Compounds and methods for treating sickle cell disease

Abstract

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

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 607,825, filed December 8, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This article provides compounds and methods related to the treatment of sickle cell disease (SCD). Background Technology

[0004] Heme disorders encompass a variety of anemias characterized by decreased production and / or increased destruction of red blood cells (RBCs). Heme disorders can also include genetic defects that result in the production of abnormal heme, accompanied by impaired ability to maintain oxygen levels. These conditions are associated with β-globulin and are commonly referred to as β-heme disorders. Examples include sickle cell disease and thalassemia.

[0005] Sickle cell disease (SCD, also known as sickle cell anemia (SCA)) is a genetic disorder that causes a process of vascular occlusion that is the cause of death in many SCD patients. SCD is caused by a point mutation in the heme (HBB) gene that produces an abnormal sickle heme (HbS or HbSS), which aggregates and produces hard, sticky sickle-shaped red blood cells. These sickle-shaped red blood cells lead to chronic inflammation, increased cell adhesion, oxidative stress, and endothelial dysfunction, ultimately resulting in the vascular occlusion process. SCD is incurable, and treatment options are typically limited to blood transfusions.

[0006] Thalassemia is a genetic disorder characterized by a lower level of heme and a reduced number of red blood cells compared to normal. The low heme and red blood cell counts in thalassemia can cause symptoms such as anemia, lethargy, fatigue, chest pain, and shortness of breath. Alpha-thalassemia and beta-thalassemia are the two main types of thalassemia; both have severe and mild forms. Severe beta-thalassemia is also known as Cooley anemia or Cooley thalassemia. Beta-thalassemia also includes beta+ thalassemia and beta0 thalassemia. Individuals with beta-thalassemia have a genetic defect that results in very little or no synthesis of the beta chain of heme. Symptoms of beta-thalassemia include anemia, hypoxia in many parts of the body, pulmonary hypertension, thrombotic events, infections, endocrine disorders, and leg ulcers. Treatment for thalassemia, such as blood transfusions and iron chelation therapy, can be helpful, but repeated transfusions can lead to iron overload and numerous side effects.

[0007] There is an unmet clinical need for developing therapeutics and therapies for blood disorders such as SCD. Summary of the Invention

[0008] In one aspect, this article provides a method for treating a blood disorder in a subject in need, comprising administering to the subject a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Equation (A),

[0011] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0012] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0013] W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4 ;in

[0014] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0015] Z either does not exist or is -C(O)-;

[0016] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0017] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0018] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0019] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0020] R W It is hydrogen or C1-C 20 Alkyl or C1-C 20 Heteroalkyl; or

[0021] R W and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0022] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0023] Each R 3a and R 3b Independently hydrogen, -OH, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0024] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0025] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0026] Or two Rs 3a The carbon atom or two R atoms it is attached to 3bTogether with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; or

[0027] An R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0028] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0029] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0030] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0031] n1 is 1, 2, or 3;

[0032] n2 is either 0 or 1;

[0033] n3 can be 0, 1, 2, or 3;

[0034] n4 is 1, 2, or 3; and

[0035] m1 is either 0 or 1.

[0036] On the other hand, this article provides a method for treating sickle cell disease (SCD) in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0037]

[0038] Equation (A),

[0039] Each Y 1 Y 2 Y 3 Y 4 Y 5Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0040] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0041] W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4 ;in

[0042] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0043] Z either does not exist or is -C(O)-;

[0044] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0045] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Alkyl or optionally substituted C1-C 10 Heteroalkyl;

[0046] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0047] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0048] R W It is hydrogen or C1-C 20 Alkyl or C1-C 20 Heteroalkyl; or

[0049] RW and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0050] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0051] Each R 3a and R 3b Independently hydrogen, -OH, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0052] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0053] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0054] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; or

[0055] An R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0056] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NRXa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0057] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0058] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0059] n1 is 1, 2, or 3;

[0060] n2 is either 0 or 1;

[0061] n3 can be 0, 1, 2, or 3;

[0062] n4 is 1, 2, or 3; and

[0063] m1 is either 0 or 1.

[0064] On the other hand, this article provides a compound having the structure of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0065]

[0066] Equation (Ia),

[0067] in:

[0068] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0069] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0070] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0071] Z either does not exist or is -C(O)-;

[0072] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0073] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0074] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0075] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0076] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0077] Each R 3a and R 3b Independently hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0078] R3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0079] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl; or

[0080] Two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0081] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0082] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0083] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0084] n1 is 1, 2, or 3;

[0085] n2 is either 0 or 1;

[0086] n3 can be 0, 1, 2, or 3;

[0087] n4 is 1, 2, or 3; and

[0088] m1 is 0 or 1;

[0089] When n3 is 0 and m1 is 1, then n4 is not 1.

[0090] On the other hand, this document provides compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0091] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples are provided for illustration only, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description.

[0092] Incorporate by reference

[0093] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent, or patent application were specifically and individually instructed to be incorporated by reference. Where any publication, patent, or patent application incorporated by reference conflicts with any disclosure contained herein, this specification is intended to substitute for and / or give precedence to any such conflicting material. Detailed Implementation

[0094] In one respect, this article provides a method using transcription regulator compounds.

[0095] How to use

[0096] In one aspect, this article provides a method for treating a blood disorder in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0097]

[0098] Formula (A'),

[0099] in:

[0100] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0101] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0102] W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4;in

[0103] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0104] Z either does not exist or is -C(O)-;

[0105] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0106] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0107] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0108] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0109] R W It is hydrogen or C1-C 20 Alkyl or C1-C 20 Heteroalkyl; or

[0110] R W and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0111] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0112] Each R 3a and R 3b Independently hydrogen, -OH, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0113] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0114] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0115] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; or

[0116] An R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0117] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0118] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0119] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0120] Each R y Independently hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or

[0121] Two Rs y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups;

[0122] n1 is 1, 2, or 3;

[0123] n2 is either 0 or 1;

[0124] n3 can be 0, 1, 2, or 3;

[0125] n4 is 1, 2, or 3; and

[0126] m1 is either 0 or 1.

[0127] On the other hand, this article provides a method for treating a blood disorder in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0128]

[0129] Equation (A),

[0130] in:

[0131] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0132] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0133] W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4 ;in

[0134] L does not exist; it is C1-C. 20 Alkylene or C1-C20 Heteroalkyl;

[0135] Z either does not exist or is -C(O)-;

[0136] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0137] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0138] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0139] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0140] R W It is hydrogen or C1-C 20 Alkyl or C1-C 20 Heteroalkyl; or

[0141] R W and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0142] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0143] Each R 3a and R 3b Independently hydrogen, -OH, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0144] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0145] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0146] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; or

[0147] An R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups;

[0148] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0149] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0150] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0151] n1 is 1, 2, or 3;

[0152] n2 is either 0 or 1;

[0153] n3 can be 0, 1, 2, or 3;

[0154] n4 is 1, 2, or 3; and

[0155] m1 is either 0 or 1.

[0156] In some embodiments, the compound of formula (A) has the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0157]

[0158] Formula (I),

[0159] in:

[0160] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0161] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0162] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0163] Z either does not exist or is -C(O)-;

[0164] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0165] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0166] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0167] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0168] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0169] Each R 3a and R 3b Independently hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0170] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0171] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0172] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0173] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)RXc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0174] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0175] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0176] n1 is 1, 2, or 3;

[0177] n2 is either 0 or 1;

[0178] n3 can be 0, 1, 2, or 3;

[0179] n4 is 1, 2, or 3; and

[0180] m1 is either 0 or 1.

[0181] In some embodiments, the hematologic disorder is sickle cell disease, β-heme disease, or thalassemia. In some embodiments, the hematologic disorder is sickle cell disease. In some embodiments, the hematologic disorder is β-heme disease. In some embodiments, the hematologic disorder is thalassemia. In some embodiments, the thalassemia is β-thalassemia.

[0182] In other embodiments, the compound optionally binds to a portion that regulates gene expression. In some embodiments, the compound is linked to the portion that regulates gene expression via an oligomeric linker.

[0183] In some embodiments, the compound binds to the gene-regulating portion via an oligomeric linker located at: W 1 W 1a W 2 ;R 2a R 2b R 2c R 2d R 2e R 2f R 2g or R 2h One of them; R 3a or R 3b One of them; R4 ;R 4a ; or R 4b In some embodiments, the compound is delivered via W 1 The oligomeric linker at the site binds to the 4} portion that regulates gene expression. In some embodiments, the compound is delivered via W 1a The oligomeric linker at the site binds to the 4} portion that regulates gene expression. In some embodiments, the compound is delivered via W 2 The oligomeric linker at the site binds to the 4} portion that regulates gene expression. In some embodiments, the compound is delivered via R 2a R 2b R 2c R 2d R 2e R 2f R 2g or R 2h The oligomeric linker at one of the sites binds to the portion that regulates gene expression. In some embodiments, the compound is delivered via R... 3a or R 3b The oligomeric linker at one of the sites binds to the portion that regulates gene expression. In some embodiments, the compound is delivered via R... 4 The oligomeric linker at the site binds to the portion that regulates gene expression. In some embodiments, the compound is delivered via R... 4a The oligomeric linker at the site binds to the portion that regulates gene expression. In some embodiments, the compound is delivered via R... 4b The oligomeric linker binds to the portion that regulates gene expression.

[0184] In some embodiments, the portion that regulates gene expression includes portions capable of binding to members of the bromodomain and superterminal domain (BET) family.

[0185] 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.

