.g., a subject that can benefit from reduced protein production. In one embodiment, the described methods can be used to treat subjects with diseases or conditions caused by genetic mutations, including missense, splicing, frameshift, and nonsense mutations, as well as whole-gene deletions, that result in defective protein production. In another embodiment, the described methods can be used to treat subjects with diseases or conditions not caused by genetic mutations. In some embodiments, the compositions and methods of the present disclosure can be used to treat subjects with diseases or conditions that can benefit from increased protein production. In some embodiments, the compositions and methods of the present disclosure can be used to treat a subject having a disease or condition that can benefit from increased protein production, hi some embodiments, the compositions and methods of the present disclosure can be used to treat a subject having a disease or condition that can benefit from decreased protein production.

[0379] In some embodiments, methods are provided for treating a disease or condition in a subject in need thereof by increasing expression of a target protein or functional RNA by the subject's cells, where the cells have a mutation that causes, for example, exon skipping or intron inclusion, or a portion thereof, of the pre-mRNA, and the pre-mRNA encodes the target protein or functional RNA. The method can include contacting the subject's cells with an SMSM compound or a pharmaceutically acceptable salt thereof that targets the pre-mRNA encoding the target protein or functional RNA or a splicing complex component, thereby preventing or inhibiting splicing of an exon from the pre-mRNA encoding the target protein or functional RNA, thereby increasing the level of the mRNA encoding the target protein or functional RNA and increasing expression of the target protein or functional RNA in the subject's cells. In some embodiments, methods are also disclosed herein for increasing expression of a target protein by cells with a mutation or an abnormal secondary or tertiary RNA structure that causes exon skipping in the pre-mRNA, where the pre-mRNA contains a mutation or an abnormal secondary or tertiary RNA structure that causes exon skipping. The method can include contacting a cell with an SMSM compound or a pharmaceutically acceptable salt thereof that targets a pre-mRNA encoding a target protein or functional RNA, thereby preventing or inhibiting splicing of an exon from the pre-mRNA encoding the target protein or functional RNA, thereby increasing the level of the mRNA encoding the functional protein and increasing expression of the protein in the cell. In some embodiments, the target protein is a tumor suppressor. In some embodiments, the target protein is a tumor promoter. In some embodiments, the target protein or functional RNA is a compensatory protein or compensatory functional RNA that functionally augments or replaces a target protein or functional RNA whose amount or activity is deficient in the subject.In some embodiments, the cells are present in or derived from a subject with a condition caused by a deficiency in the amount or activity of a protein. In some embodiments, the deficiency in the amount of the target protein is caused by haploinsufficiency of the target protein, and the subject has a first allele encoding a functional target protein and a second allele in which the target protein is not produced or encodes a non-functional target protein, and an SMSM compound or a pharmaceutically acceptable salt thereof binds to a target portion of a pre-mRNA transcribed from the first allele. In some embodiments, the target protein is produced in a fully functional form compared to an equivalent protein produced from an exon-skipped or exon-deleted mRNA. In some embodiments, the pre-mRNA is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the pre-mRNA. In some embodiments, the SMSM compound or a pharmaceutically acceptable salt thereof increases the amount of a target protein or functional RNA by modulating alternative splicing of a pre-mRNA transcribed from a gene encoding the functional RNA or target protein. In some embodiments, the SMSM compound or a pharmaceutically acceptable salt thereof increases the amount of a target protein or functional RNA by modulating aberrant splicing resulting from a mutation in the gene encoding the target protein or functional RNA.

[0380] In some embodiments, the total amount of mRNA encoding a target protein or functional RNA produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by at least about 10%, at least about 20%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 400%, or at least about 500% compared to the total amount of mRNA encoding a target protein or functional RNA produced in control cells.

[0381] In some embodiments, the total amount of mRNA encoding a target protein or functional RNA produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 20% to about 300%, about 50% to about 300%, about 100% to about 300%, about 150% to about 300%, about 20% to about 300%, or about 50% to about 300%, or about 50% to about 300%, or about 100% to about 300%, or about 150% to about 300%, or about 2 ... to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 200%, about 20% to about 250%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 150% to about 200%, about 150% to about 250%, or about 200% to about 250% increase.

[0382] In some embodiments, the total amount of target protein produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by at least about 20%, at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% compared to the total amount of target protein produced by control cells. In some embodiments, the total amount of target protein produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by about 20% to about 300%, about 50% to about 300%, about 100% to about 300%, about 150% to about 300%, about 20% to about 50%, or about 20% to about 100% compared to the total amount of target protein produced by control cells. , about 20% to about 150%, about 20% to about 200%, about 20% to about 250%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 150% to about 200%, about 150% to about 250%, or about 200% to about 250%.

