Methods and compositions for modulating splicing

Abstract

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

Description

[0001] This application is a divisional application of a patent application with an application date of February 6, 2020, application number 202080027013.1, and name “Methods and compositions for regulating splicing”.

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 801,729, filed on February 6, 2019, and U.S. Provisional Patent Application No. 62 / 801,730, filed on February 6, 2019, each of which is incorporated herein by reference in its entirety. Background Art

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

[0005] Current treatments for directing and controlling mRNA expression require methods such as gene therapy, genome editing, or a variety of oligonucleotide technologies (antisense, RNAi, etc.). Gene therapy and genome editing work upstream of mRNA transcription by affecting DNA coding and thereby changing mRNA expression. Oligonucleotides regulate the action of RNA through canonical base / base hybridization. The appeal of this approach lies in the design of the basic pharmacophore of oligonucleotides, which can be defined in a straightforward manner by pairing with known bases of the target sequence object. Each of these treatment modalities faces huge technical, clinical, and regulatory challenges. Some limitations of oligonucleotides as therapeutic agents (e.g., antisense, RNAi) include unfavorable pharmacokinetics, insufficient oral bioavailability, and insufficient blood-brain barrier penetration, which prevents delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancer). In addition, without a complex delivery system (e.g., lipid nanoparticles), oligonucleotides cannot be effectively absorbed into solid tumors. In addition, most oligonucleotides absorbed into cells and tissues remain in non-functional compartments (e.g., endosomes) and cannot enter the cytoplasm and / or nucleus where the target is located.

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

[0007] The novel small molecule splicing regulator (SMSM) described herein does not have the above-mentioned limitations, nor does it greatly limit the structure and spatial barriers of oligonucleotide therapy (for example, by blocking hybridization with pre-mRNA targets). Small molecules are essential for revealing the mechanism, regulation and function of many cellular processes (including DNA replication / transcription and translation). Although several recent reports describe the screening of small molecule splicing effectors, only a small amount of constitutive or alternative splicing regulators have been identified, and many small molecule inhibitors lack specificity, lack selectivity, lack efficacy, display toxicity or are unavailable for oral administration. Targeting RNA transcriptome with small molecule regulators represents an undeveloped method of treatment to treat a variety of RNA-mediated diseases. Therefore, it is still necessary to develop small molecule RNA regulators used as therapeutic agents. A novel regulator of splicing or splicing-dependent processes is needed in the art. Small molecule splicing regulators and uses thereof that meet this demand are provided herein.

[0008] In one aspect, described herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0009]

[0010] in

[0011] A is -CR A =CR A -;

[0012] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0013] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0014] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0015] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0016] X is -O- or -S-;

[0017] Z is CR 2 ;

[0018] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0019] R is hydrogen;

[0020] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0021] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0022] Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0023] R 15 and R 18 (i) are the same and selected from the group consisting of hydrogen and deuterium, or (ii) are the same and selected from the group consisting of F, -OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0024] a is 0;

[0025] b is 0;

[0026] c is 1; and

[0027] d is 1, provided that the compound is not a compound in Table 3 or Table 4.

[0028] In one aspect, described herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0029]

[0030] in

[0031] A is -CR A =CR A -;

[0032] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0033] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0034] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0035] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0036] X is -O- or -S-;

[0037] Z is CR 2 ;

[0038] W is substituted or unsubstituted C 1 -C 3Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0039] R is hydrogen;

[0040] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0041] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0042] Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0043] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0044] a is 0;

[0045] b is 0;

[0046] c is 1; and

[0047] d is 1, provided that the compound is not a compound in Table 3.

[0048] In one aspect, described herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0049]

[0050] in

[0051] A is -CR A =CR A -;

[0052] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0053] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0054] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C3 Heterocycloalkyl;

[0055] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0056] X is -O- or -S-;

[0057] Z is CR 2 ;

[0058] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0059] R is hydrogen;

[0060] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0061] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0062] Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0063] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0064] a is 0;

[0065] b is 0;

[0066] c is 1; and

[0067] d is 1, provided that the compound is not a compound in Table 4.

[0068] In one aspect, described herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0069]

[0070] in

[0071] A is -CR A =CR A -;

[0072] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0073] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0074] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0075] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0076] X is -O- or -S-;

[0077] Z is CR 2 ;

[0078] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0079] R is hydrogen;

[0080] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0081] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0082] Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0083] R 15 and R 18 (i) are the same and selected from the group consisting of hydrogen and deuterium, or (ii) are the same and selected from the group consisting of F, -OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0084] a is 0;

[0085] b is 0;

[0086] c is 1; and

[0087] d is 1, provided that the compound is not a compound in Table 3 or Table 4.

[0088] In one aspect, described herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0089]

[0090] in

[0091] A is -CR A =CR A -;

[0092] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0093] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0094] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0095] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0096] X is -O- or -S-;

[0097] Z is CR 2 ;

[0098] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0099] R is hydrogen;

[0100] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0101] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0102] Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0103] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0104] a is 0;

[0105] b is 0;

[0106] c is 1; and

[0107] d is 1, provided that the compound is not a compound in Table 3.

[0108] In one aspect, described herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0109]

[0110] in

[0111] A is -CR A =CR A -;

[0112] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0113] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0114] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3Heterocycloalkyl;

[0115] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0116] X is -O- or -S-;

[0117] Z is CR 2 ;

[0118] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0119] R is hydrogen;

[0120] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0121] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0122] Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0123] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0124] a is 0;

[0125] b is 0;

[0126] c is 1; and

[0127] d is 1, provided that the compound is not a compound in Table 4.

[0128] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (A):

[0129]

[0130] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (B):

[0131]

[0132] In some embodiments, the compound of formula (B) has the structure of formula (B-1):

[0133]

[0134] In some embodiments, the compound of formula (B) has the structure of formula (B-2):

[0135]

[0136] In some embodiments, the compound of formula (B) has the structure of formula (B-3):

[0137]

[0138] In some embodiments, the compound of formula (B) has the structure of formula (B-4):

[0139]

[0140] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (C):

[0141]

[0142] In some embodiments, the compound of formula (C) has the structure of formula (C-1):

[0143]

[0144] In some embodiments, the compound of formula (C) has the structure of formula (C-2):

[0145]

[0146] In some embodiments, the compound of formula (C) has the structure of formula (C-3):

[0147]

[0148] In some embodiments, the compound of formula (C) has the structure of formula (C-4):

[0149]

[0150] For any and all embodiments, substituents may be selected from the subset of alternatives listed. For example, if in some embodiments, R 2 Hydrogen, -CH 3 or -OCH 3 , then R is also disclosed 2 is hydrogen, R 2 -CH 3 and R 2 OCH 3 .

[0151] In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 are the same and are selected from F, -OR 1 , substituted or unsubstituted C 1 –C 3 Alkyl, substituted or unsubstituted C 1 –C 3Fluorinated alkyl and substituted or unsubstituted C 1 –C 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 、–CH(CH 3 ) 2 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NHCH 3 , –CH 2 N(CH 3 ) 2 , –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 OH, –OCH 2 CN, –OH, –OCH 3 , –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –OCH 3 , –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 and -OCH 3In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 All are -CH 3 .

[0152] In some embodiments, Ring Q is substituted or unsubstituted aryl.

[0153] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0154] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted heteroaryl.

[0155] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl, wherein if aryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; and each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0156] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted heteroaryl, wherein if heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; and each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0157] In some embodiments, Ring Q is substituted or unsubstituted heteroaryl.

[0158] In some embodiments, Ring Q is a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl.

[0159] In some embodiments, Ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl.

[0160] In some embodiments, Ring Q is a 6-membered monocyclic heteroaryl selected from: Each R Q independently selected from hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH 3、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 , –CF 3 , –OCH 3 、-OCH 2 CH 3 、-CH 2 OCH 3 、-OCH 2 CH 2 CH 3 and -OCH(CH 3 ) 2 ; and Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0161] In some embodiments, Ring Q is Each R Q independently selected from hydrogen, deuterium, –F, –Cl, –CN, –OH, –CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 , –CF 3 , –OCH 3 、-OCH 2 CH 3 、-CH 2 OCH 3 、-OCH 2 CH 2 CH 3 and -OCH(CH 3 ) 2 ; and Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0162] In some embodiments, each R Q are independently selected from hydrogen, -F, -Cl, -CN, -OH, -CH 3 , –CF 3 and –OCH 3 .

[0163] In some embodiments, Ring P is substituted or unsubstituted heteroaryl.

[0164] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0165]

[0166] Each R B are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 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.

[0167] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0168]

[0169] Each R B are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 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.

[0170] In some embodiments, each R B independently selected from deuterium, –F, –Cl, -CN, –CH 3 , –CF 3 , –OH and –OCH 3 In some embodiments, each R B independently selected from hydrogen, deuterium, –F, –Cl, –CN, –CH 3 , –CF 3 , –OH and –OCH 3 .

[0171] In some embodiments, each R B Independently –F or –OCH 3 In some embodiments, each R B are independently hydrogen, –F or –OCH 3 In some embodiments, RB In some embodiments, R B For –OCH 3 In some embodiments, R B For –CH 3 .

[0172] In some embodiments, R B1 Selected from hydrogen, deuterium, -CH 3 , -CF 3 and–CD 3 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 -CH 3 In some embodiments, R B1 For-CF 3 In some embodiments, R B1 For-CD 3 .

[0173] In some embodiments, Ring Q is 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0174] In some embodiments, Ring Q is selected from the group consisting of:

[0175]

[0176] In some embodiments, Ring Q is selected from the group consisting of:

[0177]

[0178] In some embodiments, Ring Q is selected from the group consisting of:

[0179]

[0180]

[0181] In some embodiments, Ring Q is selected from the group consisting of:

[0182]

[0183]

[0184] Where R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 Heterocycloalkyl.

[0185] In some embodiments, W is substituted or unsubstituted C 1 -C 3 In some embodiments, W is substituted or unsubstituted -CH 2 CH 2-. In some embodiments, W is -CH 2 CH 2 In some embodiments, W is substituted or unsubstituted -CH 2 CH 2 CH 2 In some embodiments, W is -CH 2 CH 2 CH 2 .

[0186] In some embodiments, W is substituted or unsubstituted C 3 –C 8 Cycloalkylene or substituted or unsubstituted C 2 -C 3 In some embodiments, W is substituted or unsubstituted C 3 –C 8 In some embodiments, W is substituted or unsubstituted cyclopropylene. In some embodiments, W is substituted or unsubstituted C 2 -C 3 In some embodiments, W is -CH=CH-.

[0187] In some embodiments, W is substituted or unsubstituted C 1 -C 2 In some embodiments, W is substituted or unsubstituted -CH 2 OCH 2 In some embodiments, W is -CH 2 O–, where O is attached to R 18 The carbon atom to which the group is attached.

[0188] In some embodiments, R 16 and R 17 One or more of are independently selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 Heteroalkyl.

[0189] In some embodiments, R 16 and R 17 One or more of the following are independently selected from F, -OH, -OCH 3 , –OCH 2 CH 3 , –OCH 2 CH2 OH, –OCH 2 CN, –OCF 3 , –CH 3 , –CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CN, –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 and -CH 2 CF 3 .

[0190] In some embodiments, R 16 and R 17 One or more of the following are independently selected from F, -OH, -OCH 3 , –OCF 3 , –CH 3 , –CH 2 OH, –CH 2 F, –CHF 2 and -CF 3 .

[0191] In some embodiments, R 16 is F. In some embodiments, R 16 In some embodiments, R 17 is F. In some embodiments, R 17 In some embodiments, R 16 and R 17 For hydrogen.

[0192] In some embodiments, R 16 H and R 17 is F. In some embodiments, R 16 is F and R 17 For H.

[0193] In some embodiments, R 2 Hydrogen, -CH 3 or -OCH 3 .

[0194] In some embodiments, R 2 For hydrogen.

[0195] In some embodiments, each RA are independently hydrogen, F, Cl, -CN, -CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 、–CH(CH 3 ) 2 , –OH, –OCH 3 , –OCH 2 CH 3 , –OCF 3 , –CH 2 F, –CHF 2 or -CF 3 .

[0196] In some embodiments, each R A are independently hydrogen, F, Cl, -CN, -CH 3 , –OH, –OCH 3 , –OCF 3 , –CH 2 F, –CHF 2 or -CF 3 .

[0197] In some embodiments, each R A are independently hydrogen, F, Cl, -CN, -CH 3 or -OCH 3 .

[0198] In some embodiments, each R A are independently F, Cl or -CH 3 .

[0199] In some embodiments, R A For hydrogen.

[0200] In some embodiments, X is -O-. In some embodiments, X is -S-.

[0201] In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 are the same and are selected from F, -OR 1 , substituted or unsubstituted C 1 –C 3 Alkyl, substituted or unsubstituted C 1 –C 3Fluorinated alkyl and substituted or unsubstituted C 1 –C 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 、–CH(CH 3 ) 2 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NHCH 3 , –CH 2 N(CH 3 ) 2 , –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 OH, –OCH 2 CN, –OH, –OCH 3 , –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –OCH 3 , –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 and -OCH 3In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 All are -CH 3 .

[0202] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least two of are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them are F.

[0203] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is F or C 1 –C 4 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, 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 comprises fluorine. 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them contain fluorine.

[0204] In some embodiments of the compound of formula (I) or (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, W comprises fluorine.

[0205] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 is H, D or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 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 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 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, R14 is D. In some embodiments, R 14 is H. In some embodiments, R 14 For F.

[0206] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 F, CH 2 F. CHF 2 CF 3 or CH 3 In some embodiments, R 15 F, CF 3 , CHF 2 or CH 2 F. In some embodiments, R 15 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 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 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 F, CH 2 F. CHF 2 CF 3 or CH 3 In some embodiments, R 18 F, CF 3 , CHF 2 or CH 2 F. In some embodiments, R 18 For F.

[0207] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R16 , R 17 and R 18 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least two of are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them are F.

[0208] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, R 11 , R 12, R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is F or C 1 –C 4 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, 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 comprises fluorine. 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them contain fluorine.

[0209] In some embodiments of the compound of formula (I) or (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3, CHF 2 and CH 3 CH 2 F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, W comprises fluorine.

[0210] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 and R 16 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 19 In some embodiments, R 19 H, F, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 3 , –CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CN, –CH 2 F, –CHF 2 ,

[0211] –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 and -CH 2 CF 3 In some embodiments, R 19 H, F, –OH, –OCH 3 , –OCF 3 , –CH 3 , –CH 2 OH, –CH 2 F, –CHF 2 and -CF3 In some embodiments, R 19 F or -OCH 3 .

[0212] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 In some embodiments, R 20 H, F, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 3 , –CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CN, –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 and -CH 2 CF 3 In some embodiments, R 20 H, F, –OH, –OCH 3 , –OCF 3 , –CH 3 , –CH 2 OH, –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 20 F or -OCH 3 .

[0213] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 is H, D or F. In some embodiments, R 19 is D. In some embodiments, R 19 is H. In some embodiments, R 19 is F. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 20is 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 20 is 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 For F.

[0214] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least two of are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 At least two of them are F.

[0215] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R20 and R 18 At least one of them is F or C 1 –C 4 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 In some embodiments, 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 comprises fluorine. 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them contain fluorine.

[0216] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 In some embodiments, W comprises fluorine.

[0217] In one aspect, described herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0218] In one aspect, described herein is a method of treating a condition or disease comprising administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0219] In one aspect, described herein is the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the preparation of a medicament for treating a disorder or disease.

[0220] Incorporated by Reference

[0221] All publications, patents, and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0222] Certain specific details of this specification are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate that the present disclosure can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessary confusion in the description of the embodiments. Unless the context otherwise requires, in the subsequent description and claims, the term "including" and its variants (such as "comprising") should be interpreted in an open, inclusive sense, i.e., "including but not limited to". In addition, the titles provided herein are only for convenience and do not explain the scope or meaning of the disclosure claimed for protection.

[0223] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in a sense including "and / or" unless the content clearly dictates otherwise.

[0224] 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 the present disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0225] definition

[0226] The terms "disclosed compounds," "compounds of the present disclosure," "small molecule steric modulators," "small molecule splicing modulators," "steric modulators," "splicing modulators," "compounds that modify splicing," and "modifying splicing compounds," "SMSMs," or "small molecules that bind to target RNAs" are used interchangeably herein and refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. The terms "disclosed compounds," "compounds of the present disclosure," "small molecule steric modulators," "small molecule splicing modulators," "steric modulators," "splicing modulators," "compounds that modify splicing," and "modifying splicing compounds," "SMSMs," or "small molecules that bind to target RNAs" refer to small molecule compounds that bind to cellular components (e.g., DNA, RNA, pre-mRNA, proteins, RNPs, snRNAs, carbohydrates, lipids, cofactors, nutrients, and / or metabolites) and modulate splicing of a target polynucleotide (e.g., pre-mRNA). For example, SMSM can be directly or indirectly bound to a target polynucleotide, such as RNA (e.g., pre-mRNA) via a mutated, non-mutated, protruding and / or abnormal splicing site, thereby resulting in the regulation of the splicing of the target polynucleotide. For example, SMSM can be directly or indirectly bound to a protein, such as a spliceosomal protein or a ribonucleoprotein, resulting in the regulation of the spatial regulation of the protein and the splicing of the target RNA. For example, SMSM can be directly or indirectly bound to a spliceosomal component, such as a spliceosomal protein or snRNA, thereby resulting in the regulation of the spatial regulation of the spliceosomal protein or snRNA and the splicing of the target polynucleotide. These terms explicitly exclude compounds consisting of oligonucleotides. These terms include small molecule compounds that can be bound to one or more secondary or tertiary structural elements of the target RNA. These sites include RNA triplexes, 3WJ, 4WJ, parallel Y knots, hairpins, protruding loops, pseudoknots, internal loops, and other high-order RNA structural motifs.

