Compounds and methods for treating sickle cell disease

Abstract

The present disclosure relates to compounds, compositions, and methods of treating sickle cell disease.

Description

COMPOUNDS AND METHODS FOR TREATING SICKLE CELL DISEASECROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 607,825 filed on December 8, 2023 which is hereby incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] Provided herein are compounds and methods related to treating sickle cell disease (SCD).BACKGROUND OF THE DISCLOSURE

[0003] Hemoglobinopathies encompass a number of anemias in which there is a decreased production and / or increased destruction of red blood cells (RBCs). Hemoglobinopathies can also include genetic defects that result in the production of abnormal hemoglobin with a concomitant impaired ability to maintain oxygen concentration. These disorders are associated with the beta-globin protein and are referred to generally as beta-hemoglobinopathies. This includes conditions such as sickle cell disease and thalassemia.

[0004] Sickle Cell Disease (SCD, also called sickle cell anemia (SCA)) is a genetic disorder leading to vaso-occlusive processes responsible for much of the mortality in SCD patients. SCD disease results from a point mutation in the hemoglobin (HBB) gene producing abnormal sickle hemoglobin (HbS or HbSS), which polymerizes and creates rigid and sticky sickled red blood cells. Sickled red blood cells result in chronic inflammation, elevated cell adhesion, oxidative stress, and endothelial dysfunction culminating in vaso-occlusive processes. There is no cure for SCD and treatment options are often limited to transfusion.

[0005] Thalassemia disorders are genetic disorders characterized by less hemoglobin and reduced red blood cells in the body as compared to normal. The low hemoglobin and red blood cell levels of thalassemia may cause symptoms such as anemia, drowsiness, fatigue, chest pain, and shortness of breath. Alpha thalassemia and beta thalassemia are two main types of thalassemia; they both have major and minor forms. Beta thalassemia major is also called Cooley anemia or Cooley thalassemia. Beta thalassemia also includes beta-plus thalassemia and beta-zero thalassemia. Beta thalassemia patients have genetic defects resulting in the synthesis of little or no hemoglobin beta chains. Symptoms of beta thalassemia include anemia, a lack of oxygen in many parts of the body, pulmonary hypertension, thrombotic events, infection, endocrine dysfunction and leg ulcers. Treatments of thalassemia such as blood transfusions and iron chelation can be helpful, but repeated transfusions may also cause iron overload and many side effects.

[0006] There is a clinically unmet need for the development of therapeutics and treatments for hematologic diseases such as SCD.SUMMARY OF THE DISCLOSURE

[0007] In an aspect, provided herein is a method of treating a hematologic disorder in a subject in need thereof, comprising administering to the subject a compound of Formula (A), or a pharmaceutically acceptable salt thereof:Formula (A), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently is hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl; or W2is -L-Z-R4; whereinL is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;Rwis hydrogen or C1-C20 alkyl or C1-C20 heteroalkyl; orRwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6- membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1 10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, -OH, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C„ cycloalkyl or 3 to 6-membered heterocycloalkyl; or one of R3aand one of R3btogether with atoms to which they are attached form a C3-C„ cycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-Ce cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; n3is 0, 1, 2, or 3; n4is 1, 2, or 3; and mi is 0 or 1.

[0008] In another aspect, provided herein is a method of treating sickle cell disease (SCD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof:Formula (A), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, Ci-C3haloalkyl, or -NHC(O)CH3;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl; or W2is -L-Z-R4; whereinL is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH ,. -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 alkyl, or optionally substituted C1-C10 heteroalkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;Rwis hydrogen or C1-C20 alkyl or C1-C20 heteroalkyl; orRwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6- membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl; optionally substituted C1-C10 haloalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1.10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, -OH., C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one of R3aand one of R3btogether with atoms to which they are attached form a C3-C6 cycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; n3is 0, 1, 2, or 3; n4is 1, 2, or 3; and mi is 0 or 1.

[0009] In another aspect, provided herein is a compound having the structure of Formula (la), or a pharmaceutically acceptable salt thereof:Formula (la), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or-NHC(O)CHs;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C„ cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; n3is 0, 1, 2, or 3; n4is 1, 2, or 3; and mi is 0 or 1; wherein when n3is 0 and mi is 1, then n4is not 1.

[0010] In another aspect, provided herein are compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0013] In an aspect, provided herein are methods of using transcription modulator compounds.Methods of Use

[0014] In an aspect, provided herein is a method of treating a hematologic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof:Formula (A’), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl; or W2is -L-Z-R4; whereinL is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;Rwis hydrogen or C1-C20 alkyl or C1-C20 heteroalkyl; orRwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6- membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, -OH, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C„ cycloalkyl or 3 to 6-membered heterocycloalkyl; or one of R3aand one of R3btogether with atoms to which they are attached form a C3-C„ cycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-Ce cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; each Ryis independently hydrogen, halogen, -CN, -OH, -NH2, Ci-Ce alkyl, or Ci-Ce haloalkyl; or two Rytogether with the atoms to which they are attached form a C3-C„ cycloalkyl or 3 to 6-membered heterocycloalkyl; ni is 1, 2, or 3; n2is 0 or I : n3is 0, 1, 2, or 3; n4 is 1, 2, or 3; and mi is 0 or 1.

[0015] In another aspect, provided herein is a method of treating a hematologic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof:Formula (A), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, Ci-C3haloalkyl, or -NHC(O)CH3;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl; or W2is -L-Z-R4; whereinL is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;Rwis hydrogen or C1-C20 alkyl or C1-C20 heteroalkyl; orRwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6- membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, -OH, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one of R3aand one of R3btogether with atoms to which they are attached form a C3-C6 cycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or I : m is 0, 1, 2, or 3; n4 is 1, 2, or 3; and mi is 0 or 1.

[0016] In some embodiments, the compound of Formula (A) has the structure of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; n3is 0, 1, 2, or 3; n4is 1, 2, or 3; and mi is 0 or 1.

[0017] In some embodiments, the hematologic disorder is sickle cell disease, a beta hemoglobinopathy, or thalassemia. In some embodiments, the hematologic disorder is sickle cell disease. In some embodiments, the hematologic disorder is a beta hemoglobinopathy. In some embodiments the hematologic disorder is thalassemia. In some embodiments, the thalassemia is beta-thalassemia.

[0018] In further embodiments, the compound is optionally conjugated to a moiety that modulates gene expression. In some embodiments, the compound is linked to a moiety that modulates gene expression through an oligomeric linker.

[0019] In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at W1, Wla, W2, one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2h, one of R3aor R3b, R4, R4a, or R4b. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at W1. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at Wla. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at W2. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2h. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at one of R3aor R3b. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at R4. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at R4a. In some embodiments, the compound is conjugated to a moiety, that modulates gene expression, through an oligomeric linker at R4b.

[0020] In some embodiments, the moiety that modulates gene expression comprises a moiety capable of binding to a bromodomain and extra terminal domain (BET) family member.

[0021] In some embodiments, the BET family member is BRD2, BRD3, BRD4, or BRDT. In some embodiments, the BET family member is BRD2. In some embodiments, the BET family member is BRD3. In some embodiments, the BET family member is BRD4. In some embodiments, the BET family member is BRDT.

[0022] In some embodiments, the moiety that modulates gene expression comprises a moiety capable of binding to a CBP / p300, PCAF (P300 / CBP-Associated Factor), CECR2 (cat eye syndrome chromosome region candidate 2), BRPF (bromodomain and PHD finger-containing protein), ATAD2 / ATAD2B (chromatin remodeling proteins), TRIM24 (Tripartite motif-containing 24), BAZ2 (Bromodomain Adjacent to Zinc finger), TAF 1 (TBP associated factors), BRD7 / 9, BPTF (Bromodomain PHD Finger Transcription Factor), SMARCA2 / 4, or PBRM1.

[0023] In some embodiments, the moiety that modulates gene expression is capable of binding to CBP / p300.

[0024] In some embodiments, the moiety that modulates gene expression is capable of binding to a PCAF (P300 / CBP-Associated Factor).

[0025] In some embodiments, the moiety that modulates gene expression is capable of binding to a CECR2 (cat eye syndrome chromosome region candidate 2).

[0026] In some embodiments, the moiety that modulates gene expression is capable of binding to a BRPF (bromodomain and PHD finger-containing protein).

[0027] In some embodiments, the moiety that modulates gene expression is capable of binding to a ATAD2 or ATAD2B chromatin remodeling protein.

[0028] In some embodiments, the moiety that modulates gene expression is capable of binding to a BAZ2 (Bromodomain Adjacent Zinc Finger.

[0029] In some embodiments, the moiety that modulates gene expression is capable of binding to a TAF1 (TBP associated factor).

[0030] In some embodiments, the moiety that modulates gene expression is capable of binding to a TRIM24 (tripartite motif-containing 24).

[0031] In some embodiments, the moiety that modulates gene expression is capable of binding to a BRD7 / 9.

[0032] In some embodiments, the moiety that modulates gene expression is capable of binding to a BPTF (Bromodomain PHD Finger Transcription Factor).