[0186] In some embodiments, the portion regulating gene expression includes a portion capable of binding to the following: CBP / p300, P300 / CBP-Associated Factor (PCAF), cat eye syndrome chromosome region candidate 2 (CECR2), bromodomain and PHD finger-containing protein (BRPF), ATAD2 / ATAD2B (chromatin remodeling protein), Tripartite motif-containing protein 24 (TRIM24), bromodomain adjacent to zinc finger (BAZ2), TBP-associated factor (TAF1), BRD7 / 9, bromodomain PHD finger transcription factor (BPTF), SMARCA2 / 4, or PBRM1.

[0187] In some embodiments, the portion that regulates gene expression can bind to CBP / p300.

[0188] In some embodiments, the portion that regulates gene expression can bind to the P300 / CBP-associated factor (PCAF).

[0189] In some embodiments, the portion that regulates gene expression can bind to candidate gene 2 (CECR2) in the chromosomal region of cat's eye syndrome.

[0190] In some embodiments, the portion that regulates gene expression can bind to a protein containing a bromine domain and a PHD finger (BRPF).

[0191] In some embodiments, the portion that regulates gene expression can bind to ATAD2 or ATAD2B chromatin remodeling proteins.

[0192] In some embodiments, the portion that regulates gene expression can bind to the bromine domain (BAZ2) of the adjacent zinc finger.

[0193] In some embodiments, the portion that regulates gene expression can bind to TBP-associated factor (TAF1).

[0194] In some embodiments, the portion that regulates gene expression can bind to protein 24 (TRIM24), which contains a triple motif.

[0195] In some embodiments, the portion that regulates gene expression can bind to BRD7 / 9.

[0196] In some embodiments, the portion that regulates gene expression can bind to the bromine domain PHD finger transcription factor (BPTF).

[0197] In some embodiments, the portion that regulates gene expression can bind to SMARCA2 / 4.

[0198] In some embodiments, the portion that regulates gene expression can bind to PBRM1.

[0199] compound

[0200] On the other hand, this article provides a compound having the structure of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0201]

[0202] Equation (Ia),

[0203] in:

[0204] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0205] W 1 and W 1a Each can be independently hydrogen, halogen, or C1-C3 haloalkyl, or -NHC(O)CH3;

[0206] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0207] Z either does not exist or is -C(O)-;

[0208] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0209] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0210] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0211] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0212] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0213] Each R 3a and R 3b Independently hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0214] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0215] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0216] Or two Rs 3a Or two Rs 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0217] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0218] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0219] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0220] n1 is 1, 2, or 3;

[0221] n2 is either 0 or 1;

[0222] n3 can be 0, 1, 2, or 3;

[0223] n4 is 1, 2, or 3; and

[0224] m1 is 0 or 1;

[0225] When n3 is 0 and m1 is 1, then n4 is not 1.

[0226] In some embodiments, this document provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof:

[0227]

[0228] Equation (II),

[0229] in:

[0230] Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-;

[0231] W1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0232] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0233] Z either does not exist or is -C(O)-;

[0234] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0235] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0236] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0237] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0238] Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R Xreplace;

[0239] Each R 3a and R 3b Independently hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0240] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0241] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0242] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0243] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0244] R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG;

[0245] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0246] n1 is 1, 2, or 3;

[0247] n2 is either 0 or 1; and

[0248] m1 is either 0 or 1.

[0249] In some embodiments, this document provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof:

[0250]

[0251] Equation (III),

[0252] in:

[0253] W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3;

[0254] Each Y 2 and Y 3 Independently -CH- or -N-;

[0255] L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl;

[0256] Z either does not exist or is -C(O)-;

[0257] R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in

[0258] R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl;

[0259] R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or

[0260] R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups;

[0261] Each R 2a R 2b R 2c R 2d R2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace;

[0262] Each R 3a and R 3b Independently hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in

[0263] R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG;

[0264] R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group;

[0265] Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl;

[0266] Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein

[0267] R Xa and RXb Each can be independently hydrogen, alkyl, or PEG;

[0268] R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl;

[0269] n1 is 1, 2, or 3;

[0270] n2 is either 0 or 1; and

[0271] m1 is either 0 or 1.

[0272] In some embodiments of formula (A') or (A), R W For C1-C 20 Alkyl or C1-C 20 Heteroalkyl. In some embodiments of formula (A') or (A), R W For C1-C 20 Alkyl group. In some embodiments of formula (A), R W For C1-C 20 Heteroalkyl. In some embodiments of formula (A') or (A), R W It is hydrogen.

[0273] In some embodiments of formula (A') or (A), W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl. In some embodiments of formula (A') or (A), W 2 C1-C is optionally substituted 20 Alkyl group. In some embodiments of formula (A') or (A), W 2 C1-C is optionally substituted 20 Heteroalkyl. In some embodiments of formula (A') or (A), W 2 -LZR 4 .

[0274] In some embodiments of formula (A') or (A), R W and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups.

[0275] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), W 1 It is a halogen or a C1-C3 haloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), W 1 It is a halogen. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), W1 It is a C1-C3 haloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), W 1 It is hydrogen. In some embodiments of formula (A'), (A), (I), (Ia) or (II), W 1 It is -NHC(O)CH3.

[0276] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), W 1a It is a halogen or a C1-C3 haloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), W 1a It is a halogen. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), W 1a It is a C1-C3 haloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), W 1a It is hydrogen. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), W 1a It is -NHC(O)CH3.

[0277] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), W 1 It is hydrogen and W 1a It is a C1-C3 haloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), W 1 It is hydrogen and W 1a For CF3. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), W 1 It is hydrogen and W 1a It is hydrogen.

[0278] In some embodiments of formula (A'), (A), (I), (Ia), or (II), Y 1 For -N-. In some embodiments of formula (A), (I), (Ia) or (II), Y 1 It is -CH-.

[0279] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each Y 2 For -N-. In some embodiments of equations (A'), (A), (I), (Ia), (II), or (III), each Y 2 It is -CH-.

[0280] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each Y 3 For -N-. In some embodiments of equations (A'), (A), (I), (Ia), (II), or (III), each Y 3 It is -CH-.

[0281] In some embodiments of formula (A), (I), (Ia) or (II), Y 4 For -N-. In some embodiments of formula (A'), (A), (I), (Ia) or (II), Y 4 It is -CH-.

[0282] In some embodiments of formula (A'), (A), (I), (Ia), or (II), each Y 5 For -N-. In some embodiments of equations (A'), (A), (I), (Ia), or (II), each Y 5 It is -CH-.

[0283] In some embodiments of formula (A'), (A), (I), (Ia), or (II), each Y 6 For -N-. In some embodiments of equations (A'), (A), (I), (Ia), or (II), each Y 6 It is -CH-.

[0284] In some embodiments of formula (A'), (A), (I), (Ia), or (II), Y 7 For -N-. In some embodiments of formula (A'), (A), (I), (Ia) or (II), Y 7 It is -CH-.

[0285] In some embodiments of formula (A'), (A), (I), (Ia), or (II), Y 8 For -N-. In some embodiments of formula (A'), (A), (I), (Ia) or (II), Y 8 It is -CH-.

[0286] In some embodiments of formula (A'), (A), (I), (Ia), or (II), each Y 4 Y 5 Y 6 and Y 7 Independently -CH-. In some embodiments of formula (A'), (A), (I), (Ia), or (II), each Y 4 Y 5 Y 6 and Y 7Independently -N-.

[0287] In some embodiments of formula (A'), (A), (I), (Ia), or (II), Y 1 and Y 8 Each is independently -N-. In some embodiments of formulas (A'), (A), (Ia), (I), or (II), Y 1 and Y 8 Each is independently -CH-.

[0288] In some embodiments of formula (A'), (A), (I), (Ia), or (II), each Y 2 It is -CH- or -N-, and each Y 1 Y 3 and Y 8 For -N-. In some embodiments of equations (A'), (A), (I), (Ia), or (II), each Y 2 It is -CH-, and each Y 1 Y 3 and Y 8 For -N-. In some embodiments of equations (A'), (A), (I), (Ia), or (II), each Y 1 Y 2 Y 3 and Y 8 Let N be the number of elements in the array.

[0289] In some embodiments of formulas (A'), (A), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X Replacement. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2hIndependently for C1-C 10 Alkyl or C1-C 10 Alkyl halide. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for C1-C 10 Halogenated alkyl groups. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently -CF3 or -CH2CF3. In some embodiments of formula (A'), (A), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h For -CH2CF3. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for C1-C 10 Alkyl group. In some embodiments of formula (A'), (A), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently methyl, ethyl, propyl, butyl, propyl, pentyl, or hexyl. In some embodiments of formula (A'), (A), (Ia), (II), or (III), each R 2a R 2b R2c R 2d R 2e R 2f R 2g and R 2h It is methyl. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Ethyl. In some embodiments, each R... 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is n-propyl. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is isopropyl. In some embodiments of formula (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is butyl. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is sec-butyl. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R2h It is tert-butyl. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is pentyl. In some embodiments of formula (A'), (A), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h For oneself.

[0290] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for C3-C 10 Cycloalkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently, it is a C5-C8 cycloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the cycloalkyl group is monocyclic, bicyclic, bridged, or spirocyclic. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2hIndependently, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclic [2.2.1]heptane. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently cyclohexyl or bicyclo[2.2.1]heptane. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is cyclohexyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is a bicyclic [2.2.1]heptane.

[0291] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently , , or In some embodiments of formulas (A'), (A), (I), (Ia), (II), (III), or (V), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently or In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h for In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h for In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h for .

[0292] In some embodiments of formulas (A'), (A), (Ia), (II), or (III), each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is independently methyl, ethyl, isopropyl, propyl, butyl, pentyl, hexyl, -CH2CF3, cyclohexyl or bicyclo[2.2.1]heptane.

