[go: up one dir, main page]

WO2024251211A1 - Compositions, méthodes et systèmes pour moduler l'épissage de msh3 - Google Patents

Compositions, méthodes et systèmes pour moduler l'épissage de msh3 Download PDF

Info

Publication number
WO2024251211A1
WO2024251211A1 PCT/CN2024/097830 CN2024097830W WO2024251211A1 WO 2024251211 A1 WO2024251211 A1 WO 2024251211A1 CN 2024097830 W CN2024097830 W CN 2024097830W WO 2024251211 A1 WO2024251211 A1 WO 2024251211A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
haloalkyl
hydroxyalkyl
agent
aminoalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/097830
Other languages
English (en)
Inventor
Jinxing LI
Paul R. August
Mary MCMAHON
Xing Tang
Peng YUE
Jacqueline SALOTTI
Sridhar NARAYAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Revir Therapeutics Inc
Original Assignee
Revir Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Revir Therapeutics Inc filed Critical Revir Therapeutics Inc
Publication of WO2024251211A1 publication Critical patent/WO2024251211A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • nucleotide repeat expansion of nucleotides CAG is the leading cause of Huntington’s disease, where a subject having the CAG repeat expansion at low abundance does not exhibit any symptoms.
  • the CAG nucleotide repeat accumulates (or expands) , leading to manifestation of symptoms of Huntington’s disease.
  • treatment options for nucleotide repeat expansion diseases or conditions are limited and ineffective. Often times, there is no cure once the subject exhibits symptoms associated with the nucleotide repeat expansion disease or condition. Treatment options at this particular timepoint is now only limited to palliative care.
  • compositions, methods, and systems for treating nucleotide repeat expansion diseases or conditions There is an unmet need for compositions, methods, and systems to prevent or decrease nucleotide repeat expansions in a subject. This disclosure addresses this unmet need.
  • a method for modulating splicing of MSH3 pre-mRNA comprising contacting a cell with an agent which modulates splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced, thereby modulating splicing of MSH3 pre-mRNA.
  • a method for treating a disease or condition in a subject comprising administering to the subject an agent which modulates splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced in a cell of the subject, thereby treating the disease or condition.
  • the method results in decreased expression of MSH3 protein in the cell. In some cases, the method results in decreased nucleotide repeat expansion of a target gene in the cell. In some cases, the nucleotide repeat expansion comprises a trinucleotide repeat expansion. In some cases, the nucleotide repeat expansion comprises expansion of a four-nucleotide repeat, a five-nucleotide repeat, a six-nucleotide repeat, a seven-nucleotide repeat, an eight-nucleotide repeat, a nine-nucleotide repeat, a ten-nucleotide repeat, an eleven-nucleotide repeat, or a twelve-nucleotide repeat.
  • the nucleotide repeat expansion is in an exon of the target gene. In some cases, the nucleotide repeat expansion is in an intron of the target gene. In some cases, the nucleotide repeat expansion is in a UTR of the target gene. In some cases, the nucleotide repeat expansion is in a promoter of the target gene.
  • the gene is selected from the group consisting of: ATN1, HTT, AR, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, TCF4, JPH3, DMPK, ATXN8, ZNF713, FMR1, AFF/FMR2, FXN, ZFN9, ATXN10, NOP56, C9orf72, CSTB, and any combination thereof.
  • the nucleotide repeat expansion in the cell comprises at least 20 repeats, at least 30 repeats, at least 40 repeats, at least 50 repeats, at least 60 repeats, at least 70 repeats, at least 80 repeats, at least 90 repeats, at least 100 repeats, at least 200 repeats, at least 500 repeats, at least 1000 repeats, at least 2000 repeats, at least 5000 repeats, at least 10, 000 repeats, or at least 20, 000 repeats.
  • the nucleotide repeat expansion in the target gene is decreased by at least about 0.1 fold, at least about 0.2 fold, at least about 0.5 fold, at least about 1.0 fold, at least about 2.0 fold, at least about 5.0 fold, at least about 10.0 fold, or at least about 100.0 fold, as compared to a level of nucleotide repeat expansion in the target gene in the absence of the agent.
  • the poison exon comprises a nucleic acid sequence that has at least about 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 1.
  • the poison exon is or comprises exon 21A, or a portion thereof, of MSH3.
  • the poison exon is located at or within position chr5: 80832901-80832994 of Human Genome Assembly hg38 of December 2013.
  • the poison exon comprises a nucleic acid sequence that has at least about 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3.
  • the poison exon is or comprises exon 14A_1, or a portion thereof, of MSH3.
  • the poison exon is or comprises exon 14A_2, or a portion thereof, of MSH3.
  • the poison exon is located at or within position chr5: 80763222-80763369 or position chr5: 80763222-80767932 of Human Genome Assembly hg38 of December 2013.
  • the poison exon is selected from the group consisting of any one of the poison exons listed in Table 1 or Table 2.
  • the poison exon introduces a premature termination codon (PTC) into the MSH3 mRNA transcript.
  • the agent forms a complex with the MSH3 pre-mRNA and a spliceosomal RNA.
  • the agent increases binding of a spliceosomal RNA to the MSH3 pre-mRNA.
  • the spliceosomal RNA comprises a small nuclear RNA (snRNA) .
  • the snRNA is selected from the group consisting of: U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, U6 snRNA, and any combination thereof.
  • the snRNA comprises U1 snRNA.
  • the agent is selected from the group consisting of: a small molecule, a polypeptide, an oligosaccharide, a polysaccharide, an oligonucleotide, an aptamer, a ribonucleoprotein (RNP) , an enzyme, a nuclease, and any combination thereof.
  • the agent is a small molecule.
  • the disease or condition is a nucleotide repeat disorder.
  • the disease or condition is selected from the group consisting of: dentatorubropallidoluysian atrophy (DRPLA) , Huntington’s disease (HD) , spinal and bulbar muscular atrophy (SBMA) , spinocerebellar ataxia (SCA) type 1, spinocerebellar ataxia (SCA) type 2, spinocerebellar ataxia (SCA) type 3, spinocerebellar ataxia (SCA) type 6, spinocerebellar ataxia (SCA) type 7, spinocerebellar ataxia (SCA) type 8, spinocerebellar ataxia (SCA) type 10, spinocerebellar ataxia (SCA) type 12, spinocerebellar ataxia (SCA) type 17, spinocerebellar ataxia (SCA) type 31, spinocerebellar ataxia (SCA) type 36, spinocerebellar ataxia (SCA) type 37, spinocerebellar ataxia (SCA) type
  • a system comprising: (a) an MSH3 pre-mRNA; (b) a spliceosomal RNA; and (c) an agent which modulates splicing of the MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising the poison exon is produced.
  • the system further comprises the MSH3 mRNA transcript comprising the poison exon.
  • the agent, the MSH3 pre-mRNA, and the spliceosomal RNA are in a complex.
  • the agent is an agent that induces binding of the spliceosomal RNA to the MSH3 pre-mRNA.
  • the poison exon introduces a premature termination codon into the MSH3 mRNA.
  • the poison exon comprises a nucleic acid sequence that has at least 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 1.
  • the poison exon is or comprises exon 21A, or a portion thereof, of MSH3.
  • the poison exon is located at or within position chr5: 80832901-80832994 of Human Genome Assembly hg38 of December 2013.
  • the poison exon comprises a nucleic acid sequence that has at least 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3.
  • the poison exon is or comprises exon 14A_1, or a portion thereof, of MSH3. In some cases, the poison exon is or comprises exon 14A_2, or a portion thereof, of MSH3. In some cases, the poison exon is located at or within position chr5: 80763222-80763369 or position chr5: 80763222-80767932 of Human Genome Assembly hg38 of December 2013. In some cases, the poison exon is selected from the group consisting of any one of the poison exons listed in Table 1 or Table 2. In some cases, the MSH3 pre-mRNA and the spliceosomal RNA are partially complementary.
  • the spliceosomal RNA comprises a small nuclear RNA (snRNA) .
  • the snRNA is selected from the group consisting of: U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, U6 snRNA, and any combination thereof.
  • the snRNA comprises U1 snRNA.
  • the agent is selected from the group consisting of: a small molecule, a polypeptide, a carbohydrate, a monosaccharide, a oligosaccharide, a polysaccharide, an oligonucleotide, an aptamer, a biologic, a ribonucleoprotein (RNP) , and any combination thereof.
  • the agent comprises a small molecule.
  • a vessel containing the system of any one of the preceding is provided.
  • the vessel is selected from the group consisting of: a vial, a tube, a plate, and a dish.
  • an mRNA transcript comprising an MSH3 mRNA and at least one poison exon.
  • the at least one poison exon comprises a nucleic acid sequence that has at least about 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 1.
  • the at least one poison exon is or comprises exon 21A, or a portion thereof, of MSH3.
  • the at least one poison exon is located at or within position chr5: 80832901-80832994 of Human Genome Assembly hg38 of December 2013.
  • the at least one poison exon comprises a nucleic acid sequence that has at least about 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3.
  • the at least one poison exon is or comprises exon 14A_1, or a portion thereof, of MSH3.
  • the at least one poison exon is or comprises exon 14A_2, or a portion thereof, of MSH3.
  • the poison exon is located at or within position chr5: 80763222-80763369 or position chr5: 80763222-80767932 of Human Genome Assembly hg38 of December 2013.
  • the at least one poison exon is selected from the group consisting of any one of the poison exons listed in Table 1 or Table 2. In some cases, the at least one poison exon introduces a premature termination codon (PTC) into the MSH3 mRNA.
  • PTC premature termination codon
  • a cell comprising the mRNA transcript of any one of the preceding is provided.
  • a method of screening for an agent that modulates splicing of an MSH3 pre-mRNA comprising: (a) contacting a cell with a candidate agent; (b) detecting presence or absence of a poison exon in an MSH3 mRNA transcript; and (c) identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when the poison exon is detected in the MSH3 mRNA transcript.
  • the detecting comprises sequencing the MSH3 mRNA transcript.
  • the detecting comprises detecting an amount of the MSH3 mRNA transcript comprising the poison exon.
  • the detecting comprises determining a level of MSH3 protein expression.
  • the identifying comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when the level of MSH3 protein expression is decreased as compared to a level of MSH3 protein expression in the absence of the candidate agent.
  • the detecting comprises determining or measuring a level of MSH3 mRNA transcript.
  • the identifying comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when the level of MSH3 mRNA transcript is decreased as compared to a level of MSH3 mRNA transcript in the absence of the candidate agent.
  • the detecting comprises detecting viability of the cell.
  • the identifying comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when viability is decreased as compared to in the absence of the candidate agent.
  • the method further comprises contacting the cell with an inhibitor of nonsense-mediated decay (NMD) .
  • the inhibitor of NMD is cycloheximide.
  • the method further comprises determining that the poison exon leads to NMD of the MSH3 mRNA transcript when a level of the MSH3 mRNA transcript is decreased in the absence of the inhibitor of NMD, and a level of the MSH3 mRNA transcript is increased in the presence of the inhibitor of NMD.
  • the method further comprises contacting a plurality of cells with a library of candidate agents, wherein each cell of the plurality of cells is contacted with a different candidate agent.
  • an agent that modulates splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced, for use in a method of treatment of the human or animal body by therapy.
  • an agent that modulates splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced, for use in a method of treatment of an expansion repeat disorder.