[0033] In some embodiments, the moiety that modulates gene expression is capable of binding to a SMARCA2 / 4.

[0034] In some embodiments, the moiety that modulates gene expression is capable of binding to a PBRMI.Compounds

[0035] In another aspect, provided herein is a compound having the structure of Formula (la), or a pharmaceutically acceptable salt thereof:Formula (la), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, or C1-C3 haloalkyl, or -NHC(O)CHs;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C„ cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; n3is 0, 1, 2, or 3; n4is 1, 2, or 3; and mi is 0 or 1; wherein when n3is 0 and mi is 1, then n4is not 1.

[0036] In some embodiments, provided herein is a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof:Formula (II), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, Ci-C3haloalkyl, or -NHC(O)CH3;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxhare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; is 1, 2, or 3; n2is 0 or I : and mi is 0 or 1.

[0037] In some embodiments, provided herein is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof:Formula (III), wherein:W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CH3; each Y2and Y3is independently -CH- or -N-;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH ,. -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted Ci-Cio alkyl;R4bis optionally substituted Ci-Cio alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Ci-Cio hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted Ci-Cw alkyl, optionally substituted Ci-Cio aminoalkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Ci-Cio hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1.10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxhare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; and mi is 0 or 1.

[0038] In some embodiments of Formula (A’) or (A), Rwis C1-C20 alkyl or C1-C20 heteroalkyl. In some embodiments of Formula (A’) or (A), Rwis C1-C20 alkyl. In some embodiments of Formula (A), Rwis Ci- C20 heteroalkyl. In some embodiments of Formula (A’) or (A), Rwis hydrogen.

[0039] In some embodiments of Formula (A’) or (A), W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A’) or (A), W2is optionally substituted C1-C20 alkyl. In some embodiments of Formula (A’) or (A), W2is optionally substituted C1-C20 heteroalkyl. In some embodiments of Formula (A’) or (A), W2is -L-Z-R4.

[0040] In some embodiments of Formula (A’) or (A), Rwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl.

[0041] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III) W1is halogen, or C1-C3 haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), W1is halogen. In someembodiments of Formula (A’), (A), (I), (la), (II), or (III), W1is C1-C3 haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), W1is hydrogen. In some embodiments of Formula (A’), (A), (I), (la), or (II), W1is -NHC(O)CH3.

[0042] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), Wlais halogen, or C1-C3 haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), Wlais halogen. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), Wlais C1-C3 haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), Wlais hydrogen. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), Wlais -NHC(O)CH3.

[0043] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), W1is hydrogen and Wlais Ci- C3haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), W1is hydrogen and Wlais CF3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), W1is hydrogen and Wlais hydrogen.

[0044] In some embodiments of Formula (A’), (A), (I), (la), or (II), Y1is -N-. In some embodiments of Formula (A), (I), (la), or (II), Y1is -CH-.

[0045] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Y2is -N-. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Y2is -CH-.

[0046] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Y3is -N-. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Y3is -CH-.

[0047] In some embodiments of Formula (A), (I), (la), or (II), Y4is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), Y4is -CH-.

[0048] In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y5is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y5is -CH-.

[0049] In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y6is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y6is -CH-.

[0050] In some embodiments of Formula (A’), (A), (I), (la), or (II), Y7is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), Y7is -CH-.

[0051] In some embodiments of Formula (A’), (A), (I), (la), or (II), Y8is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), Y8is -CH-.

[0052] In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y4, Y5, Y6, and Y7is independently -CH-. In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y4, Y5, Y6, and Y7is independently -N-.

[0053] In some embodiments of Formula (A’), (A), (I), (la), or (II), Y1and Y8are each independently -N- . In some embodiments of Formula (A’), (A), (la), (I), or (II), Y1and Y8are each independently -CH-.

[0054] In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y2is -CH- or -N- and each Y1, Y3, and Y8is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y2is -CH- and each Y1, Y3, and Y8is -N-. In some embodiments of Formula (A’), (A), (I), (la), or (II), each Y1, Y2, Y3, and Y8is N.

[0055] In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 haloalkyl,optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1.10; each of which is optionally substituted with one or more Rx. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2§, and R2his independently C1-C10 alkyl or C1-C10 haloalkyl. In some embodiments (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently C1-C10 haloalkyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently -CF3, or -CH2CF3. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his -CH2CF3. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently C1-C10 alkyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently methyl, ethyl, propyl, butyl, propyl, pentyl, or hexyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his methyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his ethyl. In some embodiments, each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his n-propyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his isopropyl. In some embodiments of Formula (A), (la), (II), or (III), each R2a, R2b, R2c, R2e, R2d, R2f, R2g, and R2his butyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his secbutyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his tert-butyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his pentyl. In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his hexyl.

[0056] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently C3-C10 cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently Cs-Cs cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the cycloalkyl is a monocyclic, bicyclic, bridged, or spirocyclic cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptane. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently cyclohexyl or bicyclo[2.2.1]heptane. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his cyclohexyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his bicyclo[2.2.1]heptane.

[0057] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f,R2g, and R2his independently, , , or § . In some embodiments of Formula (A’), (A),(I), (la), (II), or (III), or (V), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independentlyor.In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and bodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e,, , . In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R2a, R2b,R2c, R2d. R2e. R21R2g. and R2his independently. In some embodiments of Formula (A’), (A), (I), (la),(II), or (III), each

[0058] In some embodiments of Formula (A’), (A), (la), (II), or (III), each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently methyl, ethyl, isopropyl, propyl, butyl, pentyl, hexyl, -CH2CF3, cyclohexyl, or bicyclo [2.2.1 ]heptane .

[0059] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), at least one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his not unsubstituted C1-C10 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), at least one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), at least two of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2hare not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), at least three of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2hare not methyl.

[0060] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2ais not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2bis not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2cis not methyl. In some embodiments of Formula (A’), (A), (I), (II), (III), (IV), or (IV), R2dis not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2eis not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2fis not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2gis not methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R2his not methyl.

[0061] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3bis hydrogen; and each R3ais independently selected from hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3bis hydrogen; and each R3ais independently selected from hydrogen, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3bis hydrogen; and each R3ais independently hydrogen or - NR3cR3d.

[0062] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3bcombine together with the atom to which they are attached to form a C3-C6 cycloalkyl; and each R3ais independently selected fromhydrogen, -NR3cR3d, -NHC(0)0R3c, and -NHC(0)R3e. In some embodiments of Formula (A’), (A), (I), (la),(II), or (III), two R3bcombine together with the atom to which they are attached to form a cyclopropyl; and each R3ais independently selected from hydrogen, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3bcombine together with the atom to which they are attached to form a cyclopropyl; and each R3ais independently selected from hydrogen or -NH2.

[0063] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais hydrogen; and each R3bis independently selected from hydrogen, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais hydrogen; and each R3bis independently selected from hydrogen, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais hydrogen; and each R3bis independently hydrogen or - NR3cR3d. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais hydrogen; and each R3bis independently selected from hydrogen, -NH2, -NH(CH3), -N ^C LC fe), -NHC(O)phenyl, - NHC(O)CH3, -NHC(O)C(CH3)3, -NHC(O)CH(CH3)2, -NHC(O)CH2CH3, or -NHC(O)CH2CF3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais hydrogen; and each R3bis independently selected from hydrogen or -NH2. In some embodiments of Formula (A’), (A), (I), (la), (II), or(III), each R3ais hydrogen; and each R3bis hydrogen.

[0064] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3acombine together with the atom to which they are attached to form a C3-C6 cycloalkyl; and each R3bis independently selected from hydrogen, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la),(II), or (III), two R3acombine together with the atom to which they are attached to form a cyclopropyl; and each R3bis independently selected from hydrogen, -NR3cR3d, -NHC(O)OR3c, and -NHC(O)R3e. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3acombine together with the atoms to which they are attached to form a cyclopropyl; and each R3bis independently selected from hydrogen or -NH2.

[0065] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais independently hydrogen, -NHC(O)CH3, -NHC(O)O-CH2-(phenyl), or -NH2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais independently hydrogen or -NH2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3ais hydrogen. In some embodiments of Formula (A’), (A), (I), (la), (II), or(III), one of R3ais hydrogen and the other is -NH2.

[0066] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3bis independently hydrogen, -NHC(O)CH3, -NHC(O)O-CH2-(phenyl), or -NH2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3bis independently hydrogen or -NH2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3bis hydrogen. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), one of R3bis hydrogen and the other is -NH2.

[0067] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each R3aand each R3bare hydrogen.

[0068] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of Formula (A’), (A), (I),(la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a cyclobutyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a cyclopentyl. In some embodiments of Formula (A’), (A),(I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a 3 to 6- membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a 4-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3atogether with the carbon atom to which they are attached form a 5-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la),(II), or (III), two R3atogether with the carbon atom to which they are attached form a 6-membered heterocycloalkyl.

[0069] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a cyclobutyl. In some embodiments (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a cyclopentyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a 4-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a 5-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), two R3btogether with the carbon atom to which they are attached form a 6-membered heterocycloalkyl.