[0227] As used herein, the term "RNA" (ribonucleic acid) refers to naturally occurring or synthetic oligoribonucleotides independent 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 cell nucleus, circulating in the blood, in vitro, in a cell lysate, or in isolated or purified form), or physical form (e.g., RNA may be in single-stranded, double-stranded, or triple-stranded form (including RNA-DNA hybrids), which may include epigenetic modifications, natural post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modifications), or other modifications, may be bound to, for example, metal ions, small molecules, proteins such as chaperones or cofactors, or may be in a denatured, partially denatured, or folded state, including any natural or non-natural secondary or tertiary structure, such as quadruplexes, hairpins, triplexes, three-way junctions (3WJs), four-way junctions (4WJs), parallel Y-junctions, hairpins, bulged loops, pseudoknots, and internal loops, etc., as well as any transient form or structure adopted by the RNA). In some embodiments, the length of RNA is 20, 22, 50, 75 or 100 or more nucleotides. In some embodiments, the length of RNA is 250 or more nucleotides. In some embodiments, the length of RNA is 350, 450, 500, 600, 750 or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000 or more nucleotides. In some embodiments, the length of RNA is between 250 and 1,000 nucleotides. In some embodiments, RNA is pre-RNA, pre-miRNA or pre-transcript. In some embodiments, the RNA is a noncoding RNA (ncRNA), a messenger RNA (mRNA), a micro-RNA (miRNA), a ribozyme, a riboswitch, a lncRNA, a lincRNA, a snoRNA, a snRNA, a scaRNA, a piRNA, a ceRNA, a pseudogene, a viral RNA, a fungal RNA, a parasitic RNA, or a bacterial RNA.

[0228] As used herein, the term "target polynucleotide" or "target RNA" refers to any type of polynucleotide or RNA having a splice site that can be regulated by a small molecule compound described herein. For example, a "target polynucleotide" or "target RNA" can have a secondary or tertiary structure that can bind to a small molecule compound described herein.

[0229] "Steric alteration", "steric modification" or "steric modulation" herein refers to a change in the spatial orientation of chemical moieties relative to each other. One of ordinary skill in the art will recognize that steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsion, steric inhibition of resonance, and steric inhibition of protonation.

[0230] Any open valences appearing on carbon, oxygen, sulfur, or nitrogen atoms in the structures herein represent the presence of hydrogen unless otherwise stated.

[0231] The definitions described herein apply regardless of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein may be appended to form chemically related combinations, such as "heterocycloalkylaryl," "haloalkylheteroaryl," "arylalkylheterocycloalkyl," or "alkoxyalkyl." The last member of the combination is the group to which the rest of the molecule is bound. In terms of literal sequence, the other members of the combination are attached to the bound group in reverse order, such as the combination of arylalkylheterocycloalkyl refers to a heterocycloalkyl group substituted with an alkyl substituted with an aryl.

[0232] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitution, ie, replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0233] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0234] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule.

[0235] The term "substituted" means that the specified group carries one or more substituents. In the case of any group that can carry multiple substituents and providing a variety of possible substituents, the substituents are independently selected and do not have to be the same. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents. When indicating the number of substituents, the term "one or more" refers to from one substituent to the maximum possible number of substitutions, that is, the replacement of one hydrogen by a substituent until all hydrogens are replaced.

[0236] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethyl acetate (EtOAc); butanol (n-BuOH); 1,2-dichloroethane (DCE); dichloromethane (CH 2 Cl 2 , DCM); diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogen chloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr); N-methyl-2-pyrrolidone (NMP); iodomethane (MeI); n-propanol (n-PrOH); p-methoxybenzyl (PMB); triethylamine (Et 3N); [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride; (Pd(dppf)Cl 2 ); sodium ethanethiolate (EtSNa); sodium acetate (NaOAc); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF).

[0237] As used herein, C 1 -C x Including C 1 -C 2 , C 1 -C 3 ...C 1 -C x For example only, the name "C 1 -C 4 " means a group having 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C 1 -C 4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0238] The term "oxo" refers to a =0 substituent.

[0239] The term "thio" refers to a =S substituent.

[0240] The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0241] The term "alkyl" refers to a straight or branched hydrocarbon chain group having from one to twenty carbon atoms and attached to the rest of the molecule by a single bond. Likewise, an alkyl group containing up to 10 carbon atoms is referred to as a C 1 -C 10 Alkyl groups, for example, those containing up to 6 carbon atoms are C 1 -C 6 Alkyl groups. Alkyl groups (and other moieties defined herein) containing other numbers of carbon atoms are similarly represented. Alkyl groups include, but are not limited to, C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 2 -C 8 Alkyl, C 3 -C 8 Alkyl and C 4 -C 8 Alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl group is methyl or ethyl. In some embodiments, the alkyl group is -CH(CH 3 ) 2 or -C(CH 3 ) 3 Unless otherwise specifically stated in the specification, an alkyl group may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group. In some embodiments, an alkylene group is -CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 In some embodiments, the alkylene group is -CH 2 -. In some embodiments, the alkylene group is -CH 2 CH 2 -. In some embodiments, the alkylene group is -CH 2 CH 2 CH 2 -.

[0242] The term "alkoxy" refers to a radical of the formula -OR a A group in which R a is an alkyl group as defined. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy group is methoxy. In some embodiments, the alkoxy group is ethoxy.

[0243] The term "alkylamino" refers to a radical of the formula -NHR a or -NR a R a A group in which R ais independently an alkyl group as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0244] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R a )=CR a 2 , where R a refers to the rest of the alkenyl group, which may be the same or different. a is H or alkyl. In some embodiments, the alkenyl group is selected from vinyl (ie, ethenyl), propenyl (ie, allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH 2 , –C(CH 3 )=CH 2 、–CH=CHCH 3 , –C(CH 3 )=CHCH 3 and -CH 2 CH=CH 2 .

[0245] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group has the formula -C≡CR a , where R a refers to the rest of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH 3 -C≡CCH 2 CH 3 , –CH 2 C≡CH.

[0246] The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatics may be optionally substituted. The term "aromatic" includes both aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0247] The term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl can be optionally substituted. Examples of aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, aryl can be monovalent or divalent (i.e., arylene). Unless otherwise specifically stated in the specification, the term "aryl" or prefix "ar" (e.g., in "aralkyl") is intended to include optionally substituted aryl groups. In some embodiments, aryl is partially reduced to form cycloalkyl defined herein. In some embodiments, aryl is fully reduced to form cycloalkyl defined herein.

[0248] The term "haloalkyl" means an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by identical or different halogen atoms, in particular fluorine atoms. Examples of haloalkyl groups include monofluoro, difluoro or trifluoromethyl, ethyl or propyl, such as 3,3,3-trifluoropropyl, 2-fluorotoluene, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" means an alkyl group in which all of the hydrogen atoms of the alkyl group have been replaced by identical or different halogen atoms.

[0249] The term "haloalkoxy" means an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by identical or different halogen atoms, in particular fluorine atoms. Examples of haloalkoxy groups include mono-, di- or trifluoromethoxy, ethoxy or propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" means an alkoxy group in which all of the hydrogen atoms of the alkoxy group have been replaced by identical or different halogen atoms.

[0250] The term "bicyclic ring system" refers to two rings fused to each other through a common single or double bond (annealed bicyclic ring system), through a sequence of three or more common atoms (bridged bicyclic ring system) or through a common single atom (spiro bicyclic ring system). The bicyclic ring system can be saturated, partially unsaturated, unsaturated or aromatic. The bicyclic ring system may contain heteroatoms selected from N, O and S.

[0251] The term "carbocycle" or "carbocyclic ring" refers to a ring or ring system in which the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocycles from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0252] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, wherein each atom (i.e., skeleton atom) forming the ring is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridging compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in this case, the cycloalkyl is bonded by a non-aromatic ring carbon atom). The cycloalkyl group includes a group with 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls with 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrainyl, decalinyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. Unless otherwise specifically stated in the specification, the cycloalkyl group may be optionally substituted.

[0253] The term "bridged" refers to any ring structure having two or more rings, which comprises a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the backbone structure of the molecule and is bonded to three or more other backbone atoms. In some embodiments, the bridging atom is C, N, or P. In some embodiments, 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.

[0254] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced by one or more N, S and O atoms. Non-limiting examples of fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycles, 6-6 fused heterocycles, 5-6 fused heterocycles, 5-5 fused heterocycles, 7-5 fused heterocycles and 5-7 fused heterocycles.

[0255] The term "haloalkyl" refers to an alkyl group as defined above substituted by one or more halogen groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless specifically stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0256] The term "haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless specifically stated otherwise in the specification, a haloalkoxy group may be optionally substituted.

[0257] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. 1 -C 6 Fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0258] The term "heteroalkyl" refers to an alkyl group wherein one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), 2 -) or a combination thereof. In some embodiments, the heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In some embodiments, the heteroalkyl group is attached to the rest of the molecule at a heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1 -C 6 Heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCH 2 OMe, –OCH 2 CH 2 OH, –OCH 2 CH 2 OMe or -OCH 2 CH 2 OCH 2 CH 2 NH 2 .

[0259] The term "heteroalkylene" refers to an alkyl group as described above, wherein one or more carbon atoms of the alkyl group are replaced by O, N or S atoms. "Heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain that connects the rest of the molecule to a group. Unless otherwise specifically stated in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to, -OCH 2 CH 2 O-、-OCH 2 CH 2 OCH 2 CH 2 O- or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.

[0260] The term "heterocycloalkyl" refers to a cycloalkyl group including at least one heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, the heterocycloalkyl group may be a monocyclic or bicyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded to a non-aromatic ring atom) or a bridged ring system. The nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl group is partially or completely saturated. Examples of heterocycloalkyl groups 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-piperidone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of sugars, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the skeleton atoms of heterocycloalkyl ring). Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted.

[0261] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also referred to as heteroaryl) and heterocycloalkyl rings (also referred to as heteroaliphatic ring groups), which include at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclyl has 3 to 12 atoms in its ring system, and the condition is that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic or bridged compound. Non-aromatic heterocyclic groups (also referred to as heterocycloalkyl) include rings with 3 to 12 atoms in their ring system, and aromatic heterocyclic groups include rings with 5 to 12 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinedione, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, pinyl), diazepine, thiazepine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3h-indolyl, indolin-2-one, isoindolyl-1-one, isoindolyl-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindolyl-1,3-dithionyl, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazol-2(3H)-one, benzo[d]thiazol-2(3H)-one and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and fluoropyridyl. Where possible, the foregoing groups are C-attached (or C-linked) or N-attached. For example, groups derived from pyrrole include pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached). In addition, groups derived from imidazole include imidazole-1-yl or imidazole-3-yl (both N-attached) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (both C-attached). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0262] The term "heteroaryl" refers to an aryl group including one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryl include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine and pteridine. Illustrative examples of monocyclic heteroaryls include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine and pteridine. In some embodiments, heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furanyl. In some embodiments, heteroaryl contains 0-6 N atoms in the ring. In some embodiments, heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 4-6 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is C 1 -C 9 In some embodiments, the monocyclic heteroaryl is C 1 -C 5 In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C 6 -C 9 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.

[0263] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is typically a known chemical entity embedded in or attached to a molecule.

[0264] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from the group consisting of: D, halogen, -CN, -NH 2 、-NH(alkyl), -N(alkyl) 2, –OH, –CO 2 H, –CO 2 Alkyl, –C(=O)NH 2 、-C(=O)NH(alkyl),-C(=O)N(alkyl) 2 , –S(=O) 2 NH 2 , –S(=O) 2 NH(alkyl), –S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH 2 、–NH(CH 3 ),–N(CH 3 ) 2 , –OH, –CO 2 H, –CO 2 (C 1 -C 4 alkyl), –C(=O)NH 2 、–C(=O)NH(C 1 -C 4 alkyl), –C(=O)N(C 1 -C 4 alkyl) 2 , –S(=O) 2 NH 2 , –S(=O) 2 NH(C 1 -C 4 Alkyl), –S(=O) 2 N(C 1 -C 4 alkyl) 2 , C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Fluorinated alkyl, C 1 -C 4 Heteroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, –SC 1 -C 4 Alkyl, –S(=O)C 1 -C 4 Alkyl and -S(=O)2 (C 1 -C 4 In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH 2 , –OH, –NH(CH 3 ),–N(CH 3 ) 2 、–NH(cyclopropyl), –CH 3 , –CH 2 CH 3 , –CF 3 , –OCH 3 and-OCF 3 In some embodiments, the substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=0).

[0265] The term "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonded structures where tautomerism may occur, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interchanges include:

[0266]

[0267] The term "about" or "approximately" can refer to within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can refer to within 1 or more than 1 standard deviation as is customary in the art. Alternatively, "about" can refer to 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 for biological systems or processes, the term can refer to within an order of magnitude, within 5-fold, or within 2-fold of a value.

[0268] As used herein, the term "administering" and the like refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral routes (po), intraduodenal routes (id), parenteral injections (including intravenous (iv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravascular or infusion (inf.)), topical (top.) and rectal (pr) administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0269] As used herein, the terms "co-administered," "co-administered," and the like are intended to include administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0270] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an agent or compound administered that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated; for example, to reduce and / or alleviate one or more signs, symptoms or causes of the disease or any other desired change in a biological system. For example, an "effective amount" for therapeutic use can be the amount of an agent that clinically significantly reduces one or more symptoms of the disease. In individual cases, techniques such as dose escalation studies can be used to determine an appropriate "effective" amount.

[0271] As used herein, the term "enhance" refers to increasing or prolonging the amount, potency, or duration of a desired effect. For example, with respect to enhancing the splicing of a target, the term "enhance" can refer to the ability to increase or prolong the splicing of a target, whether in amount, potency, or duration.

[0272] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class of mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. In one aspect, the mammal is a human. As used herein, the term "animal" includes humans and non-human animals. In one embodiment, a "non-human animal" is a mammal, such as a rodent such as a rat or a mouse. In one embodiment, the non-human animal is a mouse.

[0273] As used herein, the term "treat," ...

[0274] The term "preventing" or "preventing" a disease state means that clinical symptoms leading to the disease state do not develop in a subject that is exposed to or susceptible to the disease state but does not yet experience or display symptoms of the disease state.

[0275] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active drug ingredient and one or more pharmaceutically acceptable excipients to be administered to a subject (e.g., a human in need thereof).

[0276] As used herein, the term "pharmaceutical combination" refers to a product obtained by mixing or combining more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to active ingredients, such as compounds described herein and adjuvants, which are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to active ingredients, such as compounds described herein and adjuvants, which are administered to a patient simultaneously, concurrently or sequentially as separate entities without specific time interval restrictions, wherein such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0277] The term "pharmaceutically acceptable" refers to the properties of materials that can be used to prepare pharmaceutical compositions, which materials are generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for veterinary as well as human use. "Pharmaceutically acceptable" may refer to materials (such as carriers or diluents) that do not abrogate the biological activity or properties of the compound and are relatively non-toxic, i.e., materials that can be administered to an individual without causing adverse biological effects or interacting in a deleterious manner with any component of the composition containing it.

[0278] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and mean any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant used to formulate a drug product.

[0279] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. "Pharmaceutically acceptable salts" may refer to compound preparations that do not cause significant irritation to the organism to which it is administered and / or do not eliminate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting an SMSM compound of any one of formula (I) or (II) with an acid. A pharmaceutically acceptable salt may also be obtained by reacting a compound of any one of formula (I) or (II) with a base to form a salt.

[0280] As used herein, the term "nucleic acid" generally refers to one or more nucleobases, nucleosides, or nucleotides, and they include polynucleobases, polynucleosides, and polynucleotides.

[0281] As used herein, the term "polynucleotide" generally refers to a molecule comprising two or more linked nucleic acid subunits (e.g., nucleotides), and can be used interchangeably with "oligonucleotide". For example, a polynucleotide may include one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), or variants thereof. A nucleotide generally comprises a nucleoside and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphate groups (PO 3) group. Nucleotide can include a core base, a pentose (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. Nucleotides can be nucleoside monophosphates, nucleoside diphosphates, nucleoside triphosphates or nucleoside polyphosphates. For example, nucleotides can be deoxyribonucleoside polyphosphates, such as deoxyribonucleoside triphosphates (dNTPs), and exemplary dNTPs include deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP) and deoxythymidine triphosphate (dTTP). dNTPs can also include detectable labels, such as luminescent labels or markers (e.g., fluorophores). For example, nucleotides can be purines (i.e., A or G or variants thereof) or pyrimidines (i.e., C, T or U or variants thereof). In some instances, polynucleotides are deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or derivatives or variants thereof. Exemplary polynucleotides include, but are not limited to, short interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), short hairpin RNA (shRNA), small nuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA), antisense RNA (asRNA) and heteronuclear RNA (hnRNA), and encompass nucleotide sequences and any structural embodiments thereof, such as single-stranded, double-stranded, triple-stranded, spiral, hairpin, stem-loop, protrusion, etc. In some cases, polynucleotides are circular. Polynucleotides can have various lengths. For example, the length of the polynucleotide can be at least about 7 bases, 8 bases, 9 bases, 10 bases, 20 bases, 30 bases, 40 bases, 50 bases, 100 bases, 200 bases, 300 bases, 400 bases, 500 bases, 1 kilobases (kb), 2kb, 3kb, 4kb, 5kb, 10kb, 50kb or more. The polynucleotide can be isolated from a cell or tissue. For example, the polynucleotide sequence can include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules and / or synthetic DNA / RNA analogs.