  • the expansion repeat disorder is selected from the group consisting of: wherein the disease or condition is selected from the group consisting of: dentatorubropallidoluysian atrophy (DRPLA) , Huntington’s disease (HD) , spinal and bulbar muscular atrophy (SBMA) , spinocerebellar ataxia (SCA) type 1, spinocerebellar ataxia (SCA) type 2, spinocerebellar ataxia (SCA) type 3, spinocerebellar ataxia (SCA) type 6, spinocerebellar ataxia (SCA) type 7, spinocerebellar ataxia (SCA) type 8, spinocerebellar ataxia (SCA) type 10, spinocerebellar ataxia (SCA) type 12,
  • the agent of any of the preceding is a compound having the structure of Formula (I”) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -OCH 2 -, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • R 3 and one of R 4 are taken together to form a 5 or 6-membered heterocycloalkylene or 5 or 6-membered heteroarylene;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 5 , R 6 , R 7 or R 8 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6 membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -O- (C 1 -C 6 alkylene) -5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • the agent is a compound having the structure of Formula (I’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • each R 2 is independently hydrogen.
  • D is CR 6 or E is CR 7 .
  • R 6 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some cases, R 6 is hydrogen. In some cases, ring C is a 6-membered heterocycloalkyl. In some cases, ring C is piperidine, piperazine, or morpholine. In some cases, ring C is piperazine. In some cases, ring C is piperidine.
  • Z is N or CH
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; and
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 9 is hydrogen
  • X is -O-or -NR 3 -.
  • X is absent
  • the compound has the structure of Formula (II’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is bond, -CH 2 -, -O-, -S-, or -NR 3 -;
  • Z is CH or N, wherein when X is -O-, -S-, or -NR 3 -, then Z is CH;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • X is -CH 2 -, -O-, -S-, or -NR 3 -; and Z is CH. In some cases, X is bond and Z is N. In some cases, each A is independently N or CH, wherein two of A are N. In some cases, is In some cases, is In some cases, is In some cases, is
  • compound has the structure of Formula (III’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • R 1 are taken together to form a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 1 are taken together to form a C 1 -C 3 alkylene.
  • the compound of Formula (III’ ) has the structure of Formula (IIIa’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y is C 1 -C 3 alkylene. In some cases, Y is -CH 2 CH 2 -.
  • the compound of Formula (III’ ) has the structure of Formula (IIIb’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 1 is independently hydrogen, halogen, or C 1 -C 6 alkyl. In some cases, each R 1 is independently hydrogen or methyl.
  • X is -O-or -NR 3 -. In some cases, X is -O-. In some cases, X is -NR 3 -. In some cases, R 3 is hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl. In some cases, R 3 is hydrogen, methyl, ethyl, or cyclopropyl. In some cases, R 3 is hydrogen or methyl.
  • compound has the structure of Formula (IV’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • Z is CH or N
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Z is CH. In some cases, Z is N. In some cases, two R 1 are taken together to form a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e . In some cases, two R 1 are taken together to form a C 1 -C 3 alkylene. In some cases, two R 1 are taken together to form a C 3 -C 6 cycloalkyl.
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, or hydroxyalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 1 is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R 1 is independently hydrogen or methyl.
  • A is N.
  • A is CH.
  • B is CR 5 .
  • B is N.
  • R 5 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 5 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • B is CH.
  • F is CR 8 .
  • F is N.
  • R 8 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 8 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • E is CR 7 . In some cases, E is N.
  • R 7 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 7 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • E is CH.
  • ring G a 5 to 6-membered heteroaryl optional substituted with 1 or 4 substituents selected from R e .
  • ring G is a 5-membered heteroaryl optional substituted with 1 or 2 substituents selected from R e .
  • ring G is pyrrole, imidazole, triazole, tetrazole, thiophene, oxazole, thiazole, or thiadiazole.
  • ring G is:
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ;
  • each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; and
  • q 0, 1, 2, or 3.
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl;
  • each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl;
  • q 0, 1, or 2.
  • each R 10 is independently -F, -Cl, methyl, ethyl, -OCH 3 , -CF 3 , -CHF 2 , or -CH 2 F.
  • each R 10a is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD 3 , -CF 3 , CHF 2 , CH 2 F, -CH 2 CF 3 , -CH 2 SO 2 CH 3 , cyclopropyl, oxetanyl,
  • ring G is a 6-membered heteroaryl optional substituted with 1 to 4 substituents selected from R e .
  • ring G is pyridine, pyrimidine, or triazine.
  • ring G is:
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; and
  • q 0, 1, 2, or 3.
  • each R 10 is independently -OCH 3 or -N (CH 3 ) 2 ; and q is 0, 1, or 2.
  • ring G is a 9 or 10-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and optional substituted with 1 to 4 substituents selected from R e .
  • ring G is a 9-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N; and optional substituted with 1 to 4 substituents selected from R e .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl, wherein each of the alkyl, haloalkyl, and hydroxyalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl, wherein each of the alkyl, haloalkyl, and hydroxyalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; and
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, and haloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R a is independently C 1 -C 6 alkyl
  • each R b is independently hydrogen or C 1 -C 6 alkyl
  • R c and R d are each independently hydrogen or C 1 -C 6 alkyl.
  • each R a is independently methyl, ethyl, isopropyl, or tert-butyl;
  • each R b is independently hydrogen, methyl or ethyl
  • R c and R d are each independently hydrogen, methyl, or ethyl.
  • each R e is independently -F, -OH, -CF 3 , -CHF 2 , -OCH 3 , or methyl.
  • the compound is selected from a compound of Table 3A, Table 3B, Table 3C, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound is selected from the group consisting of:
  • the compound is provided in a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of the preceding, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient.
  • FIG. 1A and FIG. 1B illustrate progression of nucleotide repeat expansion during a subject’s lifespan.
  • FIG. 1A illustrates manifestation of a nucleotide repeat expansion disease or condition triggered by the accumulation of the nucleotide repeat expansion.
  • FIG. 1B illustrates the nucleotide repeat expansion occurring at an allelic level.
  • FIG. 2 illustrates a flowchart of nucleotide repeat expansion mechanism.
  • nucleotide repeat expansion forms a hairpin in the DNA (top) , where the presence of the hairpin recruits MutS homolog (MSH) complexes for repairing the hairpin (middle) .
  • MSH MutS homolog
  • the repair of the hairpin creates a gap in the genome, where the gap is filled with additional nucleotide repeats, leading to nucleotide repeat expansion (bottom) .
  • FIG. 3 illustrates compounds capable of downregulating MSH3 mRNA expression, where the decreased expression of MSH3 can inhibit repair and the subsequent nucleotide repeat expansion of a target gene.
  • FIG. 4 illustrates the presence of an exemplary poison exon in a gene.
  • Exon n and Exon n+1 are spliced together in an mRNA transcript to encode a functional protein.
  • the poison is typically spliced out of the mRNA transcript.
  • PTC Premature Termination Codon
  • the mRNA transcript comprising the poison exon instead of being translated into a functional protein, is degraded by endogenous cellular mechanisms such as nonsense-mediated mRNA decay (NMD) .
  • NMD nonsense-mediated mRNA decay
  • FIG. 5 illustrates a non-limiting illustration of an exemplary agent of the disclosure in a complex with the pre-mRNA and the U1 snRNA.
  • the agent may enhance binding and/or stabilization of the U1 snRNA to the pre-mRNA comprising the poison exon.
  • FIG. 5 discloses SEQ ID NO: 12.
  • FIG. 6 illustrates screening and identifying of poison exons in the MSH3 gene that can be modulated by agents of the disclosure.
  • FIG. 7 illustrates examples of agents of the disclosure that modulate the splicing of Exon 21A into the MSH3 mRNA transcript.
  • FIG. 8 illustrates splicing and mRNA expression changes for targets regulated by an agent of the disclosure.
  • Compound 1 and CHX increased poison exon expression (Exon 21A) and decreased total RNA (e.g., due to NMD) .
  • FIG. 9 illustrates splicing and mRNA expression changes for targets regulated by an agent of the disclosure.
  • Compound 1 and CHX increased poison exon expression (Exon 14A_1 or Exon 14A_2) and decreased total RNA (e.g., due to NMD) .
  • FIGS. 10A-10C illustrate an exemplary system for screening and validating an agent of the disclosure.
  • FIG. 11A illustrates MSH3 total expression (assay spanning exons 13/14) in cells treated with an exemplary compound of the disclosure.
  • FIG. 11B illustrates MSH3 PE5 expression (assay spanning exons 13/14A) in cells treated with an exemplary compound of the disclosure.
  • FIG. 12A illustrates MSH3 total expression (assay spanning exons 20/21) in cells treated with an exemplary compound of the disclosure.
  • FIG. 12B illustrates MSH3 PE4 expression (assay spanning exons 20/21A) in cells treated with an exemplary compound of the disclosure.
  • FIG. 12C illustrates MSH3 protein expression in cells treated with an exemplary compound of the disclosure.
  • FIG. 13 illustrates modulation of splicing of MSH3 poison exon 14A in cynomolgus monkey and human cells treated with an exemplary compound of the disclosure, as determined by RT-PCR.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1 - 6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Carbocycle refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3-to 10-membered monocyclic rings, 6-to 12-membered bicyclic rings, and 6-to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • halogen substituted alkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane) , di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane) , 1-haloethane, 2-haloethane, 1, 2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1, 2-dihalopropane, 1, 3-dihalopropane, 2, 3-dihalopropane, 1, 2, 3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc. ) .
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 - C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • Nucleotide repeat expansion may be caused by a wild-type (WT) allele first having certain nucleotide repeats (e.g., CAG repeat for Huntington’s disease) .
  • WT wild-type
  • CAG repeat for Huntington’s disease e.g., CAG repeat for Huntington’s disease
  • FIG. 1A and FIG. 1B illustrate this concept. Without wishing to be bound by theory, as illustrated by FIG.
  • nucleotide repeats are thought to lead to formation of a hairpin loop in the genome, where the hairpin loop serves as a substrate for repair complexes such as MutS homolog (MSH) complexes for repairing the hairpin loop.
  • MSH MutS homolog
  • FIG. 2 depicts components of the MutS homolog (MSH) complex that may be targeted for modulating the repair of the nucleotide repeat. For example, by modulating and inhibiting expression of MSH3, the repair of the nucleotide repeat is inhibited or decreased, thus decreasing nucleotide repeat expansion.
  • compositions, methods, and systems for modulating splicing of MSH3 pre-mRNA such that the resulting MSH3 mRNA transcript includes at least one poison exon introduces a Premature Termination Codon (PTC) into the mRNA transcript, and leads to elimination of the MSH3 mRNA transcript containing the PTC (s) by, e.g., the nonsense-mediated mRNA decay (NMD) pathway. Elimination of the MSH3 mRNA transcript may lead to reduced expression of MSH3 protein.
  • PTC Premature Termination Codon
  • compositions, methods, and systems provided herein generally involve the use of agents (e.g., small molecules) that modulate the splicing of MSH3 pre-mRNA such that the resulting MSH3 mRNA transcript includes the poison exon (s) .