[0383] In some embodiments, the total amount of mRNA encoding a target protein or functional RNA produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold compared to the total amount of mRNA encoding a target protein or functional RNA produced in control cells. In some embodiments, the total amount of mRNA encoding a target protein or functional RNA produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, or about 4 to about 9-fold compared to the total amount of mRNA encoding a target protein or functional RNA produced in control cells.

[0384] In some embodiments, the total amount of target protein produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold compared to the total amount of target protein produced by a control. In some embodiments, the total amount of target protein produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is increased by about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, or about 4 to about 9-fold compared to the total amount of target protein produced by control cells.

[0385] In some embodiments, the total amount of mRNA encoding a target protein or functional RNA produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to the total amount of mRNA encoding a target protein or functional RNA produced in control cells.

[0386] In some embodiments, the total amount of mRNA encoding a target protein or functional RNA produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 90%, about 30% to about 10 ... 0% to approximately 60%, approximately 20% to approximately 70%, approximately 20% to approximately 80%, approximately 20% to approximately 90%, approximately 30% to approximately 40%, approximately 30% to approximately 50%, approximately 30% to approximately 60%, approximately 30% to approximately 70%, approximately 30% to approximately 80%, approximately 30% to approximately 90%, approximately 40% to approximately 50%, approximately 40% to approximately 60%, approximately 40% to approximately 70% , about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, 70% to about 80%, about 70% to about 90%, or about 80% to about 90%.

[0387] In some embodiments, the total amount of target protein produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to the total amount of target protein produced by control cells. In some embodiments, the total amount of target protein produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, or about 80% to about 100% compared to the total amount of target protein produced by control cells. %, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, 70% to about 80%, about 70% to about 90%, or about 80% to about 90%.

[0388] In some embodiments, the difference in abundance between a first splice variant and a second splice variant encoding a target protein or functional RNA isoform produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is between about 20% and about 300%, between about 50% and about 300%, between about 100% and about 300%, between about 150% and about 300%, between about 20% and about 50%, between about 20% and about 100%, between about 20% and about 3 ... An increase of about 150%, about 20% to about 200%, about 20% to about 250%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 150% to about 200%, about 150% to about 250%, about 200% to about 250%, at least about 20%, at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300%. In some embodiments, the difference in amount between a first protein isoform expressed from a first splice variant and a second protein isoform expressed from a second splice variant produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is between about 20% and about 300%, between about 50% and about 300%, between about 100% and about 300%, between about 150% and about 300%, between about 20% and about 50% compared to the difference in amount between those two protein isoforms produced from splice variants produced by control cells. an increase of 0%, about 20% to about 100%, about 20% to about 150%, about 20% to about 200%, about 20% to about 250%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 150% to about 200%, about 150% to about 250%, about 200% to about 250%, at least about 20%, at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300%.

[0389] In some embodiments, the difference in the amount of a first splice variant and a second splice variant encoding a target protein or functional RNA isoform produced in a cell contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 5-fold, or about 1.1 to about 5-fold, compared to the difference in the amount of the first splice variant and the second splice variant produced by a control cell. 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold increase. In some embodiments, the difference in abundance between a first protein isoform expressed from a first splice variant and a second protein isoform expressed from a second splice variant produced by a cell contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 1.1 to about 10 fold, about 1.5 to about 10 fold, about 2 to about 10 fold, about 3 to about 10 fold, about 4 to about 10 fold, or about 5 to about 10 fold greater than the difference in abundance between the two protein isoforms expressed from splice variants produced by a control cell. The increase may be about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold.

[0390] In some embodiments, the difference in amount between a first splice variant and a second splice variant encoding a target protein or functional RNA isoform produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 20% to about 300%, about 50% to about 300%, about 100% to about 300%, about 150% to about 300%, about 20% to about 50%, about 20% to about 100%, about 20% to about A decrease of 150%, about 20% to about 200%, about 20% to about 250%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 150% to about 200%, about 150% to about 250%, about 200% to about 250%, at least about 20%, at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300%. In some embodiments, the difference in amount between a first protein isoform expressed from a first splice variant and a second protein isoform expressed from a second splice variant produced by cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is between about 20% and about 300%, between about 50% and about 300%, between about 100% and about 300%, between about 150% and about 300%, between about 20% and about 50% compared to the difference in amount between those two protein isoforms produced from splice variants produced by control cells. A decrease of 0%, about 20% to about 100%, about 20% to about 150%, about 20% to about 200%, about 20% to about 250%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 150% to about 200%, about 150% to about 250%, about 200% to about 250%, at least about 20%, at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300%.