[0282] The polynucleotide may include one or more nucleotide variants, including non-standard nucleotides, non-natural nucleotides, nucleotide analogs and / or modified nucleotides. Examples of modified nucleotides include, but are not limited to, diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, β-D-galactosylinosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylamino Methyluracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosyl quercetin, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, quercetin, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, etc. In some cases, the phosphate portion of the nucleotide may include modifications, including modifications to the triphosphate portion. Non-limiting examples of such modifications include longer lengths of phosphate chains (e.g., phosphate chains with 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications of thiol moieties (e.g., α-thiotriphosphate β-thiotriphosphate). Nucleic acid molecules may also be modified at the base moiety (e.g., at one or more atoms that are normally available to form hydrogen bonds with complementary nucleotides and / or at one or more atoms that are normally unable to form hydrogen bonds with complementary nucleotides), the sugar moiety, or the phosphate backbone. Nucleic acid molecules may also include amine-modified groups, such as aminoallyl 1-dUTP (aa-dUTP) and aminohexyl acrylamide-dCTP (aha-dCTP), so that amine-reactive moieties such as N-hydroxysuccinimide ester (NHS) are covalently attached. Substitutes for standard DNA base pairs or RNA base pairs in the oligonucleotides disclosed herein can provide higher density in bits per cubic mm, higher safety (against accidental or purposeful synthesis of natural toxins), and easier recognition or lower secondary structure in light-programmed polymerases.Such alternative base pairs compatible with native and mutant polymerases for de novo and / or amplification synthesis are described in Betz K, Malyshev DA, Lavergne T, Welte W, Diederichs K, Dwyer TJ, Ordoukhanian P, Romesberg FE, Marx A. Nat. Chem. Biol. 2012 Jul;8(7):612-4, which is incorporated herein by reference for all purposes.

[0283] As used herein, the terms "polypeptide", "protein" and "peptide" are used interchangeably and refer to a polymer of amino acid residues linked via peptide bonds, and which may consist of two or more polypeptide chains. The terms "polypeptide", "protein" and "peptide" refer to a polymer of at least two amino acid monomers linked together by an amide bond. Amino acids may be L-optical isomers or D-optical isomers. More specifically, the terms "polypeptide", "protein" and "peptide" refer to molecules consisting of two or more amino acids in a specific order; for example, the order is determined by the base sequence of nucleotides in a gene or RNA encoding the protein. Proteins are essential for the structure, function and regulation of human cells, tissues and organs, and each protein has a unique function. Examples are hormones, enzymes, antibodies and any fragments thereof. In some cases, a protein may be a part of a protein, such as a domain, subdomain or motif of a protein. In some cases, a protein may be a variant (or mutation) of a protein, in which one or more amino acid residues are inserted, deleted and / or replaced with a naturally occurring (or at least known) amino acid sequence of a protein. A protein or a variant thereof may be naturally occurring or recombinant.

[0284] Methods for detecting and / or measuring polypeptides in biological materials are well known in the art and include, but are not limited to, Western blotting, flow cytometry, ELISA, RIA, and various proteomics techniques. An exemplary method for measuring or detecting polypeptides is an immunoassay, such as ELISA. This type of protein quantification can be based on antibodies that can capture specific antigens and a second antibody that can detect the captured antigen. Exemplary assays for detecting and / or measuring polypeptides are described in Harlow, E. and Lane, D. Antibodies: A Laboratory Manual, (1988), Cold Spring Harbor Laboratory Press.

[0285] Methods for detecting and / or measuring RNA in biological materials are well known in the art and include, but are not limited to, Northern blotting, RNA protection assays, RT PCR. Suitable methods are described in Molecular Cloning: A Laboratory Manual (4th edition), Michael R. Green, Joseph Sambrook, Peter MacCallum 2012, 2,028 pp, ISBN 978-1-936113-42-2.

[0286] As used herein, "small molecular weight compound" can be used interchangeably with "small molecule" or "small organic molecule." Small molecules refer to compounds other than peptides or oligonucleotides; and the molecular weight is usually less than about 2000 Daltons, such as less than about 900 Daltons.

[0287] Ribonucleoprotein (RNP) refers to a nucleoprotein containing RNA. RNP can be a complex of ribonucleic acid and RNA binding protein. This combination can also be referred to as protein-RNA complex. These complexes can play a variety of biological functions, including but not limited to DNA replication, gene expression, RNA metabolism and pre-mRNA splicing. Examples of RNP include ribosomes, telomerase, dome ribonucleoprotein, ribonuclease P, heterogeneous nuclear RNP (hnRNP) and small nuclear RNP (snRNP).

[0288] Nascent RNA transcripts from protein-coding genes and mRNA processing intermediates are collectively referred to as pre-mRNAs, which are usually bound to proteins in the eukaryotic nucleus. From the time when the nascent transcript first appears from RNA polymerase (e.g., RNA polymerase II) until the mature mRNA is transported into the cytoplasm, the RNA molecule is associated with a large number of splicing complex components (e.g., nucleoproteins and snRNAs). These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNAs (hnRNAs) of various sizes (e.g., pre-mRNA and nuclear RNA complexes).

[0289] Splicing complex components play a role in splicing and / or splicing regulation. Splicing complex components may include, but are not limited to, ribonucleoproteins (RNPs), splicing proteins, small nuclear RNAs (snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing complex components include, but are not limited to, those that may be required for splicing, such as constitutive splicing, alternative splicing, regulated splicing, and splicing of specific information or groups of information. A group of related proteins, serine-arginine-rich proteins (SR proteins), can play a role in constitutive pre-mRNA splicing and can also regulate alternative splicing site selection in a concentration-dependent manner. SR proteins typically have a modular structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminus (RS domain) rich in arginine and serine residues. Their activity in alternative splicing may be antagonized by members of the hnRNPA / B protein family. Splicing complex components may also include proteins 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 that may be involved in splice site selection in humans include, but are not limited to, U2 snRNA auxiliary factors (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP 20, SF1, and PTB / hnRNP1. hnRNP proteins in humans include, but are not limited to, A1, A2 / B1, L, M, K, U, F, H, G, R, I, and C1 / C2. Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1. Splicing complex components can be stably or transiently associated with snRNPs or transcripts.

[0290] The term "intron" refers to a DNA sequence within a gene and the corresponding sequence in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing shortly after or simultaneously with transcription. Introns are present in the genes of most organisms and many viruses. They can be present in a wide range of genes, including those that produce proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA).

[0291] An "exon" may be any portion of a gene that encodes a portion of the final mature RNA produced from the gene after introns have been removed by RNA splicing. The term "exon" refers to a DNA sequence within a gene and the corresponding sequence in the RNA transcript.

[0292] The "spliceosome" can be assembled from snRNA and a protein complex. The spliceosome can remove introns from the transcribed pre-mRNA.

[0293] The “moderate effective dose” (ED 50 ) is the dose at which 50% of the population expresses a specific response. The “median lethal dose” (LD 50 ) is the dose that kills 50% of the population. 50 ) is the dose at which 50% of the population exhibits a particular toxic effect. A particularly useful pharmacological metric is the “therapeutic index,” which is traditionally defined as the LD 50 With ED 50 Ratio or TD 50 With ED 50 The therapeutic index provides a simple and useful indicator of the relative adverse effects of a drug's benefits. Those drugs with a high therapeutic index have a large therapeutic window, that is, the drug can be administered in a wider range of effective doses without causing significant adverse events. In contrast, drugs with a small therapeutic index have a small therapeutic window (a small effective dose range that does not cause significant adverse events).

[0294] As used herein, the term "AUC" refers to the abbreviation of "area under the curve" in a graph of the concentration of a therapeutic agent over time in some part or tissue (eg, blood or plasma) of a subject to which the therapeutic agent has been administered.

[0295] Small molecule splicing modulators (SMSMs)

[0296] It has been found that the compounds of the present disclosure and pharmaceutically acceptable compositions thereof are effectively used as agents for treating, preventing or ameliorating diseases or conditions associated with target RNA. The present disclosure provides an unexpected discovery that certain small chemical molecules can modify splicing events in pre-mRNA molecules, referred to herein as small molecule splicing regulators (SMSMs). These SMSMs can regulate specific splicing events in specific pre-mRNA molecules. These SMSMs can operate through a variety of mechanisms to modify splicing events. For example, the SMMSs of the present disclosure can: 1) interfere with the formation and / or function and / or other properties of splicing complexes, spliceosomes and / or their components such as hnRNPs, snRNPs, SR-proteins and other splicing factors or elements, resulting in the prevention or induction of splicing events in pre-mRNA molecules. As another example; 2) prevent and / or modify post-transcriptional regulation (e.g., splicing) of gene products such as hnRNPs, snRNPs, SR-proteins and other splicing factors, which may subsequently participate in the formation and / or function of spliceosome or splicing complex components; 3) prevent and / or modify phosphorylation, glycosylation and / or other modifications of gene products, including but not limited to hnRNPs, snRNPs, SR-proteins and other splicing factors, which may subsequently participate in the formation and / or function of spliceosome or splicing complex components; 4) bind to and / or otherwise affect specific pre-mRNAs, thereby preventing or inducing specific splicing events, for example, by a mechanism that does not involve base pairing with RNA in a sequence-specific manner. The small molecules of the present disclosure are different from and unrelated to antisense or antigenic oligonucleotides.

[0297] Compounds that modify the splicing of a gene product are described herein for use in treating, preventing, and / or delaying the progression of a disease or condition (e.g., cancer). Compounds that modify the splicing of a gene product are described herein, wherein the compound induces a transcriptionally inactive variant or transcript of the gene product. Compounds that modify the splicing of a gene product are described herein, wherein the compound inhibits a transcriptionally active variant or transcript of a gene product.

[0298] In one aspect, described herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0299]

[0300] in

[0301] A is -CR A =CR A -;

[0302] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0303] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0304] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0305] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0306] X is -O- or -S-;

[0307] Z is CR 2 ;

[0308] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0309] R is hydrogen;

[0310] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0311] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0312] Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0313] R 15 and R 18 (i) are the same and selected from the group consisting of hydrogen and deuterium, or (ii) are the same and selected from the group consisting of F, -OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0314] a is 0;

[0315] b is 0;

[0316] c is 1; and

[0317] d is 1, provided that the compound is not a compound in Table 3 or Table 4.

[0318] In one aspect, described herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0319]

[0320] in

[0321] A is -CR A =CR A -;

[0322] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0323] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0324] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0325] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0326] X is -O- or -S-;

[0327] Z is CR 2 ;

[0328] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0329] R is hydrogen;

[0330] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0331] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0332] Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0333] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0334] a is 0;

[0335] b is 0;

[0336] c is 1; and

[0337] d is 1, provided that the compound is not a compound in Table 3.

[0338] In one aspect, described herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof:

[0339]

[0340] in

[0341] A is -CR A =CR A -;

[0342] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0343] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0344] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0345] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0346] X is -O- or -S-;

[0347] Z is CR 2 ;

[0348] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0349] R is hydrogen;

[0350] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0351] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0352] Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0353] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0354] a is 0;

[0355] b is 0;

[0356] c is 1; and

[0357] d is 1, provided that the compound is not a compound in Table 4.

[0358] In one aspect, described herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0359]

[0360] in

[0361] A is -CR A =CR A -;

[0362] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0363] R E is hydrogen, substituted or unsubstituted C 1 -C 3Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0364] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0365] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0366] X is -O- or -S-;

[0367] Z is CR 2 ;

[0368] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0369] R is hydrogen;

[0370] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0371] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0372] Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0373] R 15 and R 18 (i) are the same and selected from the group consisting of hydrogen and deuterium, or (ii) are the same and selected from the group consisting of F, -OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0374] a is 0;

[0375] b is 0;

[0376] c is 1; and

[0377] d is 1, provided that the compound is not a compound in Table 3 or Table 4.

[0378] In one aspect, described herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0379]

[0380] in

[0381] A is -CR A =CR A -;

[0382] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0383] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0384] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0385] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0386] X is -O- or -S-;

[0387] Z is CR 2 ;

[0388] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0389] R is hydrogen;

[0390] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0391] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0392] Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1–C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0393] R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium;

[0394] a is 0;

[0395] b is 0;

[0396] c is 1; and

[0397] d is 1, provided that the compound is not a compound in Table 3.

[0398] In one aspect, described herein is a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

[0399]

[0400] in

[0401] A is -CR A =CR A -;

[0402] E is –NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -or-S(=O)(=NR E )-;

[0403] R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 Heterocycloalkyl, substituted or unsubstituted C 2 -C 3 Alkenyl or substituted or unsubstituted C 2 -C 3 Alkynyl;

[0404] Each R A independently selected from the group consisting of hydrogen, deuterium, F, Cl, –CN, –OR 1 ,–SR 1 、-S(=O)R 1 、-S(=O) 2 R 1 , substituted or unsubstituted C 1 –C4 Alkyl, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 4 Cycloalkyl and substituted or unsubstituted C 2 –C 3 Heterocycloalkyl;

[0405] Ring Q is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0406] X is -O- or -S-;

[0407] Z is CR 2 ;

[0408] W is substituted or unsubstituted C 1 -C 3 Alkylene, substituted or unsubstituted C 1 –C 2 Heteroalkylene, substituted or unsubstituted C 2 -C 3 Alkenylene, substituted or unsubstituted C 3 –C 8 Cycloalkylene, substituted or unsubstituted C 2 –C 7 Heterocycloalkylene;

[0409] R is hydrogen;

[0410] Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0411] R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 Haloalkyl;

[0412] Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0413] R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 heteroalkyl;

[0414] a is 0;

[0415] b is 0;

[0416] c is 1; and

[0417] d is 1, provided that the compound is not a compound in Table 4.

[0418] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (A):

[0419]

[0420] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (B):

[0421]

[0422] In some embodiments, the compound of formula (B) has the structure of formula (B-1):

[0423]

[0424] In some embodiments, the compound of formula (B) has the structure of formula (B-2):

[0425]

[0426] In some embodiments, the compound of formula (B) has the structure of formula (B-3):

[0427]

[0428] In some embodiments, the compound of formula (B) has the structure of formula (B-4):

[0429]

[0430] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (C):

[0431]

[0432] In some embodiments, the compound of formula (C) has the structure of formula (C-1):

[0433]

[0434] In some embodiments, the compound of formula (C) has the structure of formula (C-2):

[0435]

[0436] In some embodiments, the compound of formula (C) has the structure of formula (C-3):

[0437]

[0438] In some embodiments, the compound of formula (C) has the structure of formula (C-4):

[0439]

[0440] 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 a flat position. In some embodiments, E is S(=O) and the oxygen atom in S(=O) is in an upright position. In some embodiments, E is S(=O)(=NR E In some embodiments, E is S(═O)(═NR E ) and the oxygen atom (=NR E ) is in the flat position, and S(=O)(=NR EIn some embodiments, E is S(=O)(=NR E ), and the oxygen atom (=NR E ) is in an upright position, and S(=O)(=NR E ) is in a flat position.

[0441] In some embodiments, R 19 is F. In some embodiments, R 20 For F.

[0442] In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 are the same and are selected from F, -OR 1 , substituted or unsubstituted C 1 –C 3 Alkyl, substituted or unsubstituted C 1 –C 3 Fluorinated alkyl and substituted or unsubstituted C 1 –C 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 、–CH(CH 3 ) 2 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NHCH 3 , –CH 2 N(CH 3 ) 2 , –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 OH, –OCH 2 CN, –OH, –OCH 3 , –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –OCH 3 , –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 and -OCH 3 In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 All are -CH 3 .

[0443] In some embodiments, Ring Q is substituted or unsubstituted aryl.

[0444] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2 -C 7 In some embodiments, each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0445] In some embodiments, Ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted heteroaryl.

[0446] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl. In some embodiments, if aryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3-C 7 Cycloalkyl and substituted or unsubstituted C 2 -C 7 In some embodiments, each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0447] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted heteroaryl. In some embodiments, if heteroaryl is substituted, it is substituted with 1 or 2 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl and substituted or unsubstituted C 2 -C 7 In some embodiments, each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3, substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0448] In some embodiments, Ring Q is substituted or unsubstituted heteroaryl.

[0449] In some embodiments, Ring Q is a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl.

[0450] In some embodiments, Ring Q is a substituted or unsubstituted 6-membered monocyclic heteroaryl.

[0451] In some embodiments, Ring Q is a 6-membered monocyclic heteroaryl selected from: In some embodiments, each R Q independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 , -CF 3 、-OCH 3 、-OCH 2 CH 3 、-CH 2 OCH 3 、-OCH 2 CH 2 CH 3 and -OCH(CH 3 ) 2 In some embodiments, Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0452] In some embodiments, Ring Q is In some embodiments, each R Q independently selected from hydrogen, deuterium, -F, -Cl, -CN, -OH, -CH 3 、-CH 2 CH 3 、-CH 2 CH2 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 In some embodiments, Ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0453] In some embodiments, each R Q are independently selected from hydrogen, -F, -Cl, -CN, -OH, -CH 3 , –CF 3 and –OCH 3 In some embodiments, R Q In some embodiments, R Q In some embodiments, R Q In some embodiments, R Q In some embodiments, R Q In some embodiments, R Q -CH 3 In some embodiments, R Q For-CF 3 In some embodiments, R Q OCH 3 .

[0454] In some embodiments, for

[0455] In some embodiments, for

[0456] In some embodiments, Ring P is substituted or unsubstituted heteroaryl.

[0457] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0458]

[0459]

[0460] Each RB are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 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.

[0461] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0462]

[0463] Each R B are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 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.