  • agents e.g., small molecules
  • the agent may enhance and/or stabilize binding of small nuclear RNA (e.g., U1 snRNA) to the pre-mRNA transcript, thereby causing splicing in of the poison exon into the MSH3 mRNA.
  • the agent may form a complex with the snRNA (e.g., U1 snRNA) and the pre-mRNA transcript.
  • compositions, methods, and systems for treating a disease or condition e.g., using the agents provided herein
  • the disease or condition is an expansion repeat disease or condition.
  • a method for modulating splicing of MSH3 pre-mRNA comprising contacting a cell with an agent which modulates splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced, thereby modulating splicing of MSH3 pre-mRNA.
  • a method for treating a disease or condition in a subject comprising administering to the subject an agent which modulates splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced in a cell of the subject, thereby treating the disease or condition.
  • the disease or condition described herein is associated with a gene comprising a nucleotide repeat expansion as described herein. Table 6 illustrates examples of diseases or conditions associated with a gene having a nucleotide repeat expansion that may be treated using the compositions, methods, and systems provided herein.
  • a system comprising: (a) an MSH3 pre-mRNA; (b) a spliceosomal RNA; and (c) an agent which modulates splicing of the MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising the poison exon is produced.
  • compositions comprising an agent for modulating splicing of MSH3 pre-mRNA such that an MSH3 mRNA transcript comprising a poison exon is produced.
  • a vessel containing any system of the disclosure.
  • the vessel may be selected from the group consisting of: a vial, a tube, a plate, and a dish.
  • a cell is provided containing any system of the disclosure.
  • an mRNA transcript comprising an MSH3 mRNA and at least one poison exon, as described herein.
  • the mRNA transcript is non-naturally occurring (e.g., ., does not exist in nature in the absence of the compositions, methods, and systems provided herein) .
  • the compositions, methods, and systems provided herein involve modulating splicing of MSH3 pre-mRNA such that the MSH3 mRNA transcript contains a poison exon.
  • the poison exon comprises a nucleic acid sequence that has at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%sequence identity to the nucleic acid sequence of SEQ ID NO: 1.
  • the poison exon consists of or comprises the nucleic acid sequence of SEQ ID NO: 1, or a portion thereof.
  • the poison exon consists of or comprises Exon 21A, or a portion thereof, of MSH3.
  • the poison exon is located at or within position chr5: 80832901-80832994 of Human Genome Assembly hg38 of December 2013.
  • the poison exon comprises a nucleic acid sequence that has at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%sequence identity to SEQ ID NO: 2 or SEQ ID NO: 3.
  • the poison exon consists of or comprises the nucleic acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3, or a portion thereof.
  • the poison exon consists of or comprises Exon 14A_1, or a portion thereof, of MSH3.
  • the poison exon consists of or comprises Exon 14A_2, or a portion thereof, of MSH3.
  • the poison exon is located at or within position chr5: 80763222-80763369 or position chr5: 80763222-80767932 of Human Genome Assembly hg38 of December 2013. In some embodiments, the poison exon is selected from the group consisting of any one of the poison exons listed in Table 1. In some embodiments, the poison exon introduces a premature termination codon (PTC) into the MSH3 mRNA transcript. In some embodiments, the poison exon may comprise a splice donor site according to any one of the splice donor sites described in Table 2. In some embodiments, the poison exon may be located at any of the chromosomal locations described in Table 2. In some embodiments, the poison exon may comprise a PTC beginning at a chromosomal location as described in Table 2.
  • PTC premature termination codon
  • the poison exon can decrease expression of the MSH3 mRNA transcript in a cell.
  • the poison exon is a cryptic exon that is not normally spliced into the MSH3 mRNA.
  • the poison exon is an exon that is not spliced into the MSH3 mRNA, in the absence of an agent that modulates splicing of the MSH3 pre-mRNA, as disclosed herein.
  • the MSH3 mRNA transcript comprising the poison exon that is produced by the compositions, methods, and systems provided herein is a non-naturally occurring MSH3 mRNA transcript.
  • the MSH3 mRNA comprising the poison exon that is produced by the compositions, methods, and systems provided herein does not ordinarily occur in nature, absent intervention with the agent provided herein.
  • the poison exon is spliced into the MSH3 mRNA transcript when contacted with an agent described herein.
  • the poison exon when spliced into the MSH3 mRNA transcript, decreases expression of the MSH3 mRNA transcript.
  • the poison exon introduces a PTC into the MSH3 mRNA transcript.
  • the PTC directs the MSH3 mRNA transcript for degradation, thereby decreasing expression of the MSH3 mRNA transcript.
  • the MSH3 mRNA transcript is degraded by nonsense-mediated mRNA decay (NMD) .
  • NMD nonsense-mediated mRNA decay
  • MSH3 expression is decreased by at least 0.1 fold, at least 0.2 fold, at least 0.5 fold, at least 1.0 fold, at least 2.0 fold, at least 5.0 fold, at least 10.0 fold, or at least about 100.0 fold, compared to a level of MSH3 in absence of the agent.
  • the compositions, methods, and systems provided herein involve the use of an agent that induces splicing of a poison exon into MSH3 mRNA transcript.
  • the agent may form a complex with the MSH3 pre-mRNA (e.g., at the poison exon) and a small nuclear RNA (snRNA) (e.g., U1 snRNA) .
  • snRNA small nuclear RNA
  • the agent may enhance and/or stabilize binding of the snRNA to the MSH3 pre-mRNA (e.g., at the poison exon) , such that a poison exon is spliced into the MSH3 mRNA.
  • the snRNA is part of the spliceosome. In some embodiments, the snRNA is complexed with small nuclear ribonucleoproteins (snRNP) . In some embodiments, the snRNA is a spliceosomal RNA. In some embodiments, the snRNA is a U1 spliceosomal RNA. In some embodiments, the presence of the poison exon in the MSH3 mRNA transcript leads to elimination or reduction of MSH3 mRNA transcript such that expression of the MSH3 protein is reduced. Generally, the poison exon introduces a premature termination codon (PTC) into the MSH3 mRNA transcript.
  • PTC premature termination codon
  • the poison exon induces degradation of the MSH3 mRNA transcript by an endogenous mechanism such as nonsense-mediated mRNA decay (NMD) .
  • the MSH3 pre-mRNA comprising the poison exon, the agent, and the snRNA are in a complex.
  • the agent causes splicing of the poison exon into the MSH3 mRNA transcript (i.e., in the absence of the agent, the poison exon is spliced out of the MSH3 mRNA transcript) .
  • the agent is a compound, such as a small molecule.
  • the agent is any compound disclosed herein.
  • the agent is for use in a method of treatment of the human or animal body by therapy.
  • the agent is for use in a method of treatment of a nucleotide expansion repeat disease or condition.
  • the spliceosomal RNA comprises a small nuclear RNA (snRNA) .
  • the snRNA is selected from the group consisting of: U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, U6 snRNA, and any combination thereof.
  • the snRNA comprises U1 snRNA.
  • the snRNA comprises U2 snRNA.
  • the snRNA comprises U4 snRNA.
  • the snRNA comprises U5 snRNA.
  • the snRNA comprises U6 snRNA.
  • the MSH3 pre-mRNA and the spliceosomal RNA are partially complementary. In some embodiments, the MSH3 pre-mRNA and the U1 snRNA are partially complementary. In some embodiments, the MSH3 pre-mRNA and the U2 snRNA are partially complementary. In some embodiments, the MSH3 pre-mRNA and the U4 snRNA are partially complementary. In some embodiments, the MSH3 pre-mRNA and the U5 snRNA are partially complementary. In some embodiments, the MSH3 pre-mRNA and the U6 snRNA are partially complementary.
  • the MSH3 pre-mRNA and the spliceosomal RNA are partially complementary, where the complexing between the MSH3 pre-mRNA and the spliceosomal RNA is caused by an agent described herein.
  • the agent described herein induces the complexing between the MSH3 pre-mRNA and the spliceosomal RNA.
  • the agent upon complexing with the MSH3 pre-mRNA and the spliceosomal RNA, induces splicing in of the poison exon into the MSH3 mRNA.
  • the poison exon and the spliceosomal RNA are partially complementary. In some embodiments, the poison exon and the U1 snRNA are partially complementary. In some embodiments, the poison exon and the U2 snRNA are partially complementary. In some embodiments, the poison exon and the U4 snRNA are partially complementary. In some embodiments, the poison exon and the U5 snRNA are partially complementary. In some embodiments, the poison exon and the U6 snRNA are partially complementary.
  • the poison exon and the spliceosomal RNA are partially complementary, where the complexing between the poison exon and the spliceosomal RNA is caused by an agent described herein.
  • the agent described herein induces the complexing between the poison exon and the spliceosomal RNA.
  • the agent upon complexing with the poison exon and the spliceosomal RNA, induces splicing in of the poison exon into the MSH3 mRNA.
  • the agent is selected from the group consisting of: a small molecule, a polypeptide, an oligosaccharide, a polysaccharide, an oligonucleotide, an aptamer, a ribonucleoprotein (RNP) , an enzyme, a nuclease (e.g., a Cas nuclease) , and any combination thereof.
  • the agent comprises a gene editing tool, (e.g., CRISPR/Cas, TALENs, zinc finger nucleases, homing endonucleases or meganucleases, etc. ) for targeting and inclusion of a poison exon into MSH3.
  • a gene editing tool e.g., CRISPR/Cas, TALENs, zinc finger nucleases, homing endonucleases or meganucleases, etc.
  • the agent is a small molecule.
  • the agent is any molecule or compound described herein.
  • the compound is represented by Formula (I” ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -OCH 2 -, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • R 3 and one of R 4 are taken together to form a 5 or 6-membered heterocycloalkylene or 5 or 6-membered heteroarylene;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 5 , R 6 , R 7 or R 8 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6 membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -O- (C 1 -C 6 alkylene) -5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • the compound is represented by Formula (I’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently halogen.
  • each R 2 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently C 1 -C 6 alkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently C 1 -C 6 haloalkyl.
  • each R 2 is independently C 1 -C 6 hydroxyalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently C 1 -C 6 aminoalkyl. In some embodiments of Formula (I”) , (I’ ) , or (I) , each R 2 is independently -OH. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently hydrogen.
  • D is CR 6 . In some embodiments of Formula (I”) , (I’ ) , or (I) , D is N.
  • R 6 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 7 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 6 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 7 is hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 6 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 7 is hydrogen.
  • R 7 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 6 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 7 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 6 is hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 7 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 6 is hydrogen.
  • ring C is a 4 to 10-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 4 to 8-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 4 to 6-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 6-membered heterocycloalkenylene.
  • ring C is a 7-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 8-membered heterocycloalkenylene.
  • ring C is a is a 4 to 10-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a is a 4 to 8-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a is a 4 to 6-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 4-membered heterocycloalkyl.
  • ring C is a 5-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 6-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 7-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 8-membered heterocycloalkyl.