[0391] In some embodiments, the difference in the amount of a first splice variant and a second splice variant encoding a target protein or functional RNA isoform produced in a cell contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 5-fold, or about 1.1 to about 5-fold, compared to the difference in the amount of the first splice variant and the second splice variant produced by a control cell. 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold decrease. In some embodiments, the difference in abundance between a first protein isoform expressed from a first splice variant and a second protein isoform expressed from a second splice variant produced by a cell contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is about 1.1 to about 10 fold, about 1.5 to about 10 fold, about 2 to about 10 fold, about 3 to about 10 fold, about 4 to about 10 fold, or about 5 to about 10 fold greater than the difference in abundance between the two protein isoforms expressed from splice variants produced by a control cell. The decrease is about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold.

[0392] The ratio of the first isoform to the second isoform can contribute to some conditions or diseases. In some embodiments, a subject without a condition or disease has a ratio of the first isoform to the second isoform of 1:1. In some embodiments, a subject with a condition or disease described herein has a ratio of the first isoform to the second isoform of about 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5. In some embodiments, a subject having a condition or disease described herein has a ratio of the first isoform to the second isoform of about 1:1 to about 1:1.1, about 1:1 to about 1:1.2, about 1:1 to about 1:1.3, about 1:1 to about 1:1.4, about 1:1 to about 1:1.5, about 1:1 to about 1:1.6, about 1:1 to about 1:1.8, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:3.5, about 1:1 to about 1:4, about 1:1 to about 1:4.5, about 1:1 to about 1:5, 1:2 to about 1:3, about 1:2 to about 1:4, about 1:2 to about 1:5, about 1:3 to about 1:4, about 1:3 to about 1:5, or about 1:4 to about 1:5.

[0393] In some embodiments, binding of an SMSM compound or a pharmaceutically acceptable salt thereof to pre-mRNA prevents splicing of one or more exons and / or introns from a population of pre-mRNAs and / or their proteins to produce an mRNA encoding a target protein or functional RNA. In some embodiments, a cell comprises a population of pre-mRNAs transcribed from a gene encoding a target protein or functional RNA, the population of pre-mRNAs containing mutations that cause splicing from one or more exons, and an SMSM compound or a pharmaceutically acceptable salt thereof binds to the mutations that cause splicing from one or more exons in the population of pre-mRNAs. In some embodiments, binding of an SMSM compound or a pharmaceutically acceptable salt thereof to the mutations that cause splicing from one or more exons prevents splicing from one or more exons from the population of pre-mRNAs to produce an mRNA encoding the target protein or functional RNA. In some embodiments, the condition is a disease or disorder. In some embodiments, the method further comprises assessing protein expression. In some embodiments, the SMSM compound or a pharmaceutically acceptable salt thereof binds to a target portion of the pre-mRNA.

[0394] In some embodiments, binding of the SMSM compound or a pharmaceutically acceptable salt thereof catalyzes the inclusion of a missing exon or the removal of an undesired retained intron or portion thereof, resulting in healthy mRNA and protein. In some embodiments, binding of the SMSM compound or a pharmaceutically acceptable salt thereof has little or no effect on non-diseased cells.

[0395] In some embodiments, SMSM inhibits cells with an IC of less than 50 nM. 50 In some embodiments, the cells are primary cells. In some embodiments, SMSM kills the cells at an IC of less than 48 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 3 nM, or 1 nM. 50and kill them.

[0396] In some embodiments, SMSM modulates splicing of splice site sequences in polynucleotides of primary cells. In some embodiments, SMSM modulates proliferation or survival of primary cells. In some embodiments, the primary cells are primary disease cells. In some embodiments, the primary disease cells are primary cancer cells. In some embodiments, SMSM is present at a concentration of at least about 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM, 1 mM, 10 mM, 100 mM, or 1 M. In some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the primary disease cells are killed. In some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the primary disease cells undergo apoptosis, hi some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the primary disease cells undergo necrosis. In some embodiments, proliferation is reduced or inhibited in at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the primary disease cells. In some embodiments, the primary disease cells are non-transformed cells.

[0397] In some embodiments, SMSM reduces the size of a tumor in a subject, ie, the size of a tumor in a subject administered SMSM or a pharmaceutically acceptable salt thereof is reduced by at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% in the subject. In some embodiments, the diameter of a tumor in a subject administered SMSM or a pharmaceutically acceptable salt thereof is reduced by at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the volume of a tumor is reduced in a subject by at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the tumor is malignant.