[0070] In some embodiments of Formula (A’) or (A), one of R3aand one of R3btogether with atoms to which they are attached form a Cs-Ce cycloalkyl. In some embodiments of Formula (A’) or (A), one of R3aand one of R3btogether with atoms to which they are attached form a cyclopropyl. In some embodiments of Formula (A’) or (A), one of R3aand one of R3btogether with atoms to which they are attached form a cyclobutyl. In some embodiments of Formula (A’) or (A), one of R3aand one of R3btogether with atoms to which they are attached form a cyclopentyl. In some embodiments of Formula (A’) or (A), one of R3aand one of R3btogether with atoms to which they are attached form a cyclohexyl.

[0071] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3cand R3dare each independently hydrogen, C1-C20 alkyl, -CH2-(phenyl), or PEG1.20. In someembodiments of Formula (A’), (A), (I), (la), (II), or (III), R3cand R3dare each independently C1-C20 alkyl, n some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3cand R3dare each independently -CH2- (phenyl). In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3cand R3dare each independently PEG1.20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3cand R3dare each hydrogen.

[0072] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis C1-C20 alkyl, C1-C20 haloalkyl, PEG1.20, Cs-Ce cycloalkyl, 4 to 6-membered heterocycloalkyl, or phenyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis C1-C20 alkyl or PEG1.20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis Cs-Ce cycloalkyl, 4 to 6-membered heterocycloalkyl, or phenyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis C1-C20 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis C1-C20 haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis PEG1.20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis Cs-Ce cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R3eis 4 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la),(II), or (III), R3eis phenyl.

[0073] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene; and R4is - NR4aR4b, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl; R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 4 to 6- membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl.

[0074] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene or C1-C20 heteroalkylene; and R4is -NR4aR4b, wherein R4ais hydrogen, optionally substituted C1-C10 alkyl, or optionally substituted C1-C10 alkyl; and R4bis optionally substituted C1-C10 alkyl, optionally substituted Ci- C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene or C1-C20 heteroalkylene; and R4is -NR4aR4b, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl; and R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene and R4is -NR4aR4b, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl; and R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or(III), L is C1-C20 alkylene and R4is -NR4aR4b, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl;and R4bis optionally substituted C1-C10 alkyl or optionally substituted C1-C10 haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene and R4is -NR4aR4b, wherein R4ais C1-C10 alkyl and R4bis C1-C10 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais Ci-Cs alkyl and R4bis Ci-Cs alkyl. In some embodiments, R4ais Ci-Ce alkyl and R4bis Ci-Ce alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais C1-C3 alkyl and R4bis C1-C3 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais methyl and R4bis methyl.

[0075] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene or C1-C20 heteroalkylene; and R4is -OR4a, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene; and R4is -OR4a, wherein R4ais hydrogen. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene; and R4is -OR4a, wherein R4ais optionally substituted C1-C10 alkyl.

[0076] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene and R4is - NR4aR4b, wherein R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 4- membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 5 -membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted morpholine, optionally substituted thiomorpholine, optionally substituted thiomorpholine oxide, optionally substituted thiomorpholine dioxide. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, or optionally substituted morpholine. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted piperidine or optionally substituted piperazine. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents are selected from alcohol, alkoxy, amino, cyano, halogen, nitro, alkyl, haloalkyl, oxo (=0), and a charged moiety. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents are selected from -Cl, -F, -CN, -NH2, - NH(CH3), -N(CH3)2, -NO3, -OH, -CH3, -CF3, and =0. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents are selected from -F and -CF3.

[0077] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais hydrogen or optionally substituted C1-C10 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais optionally substituted C1-C10 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais Ci-Cs alkyl. In some embodiments, R4ais Ci-Ce alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III),R4ais C1-C3 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais methyl or ethyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais methyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4ais hydrogen. In some embodiments of Formula (A), (I), (la),(II), or (III), the one or more optional substituents are selected from alcohol, alkoxy, amino, cyano, halogen, nitro, alkyl, haloalkyl, oxo (=0), biotin or a derivative thereof, isophthalic acid or methoxycarbonyl benzoic acid or a derivate thereof, and a charged moiety. In some embodiments of Formula (A’), (A), (I), (la), (II), or(III), the one or more optional substituents are selected from -Cl, -F, -CN, -NH2, -NH(CH3), -N(CH3)2, -NO3, -OH, -CH3, and -CF3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents are selected from -NH2, -NH(CH3), -N(CH3)2, -OH, and -CF3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is a charged moiety. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is isophthalic acid or methoxycarbonyl benzoic acid or a derivate thereof. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is methyl 3 -((Z2-azancy I (carbon l (benzoate. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is 3-((Z2- azaneyl)carbonyl)benzoic acid. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is biotin or a derivative thereof. In some embodiments of Formula (A’), (A), (I),(la), (II), or (III), the one or more optional substituents i

[0078] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis optionally substituted Ci- Cio alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 4 to 6- membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis optionally substituted Ci-Cw alkyl or optionally substituted Ci-Cw haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis optionally substituted Ci-Cw alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis optionally substituted Ci-Cw haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis optionally substituted Ci-Cio alkyl. In some embodiments, R4bis Ci-Cs alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III) R4bis Ci-Ce alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis C1-C3 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), R4bis methyl or ethyl. In some embodiments of Formula (A’), (A),(I), (la), (II), or (III), R4bis methyl. In some embodiments of Formula (A), (I), (la), (II), or (III), the one or more optional substituents are selected from alcohol, alkoxy, amino, acetamido, cyano, halogen, nitro, alkyl, haloalkyl, oxo (=0), biotin or a derivative thereof, isophthalic acid or methoxycarbonyl benzoic acid or a derivate thereof, and a charged moiety. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents are selected from -Cl, -F, -CN, -NH2, -NH(CH3), -N(CHs)2, -NO3, -OH, - CH3, -CF3, and -NH(0)CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents are selected from -NH2, -NH(CH3), -N(CH3)2, -OH, and -CF3. In someembodiments of Formula (A), (I), (la), (II), or (III), the one or more optional substituents is a charged moiety. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is isophthalic acid or methoxycarbonyl benzoic acid or a derivate thereof. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is methyl 3-((2- azaneyl)carbonyl)benzoate. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the one or more optional substituents is 3-((2-azancyl)carbonyl)bcnzoic acid. In some embodiments of Formula (A), (I), (la), (II), or (III), the one or more optional substituents is biotin or a derivative thereof. In some embodiments of Formula (A), (I), (la), (II), or (III), the one or more optional substituents is

[0079] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C20 alkylene and R4is - CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C10 alkylene and R4is -CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is Ci-Cs alkylene and R4is -CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is Ci-Ce alkylene and R4is -CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C4 alkylene and R4is -CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C3 alkylene and R4is -CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C2 alkylene and R4is -CH3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is absent and R4is -CH3.

[0080] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C10 alkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is Ci-Cs alkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is Ci-Ce alkylene. In some embodiments of Formula (A’), (A),(I), (la), (II), or (III), L is C1-C5 alkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C4 alkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C3 alkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is -CH2CH2-. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is absent.

[0081] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C10 heteroalkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is Ci-Cs heteroalkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is Ci-Ce heteroalkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C5 heteroalkylene. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), L is C1-C4 heteroalkylene. In some embodiments of Formula (A’), (A), (I), (la),(II), or (III), L is C1-C3 heteroalkylene.

[0082] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the heteroalkylene linker L comprises one or more subunits selected from -((CRlaRla)x-O)y- and -((CRlaRla)x-(NRlb)z-, wherein each Rlaand Rlbis independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl, and x, y, and z are each independently an integer from 1-15. In some embodiments, the heteroalkylene is -((CRlaRla)x-O)y-. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), the heteroalkylene is -((CRlaRla)x-(NRlb)z-. In someembodiments of Formula (A’), (A), (I), (la), (II), or (III), z, y, and z are each independently 1-10, 1-8, 1-6, 1- 4, 1-3, or 1-2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rlaand Rlbis independently hydrogen. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rlaand Rlbis independently C1-C3 alkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rlaand Rlbis independently C1-C3 haloalkyl.

[0083] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -CN, - OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, -NHC(O)RXc, -NHC(O)ORXc, - OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C„ cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, - C(O)NRXaRxb, -NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, or optionally substituted 5 to 10-membered heteroaryl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -C(O)ORXc, -C(O)NRXaRxb, -NHC(O)RXc, or optionally substituted 5- membered heteroaryl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -CN, -OH, -ORXa, -N3, or -NRXaRxb. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -CN, -OH, -OCH3, -N3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -OH, -NH2, -NHCH3, or - N(CH3)2. In some embodiments of Formula (A1), (A), (I), (la), (II), or (III), each Rxis independently - CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, -NHC(O)RXc, -NHC(O)ORXc, or -OC(O)NRXaRxb. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently -C(O)NRXaRxb, - NHC(O)RXc, or -OC(O)NRXaRxb. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently an optionally substituted Ci-Ce haloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis -CF3. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently an optionally substituted C3-Ce cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently an optionally substituted cyclohexyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently an optionally substituted 5 to 10- membered heteroaryl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently an optionally substituted 5-membered heteroaryl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each Rxis independently an optionally substituted triazine.