  • ring C is piperidine, piperazine, or morpholine. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is piperidine. In some embodiments of Formula (I”) , (I’ ) , or (I) , ring C is piperazine. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is morpholine.
  • Z is CH or N
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; and
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; and
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 9 is hydrogen
  • each R 1 is independently hydrogen or C 1 -C 6 alkyl
  • R 9 is hydrogen
  • the compound is represented by Formula (II’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is bond, -CH 2 -, -O-, -S-, or -NR 3 -, wherein
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • Z is CH or N, when X is -O-, -S-, or -NR 3 -, then Z is CH;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Formula (I” ) , (I’ ) , or (II’ ) two of A are N. In some embodiments of Formula (I” ) , (I’ ) , or (II’ ) , three of A are N. In some embodiments of Formula (I” ) , (I’ ) , or (II’ ) , each A is N. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , or (II’ ) , is
  • the compound is represented by Formula (III’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e .
  • R 9 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of Formula (II) , (II’ ) , (III) , or (III’ ) , R 9 is hydrogen or C 1 -C 6 alkyl. In some embodiments of Formula (II) , (II’ ) , (III) , or (III’ ) , R 9 is C 1 -C 6 haloalkyl.
  • R 9 is C 1 -C 6 alkyl. In some embodiments of Formula (II) , (II’ ) , (III) , or (III’ ) , R 9 is hydrogen.
  • two R 1 are taken together to form a bond, C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e .
  • two R 1 are taken together to form a bond.
  • two R 1 are taken together to form a C 1 -C 3 alkylene.
  • two R 1 are taken together to form or a C 1 -C 3 heteroalkylene.
  • the compound of Formula (III’ ) has the structure of Formula (IIIa’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y is C 1 -C 3 alkylene
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • X is -CH 2 -, -O-, or -NR 3 -, wherein
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Y is -CH 2 CH 2 CH 2 -. In some embodiments of Formula (IIIa’ ) , Y is -CH 2 CH 2 -. In some embodiments of Formula (IIIa’ ) , Y is -CH 2 -.
  • the compound of Formula (III’ ) has the structure of Formula (IIIb’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is -CH 2 -, -O-, -S-, or -NR 3 -, wherein
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Formula (II’ ) when X is -O-, -S-, or -NR 3 -, then Z is CH. In some embodiments of Formula (II) or (II’ ) , when X is bond, then Z is CH or N. In some embodiments of Formula (II) or (II’ ) , when X is bond, then Z is N. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is CH or N. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is CH. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is N. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is N.
  • X is -O-, -S-, or -NR 3 -.
  • X is -O-or -NR 3 -.
  • X is -S-.
  • X is -O-.
  • X is -NR 3 -.
  • X is -NH-.
  • X is -NCH 3 -.
  • X is -CH 2 . In some embodiments of Formula (I” ) , X is -OCH 2 -.
  • X is absent.
  • R 3 is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 hydroxyalkyl. In some embodiments of Formula (I” ) , (I’ ) , (II’ ) , (IIIa’ ) , or (IIIb) , R 3 is C 3 -C 6 cycloaalkyl.
  • R 3 is cyclopropyl or cyclobutyl. In some embodiments of Formula (I” ) , (I’ ) , (II’ ) , (III’ ) , (IIIa’ ) , or (IIIb’ ) , R 3 is cyclopropyl.
  • R 3 is hydrogen or C 1 -C 3 alkyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , or (IIIb’ ) , R 3 is C 1 -C 3 hydroxyalkyl.
  • R 3 is C 1 -C 3 haloalkyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , or (IIIb’ ) , R 3 is C 1 -C 3 alkyl.
  • R 3 is hydrogen or methyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , or (IIIb’ ) , R 3 is methyl.
  • R 3 is hydrogen.
  • the compound is represented by Formula (IV’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • Z is CH or N
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Z is N. In some embodiments of Formula (II) , (II’ ) , (IV) , or (IV’ ) , Z is CH.
  • At least one of A is N.
  • each A is N.
  • each A is independently CR 4 .
  • each A is independently N or CH.
  • each A is CH.
  • E is CR 7 .
  • F is CR 8 .
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 1 is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R 1 is independently C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently -CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -CF 3 , or -CHF 2 .
  • each R 1 is independently hydrogen, -CH 3 , -CH 2 CH 3 , or -CH (CH 3 ) 2 .
  • each R 1 is independently halogen.
  • each R 1 is independently Cl, Br, or F.
  • each R 1 is independently F.
  • each R 1 is independently hydrogen.
  • two R 1 are taken together to form a C 3 -C 6 cycloalkyl.
  • two R 1 are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • two R 1 are taken together to form a cyclopropyl.
  • two R 1 are taken together to form a cyclobutyl.
  • two R 1 are taken together to form a cyclopentyl.
  • two R 1 are taken together to form a cyclohexyl.
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R 4 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R 4 is independently hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • each R 4 is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R 4 is independently halogen. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , or (II’ ) , each R 4 is independently C 1 -C 6 alkyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , or (II’ ) , each R 4 is independently hydrogen.
  • R 3 and one of R 4 are taken together to form a 5 or 6-membered heterocycloalkylene or 5 or 6-membered heteroarylene.
  • R 5 , R 6 , R 7 or R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl.
  • R 5 , R 6 , R 7 or R 8 are independently hydrogen, halogen, -CN, C 3 -C 6 cycloalkyl, or 5 to 10-membered heteroaryl.
  • R 5 is 5 to 10-membered heteroaryl
  • R 6 , R 7 and R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • R 6 is 5 to 10-membered heteroaryl; and R 5 , R 7 and R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • R 7 is 5 to 10-membered heteroaryl; and R 5 , R 6 and R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • R 8 is 5 to 10-membered heteroaryl; and R 5 , R 6 and R 7 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • B is CR 5 , wherein R 5 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and F is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and E is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and F is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; B is N; and F is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; E is N; and F is N.
  • F is CR 8 , wherein R 8 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and E is N.
  • R 5 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 5 C 1 -C 6 alkyl In some embodiments of Formula (I”) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , R 5 C 1 -C 6 alkyl.
  • R 5 is C 1 -C 6 haloalkyl.
  • R 5 is C 1 -C 6 hydroxyalkyl.
  • R 5 is halogen or hydrogen.
  • R 5 is halogen.
  • R 5 is hydrogen.
  • R 5 is fluorine.
  • R 5 is chlorine.
  • R 6 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, and hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 6 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 6 is C 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 haloalkyl.
  • R 6 is C 1 -C 6 hydroxyalkyl.
  • R 6 is halogen or hydrogen.
  • R 6 is halogen.
  • R 6 is hydrogen.
  • R 7 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, and hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 7 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 7 is C 1 -C 6 alkyl.
  • R 7 is C 1 -C 6 haloalkyl.
  • R 7 is C 1 -C 6 hydroxyalkyl.
  • R 7 is halogen or hydrogen.
  • R 7 is halogen.
  • R 7 is hydrogen.
  • R 7 is flourine.
  • R 7 is chlorine.
  • R 7 is hydroxyl. In some embodiments of Formula (I’ ) , (I) , (II) , (III) , (IIIa) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , R 7 is methoxy.
  • R 8 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 8 is C 1 -C 6 alkyl.
  • R 8 is C 1 -C 6 haloalkyl.
  • R 8 is C 1 -C 6 hydroxyalkyl.
  • R 8 is halogen or hydrogen.
  • R 8 is halogen.
  • R 8 is hydrogen.
  • R 8 is flourine.
  • R 8 is chlorine.
  • ring G is a 5 to 6-membered heteroaryl optional substituted with 1 or 4 substituents selected from R 10 .
  • ring G is a 5-membered heteroaryl optional substituted with 1 or 2 substituents selected from R 10 .
  • ring G is pyrrole, imidazole, triazole, tetrazole, thiophene, oxazole, thiazole, or thiadiazole.
  • ring G is pyrrole, imidazole, oxazole, triazole, thiazole, or thiadiazole.
  • ring G is pyrrole, imidazole, oxazole, or thiadiazole.
  • ring G is pyrrole.
  • ring G is imidazole.
  • ring G is thiadiazole.
  • ring G is oxazole.
  • ring G is:
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ;
  • each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; and
  • q 0, 1, 2, or 3.
  • each R10 is independently halogen, -CN, -NO2, -OH, -ORa, C1 C6alkyl, C1 C6haloalkyl, C3-C6cycloalkyl, or 4 to 6-membered heterocycloalkyl; each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl; and p is 0, 1, or 2.
  • Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) is: In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , is: In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , is: In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (III’
  • ring G is a 6-membered heteroaryl optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is pyridine, pyrimidine, or triazine.
  • ring G is pyridine.
  • ring G is pyrimidine.
  • ring G is triazine.
  • ring G is:
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; and
  • q 0, 1, 2, or 3.
  • ring G is an 8 to 10-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is a 10-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is an 8-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is an 8-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is imidazo [1, 2-a] pyrazine, imidazo [1, 2-a] pyrimidine, pyrazolo [1, 5-a] pyridine, pyrazolo [1, 5-a] pyrimidine, or 2-methyl-2H-indazole.
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with
  • each R 10 is independently -CN, -NO 2 , -OH, -OR a , or -NR c R d .
  • each R 10 is independently -OH or -OR a .
  • each R 10 is independently -OH or -OMe.
  • each R 10 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl.
  • each R 10 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl.
  • each R 10 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
  • each R 10 is independently C 1 -C 6 haloalkyl.
  • each R 10 is independently -CF 3 , -CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • each R 10 is independently -CF 3 or -CHF 2 .
  • each R 10 is independently C 1 -C 6 alkyl.
  • each R 10 is independently methyl, ethyl, isopropyl, or tert-butyl.
  • each R 10 is independently methyl. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb) , (IV) , or (IV’ ) , each R 10 is independently methyl. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10 is independently halogen.
  • each R 10 is independently fluorine or chlorine.
  • each R 10 is independently fluorine.
  • each R 10 is independently chlorine.
  • each R 10 is independently -F, -Cl, -CN, methyl, ethyl, -OCH 3 , -CF 3 , -CHF 2 , or -CH 2 F.
  • each R 10 is independently -F, -Cl, methyl, -CF 3 , or -CHF 2 .
  • each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl.
  • each R 10a is independently C 3 -C 6 cycloalkyl.
  • each R 10a is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each R 10a is independently cyclopropyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently cyclopropyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently cyclopropyl.
  • each R 10a is independently 4 to 6-membered heterocycloalkyl.
  • each R 10a is independently 4-membered heterocycloalkyl.
  • each R 10a is independently 5-membered heterocycloalkyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently 6-membered heterocycloalkyl.
  • each R 10a is independently oxatanyl.
  • each R 10a is independently C 1 -C 6 haloalkyl.
  • each R 10a is independently -CF 3 , -CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • each R 10a is independently C 1 -C 6 alkyl.
  • each R 10a is independently methyl, ethyl, isopropyl, or tert-butyl.
  • each R 10a is independently methyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently hydrogen.
  • each R 10a is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD 3 , -CF 3 , CHF 2 , CH 2 F, -CH 2 CF 3 , -CH 2 SO 2 CH 3 , cyclopropyl, oxetanyl,