[0398] In some embodiments, the method comprises contacting SMSM with primary non-diseased cells. In some embodiments, up to about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of the primary non-diseased cells are killed. In some embodiments, up to about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of the primary non-diseased cells undergo apoptosis. In some embodiments, up to about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of the primary non-diseased cells undergo necrosis. In some embodiments, proliferation is reduced or inhibited in up to about 1%, 5%, 10%, 15%, 20%, 25%, or 50% of the primary non-diseased cells. In some embodiments, the primary non-diseased cells are of the same tissue as the primary diseased cells. In some embodiments, the primary non-diseased cells are differentiated cells.

[0399] SMSM can modulate splicing at splice sites of polynucleotides without exhibiting significant toxicity. In some embodiments, SMSM penetrates the blood-brain barrier (BBB) ​​when administered to a subject.

[0400] In some embodiments, SMSM has a brain / blood AUC of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, or more.

[0401] In some embodiments, the SMSM provided herein, e.g., the SMSM described herein, has an apparent permeability (Papp) as determined by an MDCK-MDR1 permeability assay of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, or at least about 100. In some embodiments, the SMSM provided herein has an apparent permeability of at least about 10, at least about 20, or at least about 50.

[0402] In some embodiments, the SMSM provided herein, e.g., the SMSM described herein, has an efflux ratio (ER) of up to about 3. In some embodiments, the SMSM provided herein has an efflux ratio in the range of about 1, about 2, about 3, or about 4 to about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, or about 20, as determined by an MDCK-MDR1 permeability assay. In some embodiments, the SMSM provided herein has an efflux ratio of about 3 to about 10. In some embodiments, the SMSM provided herein has an efflux ratio of up to about 3, up to about 2, or up to about 1. In some embodiments, the SMSM provided herein has an efflux ratio of greater than about 10. In some embodiments, the SMSM provided herein has an efflux ratio of at least about 10, at least about 20, at least about 50, at least about 100, at least about 200, or at least about 300.

[0403] In some embodiments, SMSM has a therapeutic effect of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, and having a half-life of 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 hours.

[0404] In some embodiments, SMSM is stable at room temperature for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or for at least 1, 2, 3, 4, or 5 years. In some embodiments, SMSM is stable at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or for at least 1, 2, 3, 4, or 5 years. In some embodiments, SMSM is stable in water or organic solvent at room temperature for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or for at least 1, 2, 3, 4, or 5 years. In some embodiments, SMSM is stable in water or organic solvent at 4°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or for at least 1, 2, 3, 4, or 5 years.

[0405] In some embodiments, SMSM is 0.01 to 10 nM, 0.01 to 5 nM, 0.01 to 2.5 nM, 0.01 to 1 nM, 0.01 to 0.75 nM, 0.01 to 0.5 nM, 0.01 to 0.25 nM, 0.01 to 0.1 nM, 0.1 to 100 nM, 0.1 to 50 nM, 0.1 to 25 nM, 0.1 to 10 nM, 0.1 to 7.5 nM, 0.1 to 5 nM, 0.1 to 2.5 nM, 2 to 1000 nM, 2 to 500 nM, 2 to 250 nM, 2 to 100 nM, 2 to 75 nM, 2 to 50 nM, 2 to 25 nM, 2 to 10 nM, 10 to 10 Cell viability IC of 00nM, 10-500nM, 10-250nM, 10-100nM, 10-75nM, 10-50nM, 10-25nM, 25-1000nM, 25-500nM, 25-250nM, 25-100nM, 25-75nM, 25-50nM, 50-1000nM, 50-500nM, 50-250nM, 50-100nM, 50-75nM, 60-70nM, 100-1000nM, 100-500nM, 100-250nM, 250-1000nM, 250-500nM, or 500-1000nM 50 It has.

[0406] In some embodiments, SMSM is at most 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 30 nM, 35 nM, 40nM, 45nM, 50nM, 51nM, 52nM, 53nM, 54nM, 55nM, 56nM, 57nM, 58nM, 59nM, 60nM, 61nM, 6 2nM, 63nM, 64nM, 65nM, 66nM, 67nM, 68nM, 69nM, 70nM, 71nM, 72nM, 73nM, 74nM, 75nM, 76n M, 77nM, 78nM, 79nM, 80nM,...