[0084] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each RXaand Rxhis independently hydrogen, alkyl, or PEG (polyethylene glycol). In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each RXaand Rxhis independently hydrogen, C1-C20 alkyl, or PEG1.20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III)), each RXaand Rxhis independently Ci-C 20 alkyl . In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each RXaand Rxhis independently PEG1.20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), each RXaand Rxhis independently hydrogen.

[0085] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis alkyl, PEG (polyethylene glycol), cycloalkyl, heterocycloalkyl, or phenyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis C1-C20 alkyl, PEG1.20, C3-Ce cycloalkyl, 4 to 6-membered heterocycloalkyl, or phenyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis C1-C20 alkyl or PEG1.20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis C1-C20 alkyl. In some embodiments, RXcis PEG1 20. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis C3-Ce cycloalkyl, 4 to 6- membered heterocycloalkyl, or phenyl. In some embodiments, RXcis C3-Ce cycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis 4 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), RXcis phenyl.

[0086] In some embodiments of Formula (A’), each Ryis independently hydrogen, halogen, -CN, -OH, - NH2, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments of Formula (A’), each Ryis independently hydrogen, halogen, or -OH. In some embodiments of Formula (A’), each Ryis hydrogen.

[0087] In some embodiments of Formula (A’), two Rytogether with the atoms to which they are attached form a C3-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl. In some embodiments of Formula (A’), two Rytogether with the atoms to which they are attached form a C3-Ce cycloalkyl. In some embodiments of Formula (A’), two Rytogether with the atoms to which they are attached form a 3 to 6-membered heterocycloalkyl.

[0088] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), is 1 or 2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), ni is 3. In some embodiments of Formula (A), (I), (la), (II), or (III), ni is 2. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), is 1.

[0089] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), n3is 1. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), n2is 0.

[0090] In some embodiments of Formula (A’), (A), (I), or (la), ns is 1, 2, or 3. In some embodiments of Formula (A’), (A), (I), or (la), n3is 1 or 2. In some embodiments of Formula (A’), (A), (I), or (la), n3is 3. In some embodiments of Formula (A’), (A), (I), or (la), n3is 2. In some embodiments of Formula (A’), (A), (I), or (la), n3is 1. In some embodiments of Formula (A’), (A), (I), or (la), n3is 0.

[0091] In some embodiments of Formula (A’), (A), (I), or (la), n4is 1 or 2. In some embodiments of Formula (A’), (A), (I), or (la), n4is 3. In some embodiments of Formula (A’), (A), (I), or (la), n4is 2. In some embodiments of Formula (A’), (A), (I), or (la), n4is 1.

[0092] In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), mi is 1. In some embodiments of Formula (A’), (A), (I), (la), (II), or (III), mi is 0.

[0093] In some embodiments of Formula (A’), (A), or (I), when n3is 0 and mi is 1, then n4is not 1.

[0094] In some embodiments of Formula (A’), (A), (I), or (la), is 1, m is 1, n3is 1, n4is 1 and mi is 1.

[0095] In some embodiments of Formula (A’), (A), (I), or (la), is 1, m is 1, n3is 1, n4is 1 and mi is 0.

[0096] In some embodiments of Formula (A’), (A), (I), or (la), is 0, m is 2, n3is 1, n4is 1 and mi is 1.

[0097] In some embodiments of Formula (A’), (A), (I), or (la), is 0, m is 2, n3is 1, n4is 1 and mi is 0.

[0098] Any combination of the groups described above for the various variables is contemplated herein.Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0099] In some embodiments, non-limiting examples of the compounds described herein are presented in Table 1, or a pharmaceutically acceptable salt thereof.Table 1.Pharmaceutical Compositions and Administration

[0100] 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.

[0101] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptableexcipient. 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. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0102] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fdling 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.

[0103] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimaldose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.Abbreviations and Definitions

[0104] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0105] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0106] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0107] When ranges of values are disclosed, and the notation “from ... to n2” or “between . . . and n2” is used, where and n2are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g. , 1.255 pM, 2. 1 pM, 2.9999 pM, etc.).

[0108] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0109] “oxo” refers to =0.

[0110] “Carboxyl” refers to -COOH.

[0111] “Cyano” refers to -CN.

[0112] “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-l -propyl, 2-methyl-2 -propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l- pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1- butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-ealkyl”, 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. In some embodiments, the alkyl is a Ci-Cioalkyl. In some embodiments, the alkyl is a Ci-Cealkyl. In some embodiments, the alkyl is a Ci-Csalkyl. In some embodiments, the alkyl is a Ci-C4alkyl. In some embodiments, the alkyl is a C i -CUalkyl . Unless stated otherwise specifically in the specification, an alkylgroup 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 alkyl is optionally substituted with oxo, halogen, -Ns, -CN, -C(O)OH, -C(O)OMe, -OH, - OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0113] “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. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (- CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CHs)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or - NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0114] “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. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or C - ealkynyl”, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0115] “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, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, thealkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0116] “Alkoxy” refers to a radical of the formula -ORa where Ra 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, -Ns, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0117] "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, z.e., it contains a cyclic, delocalized (4n+2) -electron system in accordance with the Htickel 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. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -N3, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0118] “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., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, 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, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cisdecalin, trans-decalin, bicyclo [2. l.l]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.I]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -Ns, -CN, -C(0)0H, C(0)0Me, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CFs, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0119] "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. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, 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.

[0120] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0121] As used herein, the term "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. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) 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.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1- chloro,2-fluoroethane .

[0122] "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.

[0123] “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.

[0124] “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.

[0125] “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. In one aspect, a heteroalkyl is a Ci-Ce 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. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0126] “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. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, 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, theheterocycloalkyl 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 quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2- Ce heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,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, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo- 1,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments,the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0127] “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. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, 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 quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, 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][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, 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. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0128] The term “oligonucleotide sequence” refers to a plurality of nucleic acids having a defined sequence and length (e.g., 2, 3, 4, 5, 6, or even more nucleotides). The term “oligonucleotide repeat sequence” refers to a contiguous expansion of oligonucleotide sequences.

[0129] The term “transcription,” well known in the art, refers to the synthesis of RNA (z.e., ribonucleic acid) by DNA-directed RNA polymerase. The term “modulate transcription” refers to a change in transcriptional level which can be measured by methods well known in the art, for example, assay of mRNA, the product of transcription. In certain embodiments, modulation is an increase in transcription. In other embodiments, modulation is a decrease in transcription.

[0130] The term “polyamide” refers to polymers of linkable units chemically bound by amide (z.e., CONH) linkages; optionally, polyamides include chemical probes conjugated therewith. Polyamides may be synthesized by stepwise condensation of carboxylic acids (COOH) with amines (RR’NH) using methods known in the art. Alternatively, polyamides may be formed using enzymatic reactions in vitro, or by employing fermentation with microorganisms.

[0131] The term “linker” or “oligomeric backbone” refers to a chain of at least 10 contiguous atoms. In certain embodiments, the linker contains no more than 20 non-hydrogen atoms. The terms linker and oligomeric backbone can be used interchangeably. In some embodiments, the linker contains no more than 40 non-hydrogen atoms. In some embodiments, the linker contains no more than 60 non-hydrogen atoms. In certain embodiments, the linker contains atoms chosen from C, H, N, O, and S. In some embodiments, every non-hydrogen atom is chemically bonded either to 2 neighboring atoms in the linker, or one neighboring atom in the linker and a terminus of the linker. In some embodiments, the linker forms an amide bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms an ester or ether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a thioester or thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms an amine or amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker comprises -(CH2OCH2)- units. In some embodiments, the linker comprises -(CH(CH3)OCH2)- units. In some embodiments, the linker comprises -(CH2NRNCH2) units, for RN = Ci-4alkyl. In some embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0132] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0133] As used herein, “optionally substituted” is a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted” or “optionally substituted” it is meant that the group is substituted with one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Ci-Ce heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), Cs-Cv-carbocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 memberedheterocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci- Ce haloalkoxy), halo, cyano, hydroxy, Ci-Ce alkoxy, Ci-Ce alkoxy(Ci-Ce)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-Ce)alkyl (e.g., -CFs), halo(Ci-Ce)alkoxy (e.g., -OCFs), Ci-Ce alkylthio, arylthio, amino, amino(Ci-Ce)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0134] The term “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.

[0135] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0136] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0137] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0138] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C).Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,160,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In some embodiments, where isotopic variations are illustrated, the remaining atoms of the compound may optionally contain unnatural portions of atomic isotopes.

[0139] In certain embodiments, the compounds disclosed herein have some or all of the ’H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0140] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0141] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0142] In some embodiments of a compound disclosed herein, one or more of the substituent groups comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments of a compound disclosed herein, one or more hydrogens are replaced with one or more deuteriums.

[0143] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of the substituents 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% of a total number of hydrogen and deuterium.

[0144] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0145] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0146] The term “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- toluene sulfonic 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. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0147] The phrase “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.

[0148] The phrase “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. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com 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, com 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; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0149] 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.