  • p is an integer from 1-9. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is an integer from 1-9. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is an integer from 1-8.
  • p is an integer from 1-6. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is an integer from 1-6. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is an integer from 1-4.
  • p is 1, 2, 3, 4, 5, 6, 7, or 8.
  • p is 1, 2, 3, 4, 5, or 6.
  • p is 1, 2, 3, or 4.
  • p is 1, 2, 3, 4, 5, or 6.
  • p is 1, 2, or 3.
  • p is 1, 2, 3, 4, 5, or 6.
  • p is 1 or 2. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1 or 2. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1, 2, 3, 4, 5, or 6.
  • p is 2. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1.
  • q is 1, 2, or 3. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , q is 3.
  • q is 1 or 2. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , q is 2.
  • q is 1. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , q is 0.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R a is independently methyl, ethyl, isopropyl, tert-butyl, -OCH 3 , -CF 3 , or -CHF 2 , In some embodiments of a compound disclosed herein, each R a is independently methyl, ethyl, isopropyl or tertbutyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, -OCH 3 , -CF 3 , or -CHF 2 , In some embodiments of a compound disclosed herein, each R b is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or methyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl.
  • each R c and R d are independently hydrogen methyl, ethyl, isopropyl, tert-butyl, -OCH 3 , -CF 3 , or -CHF 2 , In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, methyl, ethyl, isopropyl, or tert- butyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or methyl. In some embodiments of a compound disclosed herein, each R c and R d are methyl.
  • each R e is independently halogen, -CN, -OH, or C 1 -C 6 alkyl.
  • each R e is independently halogen, -OH, or C 1 -C 6 alkyl.
  • each R e is independently halogen or C 1 -C 6 alkyl.
  • each R e is independently halogen.
  • each R e is independently -F, -OH, -CF 3 , -CHF 2 , -OCH 3 , or methyl.
  • each R e is independently -F, -CF 3 , -CHF 2 , or methyl.
  • each R e is methyl.
  • one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R a , R b , R c , R d , and R e groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R a , R b , R c , R d , and R e .
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R a , R b , R c , R d , and R e is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof is one of the compounds in Table 3A, Table 3B, or Table 3C.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof is one of the compounds Table 4. In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is one of the compounds in Table 5.
  • the agent is a compound selected from the group consisting of:
  • the agent is a compound that modulates splicing of the MSH3 pre-mRNA such that a poison exon is spliced into the MSH3 mRNA transcript.
  • the agent that modulates splicing of the MSH3 pre-mRNA such that a poison exon is spliced into the MSH3 mRNA transcript is selected from any compound from Table 3A, Table 3B, or Table 3C.
  • the agent that modulates splicing of the MSH3 pre-mRNA such that a poison exon is spliced into the MSH3 mRNA transcript is selected from any compound from Table 4.
  • the agent that modulates splicing of the MSH3 pre-mRNA such that a poison exon is spliced into the MSH3 mRNA transcript is selected from any compound from Table 5.
  • the agent is an agent that modulates splicing of the MSH3 pre-mRNA as described herein and does not modulate splicing of other genes. In some cases, the agent that modulates splicing of the MSH3 pre-mRNA as described herein and does not modulate splicing of other genes is selected from Table 4.
  • the agent modulates splicing of the MSH3 pre-mRNA as described herein, and also modulates splicing of at least one other gene.
  • a single agent species can be used to modulate splicing of more than one gene.
  • the agent can modulate splicing of MSH3 pre-mRNA as described herein, and can modulate splicing of HTT pre-mRNA.
  • the agent that modulates splicing of both MSH3 pre-mRNA and HTT pre-mRNA is selected from Table 5.
  • reducing expression of MSH3 results in decreased nucleotide repeat expansion of a target gene in a cell.
  • the nucleotide repeat expansion comprises a trinucleotide repeat expansion.
  • the nucleotide repeat expansion comprises expansion of a four-nucleotide repeat, a five-nucleotide repeat, a six-nucleotide repeat, a seven-nucleotide repeat, an eight-nucleotide repeat, a nine-nucleotide repeat, a ten-nucleotide repeat, an eleven-nucleotide repeat, or a twelve-nucleotide repeat.
  • the nucleotide repeat expansion is in an exon of the target gene.
  • the nucleotide repeat expansion is in an intron of the target gene.
  • the nucleotide repeat expansion is in a UTR of the target gene. In some embodiments, the nucleotide repeat expansion is in a promoter of the target gene. In some embodiments, the nucleotide repeat expansion in the cell comprises at least 20 repeats, at least 30 repeats, at least 40 repeats, at least 50 repeats, at least 60 repeats, at least 70 repeats, at least 80 repeats, at least 90 repeats, at least 100 repeats, at least 200 repeats, at least 500 repeats, at least 1000 repeats, at least 2000 repeats, at least 5000 repeats, at least 10,000 repeats, or at least 20,000 repeats.
  • the method decreases nucleotide repeat expansion in the target gene by at least about 0.1 fold, at least about 0.2 fold, at least about 0.5 fold, at least about 1.0 fold, at least about 2.0 fold, at least about 5.0 fold, at least about 10.0 fold, or at least about 100.0 fold, as compared to a level of nucleotide repeat expansion in the target gene in the absence of the agent.
  • the target gene is selected from the group consisting of: ATN1, HTT, AR, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, TCF4, JPH3, DMPK, ATXN8, ZNF713, FMR1, AFF/FMR2, FXN, ZFN9, ATXN10, NOP56, C9orf72, CSTB, and any combination thereof.
  • the target gene is associated with a nucleotide repeat expansion disease or condition.
  • the nucleotide repeat expansion disease or condition is selected from the group consisting of: dentatorubropallidoluysian atrophy (DRPLA) , Huntington’s disease (HD) , spinal and bulbar muscular atrophy (SBMA) , spinocerebellar ataxia (SCA) type 1, spinocerebellar ataxia (SCA) type 2, spinocerebellar ataxia (SCA) type 3, spinocerebellar ataxia (SCA) type 6, spinocerebellar ataxia (SCA) type 7, spinocerebellar ataxia (SCA) type 8, spinocerebellar ataxia (SCA) type 10, spinocerebellar ataxia (SCA) type 12, spinocerebellar ataxia (SCA) type 17, spinocerebellar ataxia (SCA) type 31, spinocerebellar ataxia (SCA) type 36, spinocerebellar ataxia (SCA) type 37, spinocerebellar at
  • compositions, methods, and systems may be used to treat any one of the nucleotide repeat expansion diseases or conditions provided herein.
  • Table 6 illustrates non- limiting examples of diseases or conditions associated with a gene having a nucleotide repeat expansion (e.g., that can be treated by the compositions, methods, and systems provided herein) .
  • the method comprises: contacting a cell with a candidate agent; detecting presence or absence of a poison exon in an MSH3 mRNA transcript; and identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when the poison exon is detected in the MSH3 mRNA transcript.
  • the detecting comprises sequencing the MSH3 mRNA transcript.
  • the detecting comprises detecting an amount of the MSH3 mRNA transcript comprising the poison exon.
  • the detecting comprises determining a level of MSH3 protein expression.
  • the identifying comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when the level of MSH3 protein expression is decreased as compared to a level of MSH3 protein expression in the absence of the candidate agent.
  • the detecting comprises determining or measuring a level of MSH3 mRNA transcript.
  • the method comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when the level of MSH3 mRNA transcript is decreased as compared to a level of MSH3 mRNA transcript in the absence of the candidate agent.
  • the method comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA and the pre-mRNA of at least one additional gene.
  • the detecting comprises detecting viability of the cell.
  • the identifying comprises identifying the candidate agent as an agent that modulates splicing of the MSH3 pre-mRNA when viability of the cell is decreased as compared to in the absence of the candidate agent.
  • the method further comprises contacting the cell with an inhibitor of nonsense-mediated decay (NMD) .
  • NMD nonsense-mediated decay
  • the inhibitor of NMD is cycloheximide.
  • the method further comprises determining that the poison exon leads to NMD of the MSH3 protein when a level of MSH3 protein expression is decreased in the absence of the inhibitor of NMD, and a level of MSH3 protein expression is increased in the presence of the inhibitor of NMD. In some embodiments, the method further comprises contacting a plurality of cells with a library of candidate agents, wherein each cell of the plurality of cells is contacted with a different candidate agent.
  • the method comprises screening for candidate agents by contacting the candidate agents with a poison exon comprising nucleic acid mutation for enhancing an output associated with the contacting of the candidate agents and the poison axon comprising the nucleic acid mutation.
  • an engineered minigene donor e.g., by mutating endogenous trinucleotides to CAG as shown in FIG. 8 and FIG. 9 can drive expression of a luciferase reporter gene.
  • FIG. 10B illustrates minigene PCR showing the presence of the poison exon comprising the CAG mutation.
  • the wild-type (WT) mRNA did not have the poison exon as confirmed by the decreased nucleotide length.
  • FIG. 10A an engineered minigene donor (e.g., by mutating endogenous trinucleotides to CAG as shown in FIG. 8 and FIG. 9) can drive expression of a luciferase reporter gene.
  • FIG. 10B illustrates minigene PCR showing the presence of the poison
  • the output can be the luciferase signal.
  • the output comprises RNASeq readout.
  • the output comprises detecting cell viability of a cell comprising the MSH3 pre-mRNA comprising the poison exon and the spliceosomal RNA.
  • output comprises a reporter signal, said reporter signal is encoded by the MSH3 pre-mRNA comprising the poison exon.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited 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.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids 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, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein exist as solvates.
  • the disclosure provides for methods of treating diseases by administering the compounds in the form of such solvates.
  • the disclosure provides for methods of treating diseases by administering a composition comprising the compounds in the form of such solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • the compounds and salts of Formulas (I) , (II) , (III) , (IIIa) , (IIIb) , and (IV) can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases may be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
  • DIPEA N, N-Diisopropylethylamine
  • LAH Lithium aluminum hydride
  • PCC Pyridinium chlorochromate
  • rt or RT Room temperature, ambient, about 25 °C
  • Step 1 To a solution of 2-methylpropan-2-yl 1, 5-dimethyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (2.50 g, 9.87 mmol) in THF (30 mL) was added LiHMDS (15.8 mL, 15.8 mmol) at -65 °C. The reaction was stirred for 1.5 h and then TMSCl (1.6 mL, 12.83 mmol) was added and the reaction mixture stirring at -78 °C for another 2 h. After the reactants were consumed, the reaction was diluted with EA and H 2 O.
  • Step 2 To a solution of 2-methylpropan-2-yl 1, 5-dimethyl-3- [ (trimethylsilyl) oxy] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (3.0 g, 9.22 mmol) in acetonitrile (15 mL) was added Selectfluor (5.24 g, 14.8 mmol) and the reaction mixture was stirred at room temperature overnight. After the reactants were consumed, the reaction was quenched with water and then diluted with EA (100 mL) . The organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 3 2-Methylpropan-2-yl (1R, 4S, 5S) -4-fluoro-1, 5-dimethyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (1.3 g, 4.79 mmol) was dissolved in THF (30 mL) and LiHMDS (7.67 mL, 7.67 mmol) was added at 80 °C. The reaction was stirred at -65 °C for 1.5 h, and then TMSCl (0.79 mL, 6.23 mmol) was added. The reaction mixture was stirred for another 2 h at -78 °C. After the reactants were consumed, the reaction was diluted with EA and H 2 O.