[0293] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R2a R 2b R 2c R 2d R 2e R 2f R 2g or R 2h At least one of them is not an unsubstituted C1-C 10 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2a R 2b R 2c R 2d R 2e R 2f R 2g or R 2h At least one of them is not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2a R 2b R 2c R 2d R 2e R 2f R 2g or R 2h At least two of them are not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2a R 2b R 2c R 2d R 2e R 2f R 2g or R 2h At least three of them are not methyl.

[0294] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 2a Not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2b Not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2c Not methyl. In some embodiments of formula (A'), (A), (I), (II), (III), (IV), or (IV), R 2d Not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2eNot methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2f Not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2g Not methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 2h It is not methyl.

[0295] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3b It is hydrogen; and each R 3a Independently selected from hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3b It is hydrogen; and each R 3a Independently selected from hydrogen, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3b It is hydrogen; and each R 3a Independently hydrogen or -NR 3c R 3d .

[0296] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3b It combines with the atoms it is attached to to form a C3-C6 cycloalkyl group; and each R 3a Independently selected from hydrogen, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3b It combines with the atoms it is attached to to form a cyclopropyl group; and each R 3a Independently selected from hydrogen, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3b It combines with the atoms it is attached to to form a cyclopropyl group; and each R 3a It is independently selected from hydrogen or -NH2.

[0297] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3a It is hydrogen; and each R 3b Independently selected from hydrogen, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3a It is hydrogen; and each R 3b Independently selected from hydrogen, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3a It is hydrogen; and each R 3b Independently hydrogen or -NR 3c R 3d In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3a It is hydrogen; and each R 3b Independently selected from hydrogen, -NH2, -NH(CH3), -NH(CH2CH3), -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), (Ia), (II) or (III), each R 3a It is hydrogen; and each R 3b Independently selected from hydrogen or -NH2. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 3a It is hydrogen; and each R 3b It is hydrogen.

[0298] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R3a It combines with the atoms it is attached to to form a C3-C6 cycloalkyl group; and each R 3b Independently selected from hydrogen, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3a It combines with the atoms it is attached to to form a cyclopropyl group; and each R 3b Independently selected from hydrogen, -NR 3c R 3d -NHC(O)OR 3c and -NHC(O)R 3e In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3a It combines with the atoms it is attached to to form a cyclopropyl group; and each R 3b It is independently selected from hydrogen or -NH2.

[0299] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3a Independently, it is hydrogen, -NHC(O)CH3, -NHC(O)O-CH2-(phenyl) or -NH2. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), each R 3a Independently hydrogen or -NH2. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 3a It is hydrogen. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), an R 3a One is hydrogen and the other is -NH2.

[0300] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3b Independently, it is hydrogen, -NHC(O)CH3, -NHC(O)O-CH2-(phenyl) or -NH2. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), each R 3b Independently hydrogen or -NH2. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 3bIt is hydrogen. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), an R 3b One is hydrogen and the other is -NH2.

[0301] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R 3a and each R 3b It is hydrogen.

[0302] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3a Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R atoms form a C3-C6 cycloalkyl group. 3a Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, or cyclopentyl group. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R groups... 3a Together with the carbon atom it is attached to, it forms a cyclopropyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R groups... 3a Together with the carbon atom it is attached to, it forms a cyclobutyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3a Together with the carbon atom it is attached to, it forms a cyclopentyl group. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R groups... 3a Together with the carbon atom to which it is attached, it forms a 3- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3a Together with the carbon atom it is attached to, it forms a 4-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3a Together with the carbon atom it is attached to, it forms a 5-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3a Together with the carbon atom it is attached to, it forms a 6-membered heterocyclic alkyl group.

[0303] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R 3bTogether with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R atoms form a C3-C6 cycloalkyl group. 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, or cyclopentyl group. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R groups... 3b Together with the carbon atom it is attached to, it forms a cyclopropyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R groups... 3b Together with the carbon atom it is attached to, it forms a cyclobutyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3b Together with the carbon atom it is attached to, it forms a cyclopentyl group. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), the two R groups... 3b Together with the carbon atom to which it is attached, it forms a 3- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3b Together with the carbon atom it is attached to, it forms a 4-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3b Together with the carbon atom it is attached to, it forms a 5-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the two R... 3b Together with the carbon atom it is attached to, it forms a 6-membered heterocyclic alkyl group.

[0304] In some embodiments of formula (A') or (A), an R 3a And an R 3b Together with the atoms to which it is attached, it forms a C3-C6 cycloalkyl group. In some embodiments of formula (A') or (A), an R 3a And an R 3b Together with the atoms it is attached to, it forms a cyclopropyl group. In some embodiments of formula (A') or (A), an R 3a And an R 3b Together with the atoms it is attached to, it forms a cyclobutyl group. In some embodiments of formula (A') or (A), an R 3a And an R 3b Together with the atoms it is attached to, it forms a cyclopentyl group. In some embodiments of formula (A') or (A), an R 3a And an R 3b Together with the atoms it is attached to, it forms a cyclohexyl group.

[0305] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3c and R 3d Each is independently hydrogen, alkyl, alkyl(phenyl), or PEG. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3c and R 3d Each independently is hydrogen, C1-C 20 Alkyl, -CH2-(phenyl) or PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3c and R 3d Each independently is C1-C 20 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 3c and R 3d Each is independently -CH2-(phenyl). In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 3c and R 3d Each independently for PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3c and R 3d Each is hydrogen.

[0306] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3e It is an alkyl, haloalkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl compound. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 3e For C1-C 20 Alkyl, C1-C 20 Halogenated groups, PEG 1-20 C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, or phenyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 3e For C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3e It is a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic alkyl, or a phenyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R3e For C1-C 20 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 3e For C1-C 20 Alkyl halide. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 3e PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 3e It is a C3-C6 cycloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 3e It is a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 3e It is a phenyl group.

[0307] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene; and R 4 For -NR 4a R 4b , where R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclic alkyl; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups.

[0308] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene or C1-C 20 Heteroalkyl; and R 4 For -NR 4a R 4b , where R 4a Hydrogen, optionally substituted C1-C 10 Alkyl or optionally substituted C1-C 10 Alkyl; and R 4bC1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene or C1-C 20 Heteroalkyl; and R 4 For -NR 4a R 4b , where R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene and R 4 For -NR 4a R 4b , where R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene and R 4 For -NR 4a R 4b , where R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl or optionally substituted C1-C10 Alkyl haloide. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is C1-C. 20 Alkylene and R 4 For -NR 4a R 4b , where R 4a For C1-C 10 Alkyl and R 4b For C1-C 10 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a It is a C1-C8 alkyl group and R 4b It is a C1-C8 alkyl group. In some embodiments, R 4a It is a C1-C6 alkyl group and R 4b It is a C1-C6 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4a It is a C1-C3 alkyl group and R 4b It is a C1-C3 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4a It is methyl and R 4b It is a methyl group.

[0309] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene or C1-C 20 Heteroalkyl; and R 4 For -OR 4a , where R 4a Hydrogen or optionally substituted C1-C 10 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is C1-C. 20 Alkylene; and R 4 For -OR 4a , where R 4a L is hydrogen. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is C1-C. 20 Alkylene; and R 4 For -OR 4a , where R 4a C1-C is optionally substituted 10 alkyl.

[0310] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C20 Alkylene and R 4 For -NR 4a R 4b , where R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 3- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 4-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 5-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted morpholine, optionally substituted thiomorpholine, optionally substituted thiomorpholine oxide, or optionally substituted thiomorpholine dioxide. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, or optionally substituted morpholine. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a and R 4bTogether with the nitrogen to which it is attached, it forms an optionally substituted piperidine or an optionally substituted piperazine. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from alcohols, alkoxy groups, amino groups, cyano groups, halogen groups, nitro groups, alkyl groups, haloalkyl groups, oxo groups (=O), and charged moieties. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from -Cl, -F, -CN, -NH2, -NH(CH3), -N(CH3)2, -NO3, -OH, -CH3, -CF3, and =O. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from -F and -CF3.

[0311] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 4a Hydrogen or optionally substituted C1-C 10 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a C1-C is optionally substituted 10 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a It is a C1-C8 alkyl group. In some embodiments, R 4a It is a C1-C6 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4a It is a C1-C3 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4a It is methyl or ethyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4a It is methyl. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4aThe substance is hydrogen. In some embodiments of formula (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from alcohols, alkoxy groups, amino groups, cyano groups, halogen groups, nitro groups, alkyl groups, haloalkyl groups, oxo groups (=O), biotin or derivatives thereof, isophthalic acid or methoxycarbonylbenzoic acid or derivatives thereof, and charged moiety. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), 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), (Ia), (II), or (III), 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), (Ia), (II), or (III), one or more optional substituents are charged moieties. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are isophthalic acid or methoxycarbonylbenzoic acid or derivatives thereof. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are 3-((λ) 2 3-(azoalkyl)carbonyl)methyl benzoate. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), one or more optional substituents are 3-(λ) 2 -Azyl)carbonyl)benzoic acid. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), one or more optional substituents are biotin or a derivative thereof. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), one or more optional substituents are .