[0150] The terms “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.

[0151] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0152] The term “contacting” refers to bringing the compound (e.g., a compound of the present disclosure) into proximity of the desired target gene. The contacting may result in the binding to or result in a conformational change of the target moiety.EXAMPLES

[0153] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.Compound Synthesis

[0154] Compounds of the present disclosure can be prepared using methods illustrated in general synthetic schemes and experimental procedures detailed below. General synthetic schemes and experimental procedures are presented for purposes of illustration and are not intended to be limiting. Starting materials used to prepare compounds of the present disclosure are commercially available or can be prepared using routine methods known in the art.

[0155] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R.Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).List of Abbreviation

[0156] AC2O = acetic anhydride; AcCl = acetyl chloride; ACN = acetonitrile; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; BusSnH = tributyltin hydride; CD3OD = deuterated methanol;CDCh = deuterated chloroform; CDI = 1,1 '-Carbonyldiimidazole; DBU = l,8-diazabicyclo[5.4.0]undec-7- ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = di-iso-butyl aluminium hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N- dimethylformamide; DMSO-de = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA =diphenylphosphoryl azide; EDC.HC1 = EDCI.HC1 = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EA = ethyl acetate; EtOH = ethanol; h = hour; HATU=2-(lH-7- azabenzotriazol-l-yl)- 1,1, 3, 3 -tetramethyl uronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1 -hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminium hydride; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeOH = methanol; MP- carbonate resin = macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tertiary butyl ether; MW = microwave irradiation ; n-BuLi = n-butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMP = N-Methyl-2 -pyrrolidone; Pd(Ph3)4= tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3= tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2= bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; prep-HPLC = preparative high-performance liquid chromatography; PyBop = (benzotriazol- 1-yloxy)- tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; t-BuOH = tertbutanol; T3P = Propylphosphonic Anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSC1 = TBDMSC1 = tert-butyldimethylchlorosilane; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = tosyl chloride; XPhos = 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.SYNTHESIS OF REPRESENTATIVE COMPOUNDS

[0157] Example 1. Synthesis of Compound A-l

[0158] Scheme 1.

[0159] Step 1: To a solution of 3-(trifluoromethyl)piperidine (1.00 g, 6.53 mmol, 1.00 equiv) in ACN (10.00 mL) was added K2CO3 (2.71 g, 19.59 mmol, 3.00 equiv) and tert-butyl N-(5-bromopentyl)carbamate (1.74 g, 6.53 mmol, 1.00 equiv). Then the reaction was stirred at 70 °C overnight, fdtered, and the fdtrate was concentrated. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to afford tert-butyl N-{ 5 -[3 -(trifhroromethyl)piperidin-l-yl] pentyl} carbamate (1.80 g, 81.46%) as a yellow oil. LC / MS: mass calcd. For C16H29F3N2O2: 338.22, found: 339.55 [M+H]+.

[0160] Step 2: To a stirred solution of tert-butyl N-{5-[3-(trifhroromethyl)piperidin-l- yl]pentyl} carbamate (12.00 mg, 0.04 mmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.30 mL). The resulting mixture was stirred for 1.0 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 5-[3-(trifhioromethyl)piperidin-l-yl]pentan-l-amine (12.00 mg, crude) as yellow oil. LC / MS: mass calcd. For C11H21F3N2: 238.17, found: 239.05 [M+H]+.

[0161] Step 3: To a stirred solution of 1 -methyl -4-(l-methylimidazole-2-amido)imidazole-2 -carboxylic acid (15.00 g, 60.18 mmol, 1.00 equiv) in DMF (200.00 mL) was added PyBOP (37.58 g, 72.22 mmol, 1.20 equiv), DIEA (23.34 g, 180.56 mmol, 3.00 equiv) and P-alanine ethyl ester (8.46 g, 72.22 mmol, 1.20 equiv) in portions at room temperature. The resulting mixture was stirred for 1.0 h at room temperature. The reaction mixture was poured into ice / water (500 mL). The precipitated solids were collected by filtration and the filter cake was washed with H2O (50x3 mL), dried under vacuum to afford ethyl 3-{ [1 -methyl -4-(l- methylimidazole-2-amido)imidazol-2-yl]formamido}propanoate (17.00 g, 81.08%) as a yellow solid.LC / MS: mass calcd. For CislLoNeCU: 348.15, found: 349.05 [M+H]+.

[0162] Step 4: To a stirred solution of ethyl 3-{ [ 1 -methyl -4-(l-m ethylimidazole-2-amido)imidazol -2- yl]formamido} propanoate (8.10 g, 23.30 mmol, 1.00 equiv) in MeOH (30.00 mL) and THF (30.00 mL) wasadded LiOH (46.60 mL, 93.20 mmol, 4.00 equiv, 2M in H2O). The resulting mixture was stirred for 2.0 h at 45 °C and was then concentrated under reduced pressure and 50 mL H2O was added. The mixture was acidified to pH 5~6 with HC1 (2M in H2O) and the precipitated solids were collected by filtration and washed with water (3x50 mL), dried under vacuum to afford 3-{ [ 1 -methyl -4-(l -methylimidazole-2- amido)imidazol-2-yl]formamido}propanoic acid (6.10 g, 81.98%) as a yellow solid. LC / MS: mass calcd. For Ci2Hi6N6O4: 320.12, found: 321.05 [M+H]+.

[0163] Step 5: The procedure was the same as Step 3. 2.00 g of 3-{[l-methyl-4-(l-methylimidazole-2- amido)imidazol-2-yl]formamido} propanoic acid was used and 2.20 g of desired product was obtained as a yellow solid (77.19%). LC / MS: mass calcd. For C20H24N8O5: 456.19, found: 457.20 [M+H]+.

[0164] Step 6: The procedure was the same as Step 4, and the reaction temperature was 40 °C and reaction time was 16.0 h. 2.2 g of methyl 1 -methyl -4-(3-{ [ 1 -methyl -4-(l -methylimidazole-2- amido)imidazol-2-yl]formamido}propanamido) pyrrole-2 -carboxylate was used and 2.00 g of desired product was obtained as a yellow solid (93.79%). LC / MS: mass calcd. For C19H22N8O5: 442.17, found: 443.30 [M+H]+.

[0165] Step 7: The procedure was the same as Step 3. 4.33 g of prop-2-en-l-yl 4-(4-amino-l- methylpyrrole-2 -amido)- l-methylpyrrole-2 -carboxylate was used and 6.50 g of desired product was obtained as a brown solid (95.84%). LC / MS: mass calcd. C23H31N5O6: 473.23, found: 474.15 [M+H]+.

[0166] Step 8: The procedure was the same as Step 2. 6.5 g of prop-2-en-l-yl 4-(4-{3-[(tert- butoxycarbonyl) amino]propanamido}-l-methylpyrrole-2-amido)-l-methylpyrrole-2-carboxylate was used and 6.50 g crude of desired product was obtained as a yellow oil. LC / MS: mass calcd. C18H23N5O4: 373.18, found: 374.15 [M+H]+.

[0167] Step 9: To a stirred solution of 4-{4-[(tert-butoxycarbonyl)amino]-l-methylpyrrole-2-amido}-l- methylpyrrole-2-carboxylic acid (3.00 g, 8.28 mmol, 1.00 equiv) in DMF (34.00 mL) was added DIEA (6.42 g, 49.67 mmol, 6.00 equiv), PyBOP (5.60 g, 10.77 mmol, 1.30 equiv) and prop-2-en-l-yl 4-[4-(3- aminopropanamido) -l-methylpyrrole-2-amido]-l-methylpyrrole-2-carboxylate (3.71 g, 9.94 mmol, 1.20 equiv) at 0°C. The resulting mixture was stirred for 1.0 h at room temperature. The mixture was poured into ice water (100 mL) and the precipitated solids were collected by filtration, washed with water (3x50 mL), and dried under vacuum. The crude was purified by silica gel column chromatography and eluted with CH2C12 / MeOH (10: 1) to afford prop-2-en-l-yl 4-(4-{3-[(4-{4-[(tert-butoxycarbonyl)amino]-l- methylpyrrole-2 -amido } - 1 -methylpyrrol -2-yl)formamido]propanamido } - 1 -methylpyrrole -2 -amido)- 1 - methylpyrrole -2 -carboxylate (3.20 g, 53.85%) as a yellow oil. LC / MS: mass calcd. C35H43N9O8: 717.32, found: 718.40 [M+H]+.

[0168] Step 10: The procedure was the same as Step 2. 4.88 g of prop-2-en-l-yl 4-(4-{3-[(4-{4-[(tert- butoxycarbonyl)amino] - 1 -methylpyrrole -2 -amido } - 1 -methylpyrrol-2-yl)formamido] propanamido } - 1 - methylpyrrole -2 -amido)- l-methylpyrrole-2 -carboxylate was used and 4.88 g crude of desired product was obtained as an off-white solid. LC / MS: mass calcd. C30H35N9O6: 617.27, found: 618.35 [M+H]+.