  • Step 4 To a solution of 2-methylpropan-2-yl 1, 5-dimethyl-3- [ (trimethylsilyl) oxy] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (1.6 g, 4.66 mmol) in acetonitrile (15 mL) was Selectfluor (1.65 g, 4.66 mmol) was added and the reaction mixture was stirred at room temperature overnight. After the reactants were consumed, the reaction was quenched with water, and diluted with EA (100 mL) . The organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 5 2-Methylpropan-2-yl (1S, 2S, 4R, 5R) -2, 4-difluoro-5-methyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.69 mmol) was dissolved in EtOH (1-5 mL) and NaBH 4 (32 mg, 0.83 mmol) was added at 80 °C. The reaction was refluxed for 3h. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water and diluted with EA (50 mL) . The mixture was washed with brine and the organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 6 To a solution of 2-methylpropan-2-yl (1S, 2S, 4R, 5R) -2, 4-difluoro-3-hydroxy-5-methyl-8-azabicyclo [3.2.1] octane-8-carboxylate (80 mg, 0.29 mmol) in THF (6 mL) , NaH (16.5 mg, 0.41 mmol) was added and the reaction mixture was stirred for 20 min. Next 3, 6-dibromo-1, 2-diazine (85 mg, 0.35 mmol) was added and the reaction mixture was stirred at room temperature overnight. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water and diluted with EA (50 mL) .
  • Step 7 To a solution of 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (28 mg, 0.12) in dioxane (6 mL) was added 2-methylpropan-2-yl (1R, 2R, 3s, 4S, 5S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -2, 4-difluoro-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (55 mg, 0.12 mmol) , XantPhos Pd G4 (11.81 mg, 0.01 m-mol) and Cs 2 CO 3 (119.91 mg, 0.37 mmol) and the reaction mixture was stirred at 90 °C overnight.
  • Step 8 2-Methylpropan-2-yl 3- ( ⁇ 6- [6- (1, 3-dimethylpyrazol-4-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-2-yl] -1, 2-diazin-3-yl ⁇ oxy) -2, 4-difluoro-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (15 mg, 20.53%) was dissolved in HCl (5 mL, in dioxane) . The reaction mixture was stirred at room temperature for 3 h. After the reactants were consumed, the reaction was concentrated in vacuo.
  • Step 1 To a solution of 2-methylpropan-2-yl (1S, 3S, 4S, 5R) -4-fluoro-3-hydroxy-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (120 mg, 0.44 mmol) in THF (6 mL) was added NaH (15.80 mg, 0.66 mmol) . The reaction mixture was stirred for 20 min and then 3, 6-dibromo-1, 2-diazine (156.64 mg, 0.66 mmol) was added. The reaction mixture was further stirred at room temperature overnight. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water and diluted with EA (50 mL) .
  • Step 2 To a solution of 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (23 mg, 0.10 mmol) in dioxane (6 mL) were added 2-methylpropan-2-yl (1S, 3S, 4S, 5R) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -4-fluoro-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (43.36 mg, 0.10 mmol) , XantPhos Pd G4 (9.70 mg, 0.01 mmol) and Cs 2 CO 3 (98.33 mg, 0.30 mmol) .
  • Step 3 2-Methylpropan-2-yl (1R, 2R, 5S) -3- ( ⁇ 6- [3- (1, 3-dimethylpyrazol-4-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-6-yl] -1, 2-diazin-3-yl ⁇ oxy) -2-fluoro-1, 5-dimet-hyl-8-azabicyclo [3.2.1] octane-8-carboxylate (13 mg, 0.02 mmol) was dissolved in HCl (5 mL, in dioxane) and the reaction mixture was stirred at room temperature for 3 h.
  • Step 1 To a solution of (2S) -2- ( ⁇ [ (9H-fluoren-9-ylmethyl) oxy] carbonyl ⁇ amino) -3, 3-dimethylbutanoic acid (10 g, 28.29 mmol, 1.0 eq) and methyl aminoacetate (3.0 g, 33.95 mmol, 1.2 eq) in acetonitrile (50 mL) was added DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 mmol, 1.1 eq) , and then the reaction mixture was stirred at room temperature for 16 h.
  • Step 2 A solution of 9H-fluoren-9-ylmethyl ⁇ [ (7S) -8, 8-dimethyl-3, 6-dioxo-5-aza-2-oxanon-7-yl] amino ⁇ methanoate (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred room temperature for 16 h. After the reactants were consumed, the solution was concentrated in vacuo to afford 9H-fluoren-9-ylmethyl ⁇ [ (7S) -8, 8-dimethyl-3, 6-dioxo-5-aza-2-oxanon-7-yl] amino ⁇ methanoate (4.85 g, 11.43 mmol, 97.00%) as a yellow solid. MS m/z 171.2 [M+H] + .
  • Step 3 LiAlH 4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorous stirred solution of (3S) -3- (2-methylprop-2-yl) piperazine-2, 5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL) in an ice bath, and the mixture was further stirred at 70 °C for 16 h. After the reactants were consumed, the mixture was poured into KOH (6N) in an ice bath. The resulting mixture was further stirred for 1 h, filtered, and the filtrate was collected.
  • Step 4 DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorous stirred solution of (2S) -2- (2-methylprop-2-yl) piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3, 6-diiodo-1, 2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL) at room temperature, and the mixture was stirred at 120 °C for 16 h.
  • Step 5 Pd (dppf) Cl 2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorous stirred solution of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (250 mg, 1.20 mmol, 1.0 eq) , 3-bromo-6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq) and K 2 CO 3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL) . The mixture was stirred at 80 °C for 16 h.
  • Step 6 6- (1-Methylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (50 mg, 0.23 mmol, 1.0 eq) and 6-iodo-3- [ (3S) -3- (2-methylprop-2-yl) piperazin-1-yl] -1, 2-diazine (80 mg, 0.23 mmol, 1.0 eq) was dissolved in DMF (2 mL) and CuI (4 mg, 0.02 mmol, 0.10 eq) , K 2 CO 3 (97 mg, 0.70 mmol, 3.0 eq) and (1R, 2R) -cyclohexane-1, 2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) was added and the reaction mixture was stirred at 100 °C for 16 h.
  • Step 1 To a 100 mL round-bottomed flask was added spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -7-one (500 mg, 3.31 mmol) in MeOH (5 mL) . This was followed with the addition of NaBH 4 (0.18 mL, 4.96 mmol) at 0 °C over 5 min to give an off-white suspension. The resulting mixture was stirred for 1 h at room temperature. LCMS showed the desired MS (M+H: 154.1) . The resulting mixture was cooled to 0 °C and quenched with HCl (2 M, 0.5 mL) and then concentrated in vacuo.
  • Step 2 To a solution of spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -7-ol (460 mg, 3.00 mmol) in THF (10 mL) was added NaH (270.20 mg, 4.50 mmol) at 0 °C and the resulting mixture was stirred for 30 min at room temperature. Next 3, 6-dibromo-1, 2-diazine (928.42 mg, 3.90 mmol) was added at 0 °C and the resulting mixture was stirred for 12 h at 60 °C.
  • Step 3 To a flask containing 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (40.47 mg, 0.18 mmol) in dioxane (2 mL) was added 7- [ (6-bromo-1, 2-diazin-3-yl) oxy] spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] (50 mg, 0.16 mmol) , Cs 2 CO 3 (157.56 mg, 0.48 mmol) and 3- (1, 3-dimethyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (26.11 mg, 0.02 mmol) under nitrogen.
  • Step 2 To a solution of 6-bromo-3-chloro-1, 2, 4-triazine (200 mg, 1.03 mmol) and 2, 2, 6, 6-tetramethyl-4- (methylamino) hexahydropyridine (192.71 mg, 1.13 mmol) in toluene (10 mL) was added DIEA (0.34 mL, 2.06 mmol) and the reaction mixture was stirred at 120 °C for 3 h. LCMS showed the reaction was completed.
  • Step 3 To a solution of 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (35 mg, 0.15 mmol) and 6-bromo-3- [methyl (2, 2, 6, 6-tetramethylhexahydropyridin-4-yl) amino] -1, 2, 4-triazine (52 mg, 0.16 mmol) in dioxane (10 mL) was added BrettPhos Pd G 4 (13.61 mg, 0.01 mmol) and Cs 2 CO 3 (146.62 mg, 0.45 mmol) . The reaction mixture was stirred at 90 °C for 16 h under N 2 .
  • Step 1 To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL) was added nitrosonium tetrafluoroborate (480 mg, 4.10 mmol) portion wise at 0 °C under N 2 to obtain a yellow solution which was stirred at 0 °C for 1 h. Then oxylene (30 mL) was added the reaction mixture was refluxed at 130 °C for 3 h. Next the reaction mixture was cooled to room temperature and poured into H 2 O. The aqueous layer was extracted EA. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude mixture was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%) .
  • nitrosonium tetrafluoroborate 480
  • Step 2 To the solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl) benzene (10 mL) , was added AIBN (57 mg, 0.35 mmol) . The reaction mixture was stirred under N 2 at 100 °C for 16 h. Next, the reaction mixture was cooled to room temperature and poured into H 2 O. The aqueous layer was extracted EA. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude mixture was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 70%) .
  • Step 3 Methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 2.5 mmol) was dissolved in THF (7 mL) and NH 4 OH (7 mL) was added. The reaction was stirred at room temperature for 4 h and was then filtered and concentrated under vacuum. The crude product was used directly in the next step without further purification.
  • Step 4 To the solution of 6-bromo-4-fluoroisoindolin-1-one (100 mg, 0.43 mmol) and 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (96 mg, 0.43 mmol) in dioxane: H 2 O (5: 1) (2 mL : 0.4 mL) , potassium carbonate (118 mg, 0.86 mmol) and PdCl 2 (dppf) (31 mg, 0.043 mmol) were added. The reaction mixture was stirred under N 2 at 100 °C for 16 h.
  • Step 2 To a mixture of methyl 2-chloro-5-methylpyrimidine-4-carboxylate (5.0 g, 26.80 mmol) in CCl 4 (100 mL) was added NBS (6.20 g, 34.84 mmol) and AIBN (0.44 g, 2.68 mmol) at room temperature under N 2 , and the resulting mixture was stirred at 95 °C for 2 h. Next NBS (2.38 g, 13.40 mmol) was added and the mixture was stirred at 95 °C for 1 h. Then NBS (1.43 g, 8.04 mmol) was added and the mixture was stirred at 95 °C for 1 h.
  • Step 3 A mixture of methyl 5- (bromomethyl) -2-chloropyrimidine-4-carboxylate (4.0 g, 15.07 mmol) in NH 3 -dioxane (30 mL) was stirred at room temperature for 1 h. LCMS analysis showed the reaction was completed. The mixture was the filtrated and concentrated to afford 2-chloro-6, 7-dihydro-5H-pyrrolo [4, 3-d] pyrimidin-7-one (1.3 g, 50.98%) as a red solid.
  • Step 5 To a mixture of 2- (2, 4-dimethyl-1, 3-thiazol-5-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-d] pyrimidin-7-one (65 mg, 0.26 mmol) , 2-methylpropan-2-yl (1R, 3s, 5S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (119.70 mg, 0.29 mmol) in dioxane (20 mL) was added XantPhos Pd G4 (42.76 mg, 0.03 mmol) and Cs 2 CO 3 (257.97 mg, 0.79 mmol) at room temperature under N 2 , and the mixture was stirred at 95 °C for 16 h.
  • Step 6 To a mixture of 2-methylpropan-2-yl (1S, 3s, 5R) -3- ( ⁇ 6- [2- (2, 4-dimethyl-1, 3-thiazol-5-yl) -7-oxo-6, 7-dihydro-5H-pyrrolo [4, 3-d] pyrimidin-6-yl] -1, 2-diazin-3-yl ⁇ oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.17 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature and the mixture was stirred at room temperature for 0.5 h. LCMS analysis showed the reaction was completed.
  • Step 1 To a solution of methyl 5-bromo-2-chloroisonicotinate (5 g, 20 mmol, 1.0 eq) , methylboronic acid (1.79 g, 29.8 mmol, 1.5 eq) , K 3 PO 4 (14.8 g, 69.9 mmol, 3.5 eq) , P (Cy) 3 (1.11 g, 3.97 mmol, 0.2 eq) and Pd (OAc) 2 (448 mg, 2.00 mmol, 0.1 eq) in toluene (95 mL) and H 2 O (4.5 mL) was degassed and purged with N 2 three times.
  • Step 2 2-Chloro-5-methylisonicotinate (15.0 g, 81.7 mmol, 1.0 eq) , N-bromosuccinimide (20.3 g, 113.9 mmol, 1.4 eq) and benzoyl peroxide (448.0 mg, 1.85 mmol, 0.03 eq) were combined with carbon tetrachloride (250 mL) .
  • the reaction mixture was heated to 80 °C and stirred for 3 h.
  • the reaction mixture was cooled to rt and concentrated in vacuum.
  • the obtained residue was purified by silica gel column chromatography with PE/EA to obtain methyl 5- (bromomethyl) -2-chloroisonicotinate (17.0 g, 79%) as a brown solid.
  • LC/MS (ESI) 263.9, 265.9 [M+H] + .
  • Step 3 Methyl 5- (bromomethyl) -2-chloroisonicotinate (17.0 g, 64.6 mmol, 1.0 eq) was suspended in 28 %aqueous ammonium hydroxide and the mixture was kept stirring at rt for 8 hrs. Then the mixture was filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum and used in the next step without further purification. LC/MS (ESI) : 169.0, 171.0 [M+H] + .
  • Step 4 6-Chloro-2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (336.0 mg, 2.0 mmol, 1.0 eq) , 2, 4-dimethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole) (526.1 mg, 2.20 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8.0 mL) and PdCl 2 (dppf) . CH 2 Cl 2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask.