[0312] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclic alkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4b C1-C is optionally substituted10 Alkyl or optionally substituted C1-C 10 Alkyl halide. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4b C1-C is optionally substituted 10 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4b C1-C is optionally substituted 10 Alkyl halide. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4b C1-C is optionally substituted 10 Alkyl group. In some embodiments, R 4b It is a C1-C8 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4b It is a C1-C6 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4b It is a C1-C3 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R 4b It is methyl or ethyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R 4bThe methyl group is used. In some embodiments of formula (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from alcohols, alkoxy groups, amino groups, acetamino groups, cyano groups, halogen groups, nitro groups, alkyl groups, haloalkyl groups, oxo groups (=O), biotin or derivatives thereof, isophthalic acid or methoxycarbonylbenzoic acid or derivatives thereof, and charged moiety. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from -Cl, -F, -CN, -NH2, -NH(CH3), -N(CH3)2, -NO3, -OH, -CH3, -CF3, and -NH(O)CH3. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are selected from -NH2, -NH(CH3), -N(CH3)2, -OH, and -CF3. In some embodiments of formula (A), (I), (Ia), (II), or (III), one or more optional substituents are charged moieties. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are isophthalic acid or methoxycarbonylbenzoic acid or derivatives thereof. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), one or more optional substituents are 3-((λ) 2 3-(azoalkyl)carbonyl)methyl benzoate. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), one or more optional substituents are 3-(λ) 2 (-Az-alkyl)carbonyl)benzoic acid. In some embodiments of formula (A), (I), (Ia), (II), or (III), one or more optional substituents are biotin or a derivative thereof. In some embodiments of formula (A), (I), (Ia), (II), or (III), one or more optional substituents are .

[0313] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 20 Alkylene and R 4 -CH3. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 10 Alkylene and R 4 -CH3. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is a C1-C8 alkylene group and R is -CH3. 4-CH3. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is a C1-C6 alkylene group and R is -CH3. 4 -CH3. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is a C1-C4 alkylene group and R is -CH3. 4 -CH3. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is a C1-C3 alkylene group and R is -CH3. 4 -CH3. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), L is a C1-C2 alkylene group and R is -CH3. 4 -CH3. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is absent and R 4 It is -CH3.

[0314] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 10 Alkylene. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C8 alkylene. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C6 alkylene. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C5 alkylene. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C4 alkylene. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C3 alkylene. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is -CH2CH2-. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is absent.

[0315] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), L is C1-C 10Heteroalkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C8 heteroalkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C6 heteroalkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C5 heteroalkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C4 heteroalkyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), L is a C1-C3 heteroalkyl.

[0316] In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), the heteroalkyl linker L comprises one or more components selected from -((CR) 1a R 1a ) x -O) y - and -((CR 1a R 1a ) x -(NR 1b ) z - subunits, where each R 1a and R 1b Independently, x, y, and z are hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl, and each is an integer from 1 to 15. In some embodiments, the heteroalkylene is -((CR 1a R 1a ) x -O) y - In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), the heteroalkylene group is -((CR 1a R 1a ) x -(NR 1b ) z - In some embodiments of equations (A'), (A), (I), (Ia), (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 equations (A'), (A), (I), (Ia), (II), or (III), each R 1a and R 1b Independently hydrogen. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 1a and R 1bIndependently, it is a C1-C3 alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R 1a and R 1b It is independently a C1-C3 haloalkyl group.

[0317] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Or optionally substituted 5- to 10-membered heteroaryl groups. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc Or optionally a substituted 5-membered heteroaryl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R XIndependently -CN, -OH, -OR Xa -N3 or -NR Xa R Xb In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R X Independently -CN, -OH, -OCH3, -N3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R X Independently -OH, -NH2, -NHCH3, or -N(CH3)2. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X Independently -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc or -OC(O)NR Xa R Xb In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R X Independently -C(O)NR Xa R Xb -NHC(O)R Xc or -OC(O)NR Xa R Xb In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R X Independently, each R is an optionally substituted C1-C6 haloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X For -CF3. In some embodiments of equations (A'), (A), (I), (Ia), (II), or (III), each R X Independently, it is an optionally substituted C3-C6 cycloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X Independently, it is an optionally substituted cyclohexyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R XIndependently, each R is a optionally substituted 5- to 10-membered heteroaryl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X Independently, it is an optionally substituted 5-membered heteroaryl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R X Independently, it is an optionally substituted triazine.

[0318] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R Xa and R Xb Independently hydrogen, alkyl, or polyethylene glycol (PEG). In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R Xa and R Xb Independently hydrogen, C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R Xa and R Xb Independently for C1-C 20 Alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), each R Xa and R Xb Independent for PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), each R Xa and R Xb It is hydrogen independently.

[0319] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R Xc It is an alkyl group, polyethylene glycol (PEG), cycloalkyl group, heterocycloalkyl group, or phenyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R Xc For C1-C 20 Alkyl, PEG 1-20 C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, or phenyl. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R Xc For C1-C 20 Alkyl or PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R XcFor C1-C 20 Alkyl group. In some embodiments, R Xc PEG 1-20 In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), R Xc It is a C3-C6 cycloalkyl, a 4- to 6-membered heterocycloalkyl, or a phenyl. In some embodiments, R Xc It is a C3-C6 cycloalkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II) or (III), R Xc It is a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (A'), (A), (I), (Ia), (II), or (III), R Xc It is a phenyl group.

[0320] In some embodiments of equation (A'), each R y Independently, it is hydrogen, halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of formula (A'), each R y Independently hydrogen, halogen, or -OH. In some embodiments of formula (A'), each R y It is hydrogen.

[0321] In some embodiments of equation (A'), the two R y Together with the atoms they are attached to, they form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl groups. In some embodiments of formula (A'), the two R... y Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments of formula (A'), the two R... y Together with the atoms they are attached to, they form 3 to 6-membered heterocyclic alkyl groups.

[0322] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), n1 is 1 or 2. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), n1 is 3. In some embodiments of formulas (A), (I), (Ia), (II), or (III), n1 is 2. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), n1 is 1.

[0323] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), n2 is 1. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), n2 is 0.

[0324] In some embodiments of formulas (A'), (A), (I), or (Ia), n3 is 1, 2, or 3. In some embodiments of formulas (A'), (A), (I), or (Ia), n3 is 1 or 2. In some embodiments of formulas (A'), (A), (I), or (Ia), n3 is 3. In some embodiments of formulas (A'), (A), (I), or (Ia), n3 is 2. In some embodiments of formulas (A'), (A), (I), or (Ia), n3 is 1. In some embodiments of formulas (A'), (A), (I), or (Ia), n3 is 0.

[0325] In some embodiments of formulas (A'), (A), (I), or (Ia), n4 is 1 or 2. In some embodiments of formulas (A'), (A), (I), or (Ia), n4 is 3. In some embodiments of formulas (A'), (A), (I), or (Ia), n4 is 2. In some embodiments of formulas (A'), (A), (I), or (Ia), n4 is 1.

[0326] In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), m1 is 1. In some embodiments of formulas (A'), (A), (I), (Ia), (II), or (III), m1 is 0.

[0327] In some embodiments of equations (A'), (A), or (I), when n3 is 0 and m1 is 1, then n4 is not 1.

[0328] In some embodiments of formulas (A'), (A), (I) or (Ia), n1 is 1, n2 is 1, n3 is 1, n4 is 1 and m1 is 1.

[0329] In some embodiments of formulas (A'), (A), (I), or (Ia), n1 is 1, n2 is 1, n3 is 1, n4 is 1, and m1 is 0.

[0330] In some embodiments of equations (A'), (A), (I), or (Ia), n1 is 0, n2 is 2, n3 is 1, n4 is 1, and m1 is 1.

[0331] In some embodiments of formulas (A'), (A), (I), or (Ia), n1 is 0, n2 is 2, n3 is 1, n4 is 1, and m1 is 0.

[0332] This document covers any combination of the groups described above with respect to the various variables. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0333] In some embodiments, non-limiting examples of the compounds described herein or pharmaceutically acceptable salts thereof are presented in Table 1.

[0334] Table 1.

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366] Pharmaceutical composition and administration

[0367] The compounds described herein are administered to subjects in need, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0368] On the other hand, this document provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. Appropriate formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, (NY, 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 17th edition (Lippincott Williams & Wilkins 1999), the disclosure of which is incorporated herein by reference.

[0369] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0370] The dosage of the pharmaceutical agents described herein for treating diseases or conditions may be determined based on the subject's condition, namely the stage of the disease, the severity of symptoms caused by the disease, general health status, and age, sex, and weight, as well as other factors that are obvious to a medical professional. The pharmaceutical composition may be administered in a manner appropriate to the disease being treated, as determined by a medical professional. In addition to the factors described herein and above regarding the use of pharmaceutical agents to treat diseases or conditions, the appropriate duration and frequency of administration of the pharmaceutical agent may be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the agent may generally be determined using experimental models and / or clinical trials. The optimal dosage may be determined based on the subject's body mass, weight, or blood volume. Generally, the minimum dose sufficient to provide an effective therapy is preferred. The design and execution of preclinical and clinical studies of the pharmaceutical agents described herein (including when administered for preventative benefit) are entirely within the scope of the skill of a person skilled in the art. When two or more pharmaceutical agents are administered to treat a disease or condition, the optimal dosage of each agent may differ, for example, being less than the dosage of any single agent administered alone as a monotherapy. In certain specific embodiments, the combination of two pharmaceutical agents can act synergistically or additively, and either agent can be used in a smaller amount than when administered alone. The daily dose of the pharmaceutical agent can be, for example, between about 0.01 mg / kg and 100 mg / kg, such as between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between about 10 and 50 mg / kg, or between about 50 and 100 mg / kg body weight. In other embodiments, the daily dose of the pharmaceutical agent can be between about 0.01 mg / kg and 1000 mg / kg, between about 100 and 500 mg / kg, or between about 500 and 1000 mg / kg body weight. The optimal daily dose or dose per treatment cycle may vary depending on the disease or condition being treated and may also vary with the route of administration and treatment regimen.