[0464] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0465]

[0466] Each R B are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 In some embodiments, 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.

[0467] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0468]

[0469] Each R B are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 In some embodiments, R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 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.

[0470] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0471]

[0472] Each R B are independently selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 In some embodiments, m is 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.

[0473] In some embodiments, each R B independently hydrogen, deuterium, –F, –Cl, –CN, –CH 3 , –CF3、– OH or –OCH 3 In some embodiments, each R B Deuterium, –F, –Cl, -CN, –CH 3 , –CF 3 , –OH or –OCH 3 .

[0474] In some embodiments, each R B are independently hydrogen, –F or –OCH 3 In some embodiments, each R B Independently –F or –OCH 3 In some embodiments, R B In some embodiments, R B For –OCH 3 In some embodiments, R B For –CH 3 .

[0475] In some embodiments, R B1 For hydrogen, deuterium, –CH 3 , –CF 3或 –CD 3 In some embodiments, R B1 For hydrogen, deuterium, –CH 3 , –CF 3或 –CD 3 .

[0476] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0477]

[0478] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0479]

[0480] In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is

[0481] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0482]

[0483] In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is In some embodiments, ring P is

[0484] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0485]

[0486] In some embodiments, Ring P is a heteroaryl selected from the group consisting of:

[0487]

[0488] In some embodiments, Ring Q is 2-naphthyl substituted at the 3-position with 0, 1, and 2 substituents independently selected from the group consisting of 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 or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 2-C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; wherein each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 4 Haloalkyl, substituted or unsubstituted C 1 –C 4 Heteroalkyl, substituted or unsubstituted C 3 –C 6 Cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0489] In some embodiments, Ring Q is selected from the group consisting of:

[0490]

[0491] In some embodiments, Ring Q is selected from the group consisting of:

[0492]

[0493] In some embodiments, Ring Q is selected from the group consisting of:

[0494]

[0495]

[0496] In some embodiments, Ring Q is selected from the group consisting of:

[0497]

[0498]

[0499] in

[0500] R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl and substituted or unsubstituted C 2 –C7 Heterocycloalkyl.

[0501] In some embodiments, Ring Q is selected from the group consisting of:

[0502]

[0503] Each of the ring Q groups may be optionally replaced by 1 to 3 R B Substitute, where each R B are independently selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0504] In some embodiments, Ring Q is selected from the group consisting of:

[0505]

[0506] Each of the ring Q groups may be optionally replaced by 1 to 3 R B Substitute, where each R B are independently selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0507] In some embodiments, Ring Q is selected from the group consisting of:

[0508]

[0509] Each of the ring Q groups may be optionally substituted with 1, 2, 3, 4 or 5 R B Substitute, where each R B are independently selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0510] In some embodiments, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, Ring Q is selected from the group consisting of:

[0511]

[0512] Where R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7Cycloalkyl and substituted or unsubstituted C 2 –C 7 heterocycloalkyl; and

[0513] Each of the ring Q groups may be optionally substituted with 1, 2, 3, 4 or 5 R B Substitute, where each R B are independently selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 6 Alkoxy, deuterium substituted C 1 -C 6 Alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 Cycloalkyl, substituted or unsubstituted C 2 –C 7 In some embodiments, R B1 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, –CD 3 , substituted or unsubstituted C 1 –C 6 Fluorinated alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3–7 Cycloalkyl and substituted or unsubstituted C 2 –C 7 Heterocycloalkyl.

[0514] In some embodiments, W is substituted or unsubstituted C 1 -C 2 Alkylene.

[0515] In some embodiments, W is C substituted with 1, 2, 3 or 4 substituents each independently selected from the following substituents: 1 -C 2 Alkylene: F, –OH, –OCH 3 and -CH 3 .

[0516] In some embodiments, W is -CH 2 –, –CHF–, –CH(CH 3 )–, –CH(OH)–, –CH(OCH 3 )–,–CF 2 –, –CH 2 CH 2 –, –CHFCH 2 –, –CH 2 CHF–, –CH(CH 3 )CH 2 –, –CH 2 CH(CH 3 )–, –CH(OH)CH 2 –, –CH 2 CH(OH)–, –CH(OCH 3 )CH 2 –, –CH 2 CH(OCH 3 )–,–CF 2 CH 2 – or –CH 2 CF 2 –.

[0517] In some embodiments, W is -CHFCH 2 –, –CH 2 CHF–, –CF 2 CH 2 – or –CH 2 CF 2 In some embodiments, W is -CHFCH 2 In some embodiments, W is -CH 2 CHF-. In some embodiments, W is -CF 2 CH 2 In some embodiments, W is -CH 2 CF 2 –.

[0518] In some embodiments, W is substituted or unsubstituted C 3 -C 4 Alkylene.

[0519] In some embodiments, W is C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 3 -C 4 Alkylene: F, –OH, –OCH 3 and -CH 3 .

[0520] In some embodiments, W is -CH2 CH 2 CH 2 –, –CHFCH 2 CH 2 –, –CH 2 CHFCH 2 –, –CH 2 CH 2 CHF–, –CF 2 CH 2 CH 2 –, –CH 2 CF 2 CH 2 –, –CH 2 CH 2 CF 2 –, –CH(OH)CH 2 CH 2 –, –CH 2 CH(OH)CH 2 –, –CH 2 CH 2 CH(OH)–, –CH(OCH 3 )CH 2 CH 2 –, –CH 2 CH(OCH 3 )CH 2 –, –CH 2 CH 2 CH(OCH 3 )–、––CH(CH 3 )CH 2 CH 2 –, –CH 2 CH(CH 3 )CH 2 – or –CH 2 CH 2 CH(CH 3 )–.

[0521] 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 –.

[0522] In some embodiments, W is -CHFCH2 CH 2 –or–CF 2 CH 2 CH 2 In some embodiments, W is -CHFCH 2 CH 2 In some embodiments, W is -CF 2 CH 2 CH 2 –.

[0523] 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 –.

[0524] In some embodiments, W is substituted or unsubstituted C 1 -C 3 In some embodiments, W is substituted or unsubstituted -CH 2 CH 2 -. In some embodiments, W is -CH 2 CH 2 In some embodiments, W is substituted or unsubstituted -CH 2 CH 2 CH 2 In some embodiments, W is -CH 2 CH 2 CH 2 .

[0525] In some embodiments, W is substituted or unsubstituted C 3 –C 8 Cycloalkylene or substituted or unsubstituted C 2 -C 3 In some embodiments, W is substituted or unsubstituted C 3 –C 8 In some embodiments, W is substituted or unsubstituted cyclopropylene. In some embodiments, W is substituted or unsubstituted C 2 -C 3 In some embodiments, W is -CH=CH-.

[0526] In some embodiments, W is substituted or unsubstituted C 1 -C 2 In some embodiments, W is substituted or unsubstituted -CH 2 OCH 2 In some embodiments, W is -CH 2 O–, where O is attached to R 18 The carbon atom to which the group is attached.

[0527] In some embodiments, R 16 and R 17 One or more of are independently selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C 1 –C 4 Alkyl, substituted or unsubstituted C 1 –C 4 Fluorinated alkyl and substituted or unsubstituted C 1 –C 4 Heteroalkyl.

[0528] In some embodiments, R 16 and R 17 One or more of the following are independently selected from F, -OH, -OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 3 , –CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CN, –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 and -CH 2 CF 3 .

[0529] In some embodiments, R 16 and R 17 One or more of the following are independently selected from F, -OH, -OCH 3 , –OCF 3 , –CH 3, –CH 2 OH, –CH 2 F, –CHF 2 and -CF 3 .

[0530] In some embodiments, R 16 is F. In some embodiments, R 16 In some embodiments, R 17 is F. In some embodiments, R 17 In some embodiments, R 16 and R 17 For hydrogen.

[0531] In some embodiments, R 16 H and R 17 is F. In some embodiments, R 16 is F and R 17 For H.

[0532] In some embodiments, R 16 is not hydrogen. In some embodiments, 16 The carbon atoms of the group are in the (S)-configuration. 16 The carbon atoms of the radical are in the (R)-configuration.

[0533] In some embodiments, R 17 is not hydrogen. In some embodiments, 17 The carbon atoms of the group are in the (S)-configuration. 17 The carbon atoms of the radical are in the (R)-configuration.

[0534] In some embodiments, R 16 is not hydrogen and R 17 is not hydrogen. In some embodiments, 16 The carbon atom of the group is in the (S)-configuration and has R 17 The carbon atoms of the group are in the (S)-configuration. 16 The carbon atom of the group is in the (S)-configuration and has R 17 The carbon atoms of the group are in the (R)-configuration. 16 The carbon atom of the group is in the (R)-configuration and has R 17 The carbon atoms of the group are in the (S)-configuration. 16 The carbon atom of the group is in the (R)-configuration and has R 17 The carbon atoms of the radical are in the (R)-configuration.

[0535] In some embodiments, R 2 Hydrogen, -CH 3 or -OCH 3 .

[0536] In some embodiments, R 2 For hydrogen.

[0537] In some embodiments, each R A are independently hydrogen, F, Cl, -CN, -CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 、–CH(CH 3 ) 2 , –OH, –OCH 3 , –OCH 2 CH 3 , –OCF 3 , –CH 2 F, –CHF 2 or -CF 3 .

[0538] In some embodiments, each R A are independently hydrogen, F, Cl, -CN, -CH 3 , –OH, –OCH 3 , –OCF 3 , –CH 2 F, –CHF 2 or -CF 3 .

[0539] In some embodiments, each R A are independently hydrogen, F, Cl, -CN, -CH 3 or -OCH 3 .

[0540] In some embodiments, each R A are independently F, Cl or -CH 3 .

[0541] In some embodiments, R A For hydrogen.

[0542] In some embodiments, X is -O-. In some embodiments, X is -S-.

[0543] In some embodiments, R 15 and R 18 In some embodiments, R 15 and R18 In some embodiments, R 15 and R 18 are the same and are selected from F, -OR 1 , substituted or unsubstituted C 1 –C 3 Alkyl, substituted or unsubstituted C 1 –C 3 Fluorinated alkyl and substituted or unsubstituted C 1 –C 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 、–CH(CH 3 ) 2 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NHCH 3 , –CH 2 N(CH 3 ) 2 , –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –CH 2 OH, –OCH 2 CN, –OH, –OCH 3 , –OCH 2 CN, –OCF 3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 , –OCH 3 , –OCF3 , –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 15 and R 18 are identical and are selected from F, –CH 3 and -OCH 3 In some embodiments, R 15 and R 18 In some embodiments, R 15 and R 18 All are -CH 3 .

[0544] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least two of are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R16 and R 17 At least two of them are F.

[0545] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is F or C 1 –C 4 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, 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 comprises fluorine. 11 , R 12 , R 13 , R 14 , R 16 and R17 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them contain fluorine.

[0546] In some embodiments of the compound of formula (I) or (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, W comprises fluorine.

[0547] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 is H, D or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 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 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, R13 is D. In some embodiments, R 13 is H. In some embodiments, R 13 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 For F.

[0548] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 F, CH 2 F. CHF 2 CF 3 or CH 3 In some embodiments, R 15 F, CF 3 , CHF 2 or CH 2 F. In some embodiments, R 15 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 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 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 F, CH 2 F. CHF 2 CF 3 or CH 3 In some embodiments, R 18 F, CF 3 , CHF 2 or CH 2 F. In some embodiments, R 18 For F.

[0549] In some embodiments of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least two of are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them are F.

[0550] In some embodiments of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is F or C 1 –C 4 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, 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 comprises fluorine. 11 , R 12 , R 13 , R 14 , R 16 and R 17 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them contain fluorine.

[0551] In some embodiments of the compound of formula (I) or (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, W, R 11 , R 12 , R 13 , R 14 , R15 , R 16 , R 17 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 In some embodiments, W comprises fluorine.

[0552] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 and R 16 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, R 19 In some embodiments, R 19 H, F, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 3 , –CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CN, –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 and -CH 2 CF 3 In some embodiments, R 19H, F, –OH, –OCH 3 , –OCF 3 , –CH 3 , –CH 2 OH, –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 19 F or -OCH 3 .

[0553] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 20 In some embodiments, R 20 H, F, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 OH, –OCH 2 CN, –OCF 3 , –CH 3 , –CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CN, –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 and -CH 2 CF 3 In some embodiments, R 20 H, F, –OH, –OCH 3 , –OCF 3 , –CH 3 , –CH 2 OH, –CH 2 F, –CHF 2 and -CF 3 In some embodiments, R 20 F or -OCH 3 .

[0554] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 is H, D or F. In some embodiments, R 19is 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 20 is 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 For F.

[0555] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R19 , R 20 and R 18 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least two of are F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 At least one of is F. In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 At least two of them are F.

[0556] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, R 11 , R12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least one of them is F or C 1 –C 4 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 In some embodiments, 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 comprises fluorine. 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 and R 17 In some embodiments, R 11 , R 12 , R 13 , R 14 , R 16 and R 17 At least two of them contain fluorine.

[0557] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, W, R 11 , R 12 , R 13, R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 At least one of the compounds contains fluorine, such as F or C 1 –C 4 Fluorinated alkyl groups such as CH 2 F. CF 3 , CHF 2 and CH 3 CH 2 F. In some embodiments, W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 and R 18 In some embodiments, W comprises fluorine.

[0558] In some embodiments of the compound of Formula (I)-(II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R E is hydrogen, substituted or unsubstituted C 1 -C 3 Alkyl or substituted or unsubstituted C 3 –C 6 In some embodiments, R E In some embodiments, R E In some embodiments, R E In some embodiments, R E Ethyl

[0559] In some embodiments of the compounds of Formula (I)-(II) or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 Alkyl, -CD 3 or substituted or unsubstituted C 1 –C 4 In some embodiments, each R 1 are independently hydrogen, deuterium or C 1 –C 4 In some embodiments, each R 1 is independently hydrogen, deuterium or methyl.1 In some embodiments, R 1 In some embodiments, R 1 It is methyl.

[0560] In some embodiments, the compound of formula (I) or formula (II) is prepared from racemic starting materials (and / or intermediates) and separated into each enantiomer as an intermediate or final product by chiral chromatography. Unless otherwise indicated, it should be understood that the absolute configuration of the intermediate and the final compound to be separated is not to be determined. In some embodiments, the absolute stereochemistry of the enantiomer drawn is arbitrarily specified. In some embodiments, two enantiomers are synthesized.

[0561] In one aspect, provided herein is a compound or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound is selected from Table 1, Table 2 and Table 5.

[0562] In some embodiments, the compounds prepared in the following examples are prepared from racemic starting materials (and / or intermediates) and separated into individual enantiomers as final products or intermediates by chiral chromatography. Unless otherwise indicated, it is understood that the absolute configuration of the isolated intermediates and final compounds drawn is arbitrarily assigned and not determined.

[0563] 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.

[0564] 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%.

[0565] In some embodiments, the asymmetric carbon atoms of the compounds of formula (I) or formula (II) are present in an enantiomeric enriched form. In certain embodiments, the asymmetric carbon atoms of the compounds of formula (I) or formula (II) have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (S)- or (R)-configuration.