  • Step 5 To a round bottom flask charged with 6- (2, 4-dimethylthiazol-5-yl) -2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (36.7 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min then heated at 90 °C for 8 hrs.
  • the reaction mixture was cooled to RT and diluted with EtOAc.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 1 Potassium hydroxide (74.8 g, 1.33 mol, 4.5 eq) in water (60 mL) was added to a vigorous stirred solution of 3-oxopentanedioic acid (82.8 g, 0.566 mol, 4.5 eq) and hexane-2, 5-dione (34.0 g, 35.0 mL, 0.298 mol, 1.0 eq) in water (120 mL) at 0 °C. After the addition, ammonium chloride (47.8 g, 0.896 mol, 3.0 eq) and sodium acetate (49.0 g, 0.596 mol, 2.0 eq) in water (200 mL) were added keeping the temperature at 5 °C.
  • the pH value was adjusted to ⁇ 9 by using solid KOH.
  • the mixture was stirred at room temperature for 4 days during which time the pH value was adjusted to ⁇ 9 by using additional solid KOH.
  • Step 2 To an ice-cold solution of l, 5-dimethyl-8-azabicyclo [3.2.1] octan-3-one (3 g, 19.6 mmol, 1.0 eq) of DCM (60 mL) was added pyridine (4.0 mL, 49.0 mmol, 2.5 eq) . Triphosgene (2.33g, 7.84 mmol, 0.4 eq) was dissolved in DCM (20mL) and added to the above solution dropwise. After 30 minutes, t-BuOH (3.78 mL, 39.2 mmol, 2.0 eq) was added and the mixture was gradually warmed to RT and stirred for 8 hrs.
  • the reaction was quenched with water and diluted with DCM (300 mL) .
  • the mixture was washed with 1N HCl (1 x 50 mL) , saturated sodium bicarbonate (1 x 50 mL) , and brine (1 x 50 mL) .
  • the organic layer was collected and dried over sodium sulfate, and then concentrated in vacuo.
  • Step 3 (1R, 5S) -1, 5-Dimethyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (2.3 g, 9.1 mmol) was dissolved in EtOH (50 mL) and the solution was heated to reflux. Sodium borohydride (336 mg, 1.0 eq) and was added the mixture was stirred for 15 min. The mixture was cooled to RT and quenched with aqueous ammonium chloride. The organic solvent was removed under vacuum and the residue was redissolved in EtOAc (100 mL) . The mixture was washed with brine, and the organic layer was collected and dried over sodium sulfate, and then concentrated in vacuo.
  • Step 4 To a solution of (1R, 3s, 5S) -3-hydroxy-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (1.10g g, 4.34 mmol, 1.0 eq) in anhydrous THF (20 mL) was added NaH (60 wt %, 208 mg, 5.21 mmol, 1.2 eq) . The solution was stirred at room temperature for 30 min, then 3, 6-dibromopyridazine (1.24 g, 5.21 mmol, 1.2 eq) was added and the mixture was stirred at RT for 8 hrs.
  • Step 5 A mixture of 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (210 mg, 0.92 mmol) , 2-methylpropan-2-yl (1R, 3s, 5S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (379.36 mg, 0.92 mmol) in dioxane (30 mL) was added Xantphos Pd G4 (149.05 mg, 0.09 mmol) , Cs 2 CO 3 (897.04 mg, 2.76 mmol) at RT under N 2 and the mixture was stirred at 95 °C for 16 h.
  • Step 6 A mixture of 2-methylpropan-2-yl (1R, 3s, 5S) -3- ( ⁇ 6- [6- (1, 3-dimethylpyrazol-4-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-2-yl] -1, 2-diazin-3-yl ⁇ oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (360 mg, 0.64 mmol) in DCM (10 mL) was added HCl-dioxane (20 mL) at RT and the mixture was stirred or 1 h.
  • Step 1 A solution of pivaloyl chloride (41.96 mL, 341.03 mmol) in dry THF (50 mL) was added dropwise to a stirred and ice-cooled solution of 4-oxopentanoic acid (31.86 mL, 310.02 mmol) and triethylamine (128.92 mL, 930.07 mmol) in dry THF (300 mL) at 5 °C. The solution was stirred for 1.5 h at 5 °C, and the precipitated Et 3 N ⁇ HCl was filtered off. The solid salt was washed with THF.
  • Step 2 A solution of EtMgBr in THF (1 M, 323.14 mL, 313.14 mmol) was added dropwise over 30 min to a stirred and cooled solution of 2, 2-dimethylpropanoic 4-oxopentanoic anhydride (57 g, 284.67 mmol) in dry THF (300 mL) at -60 °C under N 2 . After the addition, the mixture was stirred for 30 min at -60 °C. Subsequently the cooling bath was removed and the mixture was stirred for an additional 1 h. The reaction was quenched with the addition of ice and NH 4 Cl solution, and was then extracted with EA.
  • Step 3 KOH (49.25 g, 877.74 mmol) in water (50 mL) was added to a vigorous stirred solution of heptane-2, 5-dione (25 g, 195.05 mmol) and 3-oxopentanedioic acid (42.30 mL, 370.60 mmol) in water (250 mL) at 0 °C.
  • NH 4 Cl (20.59 mL, 585.16 mmol) and KOAc (38.29 g, 390.11 mmol) in water (200 mL) were added at 5 °C.
  • the pH value was adjusted to ⁇ 9 by using solid KOH.
  • the mixture was stirred at room temperature for 4 days during which time the pH value was adjusted to ⁇ 9 by using additional solid KOH.
  • Step 4 To an ice-cold solution of (1S, 5R) -1-ethyl-5-methyl-8-azabicyclo [3.2.1] octan-3-one (9 g, 53.81 mmol) in DCM (80 mL) was added pyridine (10.86 mL, 134.53 mmol) . Trichloromethyl [ (trichloromethyl) oxy] methanoate (3.59 mL, 21.52 mmol) was dissolved in DCM (20 mL) and added dropwise to the reaction mixture. After 30 minutes, 2-methylpropan-2-ol (10.23 mL, 107.62 mmol) was added and the mixture was gradually warmed to RT and stirred for 8 h.
  • Step 5 2-Methylpropan-2-yl (1R) -5-ethyl-1-methyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (7.5 g, 28.05 mmol) was dissolved in EtOH (60 mL) and the solution was heated to reflux. NaBH 4 (0.31 mL, 8.42 mmol) was added and the mixture was stirred for 15 min. The mixture was cooled to RT and quenched with aqueous ammonium chloride. The organic solvent was removed under vacuum and the residue was redissolved in EA (200 mL) .
  • Step 6 To a solution of 2-methylpropan-2-yl (1R) -5-ethyl-3-hydroxy-1-methyl-8-azabicyclo [3.2.1] octane-8-carboxylate (3.7 g, 13.74 mmol) in anhydrous THF (35 mL) was added NaH (0.33 g, 13.74 mmol) . The solution was stirred at room temperature for 30 min, then 3, 6-dibromo-1, 2-diazine (3.27 g, 13.74 mmol) was added and the mixture was stirred at RT for 8 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EA (200 mL) .
  • Step 7 To a round bottom flask charged with 2-methylpropan-2-yl (1S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -1-ethyl-5-methyl-8-azabicyclo [3.2.1] octane-8-carboxylate (150 mg, 0.35 mmol) , 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (88.33 mg, 0.39 mmol) , Cs 2 CO 3 (102.23 mg, 0.31 mmol, and XantPhos Pd G4 (16.94 mg, 0.01 mmol) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min and then heated at 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 1 A solution of 1-ethoxy-1- [ (trimethylsilyl) oxy] cyclopropane (11.5 mL, 57.37 mmol, 1.0 eq) in MeOH (100 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and use directly in the next step without purification.
  • Step 2 A solution of 1-ethoxycyclopropan-1-ol (5.9 g, 57.38 mmol, 1.0 eq) and benzoic acid (1.4 g, 11.48 mmol, 0.2 eq) in toluene (6 mL) was stirred at 110 °C for 15 min. Then ethyl (triphenyl- ⁇ 5-phosphanylidene) acetate (20.0 g, 57.38 mmol, 1.0 eq) was added and the mixture was stirred at 110 °Cfor 48 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography eluted with PE to give ethyl cyclopropylideneacetate (3.1 g, 42.4%) .
  • Step 3 A solution of ethyl cyclopropylideneacetate (1.7 g, 13.47 mmol, 1.0 eq) , ethyl 3-amino-3-methylbutanoate (2.3 g, 16.17 mmol, 1.2 eq) in DIEA (2.99 mL, 18.06 mmol, 1.34 eq) was stirred at 60 °C for 3 h. The reaction was monitored by TLC and LC/MS.
  • Step 4 To a solution of ethyl 3- ( (1- (2-ethoxy-2-oxoethyl) cyclopropyl) amino) -3-methylbutanoate (980 mg, 3.64 mmol, 1.0 eq) in THF (10 mL) was added t-BuOK (5.46 mL, 5.46 mmol) at 0 °C under N 2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. LC/MS showed the desired mass. The reaction mixture was poured into saturated aqueous NH 4 Cl (10 mL) . The resulting mixture was extracted with EA (2 x 20 mL) . The organic layer was dried over Na 2 SO 4 and evaporated to dryness.
  • Step 5 A solution of ethyl 7-oxospiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -8-carboxylate (618.0 mg, 2.77 mmol, 1.0 eq) in a mixture of H 2 O (5 mL) and H 2 SO 4 (5 mL) was stirred at 120 °C for 1 h. LC/MS showed desired mass. The reaction mixture was poured into ice water. The aqueous layer was adjusted to pH over 9 and extracted with EA (3 x 20 mL) . The crude was concentrated under reduced pressure to yield 5, 5-dimethyl-4-azaspiro [2.5] octan-7-one (326.0 mg, 77.9%) . LC/MS (ESI) : 154.1 [M+H] + .
  • Step 6 To a solution of spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -7-one (86.0 mg, 0.57 mmol, 1.0 eq) in MeOH (5 mL) was added NaBH 4 (64.5 mg, 1.71 mmol, 3.0 eq) at 0 °C. The mixture was stirred at RT for 1 h. LC/MS showed desired mass. The reaction mixture was diluted with H 2 O and the pH was adjusted to 7. The aqueous layer was extracted with E (2 x 10 mL) and (DCM/propan-2-ol:IPA, 10: 1) . The organic layer was dried over Na 2 SO 4 and evaporated to dryness. The crude product was use directly in the next step without further purification. LC/MS (ESI) : 156.1 [M+H] + .
  • Step 7 To a solution of 5, 5-dimethyl-4-azaspiro [2.5] octan-7-ol (106.0 mg, 0.69 mmol, 1.0 eq) in THF (5 mL) was added NaH (39.0 mg, 0.98 mmol, 1.4 eq) at 0 °C under N 2 atmosphere. The reaction mixture was stirred at 0 °C under N 2 atmosphere for 20 min. Then, 3, 6-diiodo-1, 2-diazine (252.5 mg, 0.76 mmol, 1.1 eq) was added the mixture was stirred at 60 °C overnight.
  • the reaction was cooled to RT and diluted with DMF (5 mL) and then the reaction was stirred for another 3 h at 100 °C. LC/MS showed desired mass.
  • the reaction was cooled to RT and then pouring into water.
  • the aqueous layer was extracted with EA (3 x 10 mL) .
  • the organic layer was washed with brine, dried over Na 2 SO 4 and evaporated to dryness.
  • Step 8 A solution of 7- ( (6-iodopyridazin-3-yl) oxy) -5, 5-dimethyl-4-azaspiro [2.5] octane (48.0 mg, 0.13 mmol, 1.0 eq) , 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (32.2 mg, 0.14 mmol, 1.05 eq) , (1R, 2R) -cyclohexane-1, 2-diamine (1.5 mg, 0.01 mmol, 0.1 eq) , CuI (2.7 mg, 0.01 mmol, 0.1 eq) , K 2 CO 3 (55.7 mg, 0.40 mmol, 3.0 eq) in DMF (3 mL) was stirred at 120 °C overnight under N 2 atmosphere.
  • Step 1 To a solution of acetone dicarboxylic acid (3.0g, 0.5mmol) in water (20mL) was added cyclopropanecarbaldehyde (2.876 g, 41 mmol) and then (2, 4-dimethoxyphenyl) methanamine (2.8 g, 20.5 mmol) was added portionwise over 10 min. The resulting reaction was stirred at room temperature for 3 days. The reaction mixture was extracted with DCM (3 x 60 mL) and the combined extracts were washed with brine, dried over anhydrous Na 2 SO 4 , and dried under vacuum to give a brown residue. The isomeric piperidones were separated by silica gel chromatography with hexane/ethyl acetate (7/1, v/v) . The desired compound (3.4 g, 54 %) was obtained as a pale yellow oil.
  • Step 3 To a mixture of 2, 6-dicyclopropyl-1- (3, 4-dimethylbenzyl) piperidin-4-ol (2.0 g, 6.03 mmol) in THF (30 mL) was added NaH (0.48 g, 12.07 mmol) at RT under N 2 and the mixture was stirred for 1 h. Then 3, 6-dibromo-1, 2-diazine (1.87 g, 7.84 mmol) was added and the mixture was stirred at 50 °C for 16 h. The mixture was quenched with MeOH and concentrated under vacuum.
  • Step 4 To a mixture of 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-3-one (70 mg, 0.31 mmol) and 3-bromo-6- ( ( (2S, 6S) -2, 6-dicyclopropylpiperidin-4-yl) oxy) pyridazine (149.79 mg, 0.31 mmol) in dioxane (10 mL) was added XantPhos Pd G4 (49.68 mg, 0.03 mmol) and Cs 2 CO 3 (299.77 mg, 0.92 mmol) at RT under N 2 and the mixture was stirred at 95 °C for 3h.
  • Step 5 A mixture of 2- (6- ( ( (2S, 6S) -2, 6-dicyclopropyl-1- (3, 4-dimethylbenzyl) piperidin-4-yl) oxy) pyridazin-3-yl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo
  • Step 1 4-Bromo-2, 5-dimethyl-2H-1, 2, 3-triazole (262.0 mg, 1.5 mmol, 1.5 eq) ; 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) were added to the CH 2 Cl 2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) and the solids were degassed under N 2 .
  • Step 2 To a round bottom flask charged with 3- (2, 5-dimethyl-2H-1, 2, 3-triazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (37.4 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) 1, 4-dioxane (4 mL) was added and the reaction mixture was degassed with argon for 5 min and then heated to 90 °
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v and was then dissolved HCl in dioxane (2 mL, 4.0 mol/L) and stirred for 1 h at RT.
  • Step 1 4-Bromo-2, 5-dimethyl-2H-1, 2, 3-triazole (262.0 mg, 1.5 mmol, 1.5 eq) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct 109.3 mg, 0.15 mmol, 0.1 eq