[0371] Abbreviations and Definitions

[0372] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0373] Unless the context otherwise requires, throughout this specification and in the following claims, the word “comprise” and its variations, such as “comprises” and “comprising”, shall be considered to have an open-ended, inclusive meaning, i.e., “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0374] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include the plural references. It should also be noted that unless the context clearly indicates otherwise, the term “or” is generally used to mean “and / or.”

[0375] When a range of values ​​is disclosed, and the notation “n1…to n2” or “between n1…and n2” is used, where n1 and n2 are numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integers or consecutive and includes endpoints. As an example, the range “2 to 6 carbons” is intended to include two, three, four, five, and six carbons because carbon appears in integer units. For instance, the range “1 to 3 µM (micromoles)” (which is intended to include all values ​​between 1 µM and 3 µM) is equivalent to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0376] Unless otherwise indicated, the following terms have the following meanings as used herein:

[0377] "O" refers to =O.

[0378] "Carboxyl group" refers to -COOH.

[0379] "Cyano" refers to -CN.

[0380] "alkyl" refers to a straight-chain or branched monovalent group of a saturated hydrocarbon having one to ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever the term "C1-C6 alkyl" or "C1-6 alkyl" appears herein, the numerical range means that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is C1-C6. 10Alkyl group. In some embodiments, the alkyl group is C1-C6 alkyl. In some embodiments, the alkyl group is C1-C5 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. In some embodiments, the alkyl group is C1-C3 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group may optionally be substituted with oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group may optionally be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group may optionally be substituted with halogen.

[0381] "Alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in a cis or trans configuration around the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, for example, the numerical range of "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkenyl" where no numerical range is specified. Unless otherwise specified in this specification, the alkenyl group may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group may optionally be substituted with an oxo, halogen, -N3, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may optionally be substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may optionally be substituted with a halogen.

[0382] "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, for example, the numerical range of "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkynyl group may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with an oxo group, a halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0383] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified in this specification, alkylene may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene may optionally be substituted with oxo, halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene may optionally be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene may optionally be substituted with halogen.

[0384] "Alkoxy" refers to an alkoxy group with the formula -OR a The group, wherein R a Alkyl groups are defined alkyl groups. Unless otherwise specified in this specification, alkoxy groups may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -N3, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0385] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a self-ring carbon atom. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system may contain only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, non-localized (4n+2) π-electron system. Ring systems that derive aryl groups include, but are not limited to, groups such as benzene, fluorene, dihydroindene, indene, tetrahydronaphthalene, and naphthalene. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6-membered to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthyl, phenanthrene, anthracene, azulene, benzene, chrysene, fluorene, s-dicyclopentadienzobenzene, s-dicyclopentadienzobenzene, dihydroindene, indene, naphthalene, fen, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in this specification, aryl groups may optionally be substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl groups are 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 group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen.

[0386] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms), helical, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (e.g., C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3- to 10-membered fully saturated cycloalkyl groups or 3- to 6-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is 5- to 6-membered fully saturated cycloalkyl groups or 5- to 6-membered cycloalkenyl groups. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in this specification, cycloalkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -N3, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0387] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridging ring systems, preferably having three to twelve carbon atoms and containing at least one double bond. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group can be linked to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0388] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0389] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above, substituted with one or more halogen groups such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be further substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., chloroform, 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 combination of alkanes (or substituted alkanes) with halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen group, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[0390] "Fluoroalkyl" refers to an alkyl group as defined above that has been substituted with one or more fluorine groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0391] "Hydroxyalkyl" means an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0392] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0393] "Heteroalkyl" means an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified in this specification, heteroalkyl groups are optionally substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogens.

[0394] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise specified in this specification, the heterocyclic alkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded by non-aromatic ring atoms), helical, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having two to fifteen carbon atoms (e.g., C2-C). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (e.g., C2-C) 10 Fully saturated heterocyclic alkyl or C2-C10Heterocyclic alkyl groups consisting of two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl or C2-C6 heterocyclic alkyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkyl). Examples of such heterocyclic alkyl groups include, but are not limited to, azirropropyl, azirrobutyl, oxacyclobutyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl, oxazolylalkyl, piperidinyl, piperazine, 4-piperidinoneyl, and pyrrolidine. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring), including heteroatoms. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 3 to 8 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 3 to 7 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 3 to 6 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 4 to 6 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group of 5 to 6 members. In some embodiments, the heterocyclic alkyl group is a 3 to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3 to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3 to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4 to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5 to 6-membered heterocyclic alkenyl group. Unless otherwise specifically stated in this specification, the heterocyclic alkyl group may optionally be substituted with groups such as oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc., as described below.In some embodiments, the heterocyclic alkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, a -CN group, a -C(O)OH group, a C(O)OMe group, a -CF3 group, a -OH group, a -OMe group, a -NH2 group, or a -NO2 group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen, a methyl group, an ethyl group, a -CN group, a -CF3 group, a -OH group, or a -OMe group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0395] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, 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 nitrogen atoms. In some embodiments, the heteroaryl comprises one or two nitrogen atoms. In some embodiments, the heteroaryl comprises one nitrogen atom. The heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl is bonded through aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. 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 group is a 5-membered heteroaryl group. Examples include, but are not limited to, azirrolyl, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxopyranyl, 1,4-benzodioxane, benzonaphthuryl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenylyl, dibenzofuranyl, dibenzothienyl, furanyl Furanone, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyrrolyl, oxazolyl, epoxyethyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridineyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. (i.e., thienyl). Unless otherwise specified in this specification, heteroaryl groups may optionally be substituted with groups such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0396] The term "oligonucleotide sequence" refers to multiple 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 the sequential amplification of an oligonucleotide sequence.

[0397] The term "transcription," well-known in the art, refers to the synthesis of RNA (i.e., ribonucleic acid) by DNA-directed RNA polymerase. The term "regulation of transcription" refers to changes in the amount of transcription, which can be measured by methods well-known in the art (e.g., determination of the transcription product mRNA). In some embodiments, regulation is an increase in transcription. In other embodiments, regulation is a decrease in transcription.

[0398] The term "polyamide" refers to a polymer of linkable units chemically bonded by amide (i.e., CONH) bonds; optionally, polyamides include chemical probes bound thereto. Polyamides can be synthesized by stepwise condensation of carboxylic acids (COOH) and amines (RR'NH) using methods known in the art. Alternatively, polyamides can be formed in vitro using enzymatic reactions or by employing microbial fermentation.

[0399] The term "connector" or "oligomeric backbone" refers to a chain having at least 10 consecutive atoms. In some embodiments, the connector contains no more than 20 non-hydrogen atoms. The terms connector and oligomeric backbone are used interchangeably. In some embodiments, the connector contains no more than 40 non-hydrogen atoms. In some embodiments, the connector contains no more than 60 non-hydrogen atoms. In some embodiments, the connector contains atoms selected from C, H, N, O, and S. In some embodiments, each non-hydrogen atom is chemically bonded to two adjacent atoms in the connector, or to one adjacent atom in the connector and the end of the connector. In some embodiments, the connector forms an amide bond with at least one of the two other groups to which it is attached. In some embodiments, the connector forms an ester bond or an ether bond with at least one of the two other groups to which it is attached. In some embodiments, the connector forms a thioester bond or a thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the connector forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the connector forms an amine bond or an amide bond with at least one of the two other groups to which it is attached. In some embodiments, the connector comprises a -(CH2OCH2)- unit. In some embodiments, the connector comprises -(CH(CH3)OCH2)- units. In some embodiments, the connector comprises -(CH2NR) units. N CH2) unit, where R N = C 1-4 Alkyl group. In some embodiments, the connector comprises an arylene, cycloalkyl, or heteroalkylene moiety.

[0400] The term "bond" refers to a covalent bond between two atoms, or, when the atoms connected by a bond are considered part of a larger substructure, a covalent bond between two parts. Unless otherwise specified, a bond can be a single, double, or triple bond. The dashed line between two atoms in a molecular diagram indicates whether an additional bond may or may not be present at that location.

[0401] As used herein, “optionally substituted” is derived from a substituted group of an unsubstituted parent group, wherein one or more hydrogen atoms are replaced by another atom or group. Unless otherwise indicated, when a group is considered “substituted” or “optionally substituted,” it means that the group is substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocycloyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclo-C1-C6 alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1- C6 haloalkoxy substitution), 3- to 10-membered heterocyclic groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic-C1-C6 alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy). -C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 5- to 10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (C1-C6) alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6) alkyl (i.e., ether), Aryloxy, thiohydro (mercapto), halogen (C1-C6) alkyl (e.g., -CF3), halogen (C1-C6) alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino (C1-C6) alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, acyl, cyano acid, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group may be substituted with the above substituents.

[0402] The term "one or more" when referring to optionally present substituents 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.

[0403] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Furthermore, some chemical entities can exist in various tautomeric forms. Unless otherwise stated, the compounds described herein are intended to include all Z, E, and tautomeric forms.

[0404] In some embodiments, the compounds disclosed herein are in different isotopically concentrated forms (e.g., 2 H, 3 H, 11 C 13 C and / or 14 (C-concentration) is used. In one particular embodiment, the compound is deuterated at at least one site. These deuterated forms can be prepared by the procedures 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 metabolic stability and / or efficacy, thus increasing the duration of drug action.

[0405] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, but with hydrogen replaced by deuterium or tritium, or carbon replaced by... 13 C or 14 C-concentrated carbon-substituted compounds are within the scope of this disclosure.