[0566] In some embodiments, the compound is:

[0567]

[0568]

[0569] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0570] In some embodiments, the compound is:

[0571] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0572] In some embodiments, the compound is:

[0573] 4-Fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0574] 4-Fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0575] 4-Fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0576] 4-Fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0577] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol;

[0578] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol;

[0579] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0580] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0581] 6-(4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;

[0582] 6-(4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;

[0583] 6-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;

[0584] 6-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one;

[0585] 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide;

[0586] 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide;

[0587] 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;

[0588] 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide;

[0589] 6-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide;

[0590] 6-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-N-methylquinoline-2-carboxamide;

[0591] 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;

[0592] 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;

[0593] 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;

[0594] 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;

[0595] 7-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-1-methylquinolin-4(1H)-one;

[0596] 7-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-1-methylquinolin-4(1H)-one;

[0597] 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;

[0598] 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-1-methylquinolin-4(1H)-one;

[0599] 7-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one;

[0600] 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;

[0601] 7-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one;

[0602] 7-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one;

[0603] 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one;

[0604] 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-6-hydroxy-2-methylisoquinolin-1(2H)-one;

[0605] 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0606] 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0607] 6-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0608] 6-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0609] 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0610] 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0611] 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol;

[0612] 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol;

[0613] 2-(6-(((1R,5R,6R,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0614] 2-(6-(((1S,5S,6S,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0615] 2-(6-(((1R,5R,6R,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0616] 2-(6-(((1S,5S,6S,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0617] 2-(6-(((1R,2S,3R,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0618] 2-(6-(((1S,2R,3S,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0619] 2-(6-(((1R,2R,3R,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0620] 2-(6-(((1S,2S,3S,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0621] 4-Chloro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0622] 4-Chloro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0623] 2-Fluoro-6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)phenol;

[0624] 2-Fluoro-6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)phenol;

[0625] 3-Fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0626] 3-Fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0627] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0628] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-oxadiazol-2-yl)phenol;

[0629] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol;

[0630] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1,3,4-thiadiazol-2-yl)phenol;

[0631] 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;

[0632] 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;

[0633] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-indazol-1-yl)phenol;

[0634] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-indazol-1-yl)phenol;

[0635] 2-(6-(((1R,3r,5S,7s)-7-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0636] 4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile;

[0637] 4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile;

[0638] 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;

[0639] 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;

[0640] 4-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile;

[0641] 4-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile;

[0642] 4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile;

[0643] 4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)-3-hydroxybenzonitrile;

[0644] 5-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol;

[0645] 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;

[0646] 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;

[0647] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol;

[0648] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol;

[0649] 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyrimidin-2(1H)-one;

[0650] 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyrimidin-2(1H)-one;

[0651] 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one;

[0652] 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-(fluoromethyl)pyridin-2(1H)-one;

[0653] 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)quinolin-6-ol;

[0654] 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)quinolin-6-ol;

[0655] 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)quinoxalin-6-ol;

[0656] 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)quinoxalin-6-ol;

[0657] 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinolin-7-ol;

[0658] 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)quinolin-7-ol;

[0659] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyrazin-2-yl)phenol;

[0660] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyrazin-2-yl)phenol;

[0661] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthien-3-yl)phenol;

[0662] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthien-3-yl)phenol;

[0663] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthien-2-yl)phenol;

[0664] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylthien-2-yl)phenol;

[0665] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-2-yl)phenol;

[0666] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-2-yl)phenol;

[0667] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-3-yl)phenol;

[0668] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylfuran-3-yl)phenol;

[0669] 5-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methyloxazol-2(3H)-one;

[0670] 5-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-3-methyloxazol-2(3H)-one;

[0671] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-4-yl)phenol;

[0672] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-4-yl)phenol;

[0673] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-5-yl)phenol;

[0674] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-5-yl)phenol;

[0675] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)phenol;

[0676] 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;

[0677] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol;

[0678] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol;

[0679] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol;

[0680] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-5-yl)phenol;

[0681] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-4-yl)phenol;

[0682] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methyloxazol-4-yl)phenol;

[0683] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)phenol;

[0684] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)phenol;

[0685] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-4-yl)phenol;

[0686] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-4-yl)phenol;

[0687] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyridin-3-yl)phenol;

[0688] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyridin-3-yl)phenol;

[0689] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylpyridin-4-yl)phenol;

[0690] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylpyridin-4-yl)phenol;

[0691] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyridazin-4-yl)phenol;

[0692] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyridazin-4-yl)phenol;

[0693] 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;

[0694] 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;

[0695] 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;

[0696] 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;

[0697] 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;

[0698] 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;

[0699] 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;

[0700] 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-7-hydroxy-2-methylisoquinolin-1(2H)-one;

[0701] 6-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamide;

[0702] 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;

[0703] 6-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-hydroxy-N,N-dimethylbenzofuran-2-carboxamide;

[0704] 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;

[0705] 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;

[0706] 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0707] 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0708] 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0709] 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0710] 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0711] 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0712] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(3-methylisoxazol-4-yl)phenol;

[0713] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,5-a]pyridin-6-yl)phenol;

[0714] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)phenol;

[0715] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,5-a]pyridin-6-yl)phenol;

[0716] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)phenol;

[0717] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-7-yl)phenol;

[0718] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-7-yl)phenol;

[0719] 4-Fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0720] 4-Fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0721] 7-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)oxy)pyridazin-3-yl)isoquinolin-6-ol;

[0722] 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)isoquinolin-7-ol;

[0723] 7-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)isoquinolin-6-ol;

[0724] 6-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)isoquinolin-7-ol;

[0725] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyrazin-2-yl)phenol;

[0726] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyrazin-2-yl)phenol;

[0727] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyrazin-2-yl)phenol;

[0728] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(5-methylpyrazin-2-yl)phenol;

[0729] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyridin-2-yl)phenol;

[0730] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol;

[0731] 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;

[0732] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-3-yl)phenol;

[0733] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridin-3-yl)phenol;

[0734] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(pyridin-2-yl)phenol;

[0735] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methoxypyridazin-4-yl)phenol;

[0736] 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;

[0737] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridazin-3-yl)phenol;

[0738] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(6-methylpyridin-3-yl)phenol;

[0739] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(3-methylisoxazol-4-yl)phenol;

[0740] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(2-methylthiazol-4-yl)phenol;

[0741] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(3-methyl-1H-1,2,4-triazol-1-yl)phenol;

[0742] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol;

[0743] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-3-yl)phenol;

[0744] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-3-yl)phenol;

[0745] 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;

[0746] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-1,2,3-triazol-1-yl)phenol;

[0747] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-3-yl)phenol;

[0748] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-3-yl)phenol;

[0749] 5-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol;

[0750] 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;

[0751] 4-Fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0752] 4-Fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0753] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0754] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0755] 4-(2-Fluoro-4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;

[0756] 4-(2-Fluoro-4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)pyridin-2(1H)-one;

[0757] 4-Fluoro-2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0758] 4-(2-Fluoro-4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one;

[0759] 4-(2-Fluoro-4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-hydroxyphenyl)pyridin-2(1H)-one;

[0760] 4-Fluoro-2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0761] 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;

[0762] 4-(4-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;

[0763] 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one;

[0764] 4-(4-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-3-hydroxyphenyl)pyridin-2(1H)-one;

[0765] 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;

[0766] 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;

[0767] 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0768] 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0769] 2-(6-(((1R,3S,5S)-6,6-difluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazo 1-1-yl)phenol;

[0770] 2-(6-(((1S,3R,5R)-6,6-difluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazo 1-1-yl)phenol;

[0771] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0772] 2-(6-(((1R,2S,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0773] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0774] 2-(6-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;

[0775] 2-(6-(((1S,3R,5R)-6,6-difluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0776] 2-(6-(((1R,3S,5S)-6,6-difluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0777] 2-(6-(((1S,2R,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0778] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0779] 2-(6-(((1R,2S,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0780] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0781] 2-(6-(((1S,2R,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0782] 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0783] 2-(6-(((1R,2S,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0784] 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;

[0785] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazo 1-1-yl)phenol;

[0786] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-imidazo 1-1-yl)phenol;

[0787] 2-(6-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; or

[0788] 2-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0789] In some embodiments, exemplary SMSM compounds are summarized in Table 1.

[0790] Table 1: Exemplary SMSM compounds

[0791]

[0792]

[0793]

[0794]

[0795] In some embodiments, provided herein are pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds of Table 1.

[0796] In some embodiments, exemplary SMSM compounds are summarized in Table 2.

[0797] Table 2: Exemplary SMSM compounds

[0798]

[0799]

[0800]

[0801] In some embodiments, provided herein are pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds of Table 2.

[0802] In some embodiments, the SMSM described herein is not a compound in Table 3.

[0803] Table 3. List of compounds

[0804]

[0805]

[0806]

[0807] In some embodiments, W is not -CH 2 CH 2 -,CH 2 CH 2 CH 2 -or–CH 2 OCH 2 -.

[0808] In some embodiments, A is not -CH=CH-.

[0809] In some embodiments, R 15 , R 16 , R 17 and R 18 In some embodiments, R 15 and R 18 In some embodiments, R 16 and R 17 Not at the same time as hydrogen.

[0810] In some embodiments, when (i) W is -CH 2 CH 2 -、CH 2 CH 2 CH 2 -or–CH 2OCH 2 -, (ii) A is -CH=CH-, and (ii) R 16 and R 17 When both are hydrogen, R 15 and R 18 Not at the same time as hydrogen.

[0811] In some embodiments, when W is -CH 2 CH 2 -、CH 2 CH 2 CH 2 -or–CH 2 OCH 2 -, then R 15 , R 16 , R 17 and R 18 In some embodiments, when A is -CH=CH-, then R 15 ,R 16 ,R 17 , and R 18 In some embodiments, when A is -CH=CH-, then R 16 and R 17 Not at the same time as hydrogen.

[0812] In some embodiments, Ring Q is not

[0813]

[0814] In some embodiments, the compound is not a compound in Table 3.

[0815] In some embodiments, the SMSM described herein is not a compound in Table 4.

[0816] Table 4. List of compounds

[0817]

[0818] In some embodiments, W is not -CH 2 CH 2 - or CH 2 CH 2 CH 2 -.

[0819] In some embodiments, A is not -CH=CH-.

[0820] In some embodiments, X is not -O-.

[0821] In some embodiments, R16 and R 17 In some embodiments, R 15 and R 18 Not for –CH 3 In some embodiments, when R 16 and R 17 When both are hydrogen, then R 15 and R 18 Not for –CH 3 In some embodiments, when R 15 and R 18 For –CH 3 When R 16 and R 17 Not hydrogen at the same time.

[0822] In some embodiments, when (i) W is CH 2 CH 2 - or CH 2 CH 2 CH 2 -, (ii) A is -CH=CH-, (iii) R 16 and R 17 are all hydrogen, (iv) R 15 and R 18 For –CH 3 , and (v) when X is -O-, ring Q is an unsubstituted monocyclic aromatic group.

[0823] In some embodiments, when (i) W is CH 2 CH 2 - or CH 2 CH 2 CH 2 -, (ii) A is -CH=CH-, (iii) R 15 and R 18 For –CH 3 , and (v) X is -O-, then R 16 and R 17 Not hydrogen at the same time.

[0824] In some embodiments, Ring Q is not

[0825] In some embodiments, the compound is not a compound in Table 4.

[0826] In some cases, the SMSMs provided herein may be designated by more than one number in different sections of the application; for example, in the Tables, in the Examples, and in the Schemes, the same compound may appear more than once.

[0827] In some embodiments, SMSM described herein is prepared from racemic starting materials (and / or intermediates) and separated into each enantiomer as an intermediate or final product by chiral chromatography. Unless otherwise indicated, it should be understood that the absolute configuration of the intermediate and final compound separated is not to be determined. In some embodiments, the absolute stereochemistry of the enantiomer drawn is arbitrarily specified. In some embodiments, two enantiomers are synthesized.

[0828] 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.

[0829] In some embodiments, the SMSM described herein has a stereochemical purity of at least 75%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 80%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 85%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 90%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 95%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 96%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 97%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 98%. In some embodiments, the SMSM described herein has a stereochemical purity of at least 99%.

[0830] In some embodiments, SMSM described herein has one or more stereocenters, and each stereocenter exists independently in R or S configuration. The compounds proposed herein include all diastereoisomers, enantiomers and epimer forms and their appropriate mixtures. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers, and their appropriate mixtures. In certain embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating diastereomers and recovering optically pure enantiomers. In some embodiments, the resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, based on the difference in solubility, diastereomers are separated by separation / resolving techniques. In other embodiments, separation of stereoisomers is carried out by chromatography or by forming diastereomeric salts and separated by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0831] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted into a parent drug in vivo. Prodrugs are generally useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug cannot. The solubility of the prodrug in the pharmaceutical composition may also be higher than that of the parent drug. In some embodiments, the design of the prodrug increases effective water solubility. An example of a prodrug is, but not limited to, a compound described herein, which is administered in the form of an ester ("prodrug") to promote delivery on a cell membrane where water solubility is not conducive to migration, but once on the intracellular side where water solubility is beneficial, it is subsequently metabolically hydrolyzed to a carboxylic acid active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acidic group, wherein the peptide is metabolized to show an active portion. In certain embodiments, when administered in vivo, the prodrug is chemically converted into a biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to a biologically, pharmaceutically or therapeutically active form of the compound by one or more steps or processes.

[0832] In one aspect, prodrugs are designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug, or to alter other characteristics or properties of a drug. Using knowledge of in vivo pharmacokinetic, pharmacodynamic processes and drug metabolism, once a pharmaceutically active compound is known, prodrugs of the compound can be designed (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401, Rooseboom et al., Pharmacological Reviews, 56: 53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14).

[0833] In certain cases, certain compounds described herein may be a prodrug of another derivative or active compound.

[0834] In some embodiments, sites on the aromatic ring portion of the compounds described herein are susceptible to various metabolic reactions, and therefore the introduction of appropriate substituents on the aromatic ring structure will reduce, minimize or eliminate the metabolic pathway. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are halogens or alkyls (by way of example only).

[0835] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioactive isotope) or labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0836] The compounds described herein include isotopically labeled compounds which are identical to those depicted in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as 2 H. 3 h. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F. 3 6 In one aspect, an isotopically labeled compound as described herein, for example one in which a radioactive isotope such as 3 H and 14 C, can be used in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0837] In additional or further embodiments, the compounds described herein are metabolized when administered to an organism in need thereof to produce a metabolite, which is then used to produce a desired effect, including a desired therapeutic effect.

[0838] The compounds described herein can be formed and / or used as pharmaceutically acceptable salts. The types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, which are formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.; or an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 1,2-ethanedi ... (2) Salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions). In some cases, the compounds described herein may be coordinated with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds comprising acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0839] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates. Solvates contain stoichiometric or non-stoichiometric solvents and can be formed in a crystallization process using a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of compounds described herein can be conveniently prepared or formed during the methods described herein. In addition, compounds provided herein can exist in the form of non-solvates and solvates. Generally, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0840] In some embodiments, the SMSM has a molecular weight of up to about 2000 Daltons, 1500 Daltons, 1000 Daltons, or 900 Daltons. In some embodiments, the SMSM has a molecular weight of at least 100 Daltons, 200 Daltons, 300 Daltons, 400 Daltons, or 500 Daltons. In some embodiments, the SMSM does not contain a phosphodiester bond.

[0841] Methods for preparing compounds

[0842] The compounds described herein can be synthesized using standard synthetic techniques or using a combination of methods known in the art and methods described herein. Unless otherwise indicated, conventional mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacological methods can be used. Standard organic chemistry techniques can be used to prepare compounds, for example, those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein can be used, such as changing solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. Starting materials can be obtained from commercial sources or can be easily prepared. As an example only, a scheme for preparing SMSM is provided.

[0843] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 1:

[0844]

[0845] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 2:

[0846]

[0847] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 3:

[0848]

[0849] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 4:

[0850]

[0851] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 5:

[0852]

[0853] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 6:

[0854]

[0855] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 7:

[0856]

[0857] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 8:

[0858]

[0859] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 9:

[0860]

[0861] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 10:

[0862]

[0863] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 11:

[0864]

[0865] In some embodiments, the scheme for preparing the SMSM described herein is Scheme 12:

[0866]

[0867] Suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; T L Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley Interscience, New York, 1992. Additional suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd Revised and Supplemented Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 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. .

[0868] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio or carboxyl groups, where they are desired in the final product, to avoid their unwanted participation in the reactions. A detailed description of techniques suitable for creating protecting groups as well as their removal is described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference).

[0869] SMSM can be prepared using known techniques and further chemically modified, in some embodiments, to facilitate intranuclear transfer to, for example, a splicing complex component, a spliceosome, or a pre-mRNA molecule. One of ordinary skill in the art will appreciate standard medicinal chemistry methods for chemical modification for intranuclear transfer (e.g., to reduce charge, optimize size, and / or alter lipophilicity).

[0870] Pharmaceutical composition

[0871] 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 acceptable preparations. Appropriate formulations depend on the selected route of administration. For example, a summary of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0872] The pharmaceutical composition can be a mixture of the SMSM described herein and one or more other chemical components (i.e., pharmaceutically acceptable components), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates the administration of the compound to an organism.

[0873] The compositions described herein can be administered to a subject in a variety of ways, including parenteral, intravenous, intradermal, intramuscular, colonic, rectal or intraperitoneal. In some embodiments, the small molecule splicing regulator or a pharmaceutically acceptable salt thereof is administered by intraperitoneal injection, intramuscular injection, subcutaneous injection or intravenous injection of the subject. In some embodiments, the pharmaceutical composition can be administered parenterally, intravenously, intramuscularly or orally. The oral agent containing the small molecule splicing regulator can be in any form suitable for oral administration, such as a liquid, tablet, capsule, etc. The oral formulation can be further coated or treated to prevent or reduce its dissolution in the stomach. The composition of the present disclosure can be administered to a subject using any appropriate method known in the art. Suitable formulations and delivery methods for the present disclosure are generally well known in the art. For example, the small molecule splicing regulator described herein can be formulated into a pharmaceutical composition with a pharmaceutically acceptable diluent, carrier or excipient. The composition may contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, including pH adjusters and buffers, tonicity adjusters, wetting agents, etc., for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.

[0874] The pharmaceutical preparations described herein can be administered to a subject in a variety of ways by a variety of routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, oral, topical or transdermal routes of administration. The pharmaceutical preparations described herein include but are not limited to aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and immediate release and controlled release mixed formulations.

[0875] In some embodiments, the pharmaceutical formulation is in tablet form. In other embodiments, the pharmaceutical formulation comprising the SMSM described herein is in capsule form. In one aspect, the liquid formulation dosage form for oral administration is in the form of an aqueous suspension or solution selected from, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0876] For administration by inhalation, the SMSM described herein can be formulated as an aerosol, mist or powder. For buccal or sublingual administration, the composition can take the form of tablets, lozenges or gels formulated in a conventional manner. In some embodiments, the SMSM described herein can be prepared as a transdermal dosage form. In some embodiments, the SMSM described herein can be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous or intravenous injection. In some embodiments, the SMSM described herein can be topically applied and can be formulated into a variety of topically applicable compositions, such as solutions, suspensions, lotions, gels, pastes, medicinal sticks, balms, creams or ointments. In some embodiments, the SMSM described herein can be formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, colloid suppositories or retention enemas.

[0877] Editing

[0878] Extensive post-transcriptional processing occurs prior to eukaryotic pre-mRNA maturation and export from the nucleus to the cytoplasm, including the addition of a 7-methylguanosine cap at the 5' end, cleavage and addition of a poly-A tail at the 3' end, and removal of intervening sequences or introns by the spliceosome. The vast majority of higher eukaryotic genes contain multiple introns, which are spliced ​​with high accuracy and fidelity to maintain the reading frame of the exons. Splicing of pre-mRNA can utilize recognition of intron and exon boundaries and internal short consensus sequences by a series of small nuclear ribonucleoprotein (snRNP) complexes (e.g., snRNP U1, U2, U4, U5, U6, U11, U12m U4atc and U6 atc) and a large number of proteins, including spliceosomal proteins and positive and negative acting splicing regulators.