[0169] Step 11: The procedure was the same as Step 3. 1.74 of (2S)-2-[(tert-butoxycarbonyl)amino]-4- {[(9H-fluoren-9-ylmethoxy)carbonyl]amino} butanoic acid was used and 2.70 g of desired product was obtained as a white solid (65.71%). LC / MS: mass calcd. For C54H61N11O11: 1039.46, found: 1040.40 [M+H]

[0170] Step 12: To a stirred solution of prop-2-en-l-yl 4-(4-{3-[(4-{4-[(2S)-2-[(tert- butoxycarbonyl)amino] -4- { [(9H-fluoren-9-ylmethoxy)carbonyl] amino }butanamido] - 1 -methylpyrrole-2- amido } - 1 -methylpyrrol-2-yl)formamido]propanamido } - 1 -methylpyrrole -2 -amido)- 1 -methylpyrrole-2- carboxylate (2.70 g, 2.59 mmol, 1.00 equiv) in DMF (30.00 mb) was added DEA (6.00 m ) at 0 °C and the resulting mixture was stirred for 1.0 h at room temperature. After reaction, the solid was fdtered and the fdtration was purified by reverse phase column directly with the following conditions: Cl 8 column; mobile phase, ACN in water (0.05% TFA), 30% to 60% gradient in 20 min; detector, UV 254 nm. The fractions were combined and concentrated to afford prop-2-en-l-yl 4-(4-{3-[(4-{4-[(2S)-4-amino-2-[(tert- butoxycarbonyl)amino]butanamido] - 1 -methylpyrrole -2-amido } - 1 -methylpyrrol -2- yl)formamido]propanamido}-l-methylpyrrole-2 -amido)- l-methylpyrrole-2 -carboxylate (2.10 g, 87.04%) as a white solid. LC / MS: mass calcd. For C39H51N11O9: 817.39, found: 818.40 [M+H]+.

[0171] Step 13: To a stirred solution of ethyl 4-nitro-lH-imidazole-2 -carboxylate (2.00 g, 10.80 mmol, 1.00 equiv) and 2-norbomanol (2.42 g, 21.61 mmol, 2.00 equiv) in THF (50.00 mL) was added DIAD (4.37 g, 21.61 mmol, 2.00 equiv) and PPh3(5.67 g, 21.61 mmol, 2.00 equiv) at 0 °C under nitrogen. The resulting mixture was stirred for 17.0 h at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ClUCF / McOH (5: 1) to afford ethyl 1- {bicyclo[2.2.1] heptan-2-yl}-4-nitroimidazole-2 -carboxylate (900.00 mg, 29.83%) as a yellow solid. LC / MS: mass calcd. For Ci3Hi7N3O4: 279.12, found: 280.05 [M+H]+.

[0172] Step 14: To a stirred solution of ethyl l-{bicyclo[2.2.1]heptan-2-yl}-4-nitroimidazole-2- carboxylate (1.00 g, 3.58 mmol, 1.00 equiv) in EA (30.00 mL) was added Pd / C (200.00 mg, 20% w / w). The reaction mixture was stirred for 2.0 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EA (3x30 mL). The filtrate was concentrated under reduced pressure to afford ethyl 4-amino-l-{bicyclo[2.2.1]heptan-2-yl}imidazole-2 -carboxylate (850.00 mg, 95.22%) as a white solid. LC / MS: mass calcd. For C13H19N3O2: 249.15, found: 250.05 [M+H]+.

[0173] Step 15: To a stirred solution of ethyl 4-amino-l-{bicyclo[2.2. l]heptan-2-yl}imidazole-2- carboxylate hydrochloride (300.00 mg, 1.05 mmol, 1.00 equiv) in Pyridine (5.00 mL) was added DMAP (641.27 mg, 5.25 mmol, 5.00 equiv), EDCI (503.11 mg, 2.62 mmol, 2.50 equiv) and 1 -methyl -4-(3-{[l- methyl-4-(l-methylimidazole-2-amido)imidazol-2-yl]formamido}propanamido)pyrrole-2 -carboxylic acid (464.47 mg, 1.05 mmol, 1.00 equiv) at 0 °C and the resulting mixture was stirred for 16.0 h at room temperature. The mixture was filtered and the filtrate was purified directly by reverse flash chromatography with the following conditions: C18 column; mobile phase, ACN in water (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The fractions were combined and concentrated. This resulted in ethyl l-{bicyclo[2.2.1]heptan-2-yl}-4-[l-methyl-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)imidazol-2-yl] formamido}propanamido)pyrrole-2-amido]imidazole-2 -carboxylate (500.00 mg, 70.69%) as a yellow solid. LC / MS: mass calcd. For C32H39N11O6: 673.31, found: 674.40 [M+H]+.

[0174] Step 16: The procedure was the same as Step 4. 500.00 mg of ethyl l-{bicyclo[2.2.1]heptan-2- yl } -4-[ 1 -methyl -4-(3 - { [ 1 -methyl -4-( 1 -methylimidazole-2-amido)imidazol-2- yl]formamido}propanamido)pyrrole-2-amido]imidazole-2 -carboxylate was used and 460.00 mg of desired product was obtained as yellow solid (96.00%). LC / MS: mass calcd. For C30H35N11O6: 645.28, found: 646.35 [M+H]+.

[0175] Step 17: To a stirred solution of l-{bicyclo[2.2.1]heptan-2-yl}-4-[l-methyl-4-(3-{[l-methyl-4-(l- methylimidazole-2-amido)imidazol-2-yl]formamido}propanamido) pyrrole-2-amido]imidazole-2 -carboxylic acid (180.00 mg, 0.28 mmol, 1.00 equiv) in DMF (2.00 mL) was added DMAP (170.29 mg, 1.40 mmol, 5.00 equiv), EDCI (133.60 mg, 0.70 mmol, 2.50 equiv) and prop-2-en-l-yl 4-(4-{3-[(4-{4-[(2S)-4-amino-2- [(tert-butoxycarbonyl)amino]butanamido] - 1 -methylpyrrole-2 -amido} - 1 -methylpyrrol-2- yl)formamido]propanamido}-l-methylpyrrole-2 -amido)- l-methylpyrrole-2 -carboxylate (228.01 mg, 0.28 mmol, 1.00 equiv) in portions at 0 °C. The resulting mixture was stirred for 1.0 h at room temperature and when then fdtered. The fdtrate was purified directly by reverse flash chromatography with the following conditions: C18 column; mobile phase, ACN in water (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in prop-2-en-l-yl 4-(4-{3-[(4-{4-[(2S)-4-[(l-{bicyclo[2.2. l]heptan-2- yl } -4-[ 1 -methyl -4-(3 - { [ 1 -methyl -4-( 1 -methylimidazole-2-amido)imidazol-2-yl] formamido }propanamido) pyrrole-2-amido]imidazol-2-yl)formamido]-2-[(tert-butoxycarbonyl)amino] butanamido]-l-methylpyrrole- 2-amido } - 1 -methylpyrrol-2-yl)formamido] propanamido } - 1 -methylpyrrole-2 -amido)- 1 -methylpyrrole-2 - carboxylate (300.00 mg, 74.44%) as a yellow solid.LC / MS: mass calcd. For C69H84N22O14: 1444.64, found: 1445.45 [M+H]+.

[0176] Step 18: To a stirred solution of prop-2-en-l-yl 4-(4-{3-[(4-{4-[(2S)-4-[(l-{bicyclo[2.2. l]heptan- 2-yl } -4-[ 1 -methyl -4-(3 - { [ 1 -methyl -4-( 1 -methylimidazole-2-amido)imidazol-2- yl]formamido}propanamido)pyrrole-2-amido]imidazol-2-yl) formamido] -2-[(tert- butoxycarbonyl)amino]butanamido] - 1 -methylpyrrole -2-amido } - 1 -methylpyrrol -2- yl)formamido]propanamido}- l-methylpyrrole-2 -amido)- l-methylpyrrole-2 -carboxylate (290.00 mg, 0.20 mmol, 1.00 equiv) in DMF (3.00 mL) was added phenylsilane (43.42 mg, 0.40 mmol, 2.00 equiv) and Pd(PPh3)4 (23.18 mg, 0.02 mmol, 0.10 equiv) and the reaction was stirred for 1.0 h at room temperature. The resulting mixture was poured into ice water (20 mL) and the mixture was acidified to pH 3~5 with 2 M HC1. The precipitated solids were collected by filtration and washed with H2O (3x10 mL) and dried under vacuum to afford 4-(4-{3-[(4-{4-[(2S)-4-[(l-{bicyclo[2.2.1]heptan-2-yl}-4-[l-methyl-4-(3-{[l-methyl-4-(l- methylimidazole-2-amido)imidazol-2-yl]formamido}propanamido)pyrrole-2-amido]imidazol-2-yl) formamido] -2-[(tert-butoxycarbonyl)amino]butanamido] - 1 -methylpyrrole-2 -amido } - 1 -methylpyrrol-2- yl)formamido]propanamido}- l-methylpyrrole-2 -amido)- l-methylpyrrole-2 -carboxylic acid (220.00 mg, 78.02%) as a yellow solid. LC / MS: mass calcd. For C66H80N22O14: 1404.62, found: 1405.45 [M+H]+.