[0406] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting these compounds. For example, the compounds may contain isotopes such as deuterium (… 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Marker. Covers the tags. 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 I. Isotopic substitution. All isotopic variants of the compounds of the present invention (whether or not radioactive) are covered within the scope of the present invention. In some embodiments, when describing isotopic variants, the remaining atoms of the compound may optionally contain non-natural portions of atomic isotopes.

[0407] In some embodiments, some or all of the compounds disclosed herein 1 H atom 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and include the following synthetic methods as examples only.

[0408] Deuterium-substituted compounds were synthesized using various methods described, for example, in the following literature: Dean, Dennis C. (ed.), Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [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.

[0409] Deuterated starting materials are readily available and can be synthesized using the methods described herein to achieve the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0410] In some embodiments of the compounds disclosed herein, the percentage of deuterium contained in one or more substituents is higher than the natural abundance of deuterium. In some embodiments of the compounds disclosed herein, one or more hydrogen atoms are substituted with one or more deuterium atoms.

[0411] In some embodiments of the compounds disclosed herein, the deuterium abundance of each substituent 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 the total amount of hydrogen and deuterium.

[0412] The compounds disclosed herein also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvable polymorphs (including anhydrous forms), configurational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0413] In some cases, the compounds described herein may exist as diastereomers, enantiomers, or other stereoisomers. When absolute stereochemistry is not specified, the compounds presented herein include all diastereomers, enantiomers, and epimers, and suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating them 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, this disclosure is incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[0414] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from various organic and inorganic relative ions well-known in the field. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from 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, and aluminum. Organic bases that can be derived into salts include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0415] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are matched with a reasonable benefit / risk ratio.

[0416] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” and harmless to the patient in terms of compatibility with other components of the formulation. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, (10) Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) diols, such as propylene glycol; (12) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) esters, such as ethyl oleate and ethyl laurate; (14) agar; (15) buffers, such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) pyrogen-free water; (18) isotonic saline; (19) Ringer's solution; (20) ethanol; (21) phosphate buffer solution; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0417] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses, which is sufficient to produce the desired therapeutic effect.

[0418] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, alleviating, or improving at least one symptom of a disease or condition; preventing other symptoms; suppressing a disease or condition, such as curbing its progression; reducing a disease or condition; causing a disease or condition to subside; alleviating symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition.

[0419] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0420] The term "contact" refers to bringing a compound (such as the compound disclosed herein) into close proximity to a desired target gene. Contact can cause binding to the target moiety or cause a conformational change in the target moiety.

[0421] Example

[0422] The following examples are given for the purpose of illustrating various embodiments of the invention and are not intended to limit the invention in any way. The examples of the invention and the methods described herein represent preferred embodiments, are exemplary, and are not intended to limit the scope of the invention. Variations and other uses will be apparent to those skilled in the art, encompassing the spirit and scope of the invention as defined by the claims.

[0423] Compound Synthesis

[0424] The compounds disclosed herein can be prepared using the methods described in the general synthetic procedures and experimental procedures detailed below. The general synthetic procedures and experimental procedures are provided for illustrative purposes and are not intended to be limiting. Starting materials used to prepare the compounds of this disclosure are commercially available or can be prepared using conventional methods known in the art.

[0425] The synthetic chemical transformations and methods applicable to the synthesis of the compounds described herein are known in the art and include, for example, those described in the following literature: R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition (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).

[0426] List of abbreviations

[0427] Ac2O = Acetic anhydride; AcCl = Acetyl chloride; ACN = Acetonitrile; AcOH = Acetic acid; AIBN = Azobisisobutyronitrile; aq. = Aqueous; Bu3SnH = Hydrogenated tributyltin; CD3OD = Deuterated methanol; CDCl3 = Deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undecyl-7-ene; DCM = Dichloromethane; DEAD = Diethyl azodicarbonate; DIBAL-H = Hydrogenated diisobutylaluminum; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d6 = Deuterated dimethyl sulfoxide; DMS O = dimethyl sulfoxide; DPPA = diphenylphosphoazide; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EA = ethyl acetate; EtOH = ethanol; h = hours; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylureamonium hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LiHMDS = lithium bis(trimethylsilamide); MeCN = acetonitrile; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methyl Polystyrene carbonate resin; MsCl = methanesulfonyl chloride; MTBE = methyl tert-butyl ether; MW = microwave irradiation; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amidide; NaOMe = sodium methoxide; NaOtBu = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(diphenylmethyleneacetone)dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; preparative HPLC = preparative high performance liquid chromatography; PyB op = hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidinephosphonium; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropyloxybiphenyl; sat. = saturated; ss = saturated solution; t-BuOH = tert-butanol; T3P = propylphosphonic anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSCl = TBDMSCl = tert-butyldimethylchlorosilane; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = toluenesulfonyl chloride; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0428] Synthesize representative compounds

[0429] Example 1. Synthesis of compound A-1

[0430] Process 1.

[0431]

[0432]

[0433] Step 1: K₂CO₃ (2.71 g, 19.59 mmol, 3.00 equivalent) and N-(5-bromopentyl)carbamate tert-butyl ester (1.74 g, 6.53 mmol, 1.00 equivalent) were added to a solution of 3-(trifluoromethyl)piperidine (1.00 g, 6.53 mmol, 1.00 equivalent) in ACN (10.00 mL). The reaction mixture was then stirred overnight at 70 °C, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give N-{5-[3-(trifluoromethyl)piperidin-1-yl]pentyl}carbamate tert-butyl ester (1.80 g, 81.46%) as a yellow oil. LC / MS: C 16 H 29 Calculated mass of F3N2O2: 338.22, Experimental mass: 339.55 [M+H] + .

[0434] Step 2: TFA (0.30 mL) was added to a stirred solution of N-{5-[3-(trifluoromethyl)piperidin-1-yl]pentyl}carbamate (12.00 mg, 0.04 mmol, 1.00 equivalent) in DCM (1.00 mL). The mixture was stirred at room temperature for 1.0 h. The mixture was concentrated under reduced pressure to give 5-[3-(trifluoromethyl)piperidin-1-yl]pentyl-1-amine (12.00 mg, crude product) as a yellow oil. LC / MS: C 11 H 21 Calculated mass of F3N2: 238.17, Experimental mass: 239.05 [M+H] + .

[0435] Step 3: PyBOP (37.58 g, 72.22 mmol, 1.20 equivalent), DIEA (23.34 g, 180.56 mmol, 3.00 equivalent), and β-alanine ethyl ester (8.46 g, 72.22 mmol, 1.20 equivalent) were added fractionally to a stirred solution of 1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-carboxylic acid (15.00 g, 60.18 mmol, 1.00 equivalent) in DMF (200.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1.0 h. The reaction mixture was then poured into ice / water (500 mL). The precipitated solid was collected by filtration, and the filter cake was washed with H2O (50 × 3 mL) and dried under vacuum to give ethyl 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formamide}propionate (17.00 g, 81.08%) as a yellow solid. LC / MS: C 15 H 20 Calculated mass of N6O4: 348.15, experimental mass: 349.05 [M+H] + .

[0436] Step 4: LiOH (46.60 mL, 93.20 mmol, 4.00 equivalent, 2M in H2O) was added to a stirred solution of ethyl 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formamide}propionate (8.10 g, 23.30 mmol, 1.00 equivalent) in MeOH (30.00 mL) and THF (30.00 mL). The resulting mixture was stirred at 45 °C for 2.0 h and then concentrated under reduced pressure, with 50 mL of H2O added. The mixture was acidified to pH 5-6 with HCl (2M in H₂O), and the precipitated solid was collected by filtration and washed with water (3 × 50 mL). It was then dried under vacuum to give 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formamide}propionic acid (6.10 g, 81.98%) as a yellow solid. LC / MS: C 12 H 16 Calculated mass of N6O4: 320.12, Experimental mass: 321.05 [M+H] + .

[0437] Step 5: The procedure is the same as in Step 3. Using 2.00 g of 3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formamide}propionic acid, 2.20 g of the desired product (77.19%) as a yellow solid was obtained. LC / MS: C 20 H 24Calculated mass of N8O5: 456.19 g / L, Experimental mass: 457.20 g / L [M+H] + .

[0438] Step 6: The procedure is the same as in Step 4, but the reaction temperature is 40°C and the reaction time is 16.0 hours. Using 2.2 g of methyl 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formamide}propionamide)pyrrole-2-carboxylate, 2.00 g of the desired product (93.79%) as a yellow solid was obtained. LC / MS: C 19 H 22 Calculated mass of N8O5: 442.17, Experimental mass: 443.30 [M+H] + .

[0439] Step 7: The procedure is the same as in Step 3. Using 4.33 g of 4-(4-amino-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester, 6.50 g of the desired product (95.84%) as a brown solid was obtained. LC / MS: C 23 H 31 Calculated mass of N5O6: 473.23, Experimental mass: 474.15 [M+H] + .

[0440] Step 8: The procedure is the same as in Step 2. Using 6.5 g of 4-(4-{3-[(tert-butoxycarbonyl)amino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester, 6.50 g of the desired crude product as a yellow oil was obtained. LC / MS: C 18 H 23 Calculated mass of N5O4: 373.18, Experimental mass: 374.15 [M+H] + .