[0879] Serine-arginine (SR)-domain-containing proteins generally function to promote constitutive splicing. They can also regulate alternative splicing by binding to intronic or exonic splicing enhancer (ISE) or ESE sequences, respectively. Other pre-mRNA binding proteins (e.g., hnRNPs) regulate splicing by binding to intronic or exonic splicing suppressor (ISS or ESS, respectively) sequences and can also act as general splicing regulators. The SR protein family is a class of at least 10 proteins that, in addition to RNA binding, have characteristic serine / arginine-rich domains. SR proteins are generally believed to enhance splicing by simultaneously binding to the core component U1 snRNP U170K at the 5' splice site and to U2AF35 at the 3' splice site, thereby bridging the two ends of the intron. Although this specialized function of SR proteins seems redundant, since any single SR protein can ensure that a pre-mRNA is constitutively spliced, the roles of various SR proteins in the alternative splicing of specific pre-mRNAs are different, partly due to their ability to recognize and bind to unique consensus sequences. Phosphorylation of the RS domain of SR proteins can lead to regulation of their protein interactions, RNA binding, localization, trafficking, and role in alternative splicing. Several cellular kinases have been identified that phosphorylate SR proteins, including SR protein kinases (SRPKs), Cdc2-like kinases (Clks), pre-mRNA processing mutant 4 (PRP4), and topoisomerase I. Optimal phosphorylation may be required for proper functioning of SR proteins, as both hypo- and hyper-phosphorylation of the RS domain may be detrimental to its role in constitutive and alternative splicing.

[0880] In higher eukaryotes, most genes include one or more introns, which cause exons to be spliced ​​together to generate mature mRNA and microRNA (miRNA). In the host cell nucleus, pre-mRNA splicing is to remove introns from pre-mRNA and link exons together to generate mature mRNA and pre-miRNA, which are then exported to the cytoplasm to be translated into the mechanism of polypeptide gene products. The splicing of pre-mRNA can occur in cis, where two exons come from two adjacent co-transcribed sequences, or trans, when two exons come from different pre-mRNA transcripts. The ratio of different protein products (isotypes) may be due to the frequency of selective splicing events in pre-mRNA, which causes different numbers of different splicing variants. In some embodiments, the selective splicing of pre-mRNA may cause 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 protein isoforms to be expressed.

[0881] Abnormalities in splicing are thought to be responsible for approximately half of all genetic diseases. Aberrant splicing due to mutations in consensus sequences involved in exon-intron boundary recognition may contribute to up to 15% of genetic diseases. In addition, defects in the splicing system itself due to loss or gain of function of splicing factors and regulators are responsible for a wide range of human diseases ranging from cancer to neurodegenerative diseases. Both constitutive and alternative splicing are regulated by upstream signaling pathways. This regulation may be essential during development, in the tissue-specific expression of certain isoforms, during the cell cycle, and in response to external signaling molecules.

[0882] Alternative splicing allows a single gene to express different mRNA isoforms, thus playing a major role in promoting cellular complexity in higher eukaryotes without the need to expand the genome. Splicing can also be regulated by upstream signaling pathways. For example, upstream signaling pathways can regulate alternative splicing and increase or decrease the expression levels of different isoforms of mRNA.

[0883] Alternative splicing events are highly regulated by multiple splicing factors in a tissue type, developmental stage and signal transduction dependent manner. In addition, the non-mutation gene causes of splicing defects and the defects of the splicing system itself, such as due to the loss / acquisition of splicing factor functions or their relative stoichiometry, have led to a variety of human diseases from cancer to neurodegenerative diseases. In many diseases, the disease state is caused by the change in the ratio of different isoforms of two or more proteins expressed by genes. In some embodiments, the change in the protein product ratio is due to the change in the frequency of the alternative splicing events in the pre-mRNA, causing the ratio of the splicing variants produced to change. In some embodiments, the alternative splicing of pre-mRNA may result in 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 kinds of protein isoforms being expressed. In some embodiments, the change in the splicing variant ratio is caused by genetic mutation.

[0884] In eukaryotes, the vast majority of splicing processes are catalyzed by the spliceosome, an RNA-protein complex that occurs in a distinct step and may contain a subset of hundreds of different proteins in addition to the five spliceosomal snRNAs. These factors determine the precise positioning of the spliceosome over the 5' and 3' splice site sequences. The need for so many factors reflects the observation that exon recognition can be influenced by many pre-mRNA features, such as exon length, sequence identity, the presence of enhancer and silencer elements, the strength of upstream splicing signaling, promoter structure, as well as RNA synthesis rate, secondary and tertiary RNA structure.

[0885] All mammalian diseases are ultimately mediated by the transcriptome. As long as messenger mRNA (mRNA) is part of the transcriptome and all protein expression is derived from mRNA, it is possible to intervene in protein-mediated diseases by modulating the expression of related proteins and, in turn, by regulating the translation of the corresponding upstream mRNA. However, mRNA is only a small part of the transcriptome: other transcribed RNAs also regulate cell biology directly through the structure and function of RNA structures (e.g., ribonucleoproteins) and through protein expression and action (including (but not limited to) microRNAs (miRNAs), long noncoding RNAs (lncRNAs), long intergenic noncoding RNAs (lincRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), small Cajal body-specific RNAs (scaRNAs), piwi-interacting RNAs (piRNAs), competing endogenous (ceRNAs), and pseudogenes). Drugs that intervene at this level have the potential to modulate any and all cellular processes. In most cases, existing therapeutic approaches (such as antisense RNA or siRNA) have not overcome major challenges such as drug delivery, absorption, target organ distribution, pharmacokinetics, and cellular penetration. In contrast, small molecules have a long history of successfully overcoming these obstacles, and these properties make them suitable for use as drugs, which can be easily optimized through a series of analogs to overcome these challenges. In stark contrast, the use of small molecules as RNA ligands for therapeutic benefit has received little attention from the drug discovery community.

[0886] The DNA sequence in the chromosome is transcribed into pre-mRNA, which contains coding regions (exons) and usually also contains intervening non-coding regions (introns). Introns are removed from pre-mRNA by splicing. Pre-mRNA splicing is carried out by a two-step mechanism. In the first step, the 5' splice site is cut to obtain a "free" 5' exon and a lasso intermediate. In the second step, the 5' exon is connected to the 3' exon and the intron is released as a lasso product. These steps are catalyzed in a complex of small nuclear ribonucleoproteins and proteins called spliceosomes.

[0887] 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.

[0888] Introns are parts of eukaryotic DNA that are inserted between the coding portions of the DNA, or "exons". Introns and exons are transcribed into RNA, which is called a "primary transcript, mRNA precursor" (or "pre-mRNA"). Introns can be removed from pre-mRNA so that a native protein encoded by the exons can be produced (as the term "native protein" as used herein refers to a naturally occurring, wild-type or functional protein). Removal of introns from pre-mRNA and subsequent joining of exons is performed during the splicing process.

[0889] The splicing process is a series of reactions that are carried out on RNA after transcription but before translation and are mediated by splicing factors. Thus, "pre-mRNA" may be an RNA that contains both exons and introns, and mature mRNA ("mRNA") may be an RNA that removes introns and links exons together in sequence so that proteins can be translated from it by ribosomes.

[0890] Introns can be defined by a set of "splicing elements", which are part of the splicing system, may be required for splicing, and are relatively short, conserved RNA segments that bind various splicing factors that carry out the splicing reaction. Therefore, each intron is defined by a 5' splice site, a 3' splice site, and a branch point located between them. Splicing elements also include exonic splicing enhancers and silencers located in exons, and intronic splicing enhancers and silencers located in introns at a certain distance from splice sites and branch points. In addition to splice sites and branch points, these elements also control optional abnormal and constitutive splicing.

[0891] The initial RNA transcript (pre-mRNA) of most eukaryotic genes is retained in the cell nucleus until noncoding intronic sequences are removed by the spliceosome to produce mature messenger RNA (mRNA). The splicing that occurs varies, so the synthesis of alternative protein products from the same primary transcript may be affected by tissue-specific or developmental signaling. It is believed that a large proportion of human genetic diseases, including many cancers, are caused by deviations from the normal pattern of pre-mRNA splicing. The spliceosome is a complex that contains ribonucleoprotein (snRNP) particles composed of small nuclear RNAs and proteins. The snRNA component of the spliceosome can promote two transesterification reactions of splicing.

[0892] 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 only in a subset of eukaryotes and splices rare U12-type introns. The U2-dependent spliceosome is assembled from the U1, U2, U5, and U4 / U6 snRNPs, as well as a number of non-snRNP proteins. The U2 snRNP is recruited by two weakly binding protein subunits, SF3a and SF3b, during the first ATP-dependent step in spliceosome assembly. SF3b consists of seven conserved proteins, including PHF5α, SF3b155, SF3b145, SF3b130, SF3b49, SF3b14a, and SF3b10.

[0893] Splicing or RNA splicing generally refers to the editing of nascent precursor messenger RNA (pre-mRNA) transcripts into mature messenger RNA (mRNA). Splicing is a biochemical process that involves the removal of introns followed by exon ligation. The sequential transesterification reaction is initiated by a nucleophilic attack of a branched adenosine (branch point; BP) in a downstream intron on the 5' splice site (5'ss), which results in the formation of an intronic 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 intronic lariat and the formation of a spliced ​​RNA product.

[0894] Splicing can be regulated by various cis-acting elements and trans-acting factors. The cis-acting element is the sequence of mRNA, and may include a core consensus sequence and other regulatory elements. The core consensus sequence may generally refer to a conserved RNA sequence motif, including 5'ss, 3'ss, a polypyrimidine tract and a BP region, which may play a role in recruiting the spliceosome. BP refers to a partially conserved sequence of pre-mRNA, typically less than 50 nucleotides upstream of the 3'ss. During the first step of the splicing reaction, BP reacts with the 5'ss. Other regulatory cis-acting elements may include exon splicing enhancers (ESEs), exon splicing silencers (ESSs), intron splicing enhancers (ISEs) and intron splicing silencers (ISSs). Trans-acting factors may be proteins or ribonucleoproteins that bind to cis-acting elements.

[0895] Splice site recognition and regulated splicing can be accomplished primarily through two dynamic macromolecular machinery, the major (U2-dependent) and minor (U12-dependent) spliceosomes. Each spliceosome contains five snRNPs: the major spliceosome is U1, U2, U4, U5, and U6 snRNPs (which process approximately 95.5% of all introns); the minor spliceosome is U11, U12, U4atac, U5, and U6 snRNPs. 6atac snRNP. 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 protein (PTBP) can bind to the polypyrimidine tracts of introns and may promote RNA circularization.

[0896] Alternative splicing is a mechanism by which a single gene can ultimately produce several different proteins. Alternative splicing can be achieved by the coordinated action of a variety of different proteins associated with pre-mRNA (called "alternative splicing regulatory proteins"), and results in the inclusion of unique alternative exons in mature mRNA. The alternative forms of these gene transcripts can produce different isoforms of specific proteins. The pre-mRNA molecule sequence that can be combined with the alternative splicing regulatory protein can be found in introns or exons, including but not limited to ISS, ISE, ESS, ESE and polypyrimidine tracts. Many mutations can change splicing patterns. For example, mutations can be cis-acting elements, and can be located at core consensus sequences (such as 5'ss, 3'ss and BP) or regulatory elements that regulate spliceosome recruitment, including ESE, ESS, ISE and ISS.

[0897] Cryptic splice sites, such as cryptic 5'ss and cryptic 3'ss, may refer to splice sites that are not normally recognized by the spliceosome and are therefore dormant. Cryptic splice sites may be recognized or activated, for example, by mutations in cis-acting elements or trans-acting factors, or structural configurations (such as protrusions).

[0898] Splicing regulation

[0899] The present disclosure contemplates the use of small molecules with favorable drug properties, which regulate the splicing activity of target RNA. Provided herein is a small molecule splicing regulator (SMSM) that regulates the splicing of a target polynucleotide. In some embodiments, SMSM binds to and regulates a target RNA. In some embodiments, a SMSM library is provided herein, and the SMSM binds to and regulates one or more target RNAs. In some embodiments, the target RNA is mRNA. In some embodiments, the target RNA is an mRNA of a non-coding RNA. In some embodiments, the target RNA is a pre-mRNA. In some embodiments, the target RNA is an hnRNA. In some embodiments, a small molecule regulates the splicing of a target RNA. In some embodiments, a small molecule provided herein regulates splicing at the sequence of the target RNA. In some embodiments, a small molecule provided herein regulates splicing at the hidden splicing site sequence of the target RNA. In some embodiments, a small molecule provided herein is combined with a target RNA. In some embodiments, a small molecule provided herein is combined with a splicing complex component. In some embodiments, a small molecule provided herein is combined with a target RNA and a splicing complex component.

[0900] Therefore, provided herein is a method for preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting a pre-mRNA molecule and / or other elements of a splicing system (e.g., in a cell) with a compound provided herein to prevent or induce a splicing event in a pre-mRNA molecule. The splicing event prevented or induced can be, for example, an abnormal splicing event, a constitutive splicing event, or an alternative splicing event.

[0901] 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, aberrant and / or constitutive splicing as described herein (e.g., within a cell) under conditions whereby a positive (prevention or induction of splicing) or negative (no prevention or induction of splicing) effect is produced and detected, and identifying the compound that produces a positive effect as a compound capable of preventing or inducing a splicing event.

[0902] In some embodiments, the small molecule compounds described herein in a pharmaceutically acceptable carrier prevent or induce variable or abnormal splicing events in pre-mRNA molecules. As described above, the small molecule compounds provided herein are not antisense or antigenic oligonucleotides. Tables 1, 2, and 5 show the chemical structures and names of exemplary compounds and are not intended to be all inclusive.

[0903] In some embodiments, a composition comprises a composition of a small molecule splicing regulator compound (SMSM); wherein the SMSM interacts with an unpaired protruding nucleobase of an RNA duplex, and wherein the RNA duplex comprises a splicing site. A composition comprising a complex is provided herein, the complex comprising a small molecule splicing regulator compound (SMSM) bound to an RNA duplex, wherein the SMSM interacts with an unpaired protruding nucleobase of an RNA duplex, and wherein the RNA duplex comprises a splicing site. In some embodiments, the duplex RNA comprises an alpha helix. In some embodiments, the unpaired protruding nucleobase is located on the outer portion of the helix of the duplex RNA. In some embodiments, the unpaired protruding nucleobase is located within the inner portion of the helix of the duplex RNA. In some embodiments, SMSM forms one or more intermolecular interactions with duplex RNA. In some embodiments, SMSM forms one or more intermolecular interactions with an unpaired protruding nucleobase. In some embodiments, the intermolecular interaction is selected from the group comprising: ionic interaction, hydrogen bond, dipole-dipole interaction or van der Waals interaction. In some embodiments, the first part of SMSM interacts with the unpaired protruding nucleobase of the first RNA strand of the RNA duplex. In some embodiments, the second part of SMSM interacts with one or more nucleobases of the second RNA strand of the RNA duplex, wherein the first RNA strand is not the second RNA strand. In some embodiments, the exchange rate of the unpaired protruding nucleobase from the inside of the helix of the duplex RNA to the outer part of the helix is ​​reduced. In some embodiments, SMSM reduces the rotation rate of the unpaired protruding nucleobase. In some embodiments, SMSM reduces the rotation rate of the unpaired protruding nucleobase around the phosphate backbone of the RNA strand of the RNA duplex. In some embodiments, SMSM regulates the distance between the unpaired protruding nucleobase and the second nucleobase of the duplex RNA. In some embodiments, SMSM reduces the distance between the unpaired protruding nucleobase and the second nucleobase of the duplex RNA. In some embodiments, the unpaired protruding nucleobase is located in the interior of the helix of the duplex RNA of the complex. In some embodiments, SMSM reduces the size of the protrusion of the RNA duplex. In some embodiments, SMSM removes bulges of RNA duplexes. In some embodiments, SMSM stabilizes bulges of RNA duplexes. In some embodiments, SMSM regulates splicing at splice sites of RNA duplexes. In some embodiments, SMSM increases splicing at splice sites of RNA duplexes. In some embodiments, SMSM reduces splicing at splice sites of RNA duplexes. In some embodiments, unpaired bulge nucleobases have modulated base stacking within the RNA strand of the RNA duplex.In some embodiments, the unpaired bulge nucleobase has increased base stacking within the RNA strand of the RNA duplex. In some embodiments, the unpaired bulge nucleobase has reduced base stacking within the RNA strand of the RNA duplex. In some embodiments, SMSM is not an aptamer. In some embodiments, the RNA duplex includes a pre-mRNA. In some embodiments, in the absence of SMSM, the unpaired bulge nucleobase is free to rotate around the phosphate backbone of the RNA strand of the RNA duplex.

[0904] In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM has an IC of less than 50 nM. 50 Killing the cell. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM regulates splicing at a splicing site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA, and wherein the total amount of the mRNA is increased by at least about 10% compared to the total amount of the mRNA encoding the target protein or the functional RNA produced in a control cell. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM regulates splicing at a splicing site sequence of a pre-mRNA encoding an mRNA, wherein the mRNA encodes a target protein or a functional RNA, and wherein the total amount of the mRNA, the target protein, and / or the functional RNA is at least 10% less than the total amount of the mRNA, the target protein, and / or the functional RNA in a control cell.