[0177] Step 19: The procedure was the same as Step 3. 50.00 mg of 4-(4-{3-[(4-{4-[(2S)-4-[(l- {bicyclo[2.2.1]heptan-2-yl}-4-[l-methyl-4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)imidazol-2- yl]formamido}propanamido)pyrrole-2-amido]imidazol-2-yl)formamido]-2-[(tert- butoxycarbonyl)amino]butanamido] - 1 -methylpyrrole -2-amido } - 1 -methylpyrrol -2- yl)formamido]propanamido}-l-methylpyrrole-2 -amido)- l-methylpyrrole-2 -carboxylic acid was used and 36.00 mg of the desired product was obtained as a yellow solid (62.24%). LC / MS: mass calcd. For C77H99F3N24Oi3: 1624.78, found: 813.80 [M / 2+H]+.

[0178] Step 20: To a stirred solution of tert-butyl N-[(lS)-3-[(l-{bicyclo[2.2.1]heptan-2-yl}-4-[l-methyl- 4-(3-{[l-methyl-4-(l-methylimidazole-2-amido)imidazol-2-yl]formamido} propanamido)pyrrole-2- amido]imidazol-2-yl)formamido]-l-[(l-methyl-5-{[l-methyl-5-({2-[(l-methyl-5-{[l-methyl-5-({5-[3- (trifluoromethyl)piperidin-l-yl]pentyl} carbamoyl)pyrrol-3-yl]carbamoyl}pyrrol-3- yl)carbamoyl] ethyl }carbamoyl)pyrrol-3 -yl]carbamoyl }pyrrol-3 -yl)carbamoyl] propyl] carbamate (30.00 mg, 0.02 mmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.20 mL) dropwise at room temperature. The resulting mixture was stirred for 1.0 h at room temperature and then concentrated under reduced pressure. The residue was purified by prep-HPLC: Column: Kinetex EVO C18, 21.2*250 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 29%B to 54%B in 12 min; Wave Length: 254nm / 220nm; RTl(min): 11.13. The fractions were combined and lyophilized directly. This resulted in N-(2-{[2-({5-[(2-{[(3S)-3-amino-3-[(l-methyl-5-{[l-methyl-5-({2-[(l- methyl-5 - { [ 1 -methyl-5 -( { 5 -[3 -(trifluoromethyl) piperidin- 1 -yl]pentyl } carbamoyl)pyrrol-3 - yl] carbamoyl } pyrrol-3 -yl)carbamoyl] ethyl } carbamoyl)pyrrol-3 -yl] carbamoyl } pyrrol-3 - yl)carbamoyl] propyl] carbamoyl } - 1 - {bicyclo [2.2. 1 ]heptan-2-yl } imidazol-4-yl)carbamoyl] - 1 -methylpyrrol-3 - yl} carbamoyl)ethyl]carbamoyl}-l-methylimidazol-4-yl)-l-methylimidazole-2 -carboxamide (5.10 mg, 17.76%) as a white solid. HRMS: mass calcd. For C72H91F3N24O11: 1524.7251, found: 1525.7263 [M+H]+.

[0179] Example 2. Synthesis of Additional Compounds of the Disclosure

[0180] The compounds of the application were made by the methods similar to Examples 1. A summary of the analytical data is represented in Table 2.Table 2. Mass spectrometry data for the compounds of the disclosure.BIOLOGICAL EXAMPLES

[0181] Example B-l.

[0182] HUDEP-2 cells were passaged in expansion media prior to differentiation. Cells were differentiated in EDM2 media for 3 days, followed by EDM3 media for 4 days as previously described (Vinjamur et al., 2017). Treatment occurred during differentiation alone, or for 7 days in expansion media and during differentiation. Following differentiation, cells were analyzed by flow cytometry and qPCR.

[0183] Flow cytometry samples were briefly treated with a viability stain prior to washing and fixation with BD Fix / Perm kit fixative solution. Next the cells were washed, permeabilized in BD Fix / Perm kit permeabilization buffer, and incubated with diluted CD233, CD235a, and HbF antibodies for 1 hour on ice. Cells were then washed, resuspended in FACS staining buffer and analyzed on a Novocyte flow cytometer. Cells were gated based on live staining, and maturation markers CD233 and CD235a for HbF analysis.

[0184] Representative data on relative percent F-cell induction is presented in Table 3. A is < 1.5; B > 1.5 to 2.0; C > 2.0.Table 3. Representative biochemical data.

[0185] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a hematologic disorder in a subject in need thereof, comprising administering to the subject a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof:Formula (A), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently is hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl; or W2is -L-Z-R4; whereinL is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;Rwis hydrogen or C1-C20 alkyl or C1-C20 heteroalkyl; orRwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1 10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, -OH, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or - NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; or one of R3aand one of R3btogether with atoms to which they are attached form a C3-C6 cycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxhare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; is 1, 2, or 3; m is 0 or I : m is 0, 1, 2, or 3; n4 is 1, 2, or 3; and mi is 0 or 1. A method of treating sickle cell disease (SCD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof:Formula (A), wherein: each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs;W2is optionally substituted C1-C20 alkyl or optionally substituted C1-C20 heteroalkyl; or W2is -L-Z-R4; whereinL is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C’s-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; orR4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl;Rwis hydrogen or C1-C20 alkyl or C1-C20 heteroalkyl; orRwand W2together with the nitrogen atom to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1.10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, -OH, C1-C3 alkyl, -NR3cR3d, -NHC(O)OR3c, or - NHC(O)R3e, whereinR3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl; or one of R3aand one of R3btogether with atoms to which they are attached form a Cs-Ce cycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxhare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;is 1, 2, or 3; m is 0 or 1 ; m is 0, 1, 2, or 3; n4 is 1, 2, or 3; and mi is 0 or 1.

3. The method of claim 1 or 2, wherein W2is -L-Z-R4and Rwis hydrogen.4 The method of claim 1 or 2, wherein the compound of Formula (A) has the structure of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein:W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(0)CH3; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionallysubstituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; m is 0, 1, 2, or 3; n4 is 1, 2, or 3; and mi is 0 or 1. The method of any one of claims 1-4, wherein when m is 0 and mi is 1, then m is not 1. The method of any one of claims 1-4, wherein m is 1 or 2. The method of any one of clams 1-4, wherein m is 0. The method of any one of claims 1-7, wherein m is 1. The method of any one of claims 1-7, wherein m is 2. The method of claim 4, wherein the compound has the structure of Formula (II), or a pharmaceutically acceptable salt thereof:Formula (II),wherein:W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10, each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; and mi is 0 or 1.

11. The method of any one of claims 1-10, wherein Y4, Y5, Y6, and Y7are each independently -CH-.

12. The method of any one of claims 1-11, wherein Y1and Y8are each independently -N-.

13. The method of claim 10, wherein the compound has the structure of Formula (III), or a pharmaceutically acceptable salt thereof:Formula (III), wherein:W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs; each Y2and Y3is independently -CH- or -N-;L1is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10, each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2 is 0 or 1 ; and mi is 0 or 1.

14. The method of any one of claims 1-13, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently Ci-Cio alkyl, Ci-Cio haloalkyl, or C3-C10 cycloalkyl, or PEG1.10, each of which is optionally substituted with one or more Rx.

15. The method of claim 14, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently methyl, ethyl, propyl, butyl, pentyl, hexyl, -CH2CF3, cyclohexyl, or bicyclo[2.2.1]heptanyl.

16. The method of claim 14, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his methyl.

17. The method of any one of claims 1-13, wherein at least one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his not unsubstituted C1-C10 alkyl.

18. The method of claim 17, wherein at least one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his not methyl.

19. The method of any one of claims 1-18, wherein m is 0.

20. The method of any one of claims 1-18, wherein m is 1.

21. The method of any one of claims 1-18 or 20, wherein Y2is -N-.

22. The method of any one of claims 1-18 or 20, wherein Y2is -CH-.

23. The method of any one of claims 1-22, wherein is 1.

24. The method of any one of claims 1-22, wherein is 2.

25. The method of any one of claims 1-22, wherein is 3.

26. The method of any one of claims 1-25 wherein each Y3is independently -N-.

27. The method of any one of claims 1-25, wherein each Y3is independently -CH-.

28. The method of any one of claims 1-27, wherein mi is 0.

29. The method of any one of clams 1-27, wherein mi is 1.

30. The method of any one of claims 1-29, wherein each R3bis hydrogen; and each R3ais independently hydrogen, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e.

31. The method of claim 30, wherein each R3ais independently hydrogen or -NH2.

32. The method of any one of claims 1-29, wherein two R3atogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl.

33. The method of any one of claims 1-29, wherein two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl.

34. The method of any one of claims 1-29, wherein each R3aand each R3bare hydrogen.

35. The method of any one of claims 1-34, whereinL is C1-C20 alkylene and R4is -NR4aR4b, whereinR4ais hydrogen or optionally substituted C1-C10 alkyl;R4bis optionally substituted Ci-Cio alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Ci-Cio hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl.

36. The method of claim 35, wherein R4ais hydrogen or optionally substituted Ci-Cio alkyl; and R4bis optionally substituted Ci-Cio alkyl, optionally substituted Ci-Cio aminoalkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Ci-Cio hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl.