[0441] Step 9: Add DIEA (6.42 g, 49.67 mmol, 6.00 equivalent), PyBOP (5.60 g, 10.77 mmol, 1.30 equivalent), and 4-[4-(3-aminopropionylamino)-1-methylpyrrole-2-acylamino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (3.71 g, 9.94 mmol, 1.20 equivalent) to a stirred solution of 4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (3.71 g, 9.94 mmol, 1.20 equivalent) in DMF (34.00 mL) at 0 °C. Stir the resulting mixture at room temperature for 1.0 h. The mixture was poured into ice water (100 mL) and the precipitate was collected by filtration. The precipitate was washed with water (3 × 50 mL) and dried under vacuum. The crude substance was purified by silica gel column chromatography and eluted with CH₂Cl₂ / MeOH (10:1) to give a yellow oily 4-(4-{3-[(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrolo-2-acylamino}-1-methylpyrrolo-2-yl)carboxylic acid propionylamino}-1-methylpyrrolo-2-acylamino)-1-methylpyrrolo-2-carboxylic acid prop-2-en-1-yl ester (3.20 g, 53.85%). LC / MS: C 35 H 43 Calculated mass of N9O8: 717.32, Experimental mass: 718.40 [M+H] + .

[0442] Step 10: The procedure is the same as in Step 2. Using 4.88 g of 4-(4-{3-[(4-{4-[(tert-butoxycarbonyl)amino]-1-methylpyrrolo-2-acylamino}-1-methylpyrrolo-2-yl)formylamino]propionylamino}-1-methylpyrrolo-2-acylamino)-1-methylpyrrolo-2-carboxylic acid prop-2-en-1-yl ester, 4.88 g of the desired crude product as a grayish-white solid was obtained. LC / MS: C 30 H 35 Calculated mass of N9O6: 617.27 g / L, Experimental mass: 618.35 g / L [M+H] + .

[0443] Step 11: The procedure is the same as in Step 3. 1.74 g of (2S)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}butyric acid was used, and 2.70 g of the desired product (65.71%) as a white solid was obtained. LC / MS: C 54 H 61 N 11 O 11Calculated mass: 1039.46, Experimental mass: 1040.40 [M+H] + .

[0444] Step 12: Add DEA (6.00 mL) to a stirred solution of 4-(4-{3-[(4-{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}butyrylamino]-1-methylpyrrole-2-acylamino}-1-methylpyrrole-2-yl)formylamino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (2.70 g, 2.59 mmol, 1.00 equivalent) in DMF (30.00 mL) at 0 °C, and stir the resulting mixture at room temperature for 1.0 h. After the reaction, the solid was filtered and the filtrate was purified directly through a reverse-phase column under the following conditions: C18 column; mobile phase, water containing ACN (0.05% TFA), 30% to 60% gradient over 20 minutes; detector, UV 254 nm. The elution fraction was separated and concentrated to give 4-(4-{3-[(4-{4-[(2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrolo-2-acylamino}-1-methylpyrrolo-2-yl)formylamino]propionylamino}-1-methylpyrrolo-2-acylamino)-1-methylpyrrolo-2-carboxylic acid prop-2-en-1-yl ester (2.10 g, 87.04%) as a white solid. LC / MS: C 39 H 51 N 11 Calculated mass of O9: 817.39, Experimental mass: 818.40 [M+H] + .

[0445] Step 13: DIAD (4.37 g, 21.61 mmol, 2.00 equivalent) and PPh3 (5.67 g, 21.61 mmol, 2.00 equivalent) were added to a stirred solution of ethyl 4-nitro-1H-imidazolium-2-carboxylate (2.00 g, 10.80 mmol, 1.00 equivalent) and 2-norbornanol (2.42 g, 21.61 mmol, 2.00 equivalent) in THF (50.00 mL) under nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 17.0 h and then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (5:1) to give ethyl 1-{bicyclo[2.2.1]hept-2-yl}-4-nitroimidazolium-2-carboxylate (900.00 mg, 29.83%) as a yellow solid. LC / MS: C 13 H 17Calculated mass of N3O4: 279.12, Experimental mass: 280.05 [M+H] + .

[0446] Step 14: Pd / C (200.00 mg, 20% w / w) was added to a stirred solution of 1-{bicyclo[2.2.1]hept-2-yl}-4-nitroimidazole-2-carboxylate (1.00 g, 3.58 mmol, 1.00 equivalent) in EA (30.00 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2.0 h. The resulting mixture was filtered, and the filter cake was washed with EA (3 × 30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-1-{bicyclo[2.2.1]hept-2-yl}imidazole-2-carboxylate (850.00 mg, 95.22%) as a white solid. LC / MS: C 13 H 19 Calculated mass of N3O2: 249.15, Experimental value: 250.05 [M+H] + .

[0447] Step 15: Add DMAP (641.27 mg, 5.25 mmol, 5.00 equivalent), EDCI (503.11 mg, 2.62 mmol, 2.50 equivalent), and 1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-carboxylic acid (464.47 mg, 1.05 mmol, 1.00 equivalent) to a stirred solution of 4-amino-1-{bicyclo[2.2.1]hept-2-yl}imidazol-2-yl}pyrrole-2-carboxylic acid in pyridine (5.00 mL) at 0 °C, and stir the resulting mixture at room temperature for 16.0 h. The mixture was filtered and the filtrate was purified directly by reverse-phase rapid chromatography under the following conditions: C18 column; mobile phase, water containing ACN (0.05% TFA), 10% to 50% gradient over 10 minutes; detector, UV 254 nm. The eluates were combined and concentrated. This yielded ethyl 1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-carboxylate (500.00 mg, 70.69%) as a yellow solid. LC / MS: C 32 H 39 N 11 Calculated mass of O6: 673.31, Experimental mass: 674.40 [M+H] + .

[0448] Step 16: The procedure is the same as in Step 4. 500.00 mg of 1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-carboxylic acid ethyl ester was used to obtain 460.00 mg of the desired product (96.00%) as a yellow solid. LC / MS: C 30 H 35 N 11 Calculated mass of O6: 645.28, Experimental mass: 646.35 [M+H] + .

[0449] Step 17: At 0°C, add DMAP (170.29 mg, 1.40 mmol, 5.00 equivalent) and EDCI (133.60 mg, 0.70 mmol, 1.00 equivalent) part-by-part to a stirred solution of 1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-carboxylic acid (180.00 mg, 0.28 mmol, 1.00 equivalent) in DMF (2.00 mL) in portions. 228.01 mg (2.50 equivalents) and 4-(4-{3-[(4-{4-[(2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrolo-2-acylamino}-1-methylpyrrolo-2-yl)formylamino]propionylamino}-1-methylpyrrolo-2-acylamino)-1-methylpyrrolo-2-carboxylic acid prop-2-en-1-yl ester (228.01 mg, 0.28 mmol, 1.00 equivalents). The resulting mixture was stirred at room temperature for 1.0 h and then filtered. The filtrate was purified directly by reversed-phase rapid chromatography under the following conditions: C18 column; mobile phase, water containing ACN (0.05% TFA), 10% to 50% gradient over 10 min; detector, UV 254 nm. This produces a yellow solid, 4-(4-{3-[(4-{4-[(2S)-4-[(1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-yl)formylamino]-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrole-2-acylamino}-1-methylpyrrole-2-yl)formylamino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid prop-2-en-1-yl ester (300.00 mg, 74.44%). LC / MS: C 69H 84 N 22 O 14 Calculated mass: 1444.64, Experimental mass: 1445.45 [M+H] + .

[0450] Step 18: Add phenylsilane (43.42 mg) to a stirred solution of 4-(4-{3-[(4-{4-[(2S)-4-[(1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrolo-2-acylamino]imidazol-2-yl)formylamino]-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrolo-2-acylamino}-1-methylpyrrolo-2-yl)formylamino]propionylamino}-1-methylpyrrolo-2-acylamino)-1-methylpyrrolo-2-carboxylic acid prop-2-en-1-yl ester (290.00 mg, 0.20 mmol, 1.00 equivalent) in DMF (3.00 mL). The mixture was prepared by stirring Pd(PPh3)4 (23.18 mg, 0.02 mmol, 0.10 equivalent) at room temperature for 1.0 h. The resulting mixture was poured into ice water (20 mL) and acidified to pH 3–5 with 2 M HCl. The precipitated solid was collected by filtration, washed with H2O (3 × 10 mL), and dried under vacuum to give 4-(4-{3-[(4-{4-[(2S)-4-[(1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-yl)formylamino]-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrole-2-acylamino}-1-methylpyrrole-2-yl)formylamino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-acylamino (220.00 mg, 78.02%) as a yellow solid. LC / MS: C 66 H 80 N 22 O 14 Calculated mass: 1404.62, Experimental mass: 1405.45 [M+H] + .

[0451] Step 19: The procedure is the same as in Step 3. Using 50.00 mg of 4-(4-{3-[(4-{4-[(2S)-4-[(1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-yl)formylamino]-2-[(tert-butoxycarbonyl)amino]butyrylamino]-1-methylpyrrole-2-acylamino}-1-methylpyrrole-2-yl)formylamino]propionylamino}-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-acylamino)-1-methylpyrrole-2-carboxylic acid, 36.00 mg of the desired product (62.24%) as a yellow solid was obtained. LC / MS: C 77 H 99 F3N 24 O 13 Calculated mass: 1624.78, experimental value: 813.80 [M / 2+ H]+.