[0905] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, wherein the SMSM modulates splicing at a splice site sequence of a pre-mRNA encoding a first mRNA isoform and a second mRNA isoform associated with a disease or condition, wherein the total amount of the first mRNA isoform is reduced by at least about 10% compared to the total amount of the first mRNA isoform in a control cell, and / or the total amount of the second mRNA isoform is increased by at least about 10% compared to the total amount of the first mRNA isoform in a control cell. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell, the cell comprising an amount of a first mRNA isoform and an amount of a second mRNA isoform present in the cell; wherein the ratio of the first mRNA isoform to the second mRNA isoform is reduced by at least 1.2-fold; wherein the first mRNA and the second mRNA are encoded by a pre-mRNA comprising a splice site sequence, and wherein the first mRNA isoform is associated with a disease or condition and the second mRNA isoform.

[0906] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the SMSM modulates exon inclusion, exon exclusion, pseudoexon inclusion, intron retention, or splicing at a cryptic splice site of the polynucleotide, and wherein the SMSM modulates splicing of the splice site sequence. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the splice site sequence comprises a splice site sequence selected from the group consisting of splice site sequences of Table 2A, Table 2B, Table 2C, and Table 2D. A method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises a sequence selected from the group consisting of GGAguaag and AGAguaag. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises at least one bulge nucleotide at the -3, -2, -1, +1, +2, +3, +4, +5, or +6 position of the splice site sequence. In some embodiments, a method of modulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, wherein the splice site sequence comprises a mutant nucleotide at the -3, -2, -1, +1, +2, +3, +4, +5, or +6 position of the splice site sequence.

[0907] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of: NGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U, G, or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c, or g; k is g or u. In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating splicing of the polynucleotide, wherein the splice site sequence comprises a sequence selected from the group consisting of: NNBgunnnn, NNBhunnnn, and NNBgvnnnn; wherein N or n is A, U, G, or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c, or g; k is g or u. In some embodiments, the splice site sequence comprises a sequence selected from the group consisting of: NNBgurrrn, NNBguwwdn, NNBguvmvn, NNBguvbbn, NNBgukddn, NNBgubnbd, NNBhunngn, NNBhurmhd, and NNBgvdnvn; wherein N or n is A, U, G, or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c, or g; k is g or u. In some embodiments, the nucleotides at positions -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence are bulge nucleotides. In some embodiments, the nucleotides at positions -3, -2, -1, +1, +2, +3, +4, +5, or +6 of the splice site sequence are mutant nucleotides. In some embodiments, the splice site sequence comprises a sequence selected from the group consisting of: a splice site sequence of Table 2A, Table 2B, Table 2C, and Table 2D.

[0908] In some embodiments, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell comprising a polynucleotide having a splice site sequence, thereby regulating the splicing of the polynucleotide, wherein the polynucleotide is encoded by a gene selected from the group consisting of Table 2A, Table 2B, Table 2C, and Table 2D. In some embodiments, the gene is HTT. In some embodiments, regulating the splicing of the polynucleotide comprises inhibiting the skipping of exon 7. In some embodiments, the gene is DMD. In some embodiments, regulating the splicing of the polynucleotide comprises promoting the skipping of exon 51.

[0909] In addition, a method of regulating splicing comprises contacting a small molecule splicing modulator compound (SMSM) with a cell; wherein the SMSM interacts with an unpaired bulge nucleobase of an RNA duplex in the cell; wherein the duplex RNA comprises a splice site sequence; and wherein the SMSM regulates the splicing of the RNA duplex. In some embodiments, a method of regulating the relative position of a first nucleobase relative to a second nucleobase, wherein the first nucleobase and the second nucleobase are within a duplex RNA, the method comprising contacting a small molecule splicing modulator compound (SMSM) with the duplex RNA or a pharmaceutically acceptable salt thereof, wherein the first nucleobase is an unpaired bulge nucleobase of the RNA duplex; wherein the duplex RNA comprises a splice site sequence.

[0910] In some embodiments, the duplex RNA comprises a spiral. In some embodiments, before contacting with SMSM, the protruding core base is located on the outer part of the spiral of the duplex RNA. In some embodiments, SMSM forms one or more intermolecular interactions with the duplex RNA. In some embodiments, SMSM forms one or more intermolecular interactions with unpaired protruding core bases. In some embodiments, the intermolecular interaction is selected from the group comprising the following: ionic interaction, hydrogen bond, dipole-dipole interaction or van der Waals interaction. In some embodiments, the exchange rate of unpaired protruding core bases from the inside of the spiral of the duplex RNA to the outer part of the spiral is reduced. In some embodiments, the rotation rate of unpaired protruding core bases is reduced. In some embodiments, the rotation rate of unpaired protruding core bases around the phosphate backbone of the RNA chain of the RNA duplex is reduced. In some embodiments, after contacting SMSM, the distance between the unpaired protruding core base and the second core base of the duplex RNA is adjusted. In some embodiments, the distance between the unpaired protruding core base and the second core base of the duplex RNA is reduced. In some embodiments, the unpaired bulge nucleobase is located inside the helix of the duplex RNA. In some embodiments, the size of the bulge of the RNA duplex is reduced. In some embodiments, the bulge of the RNA duplex is removed or maintained. In some embodiments, the splicing at the splicing site of the RNA duplex is promoted. In some embodiments, after contacting SMSM, the base stacking of the unpaired bulge nucleobase in the RNA strand of the RNA duplex increases. In some embodiments, the distance between the unpaired bulge nucleobase and the second nucleobase of the duplex RNA increases or is maintained. In some embodiments, after contacting SMSM, the bulge of the RNA duplex is stabilized. In some embodiments, the unpaired bulge nucleobase is located on the outer part of the helix of the duplex RNA. In some embodiments, the size of the bulge of the RNA duplex increases. In some embodiments, the splicing at the splicing site of the RNA duplex is inhibited. In some embodiments, splicing is inhibited at the splicing site. In some embodiments, after contacting SMSM, the base stacking of the unpaired bulge nucleotides in the RNA strand of the RNA duplex is reduced. In some embodiments, the RNA duplex comprises pre-mRNA.

[0911] In some embodiments, a method of treating a subject with a tumor, comprising 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 with a tumor, comprising administering a small molecule splicing regulator compound (SMSM) to the subject, wherein the growth of the tumor is inhibited by at least 20. In some embodiments, a method of treating, preventing a condition or disease and / or delaying its progression, comprising administering a small molecule splicing regulator compound (SMSM) to a subject, wherein the SMSM regulates the splicing of a splicing site of a polynucleotide in a cell of the subject, wherein the condition or disease is associated with the splicing of the splicing site. In some embodiments, the subject suffers from a disease or condition. In some embodiments, a method of treating a subject with a disease or condition, comprising administering a small molecule splicing regulator compound (SMSM) to a subject suffering from a disease or condition selected from the group consisting of: diseases of Table 2A, Table 2B, Table 2C, and Table 2D. In some embodiments, a method of treating a subject with a disease or condition comprises administering a small molecule splicing modulator compound (SMSM) to a subject with the disease or condition, wherein the SMSM is selected from the group consisting of: SMSM of Table 1, Table 2, and Table 5. In some embodiments, a method of treating a subject with a disease or condition comprises administering a small molecule splicing modulator compound (SMSM) to a subject with the disease or condition, wherein the SMSM binds to a pre-mRNA comprising a splice site sequence selected from the group consisting of: splice site sequences of 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 an additional therapeutic molecule to the subject. In some embodiments, the SMSM is a compound described herein. In some embodiments, the SMSM is selected from the group consisting of: SMSM of Table 1, Table 2, and Table 5.

[0912] In some embodiments, regulating splicing comprises preventing, inhibiting or reducing splicing at a splice site sequence of the polynucleotide. In some embodiments, regulating splicing comprises enhancing, promoting or increasing splicing at a splice site sequence of the polynucleotide. In some embodiments, the splice site sequence is a 5' splice site sequence, a 3' splice site sequence, a branch point splice site sequence or a cryptic splice site sequence. In some embodiments, the splice site comprises a mutation, the splice site comprises a bulge, the splice site comprises a mutation and a bulge, the splice site does not include a mutation, the splice site does not include a bulge, or the splice site does not include a mutation and does not include a bulge. In some embodiments, the bulge is a bulge caused by a mutation. In some embodiments, the bulge nucleotide is a mutant nucleotide. In some embodiments, the bulge nucleotide is not a mutant nucleotide. In some embodiments, SMSM reduces the K of a splicing complex component to a polynucleotide. D In some embodiments, SMSM increases the K of splicing complex components to polynucleotides. D. In some embodiments, SMSM inhibits the binding of splicing complex components to polynucleotides at a splice site sequence, upstream of a splice site sequence, or downstream of a splice site sequence. In some embodiments, SMSM promotes the binding of splicing complex components to polynucleotides at a splice site sequence, upstream of a splice site sequence, or downstream of a splice site sequence. In some embodiments, the polynucleotide is RNA. In some embodiments, the RNA is pre-mRNA. In some embodiments, the RNA is a heterogeneous nuclear RNA. In some embodiments, the splice site sequence is a 5' splice site sequence, a 3' splice site sequence, a branch point (BP) splice site sequence, an exon splicing enhancer (ESE) sequence, an exon splicing silencer (ESS) sequence, an intron splicing enhancer (ISE) sequence, an intron splicing silencer (ISS) sequence, a polypyrimidine tract sequence, or any combination thereof. In some embodiments, the length of the polynucleotide is at least 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 250, 500, 750, 1,000, 2,000, 5,000, 10,000, 50,000, 100,000, 500,000 or 1,000,000 nucleotides. In some embodiments, SMSM binds to the splice site sequence of the polynucleotide. In some embodiments, SMSM interacts with the protrusion of the splice site sequence of the polynucleotide. In some embodiments, the polynucleotide comprises a cis-acting element sequence. In some embodiments, the cis-acting element sequence does not comprise a protrusion. In some embodiments, the cis-acting element sequence does not comprise a mutation. In some embodiments, the cis-acting element sequence includes a mutation, a protrusion or a combination thereof at 1-1000 nucleobases upstream or 1-1000 nucleobases downstream of the cis-acting element sequence. In some embodiments, the cis-acting element sequence comprises a regulatory element sequence, and the regulatory element sequence regulates the recruitment of splicing complex components to the polynucleotide. In some embodiments, the cis-acting element sequence comprises a regulatory element sequence, and the regulatory element sequence regulates the recruitment of spliceosomes to the polynucleotide. In some embodiments, the regulatory element sequence includes an exon splicing enhancer (ESE) sequence, an exon splicing silencer (ESS) sequence, an intron splicing enhancer (ISE) sequence, an intron splicing silencer (ISS) sequence, and combinations thereof. In some embodiments, SMSM binds to the splicing complex components.In some embodiments, the splicing complex components are 9G8, A1 hnRNP, A2 hnRNP, ASD-1, ASD-2b, ASF, B1 hnRNP, C1 hnRNP, C2 hnRNP, CBP20, CBP80, CELF, F hnRNP, FBP11, Fox-1, Fox-2, GhnRNP, H hnRNP, hnRNP 1, hnRNP 3, hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulatory protein (KSRP), L hnRNP, M hnRNP, mBBP, muscle-blind-like protein (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, SF3 a, SF3B, SFRS10, Sm protein, SR protein, SRm300, SRp20, SRp30c, SRP35C, SRP36, SRP38, SRp40, SRp55, SRp75, SRSF, STAR, GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR, TRA2, TRA2a / b, U hnRNP, U1snRNP, U11 snRNP, U12 snRNP, U1-C, U2snRNP, U2AF1-RS2, U2AF35, U2AF65, U4 snRNP, U5snRNP, 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, U6snRNA, U11 snRNA, U12 snRNA, U4atac snRNA, U5 snRNA, U6 atac 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, snRNP includes U1 snRNP, U2 snRNP, U4 snRNP, U5 snRNP, U6snRNP, U11 snRNP, U12 snRNP, U4atac snRNP, U5 snRNP, U6 atac snRNP or any combination thereof. In some embodiments, the protein is a serine / arginine-rich (SR) protein. In some embodiments, the splice site sequence comprises a base that does not match the base of the snRNA sequence. In some embodiments, the protrusion is due to a mismatch between the base pairing of the splice site sequence and the snRNA sequence.

[0913] In some embodiments, a method includes a method for up-regulating the expression of a native protein in a cell containing a DNA encoding the native protein, wherein the DNA comprises a mutation or no mutation, and the mutation causes the down-regulation of the native protein by its abnormal and / or alternative splicing. For example, the DNA can encode a pre-mRNA with a mutation or abnormal secondary or tertiary structure, thereby causing the down-regulation of one or more protein isoforms. The method may include introducing a small molecule provided herein to prevent abnormal splicing events into a cell, thereby removing native introns by correct splicing, and producing the native protein by the cell. In some embodiments, a method is provided, which includes introducing a small molecule provided herein to regulate alternative splicing events into a cell, to produce a protein with different functions from the protein produced by not regulating alternative splicing.

[0914] In some embodiments, a method includes a method for down-regulating the expression of the native protein in a cell comprising a DNA encoding a native protein, wherein the DNA comprises a mutation or no mutation, and the mutation causes the upregulation of the native protein by its abnormal and / or alternative splicing. For example, the DNA can encode a pre-mRNA with a mutation or abnormal secondary or tertiary structure, which causes the upregulation of one or more protein isoforms. The method may include introducing a small molecule provided herein to prevent abnormal splicing events into a cell, thereby removing the native introns by correct splicing, and producing the native protein by the cell. In some embodiments, a method is provided, which includes introducing a small molecule provided herein to regulate the alternative splicing events into a cell, to produce a protein with different functions from the protein produced by not regulating the alternative splicing. For example, a method may include preventing abnormal splicing and / or preventing alternative splicing events in a pre-mRNA molecule containing a mutation or abnormal secondary or tertiary structure. When present in a pre-mRNA, a mutation or abnormal secondary or tertiary structure may cause a pre-mRNA splicing error, and produce an abnormal mRNA or mRNA fragment different from the mRNA usually produced by a pre-mRNA without a mutation or abnormal secondary or tertiary structure. For example, a pre-mRNA molecule may include: (i) a first set of splicing elements defining a natural intron, which can be removed by splicing when there is no mutation or abnormal secondary or tertiary structure to produce a first mRNA molecule encoding a natural protein, and (ii) a second set of splicing elements induced by a mutation or abnormal secondary or tertiary structure, which defines an abnormal intron different from the natural intron, and when there is a mutation or abnormal secondary or tertiary structure, the abnormal intron is removed by splicing to produce an abnormal second mRNA molecule different from the first mRNA molecule. The method may include contacting a pre-mRNA molecule and / or other factors and / or elements of a splicing system as described herein (e.g., in a cell) with a compound as described herein to prevent or promote abnormal splicing events in the pre-mRNA molecule, thereby removing the natural intron by correct splicing and increasing the production of the natural protein in the cell.

[0915] In some embodiments, a method includes a method of upregulating RNA expression that would otherwise be downregulated by modulating alternative splicing events in the RNA. The method may include contacting pre-mRNA molecules and / or other elements and / or factors of the splicing system with a compound as described herein to modulate alternative splicing events, thereby inhibiting native splicing events and promoting alternative splicing events that upregulate RNA expression that is downregulated under the control of native splicing events.

[0916] In some embodiments, a method comprising downregulating RNA expression that would otherwise be upregulated by modulating alternative splicing events in the RNA. The method may include contacting pre-mRNA molecules and / or other elements and / or factors of the splicing system with a compound as described herein to modulate alternative splicing events, thereby inhibiting native splicing events and promoting alternative splicing events that downregulate RNA expression that is upregulated under the control of native splicing events.

[0917] The methods, compounds and compositions described herein have multiple uses. For example, they are useful in any process where it is necessary to have a means to downregulate the expression of the RNA to be expressed until a certain time, and thereafter it is necessary to upregulate the expression of the RNA. For this purpose, the RNA to be expressed can be any RNA encoding the protein to be produced, as long as the gene contains a natural intron. RNA can be mutated in any suitable manner, such as site-specific mutagenesis (see, T. Kunkel, U.S. Patent No. 4,873,192) to intentionally produce an abnormal second group of splicing elements, which defines an abnormal intron, which substantially downregulates the expression of the gene. The sequence encoding RNA can be inserted into a suitable expression vector by standard recombinant techniques, and the expression vector is inserted into a host cell (e.g., a eukaryotic cell such as yeast, insect or mammalian cell (e.g., human, rat)). Host cells can then be cultured in culture by standard techniques. When it is necessary to upregulate the expression of a mutant gene, a suitable compound of the present disclosure in a suitable preparation can be added to the culture medium to upregulate the expression of the gene.

[0918] Also provided herein is a method for changing the ratio of splice variants produced from a gene. The method may include contacting the pre-mRNA molecule and / or other elements and / or factors of the splicing system with one or more compounds as described herein to regulate alternative splicing events. One or more compounds disclosed herein may be used to act on 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 in the pre-mRNA. In some embodiments, the first splice variant may be downregulated or suppressed and / or the second splice variant may be upregulated, causing the ratio of the splice variants of two or more RNAs to change. In some embodiments, the first splice variant may be upregulated and the second splice variant may not be affected, thereby changing the ratio of RNA. In some embodiments, the first splice variant may be downregulated and the second splicing event may not be affected, thereby changing the ratio of RNA.

[0919] The methods, compounds, and formulations described herein can also be used as in vitro or in vivo tools to examine and modulate splicing events in human or animal RNA encoded by genes, such as those developmentally and / or tissue-regulated splicing events (e.g., alternative splicing events).