Claims

1. A compound of formula (I) [Formula 1] During the ceremony, A is -CR Ａ =CR Ａ - and E is -NR-, R Ａ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, --CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 heteroalkyl; Ring Q is a substituted or unsubstituted 2-hydroxy-phenyl, a substituted or unsubstituted 2-hydroxy-naphthyl, a substituted or unsubstituted 6-membered monocyclic heteroaryl, or a substituted or unsubstituted 6-5, 6-6, or 5-6 fused bicyclic heteroaryl; X is -O-, Z is CR ２ and W is a substituted or unsubstituted C １ -C ３ Alkylene, or substituted or unsubstituted C １ -C ２ is heteroalkylene, R is hydrogen; R ２ is hydrogen, deuterium, C 1 -C 4 alkyl, -CD ３ or C 1 -C 4 haloalkyl; R １１ , R １２ , R １３ , R １４ , R １６ , and R １７ are each independently selected from the group consisting of hydrogen, deuterium, F, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, and C 1 -C 4 heteroalkyl; where R 16 is F or R 17 is F; R １５ and R １８are (i) the same and selected from the group consisting of hydrogen and deuterium, or (ii) the same and selected from the group consisting of F, and C １ -C ４ is selected from the group consisting of alkyl, a is 0, b is 0, c is 1, and A compound, or a pharma- ceutically acceptable salt thereof, wherein d is 1.

2. The compound of formula (I) has the formula (C): [Case 2] 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

3. R １５ and R １８ are hydrogen, or R １５ and R １８ Both are -CH ３ 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

4. Ring Q is 2-hydroxy-phenyl substituted with a substituted or unsubstituted heteroaryl, where the heteroaryl is substituted with deuterium, halogen, -OH, -NO ２ , -CN, -SR １ , -S(=O)R １ , -S(=O) ２ R １ , -N(R １ ) ２ , -C(=O)R １ , -OC(=O)R １ , -C(=O)OR １ , -C(=O)N(R １ ) ２ , substituted by 1 or 2 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; R １ are each independently hydrogen, deuterium, C 1 -C 4 alkyl, -CD ３4. The compound of claim 1, wherein R is C 1 -C 4 haloalkyl or C 1 -C 4 heteroalkyl, or a pharma- ceutically acceptable salt thereof.

5. Ring Q is [C3] Wherein R Ｑ are each independently hydrogen, deuterium, —F, —Cl, —CN, —OH, or —CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ , -OCH ３ , -OCH ２ CH ３ , -CH ２ OCH ３ , -OCH ２ CH ２ CH ３ , and -OCH(CH ３ ) ２ and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a pharma- ceutically acceptable salt thereof.

6. Ring P is [C4] is a heteroaryl selected from the group consisting of In the formula, R Ｂ each independently represents hydrogen, deuterium, halogen, hydroxy, cyano, C 1 -C 6 alkyl, -CD ３ , C 1 -C 6 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, deuterium-substituted C １ -C ６ alkoxy, and -OCD 3 ; R Ｂ１ is hydrogen, deuterium, C 1 -C 6 alkyl, -CD ３, C 1 -C 6 fluoroalkyl, and C １ -C ６ heteroalkyl; 6. The compound of claim 5, wherein m is 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

7. The compound of claim 5, or a pharma- ceutically acceptable salt thereof, wherein ring P is a substituted or unsubstituted 5-membered heteroaryl.

8. When ring Q is a substituted or unsubstituted heteroaryl, and the heteroaryl is substituted, it is selected from the group consisting of D, halogen, —CN, —NH ２ , -OH, -NH(CH ３ ), -N(CH ３ ) ２ , -NH(cyclopropyl), -CH ３ , -CH ２ CH ３ , -CF ３ , -OCH ３ , and -OCF ３ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, substituted by one or more substituents each independently selected from:

9. (a) Ring Q is [C5] or (b) Ring Q is [C6-1] [C6-2] is selected from the group consisting of In the formula, R Ｂ１ is hydrogen, deuterium, C 1 -C 6 alkyl, -CD ３ , C 1 -C 6 fluoroalkyl, and C １ -C ６ 4. The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, selected from: heteroalkyl.

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

11. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein W is -CH2CH2CH2-.

12. R １６ is H, and R １７ is F, or R １６ is F and R １７ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein

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

14. Ring Q is [C7] where R Q is hydrogen; Ring P is a substituted or unsubstituted 5-membered heteroaryl which, when further substituted, is substituted with one or more substituents each independently selected from D, halogen, -CN, -NH2, -OH, =O, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3; each R A is hydrogen; R 2 is hydrogen; W is -CH2CH2CH2-; R 16 is H and R 17 is F, or R 16 is F and R 17 is H; and R 15 and R 18 are both hydrogen; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

15.

8. 2. The compound of claim 1, wherein:

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