37. The method of claim 33, wherein R4ais hydrogen or optionally substituted Ci-Cio alkyl; and R4bis optionally substituted Ci-Cio alkyl or optionally substituted Ci-Cio haloalkyl.

38. The method of claim 35 or 36, wherein R4ais hydrogen.

39. The method of claim 37, wherein R4ais Ci-Cio alkyl and R4bis Ci-Cio alkyl.

40. The method of claim 39, wherein R4ais methyl and R4bis methyl.

41. The method of claim 35, wherein R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl.

42. The method of claim 41, wherein R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 6-membered heterocycloalkyl, optionally substituted with one or more halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

43. The method of any one of claims 1-34, wherein L is C1-C20 alkylene and R4is -CH3.

44. The method of any one of claims 35-43, wherein L is Ci-Cs alkylene.

45. The method of claim 44, wherein L is Ci-Ce alkylene.

46. The method of claim 43, wherein L is absent.

47. The method of any one of claims 1-46, wherein Z is absent.

48. The method of any one of claims 1-46, wherein Z is -C(O)-.

49. The method of any one of claims 1-48, wherein the compound is optionally conjugated to a moiety that modulates gene expression.

50. A compound having the structure of Formula (la), or a pharmaceutically acceptable salt thereof:Formula (la), wherein:W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a Cs-Ce cycloalkyl or 3 to 6-membered heterocycloalkyl;each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C„ cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2is 0 or 1 ; n3is 0, 1, 2, or 3; n4is 1, 2, or 3; and mi is 0 or 1; wherein when n3is 0 and mi is 1, then n4is not 1.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein n3is 2.

52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein n3is 1.

53. The compound of any one of claims 50-52, or a pharmaceutically acceptable salt thereof, wherein n4is 2.

54. The compound of any one of claims 50-52, or a pharmaceutically acceptable salt thereof, wherein n4is 1.

55. The compound of claim 50, wherein the compound has the structure of Formula (II), or a pharmaceutically acceptable salt thereof:Formula (II), wherein:W1and Wlaare each independently hydrogen, halogen, Ci-C3haloalkyl, or -NHC(O)CH3; each Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8is independently -CH- or -N-;L is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent or -C(O)-;R4is -CH ,. -0R4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted Ci-Cio alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Ci-Cw hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted Ci-Cw alkyl, optionally substituted Ci-Cw aminoalkyl, optionally substituted Ci-Cio haloalkyl, optionally substituted Ci-Cio hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEGMO; each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxhare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; is 1, 2, or 3; n2is 0 or 1 ; and mi is 0 or 1.

56. The compound of any one of claims 50-55, or a pharmaceutically acceptable salt thereof, wherein Y4, Y5, Y6, and Y7are each -CH-.

57. The compound of any one of claims 50-56, or a pharmaceutically acceptable salt thereof, wherein Y1and Y8are each -N-.

58. The compound of claim 50, wherein the compound has the structure of Formula (III), or a pharmaceutically acceptable salt thereof:Formula (III), wherein:W1and Wlaare each independently hydrogen, halogen, C1-C3 haloalkyl, or -NHC(O)CHs; each Y2and Y3is independently -CH- or -N-;L1is absent, C1-C20 alkylene, or C1-C20 heteroalkylene;Z is absent;R4is -CH3, -OR4a, or -NR4aR4b; whereinR4ais hydrogen, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 heteroalkyl, or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl; each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted PEG1-10, each of which is optionally substituted with one or more Rx; each R3aand R3bis independently hydrogen, C1-C3, -NR3cR3d, -NHC(O)OR3c, or -NHC(O)R3e, wherein R3cand R3dare each independently hydrogen, alkyl, alkyl(phenyl), or PEG;R3eis alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or two R3aor two R3btogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 3 to 6-membered heterocycloalkyl; each Rxis independently -CN, -OH, -ORXa, -N3, -NRXaRxb, -CO(O)RXc, -C(O)ORXc, -C(O)NRXaRxb, - NHC(O)RXc, -NHC(O)ORXc, -OC(O)NRXaRxb, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5 to 10-membered heteroaryl; whereinRXaand Rxbare each independently hydrogen, alkyl, or PEG;RXcis alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; ni is 1, 2, or 3; n2 is 0 or 1 ; and mi is 0 or 1.

59. The compound of any one of claims 50-58, or a pharmaceutically acceptable salt thereof, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently Ci-Cw alkyl, Ci-Cw haloalkyl, or C,- Cio cycloalkyl, or PEGi-io, each of which is optionally substituted with one or more Rx.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his independently methyl, ethyl, propyl, butyl, pentyl, hexyl, -CH2CF3, cyclohexyl, or bicyclo[2.2.1]heptanyl.

61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein each R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his methyl.

62. The compound of any one of claims 50-60, or a pharmaceutically acceptable salt thereof, wherein at least one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his not unsubstituted Ci-Cw alkyl.

63. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein at least one of R2a, R2b, R2c, R2d, R2e, R2f, R2g, or R2his not methyl.

64. The compound of any one of claims 50-63, or a pharmaceutically acceptable salt thereof, wherein m is 0.

65. The compound of any one of claims 50-63, or a pharmaceutically acceptable salt thereof, wherein m is 1.

66. The compound of any one of claims 50-63 or 65, or a pharmaceutically acceptable salt thereof, wherein Y2is -N-.

67. The compound of any one of claims 50-63 or 65, or a pharmaceutically acceptable salt thereof, wherein Y2is -CH-.

68. The compound of any one of claims 50-67, or a pharmaceutically acceptable salt thereof, wherein ni is 1.

69. The compound of any one of claims 50-67, or a pharmaceutically acceptable salt thereof, wherein ni is 2.

70. The compound of any one of claims 50-67, or a pharmaceutically acceptable salt thereof, wherein ni is 3.

71. The compound of any one of claims 50-70, or a pharmaceutically acceptable salt thereof, wherein each Y3is independently -N-.

72. The compound of any one of claims 50-70, or a pharmaceutically acceptable salt thereof, wherein each Y3is independently -CH-.

73. The compound of any one of claims 50-72, or a pharmaceutically acceptable salt thereof, wherein mi is 0.

74. The compound of any one of clams 50-72, or a pharmaceutically acceptable salt thereof, wherein mi is 1.

75. The compound of any one of claims 50-74, or a pharmaceutically acceptable salt thereof, wherein each R3bis hydrogen; and each R3ais independently hydrogen, -NR3cR3d, -NHC(O)OR3c, or - NHC(O)R3e.

76. The compound of claim 75, or a pharmaceutically acceptable salt thereof, wherein each R3ais independently hydrogen or -NH2.

77. The compound of any one of claims 50-74, or a pharmaceutically acceptable salt thereof, wherein each R3aand each R3bare hydrogen.

78. The compound of any one of claims 50-77, or a pharmaceutically acceptable salt thereof, wherein L is C1-C20 alkylene; and R4is -NR4aR4b, whereinR4ais hydrogen or optionally substituted C1-C10 alkyl;R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6-membered heterocycloalkyl.

79. The compound of claim 78, or a pharmaceutically acceptable salt thereof, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl; and R4bis optionally substituted C1-C10 alkyl, optionally substituted C1-C10 aminoalkyl, optionally substituted C1-C10 haloalkyl, optionally substituted C1-C10 hydroxyalkyl, optionally substituted Cs-Ce cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl.

80. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein R4ais hydrogen or optionally substituted C1-C10 alkyl; and R4bis optionally substituted C1-C10 alkyl or optionally substituted C1-C10 haloalkyl.

81. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein R4ais hydrogen.

82. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R4ais C1-C10 alkyl and R4bis C1-C10 alkyl.

83. The compound of claim 82, or a pharmaceutically acceptable salt thereof, wherein R4ais methyl and R4bis methyl.

84. The compound of claim 78, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 3 to 6- membered heterocycloalkyl.

85. The compound of claim 84, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the nitrogen to which they are attached form an optionally substituted 6-membered heterocycloalkyl, optionally substituted with one or more halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

86. The compound of any one of claims 50-77, or a pharmaceutically acceptable salt thereof, wherein L is C1-C20 alkylene and R4is -CH3.

87. The compound of any one of claims 78-86, or a pharmaceutically acceptable salt thereof, wherein L is Ci-Cs alkylene.

88. The compound of claim 87, or a pharmaceutically acceptable salt thereof, wherein L is Ci-Ce alkylene.

89. The compound of claim 88, or a pharmaceutically acceptable salt thereof, wherein L is absent90. The compound of any one of claims 50-89, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

91. The compound of any one of claims 50-89, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

92. The compound of any one of claims 50-91, or a pharmaceutically acceptable salt thereof, wherein W1is hydrogen and Wlais -CF3.

93. The compound of any one of claims 50-91, or a pharmaceutically acceptable salt thereof, wherein W1is hydrogen and Wlais hydrogen.

94. A compound selected from Table 1, or pharmaceutically acceptable salts thereof.

95. A pharmaceutical composition comprising a compound of any one of claims 50-94, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.