[0920] The compounds and formulations described herein can also be used as therapeutic agents for treating diseases involving abnormal and / or alternative splicing. Therefore, in some embodiments, a method for treating a subject suffering from a condition or disorder related to a selective or abnormal splicing event in a pre-mRNA molecule comprises administering to the subject a therapeutically effective amount of a compound described herein to regulate an alternative splicing event or prevent an abnormal splicing event, thereby treating the subject. The method can, for example, restore the correct splicing event in a pre-mRNA molecule. The method can, for example, utilize a small molecule compound described herein in a pharmaceutically acceptable carrier.

[0921] The preparations comprising the small molecules described herein may comprise a physiologically or pharmaceutically acceptable carrier, such as an aqueous carrier. Therefore, the preparations used in the methods described herein include, but are not limited to, those suitable for oral administration, parenteral administration, including subcutaneous, intradermal, intramuscular, intravenous and intraarterial administration, and topical administration (e.g., aerosolized preparations of inhalable particles are applied to the lungs of patients with cystic fibrosis or lung cancer, or transdermal creams or lotion preparations for psoriasis patients). The preparations may conveniently exist in unit dosage form and may be prepared by any method known in the art. In any given case, the most suitable route of administration may depend on the subject, the nature and severity of the disease being treated, and the specific active compound used, which will be easily determined by those skilled in the art.

[0922] Also provided herein are compounds described herein with the above-mentioned features for use in the preparation of a method for up-regulating or down-regulating the RNA expression in a patient suffering from a disease associated with an abnormal or alternative splicing of a pre-mRNA molecule as described above. In some embodiments, the drug up-regulates gene expression. In other embodiments, the drug down-regulates gene expression. In the manufacture of a drug according to the present disclosure, the compound can be mixed with, in particular, a pharmaceutically acceptable carrier. The carrier can be solid or liquid. One or more compounds can be incorporated into the preparations described herein in any combination, and the preparations can be prepared by any well-known pharmaceutical techniques, such as mixing the components and / or including one or more adjunctive therapeutic ingredients.

[0923] The inventors herein have identified low molecular weight compounds (sometimes referred to herein as small molecules) that block mRNA splicing and / or enhance (promote, strengthen) mRNA splicing. Splicing that can be regulated by the methods described herein includes alternative splicing, such as exon skipping, intron retention, pseudoexon skipping, exon exclusion, partial intron exclusion, etc. Depending on factors such as the splicing sequences involved and RNA (or genes encoding RNA) or exons, splicing regulation can be accomplished in the presence or absence of antisense oligonucleotides (AOs) specific for the target splicing sequences. In some embodiments, small molecules and AOs act synergistically.

[0924] In some aspects, a method includes contacting a splicing modulating compound (e.g., SMSM) with a pre-mRNA that modulates splicing of the pre-mRNA to facilitate expression of a transcript that promotes cell proliferation. For example, SMSM described herein can increase one or more isoforms of a transcript that promotes cell proliferation. For example, SMSM described herein can reduce expression of one or more isoforms of a transcript that prevents or inhibits cell proliferation.

[0925] In some aspects, a method includes contacting a splicing modulating compound (e.g., SMSM) with a pre-mRNA that modulates the splicing of the pre-mRNA to facilitate expression of a transcript that prevents or inhibits cell proliferation. For example, SMSM described herein can increase one or more isoforms of a transcript that prevents or inhibits cell proliferation. For example, SMSM described herein can reduce expression of one or more isoforms of a transcript that promotes cell proliferation.

[0926] In some embodiments, a method of regulating splicing of a pre-mRNA comprises using SMSM to reduce the expression or function of one or more isoforms of a transcript in a subject. The method may include administering SMSM or a composition comprising SMSM to a subject, wherein the SMSM binds to a pre-mRNA or a splicing complex component and regulates the splicing of the pre-mRNA to favor the expression of one or more isoforms of the transcript. The method may include administering SMSM or a composition comprising SMSM to a subject, wherein the SMSM binds to a pre-mRNA or a splicing complex component and regulates the splicing of the pre-mRNA to disfavor the expression of one or more isoforms of the transcript.

[0927] In some embodiments, the present disclosure provides a method of treating a subject suffering from a disease or condition associated with abnormal splicing of pre-mRNA. The method may include administering SMSM or a composition comprising SMSM to the subject, wherein the SMSM binds to pre-mRNA or a splicing complex component and regulates the splicing of pre-mRNA to inhibit the expression of one or more isoforms of the transcript. The method may include administering SMSM or a composition comprising SMSM to the subject, wherein the SMSM binds to pre-mRNA or a splicing complex component and regulates the splicing of pre-mRNA to increase the expression of one or more isoforms of the transcript.

[0928] Many diseases are associated with the expression of abnormal gene products (e.g., RNA transcripts or proteins) of genes. For example, an abnormal number of RNA transcripts may lead to disease due to corresponding changes in protein expression. Changes in the number of specific RNA transcripts may be caused by a variety of factors. First, changes in the number of RNA transcripts may be due to abnormal transcription levels of specific genes, such as perturbations of transcription factors or parts of the transcription process, resulting in changes in the expression level of specific RNA transcripts. Secondly, changes in the splicing of specific RNA transcripts, such as perturbations of specific splicing processes or genetic mutations that lead to modified splicing, may change the level of specific RNA transcripts. Changes in the stability of specific RNA transcripts or changes in components that maintain the stability of RNA transcripts, such as the poly-A tail incorporation process or the effects on certain factors or proteins that bind and stabilize RNA transcripts, may lead to changes in the level of specific RNA transcripts. The translation level of specific RNA transcripts can also affect the number of these transcripts, affecting or upregulating the decay process of RNA transcripts. Finally, abnormal RNA transport or RNA sequestration may also lead to changes in the functional level of RNA transcripts and may affect the stability, further processing or translation of RNA transcripts.

[0929] In some embodiments, provided herein are methods of regulating the amount of one, two, three or more RNA transcripts encoded by a pre-mRNA, comprising contacting a cell with a SMSM compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is contacted with a SMSM compound or a pharmaceutically acceptable salt thereof in a cell culture. In other embodiments, the cell is contacted with a SMSM compound or a pharmaceutically acceptable salt thereof in a subject (e.g., a non-human animal subject or a human subject).

[0930] In some embodiments, provided herein are methods for treating, preventing, and / or delaying the progression of a disease or disorder, comprising administering to a subject, particularly a mammal, an effective amount of a small molecule splicing regulator as described herein.

[0931] In some embodiments, provided herein are compositions and methods for treating diseases or conditions, including spatial modulator compounds or pharmaceutically acceptable salts thereof that promote the prevention or correction of exon skipping of pre-mRNA. The present disclosure also provides for increasing mature mRNA production in cells of subjects in need thereof (e.g., subjects that can benefit from an increase in protein production), and then increasing compositions and methods for protein production. The present disclosure also provides for reducing mature mRNA production in cells of subjects in need thereof (e.g., subjects that can benefit from a reduction in protein production), and then reducing compositions and methods for protein production. In one embodiment, the described method can be used to treat subjects with diseases or conditions caused by gene mutations, including missense, splicing, frameshift and nonsense mutations, and full gene deletions, which result in insufficient protein production. In another embodiment, the described method can be used to treat subjects with diseases or conditions that are not caused by gene mutations. In some embodiments, the compositions and methods of the present disclosure are used to treat subjects with diseases or conditions, and the subjects can benefit from increased production of proteins. In some embodiments, the compositions and methods of the present disclosure are used to treat a subject with a disease or condition that can benefit from increased production of a protein. In some embodiments, the compositions and methods of the present disclosure are used to treat a subject with a disease or condition that can benefit from decreased production of a protein.

[0932] In some embodiments, provided herein is a method for treating a disease or condition in a subject in need thereof by increasing the expression of a target protein or functional RNA of a subject's cell, wherein the cell has a mutation causing, for example, exon skipping or intron inclusion or a portion thereof of a pre-mRNA, wherein the pre-mRNA encodes a target protein or functional RNA. The method may include contacting a subject's cell with a SMSM compound or a pharmaceutically acceptable salt thereof targeting a pre-mRNA encoding a target protein or functional RNA or a splicing complex component, thereby preventing or inhibiting exon splicing from a pre-mRNA encoding a target protein or functional RNA, thereby increasing the level of mRNA encoding a target protein or functional RNA, and increasing the expression of a target protein or functional RNA in a subject's cell. In some embodiments, also disclosed herein is a method for increasing expression of a target protein of a cell having a mutation causing exon skipping of a pre-mRNA or an abnormal secondary or tertiary RNA structure, wherein the pre-mRNA comprises a mutation causing exon skipping or an abnormal secondary or tertiary RNA structure. The method may include contacting a cell with a SMSM compound or a pharmaceutically acceptable salt thereof targeting a pre-mRNA encoding a target protein or functional RNA, thereby preventing or inhibiting exon splicing from a pre-mRNA encoding a target protein or functional RNA, thereby increasing the level of RNA encoding a functional protein, and increasing the 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 enhances or replaces a target protein or functional RNA that is insufficient in quantity or activity in a subject. In some embodiments, the cell is in a subject with a condition caused by insufficient quantity or activity of a protein, or from the subject. In some embodiments, the insufficient amount of the target protein is caused by a haploinsufficient dose of the target protein, wherein the subject has a first allele encoding a functional target protein, and a second allele from which the target protein is not produced or a second allele encoding a non-functional target protein, and wherein the SMSM compound or a pharmaceutically acceptable salt thereof is bound to the targeting portion of the 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 by an mRNA in which exons are skipped or deleted. 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 with the pre-mRNA. In some embodiments, the SMSM compound or a pharmaceutically acceptable salt thereof increases the amount of the target protein or functional RNA by regulating the selective splicing of the pre-mRNA transcribed from the 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 regulating abnormal splicing resulting from a mutation in a gene encoding the target protein or functional RNA.

[0933] In some embodiments, the total amount of mRNA encoding the target protein or functional RNA produced in cells contacted with the 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 the target protein or functional RNA produced in control cells.

[0934] In some embodiments, the total amount of mRNA encoding the target protein or functional RNA produced in cells contacted with the 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%, 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% as compared to the total amount of mRNA encoding the target protein or functional RNA produced in control cells.

[0935] 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%, 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% as compared to the total amount of target protein produced by control cells.

[0936] In some embodiments, the total amount of mRNA encoding the target protein or functional RNA produced in cells contacted with the SMSM compound or a pharmaceutically acceptable salt thereof is increased by at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times compared to the total amount of mRNA encoding the target protein or functional RNA produced in control cells. In some embodiments, the total amount of mRNA encoding the target protein or functional RNA produced in cells contacted with the SMSM compound, or a pharmaceutically acceptable salt thereof, increases by about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 6 times, about 1.1 to about 7 times, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, or about 4 to about 9 times compared to the total amount of mRNA encoding the target protein or functional RNA produced in control cells.

[0937] 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 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 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 6 times, about 1.1 to about 7 times, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, or about 4 to about 9 times compared to the total amount of target protein produced by control cells.

[0938] In some embodiments, the total amount of mRNA encoding the target protein or functional RNA produced in cells contacted with the 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 the target protein or functional RNA produced in control cells.

[0939] In some embodiments, the total amount of mRNA encoding the target protein or functional RNA produced in cells contacted with the SMSM compound or a pharmaceutically acceptable salt thereof is reduced by 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 2 ... To about 70%, 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%.

[0940] 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 reduced by 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%, about 20% to about 8 ... %, 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%.

[0941] In some embodiments, the difference between the amount of 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 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%, about 20% to about 100%, about 20% to about 150%, about 20% to about 20 ...300%, about 100% to about 300%, 00%, 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 200%, about 200% to about 250%, at least about 200%, 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 between the amount of 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 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%, about 20% to about 100%, about 20% to about 150%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 30 ... 0%, 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 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%.

[0942] In some embodiments, the difference between the amount of 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 increased by about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 6 times, about 1.1 to about 10 ... about 7 times, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, about 4 to about 9 times, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times. In some embodiments, the difference between the amount of 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 increased by about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 10 ... about 6 times, about 1.1 to about 7 times, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, about 4 to about 9 times, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times.

[0943] In some embodiments, the difference in the amount between the first splice variant and the second splice variant encoding the target protein or functional RNA isoform produced in cells contacted with an SMSM compound or a pharmaceutically acceptable salt thereof is reduced 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%, about 20% to about 100%, about 20% to about 150%, about 20% to about 20 ...300%, about 100% to about 300%, 00%, 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 200%, about 200% to about 250%, at least about 200%, 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 between the amount of 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 reduced 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%, about 20% to about 100%, about 20% to about 150%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 150%, about 20% to about 300%, about 20% to about 50%, about 20% to about 100%, about 20% to about 150%, about 20% to about 300%, about 20% to about 300%, about 20% to about 50%, about 20% to about 150%, about 20% to about 30 ... 0%, 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 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%.

[0944] In some embodiments, the difference between the amount of 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 reduced by about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 6 times, about 1.1 to about 10 ... about 7 times, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, about 4 to about 9 times, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times. In some embodiments, the difference between the amount of 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 reduced by about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 10 ... about 6 times, about 1.1 to about 7 times, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, about 4 to about 9 times, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times.

[0945] The ratio of the first isoform to the second isoform can result in many disorders and diseases. In some embodiments, a subject without a disorder or disease has a ratio of the first isoform to the second isoform of 1:1. In some embodiments, a subject with a disorder 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.

[0946] In some embodiments, the combination of SMSM compounds and pre-m-RNA prevents the splicing of one or more exons and / or introns and / or proteins thereof from the pre-mRNA population to produce mRNA encoding a target protein or functional RNA. In some embodiments, the cell comprises a pre-mRNA population transcribed from a gene encoding a target protein or functional RNA, wherein the pre-mRNA population comprises a mutation that causes one or more exons to be spliced ​​out, and wherein the SMSM compound or a pharmaceutically acceptable salt thereof is bound to a mutation that causes one or more exons to be spliced ​​out in the pre-mRNA population. In some embodiments, the SMSM compound or a pharmaceutically acceptable salt thereof is bound to a mutation that causes one or more exons to be spliced ​​out to prevent the splicing of one or more exons from the pre-mRNA population to produce mRNA encoding a 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 is bound to the targeting portion of the pre-mRNA.

[0947] In some embodiments, the binding of a SMSM compound or a pharmaceutically acceptable salt thereof catalyzes the inclusion of a deleted exon or the removal of an unwanted retained intron or portion thereof, thereby producing healthy mRNA and protein. In some embodiments, the binding of a SMSM compound or a pharmaceutically acceptable salt thereof has little to no effect on non-diseased cells.

[0948] In some embodiments, SMSM has an IC of less than 50 nM.50 Kill cells. In some embodiments, the cells are primary cells. In some embodiments, SMSM has 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. 50 Kill cells.

[0949] In some embodiments, SMSM regulates splicing at the polynucleotide splice site sequence of primary cells. In some embodiments, SMSM regulates the proliferation or survival of primary cells. In some embodiments, primary cells are primary diseased cells. In some embodiments, primary diseased cells are primary cancer cells. In some embodiments, SMSM is present at a concentration of at least about 1nM, 10nM, 100nM, 1μM, 10μM, 100μM, 1mM, 10mM, 100mM or 1M. In some embodiments, at least about 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: Formula (I) in A is -CR A =CR A -; E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Each R A independently selected from the group consisting of 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 a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is -O- or -S-; Z is CR 2 ; 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; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 (i) are the same and selected from the group consisting of hydrogen and deuterium, or (ii) are the same and selected from the group consisting of F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0; b is 0; c is 1; and d is 1, provided that the compound is not a compound in Table 3 or Table 4.

2. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in A is -CR A =CR A -; E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Each R A independently selected from the group consisting of 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 a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is -O- or -S-; Z is CR 2 ; 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; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium; a is 0; b is 0; c is 1; and d is 1, provided that the compound is not a compound in Table 3.

3. A compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in A is -CR A =CR A -; E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Each R A independently selected from the group consisting of 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 a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is -O- or -S-; Z is CR 2 ; 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; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 and R 17 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0; b is 0; c is 1; and d is 1, provided that the compound is not a compound in Table 4.

4. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in A is -CR A =CR A -; E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Each R A independently selected from the group consisting of 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 a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is -O- or -S-; Z is CR 2 ; 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; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 (i) are the same and selected from the group consisting of hydrogen and deuterium, or (ii) are the same and selected from the group consisting of F, -OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0; b is 0; c is 1; and d is 1, provided that the compound is not a compound in Table 3 or Table 4.

5. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in A is -CR A =CR A -; E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Each R A independently selected from the group consisting of 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 a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is -O- or -S-; Z is CR 2 ; 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; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are identical and are selected from the group consisting of: hydrogen and deuterium; a is 0; b is 0; c is 1; and d is 1, provided that the compound is not a compound in Table 3.

6. A compound of formula (II) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof: in A is -CR A =CR A -; E is -NR-, -O-, -S-, -S(=O)-, -S(=O)2-, or -S(=O)(=NR E )-; R E is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted C2-C3 alkenyl or substituted or unsubstituted C2-C3 alkynyl; Each R A independently selected from the group consisting of 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 a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; X is -O- or -S-; Z is CR 2 ; 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; Each R 1 are independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3 or substituted or unsubstituted C1-C4 haloalkyl; Each R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 and R 20 independently selected from the group consisting of hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; R 15 and R 18 are the same and are selected from the group consisting of: F, –OR 1 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl and substituted or unsubstituted C1-C4 heteroalkyl; a is 0; b is 0; c is 1; and d is 1, provided that the compound is not a compound in Table 4.

7. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (A):

8. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has the structure of formula (B):

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the compound of formula (I) has a structure of formula (C):

10. The compound according to any one of claims 4 to 6, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein R 19 For F.

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