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions, des méthodes et des systèmes pour moduler l'épissage de pré-ARNm de MSH3 de sorte que le transcrit d'ARNm de MSH3 résultant comprend un exon poison. L'invention concerne en outre des compositions, des méthodes et des systèmes pour traiter une maladie ou une pathologie associée à une expansion de répétitions nucléotidiques dans un gène.
PCT/CN2024/097830 2023-06-06 2024-06-06 Compositions, méthodes et systèmes pour moduler l'épissage de msh3 Pending WO2024251211A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363506564P 2023-06-06 2023-06-06
US63/506,564 2023-06-06
US202363580945P 2023-09-06 2023-09-06
US63/580,945 2023-09-06

Publications (1)

Publication Number Publication Date
WO2024251211A1 true WO2024251211A1 (fr) 2024-12-12

Family

ID=93795062

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/097830 Pending WO2024251211A1 (fr) 2023-06-06 2024-06-06 Compositions, méthodes et systèmes pour moduler l'épissage de msh3

Country Status (1)

Country Link
WO (1) WO2024251211A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007124171A2 (fr) * 2006-04-20 2007-11-01 Massachusetts Institute Of Technology Compositions et procédés pour traiter des maladies à expansion de triplets
US20170183655A1 (en) * 2014-05-07 2017-06-29 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions and uses for treatment thereof
WO2020190793A1 (fr) * 2019-03-15 2020-09-24 Skyhawk Therapeutics, Inc. Compositions et procédés de correction d'épissage aberrant
WO2022006550A1 (fr) * 2020-07-02 2022-01-06 Remix Therapeutics Inc. Dérivés de 2-(indazol-5-yl)-6-(piperidin-4-yl)-1,7-naphthyridine et composés y relatifs en tant que modulateurs pour l'épissage d'acides nucléiques et pour le traitement de maladies proliférantes
US20220072028A1 (en) * 2018-12-03 2022-03-10 Triplet Therapeutics, Inc. Methods for the treatment of trinucleotide repeat expansion disorders associated with msh3 activity
US20230047208A1 (en) * 2020-01-02 2023-02-16 The General Hospital Corporation RNA Splicing Modulation
US20230054781A1 (en) * 2019-02-06 2023-02-23 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007124171A2 (fr) * 2006-04-20 2007-11-01 Massachusetts Institute Of Technology Compositions et procédés pour traiter des maladies à expansion de triplets
US20170183655A1 (en) * 2014-05-07 2017-06-29 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions and uses for treatment thereof
US20220072028A1 (en) * 2018-12-03 2022-03-10 Triplet Therapeutics, Inc. Methods for the treatment of trinucleotide repeat expansion disorders associated with msh3 activity
US20230054781A1 (en) * 2019-02-06 2023-02-23 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
WO2020190793A1 (fr) * 2019-03-15 2020-09-24 Skyhawk Therapeutics, Inc. Compositions et procédés de correction d'épissage aberrant
US20230047208A1 (en) * 2020-01-02 2023-02-16 The General Hospital Corporation RNA Splicing Modulation
WO2022006550A1 (fr) * 2020-07-02 2022-01-06 Remix Therapeutics Inc. Dérivés de 2-(indazol-5-yl)-6-(piperidin-4-yl)-1,7-naphthyridine et composés y relatifs en tant que modulateurs pour l'épissage d'acides nucléiques et pour le traitement de maladies proliférantes

Similar Documents

Publication Publication Date Title
US11964989B2 (en) KRas G12D inhibitors
CN114127053B (zh) 一种取代吡嗪化合物、其制备方法和用途
KR100876622B1 (ko) 피라졸로[1,5-ａ]피리딘 화합물 및 그 의약
JP2020511520A (ja) ピラゾロ［３，４−ｄ］ピリミジン−３−オンの大環状誘導体、その医薬組成物及び応用
WO2024094150A1 (fr) Inhibiteurs de l&#39;inflammasome nlrp3 et leurs utilisations
WO2024017201A1 (fr) Inhibiteurs de cbl-b et leurs procédés d&#39;utilisation
WO2024131939A1 (fr) Inhibiteurs de cbl-b et leurs méthodes d&#39;utilisation
AU2017373758B2 (en) Compounds and pharmaceutical compositions for modulating SGK activity, and methods thereof
WO2023241627A1 (fr) Inhibiteurs doubles de cdk8/19 et leurs procédés d&#39;utilisation
CA3231988A1 (fr) Compose macrocycle azaindazole et son utilisation
KR20250051740A (ko) 키나아제 억제제를 제조하는 방법
WO2024251211A1 (fr) Compositions, méthodes et systèmes pour moduler l&#39;épissage de msh3
EP3704122B1 (fr) Agonistes de triazole fusionnés du récepteur apj
WO2024240153A1 (fr) Inhibiteurs de l&#39;inflammasome nlrp3 et leurs utilisations
WO2024140679A1 (fr) Antagonistes de hpk1 spirocycliques et utilisations associées
WO2024193541A1 (fr) Inhibiteurs de l&#39;inflammasome nlrp3 et leurs utilisations
EP4619397A1 (fr) Inhibiteurs de kinases inductibles par sel (sik) et leurs procédés d&#39;utilisation
CN118994158A (zh) 一类含氮杂环类化合物、制备方法和用途
WO2024251212A1 (fr) Composés d&#39;isoindolinone et de dihydropyrrolopridinone et leurs utilisations
WO2025140532A1 (fr) Nouveaux composés utilisés en tant qu&#39;agonistes de glp-1r et leurs utilisations
WO2025140533A1 (fr) Nouveaux composés utilisés en tant qu&#39;agonistes de glp-1 r et leurs utilisations
KR102614279B1 (ko) 테트라히드로옥세피노피리딘 화합물
WO2024061300A1 (fr) Inhibiteurs de trex1 et utilisations associées
WO2025232839A1 (fr) Inhibiteurs de l&#39;inflammasome nlrp3 et leurs utilisations
WO2025067468A1 (fr) Inhibiteurs de cbl-b et leurs méthodes d&#39;utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24818742

Country of ref document: EP

Kind code of ref document: A1