[0452] Step 20: At room temperature, add tert-butyl carbamate (30.00 mg, 0.02 mg) to N-[(1S)-3-[(1-{bicyclo[2.2.1]hept-2-yl}-4-[1-methyl-4-(3-{[1-methyl-4-(1-methylimidazol-2-acylamino)imidazol-2-yl]formylamino}propionylamino)pyrrole-2-acylamino]imidazol-2-yl)formylamino]-1-[(1-methyl-5-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-({5-[3-(trifluoromethyl)piperidin-1-yl]pentyl}aminocarbamoyl)pyrrole-3-yl]aminocarbamoyl}pyrrole-3-yl)aminocarbamoyl]ethyl}aminocarbamoyl)pyrrole-3-yl]aminocarbamoyl}pyrrole-3-yl)aminocarbamoyl]propyl]propyl]carbamate (30.00 mg, 0.02 mg). TFA (0.20 mL) was added dropwise to a stirred solution in DCM (1.00 mL) at mmol (1.00 equivalent). The resulting mixture was stirred at room temperature for 1.0 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC: column: Kinetex EVO C18, 21.2 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 29% B to 54% B over 12 min; wavelength: 254 nm / 220 nm; RT1 (min): 11.13. The eluent was separated and lyophilized directly. This produces a white solid N-(2-{[2-({5-[(2-{[(3S)-3-amino-3-[(1-methyl-5-{[1-methyl-5-({2-[(1-methyl-5-{[1-methyl-5-({5-[3-(trifluoromethyl)piperidin-1-yl]pentyl}carbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl]ethyl}carbamoyl)pyrrolo-3-yl]carbamoyl}pyrrolo-3-yl)carbamoyl]propyl]carbamoyl}-1-{bicyclo[2.2.1]hept-2-yl}imidazol-4-yl)carbamoyl]-1-methylpyrrolo-3-yl}carbamoyl)ethyl]carbamoyl}-1-methylimidazol-4-yl)-1-methylimidazol-2-carboxamide (5.10) mg, 17.76%). HRMS: C 72 H 91 F3N 24 O 11 Calculated mass: 1524.7251, Experimental value: 1525.7263 [M+H] + .

[0453] Example 2. Synthesis of other compounds disclosed herein

[0454] The compounds of this application were prepared by a method similar to that of Example 1. An overview of the analytical data is presented in Table 2.

[0455] Table 2. Mass spectrometry data of the compounds disclosed herein.

[0456]

[0457]

[0458]

[0459]

[0460] Biological Examples

[0461] Example B-1.

[0462] HUDEP-2 cells were passaged in expansion medium before differentiation. Cells differentiated for 3 days in EDM2 medium and then for 4 days in EDM3 medium, as previously described (Vinjamur et al., 2017). Treatments were performed only during differentiation, or in expansion medium and for 7 days during differentiation. After differentiation, cells were analyzed by flow cytometry and qPCR.

[0463] Samples for flow cytometry analysis were briefly treated with viability staining, then washed and fixed with BD Fix / Perm fixation solution. Next, cells were washed, permeabilized in BD Fix / Perm permeation buffer, and incubated on ice for 1 hour with diluted CD233, CD235a, and HbF antibodies. Cells were then washed again, resuspended in FACS staining buffer, and analyzed using a Novocyte flow cytometer. Cells were selected for HbF analysis based on viability staining and the maturation markers CD233 and CD235a.

[0464] Representative data on the relative percentage of F cells induced are presented in Table 3. A is < 1.5; B is ≥ 1.5 to 2.0; C is ≥ 2.0.

[0465] Table 3. Representative biochemical data.

[0466]

[0467]

[0468]

[0469]

[0470] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that the invention can be practiced using various alternatives to the embodiments of the invention described herein. The scope of the invention is intended to be defined by the following claims, and thereby covers the methods and structures within the scope of these claims and their equivalents.

Claims

1. A method of treating a blood disorder in a subject in need, comprising administering to the subject a compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof: Equation (A), in: Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-; W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4 ;in L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z either does not exist or is -C(O)-; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; R W It is hydrogen or C1-C 20 Alkyl or C1-C 20 Heteroalkyl; or R W and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, -OH, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; n3 can be 0, 1, 2, or 3; n4 is 1, 2, or 3; and m1 is either 0 or 1.

2. A method for treating sickle cell disease (SCD) in a subject in need, 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: Equation (A), in: Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-; W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; W 2 C1-C is optionally substituted 20 Alkyl or optionally substituted C1-C 20 Heteroalkyl; or W 2 -LZR 4 ;in L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z either does not exist or is -C(O)-; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; R W It is hydrogen or C1-C 20 Alkyl or C1-C 20 Heteroalkyl; or R W and W 2 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, -OH, C1-C3 alkyl, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Or an R 3a And an R 3b Together with the atoms they are attached to, they form C3-C6 cycloalkyl groups; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; n3 can be 0, 1, 2, or 3; n4 is 1, 2, or 3; and m1 is either 0 or 1.

3. The method according to claim 1 or 2, wherein W 2 -LZR 4 And R W It is hydrogen.

4. The method according to claim 1 or 2, wherein the compound of formula (A) has the structure of formula (I), or a pharmaceutically acceptable salt thereof: Formula (I), in: W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-; L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z either does not exist or is -C(O)-; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, C1-C3, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; n3 can be 0, 1, 2, or 3; n4 is 1, 2, or 3; and m1 is either 0 or 1.

5. The method according to any one of claims 1 to 4, wherein when n3 is 0 and m1 is 1, then n4 is not 1.

6. The method according to any one of claims 1 to 4, wherein n3 is 1 or 2.

7. The method according to any one of claims 1 to 4, wherein n3 is 0.

8. The method according to any one of claims 1 to 7, wherein n4 is 1.

9. The method according to any one of claims 1 to 7, wherein n4 is 2.

10. The method according to claim 4, wherein the compound has the structure of formula (II), or a pharmaceutically acceptable salt thereof: Equation (II), in: W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-; L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z either does not exist or is -C(O)-; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, C1-C3, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; and m1 is either 0 or 1.

11. The method according to any one of claims 1 to 10, wherein Y 4 Y 5 Y 6 and Y 7 Each is independently -CH-.

12. The method according to any one of claims 1 to 11, wherein Y 1 and Y 8 Each is independently -N-.

13. The method according to claim 10, wherein the compound has the structure of formula (III), or a pharmaceutically acceptable salt thereof: Equation (III), in: W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; Each Y 2 and Y 3 Independently -CH- or -N-; L 1 It does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z does not exist; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, C1-C3, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; and m1 is either 0 or 1.

14. The method according to any one of claims 1 to 13, wherein each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for C1-C 10 Alkyl, C1-C 10 Halogenated, or C3-C 10 cycloalkyl or PEG 1-10 Each of them may choose to pass through one or more R X replace.

15. The method of claim 14, wherein each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, -CH2CF3, cyclohexyl or bicyclo[2.2.1]heptyl.

16. The method of claim 14, wherein each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is a methyl group.

17. The method according to any one of claims 1 to 13, wherein R 2a R 2b R 2c R 2d R 2e R 2f R 2g Or R 2h At least one of them is not an unsubstituted C1-C 10 alkyl.

18. The method of claim 17, wherein R 2a R 2b R 2c R 2d R 2e R 2f R 2g Or R 2h At least one of them is not methyl.

19. The method according to any one of claims 1 to 18, wherein n2 is 0.

20. The method according to any one of claims 1 to 18, wherein n2 is 1.

21. The method according to any one of claims 1 to 18 or 20, wherein Y 2 It is -N-.

22. The method according to any one of claims 1 to 18 or 20, wherein Y 2 It is -CH-.

23. The method according to any one of claims 1 to 22, wherein n1 is 1.

24. The method according to any one of claims 1 to 22, wherein n1 is 2.

25. The method according to any one of claims 1 to 22, wherein n1 is 3.

26. The method according to any one of claims 1 to 25, wherein each Y 3 Independently -N-.

27. The method according to any one of claims 1 to 25, wherein each Y 3 Independently -CH-.

28. The method according to any one of claims 1 to 27, wherein m1 is 0.

29. The method according to any one of claims 1 to 27, wherein m1 is 1.

30. The method according to any one of claims 1 to 29, wherein each R 3b It is hydrogen; and each R 3a Independently hydrogen, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e .

31. The method of claim 30, wherein each R 3a It can be hydrogen or -NH2 independently.

32. The method according to any one of claims 1 to 29, wherein the two R 3a Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3 to 6-membered heterocyclic alkyl.

33. The method according to any one of claims 1 to 29, wherein the two R 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3 to 6-membered heterocyclic alkyl.

34. The method according to any one of claims 1 to 29, wherein each R 3a and each R 3b It is hydrogen.

35. The method according to any one of claims 1 to 34, wherein L is C1-C 20 Alkylene and R 4 For -NR 4a R 4b ,in R 4a Hydrogen or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups.

36. The method of claim 35, wherein R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl.

37. The method of claim 33, wherein R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl or optionally substituted C1-C 10 Halogenated groups.

38. The method according to claim 35 or 36, wherein R 4a It is hydrogen.

39. The method of claim 37, wherein R 4a For C1-C 10 Alkyl and R 4b For C1-C 10 alkyl.

40. The method of claim 39, wherein R 4a It is methyl and R 4b It is a methyl group.

41. The method of claim 35, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups.

42. The method of claim 41, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocyclic alkyl group, which is optionally substituted with one or more halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups.

43. The method according to any one of claims 1 to 34, wherein L is C1-C 20 Alkylene and R 4 It is -CH3.

44. The method according to any one of claims 35 to 43, wherein L is a C1-C8 alkylene group.

45. The method of claim 44, wherein L is a C1-C6 alkylene group.

46. ​​The method of claim 43, wherein L is not present.

47. The method according to any one of claims 1 to 46, wherein Z is not present.

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

49. The method according to any one of claims 1 to 48, wherein the compound optionally binds to a portion that regulates gene expression.

50. A compound having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof: Equation (Ia), in: W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-; L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z either does not exist or is -C(O)-; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, C1-C3, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; n3 can be 0, 1, 2, or 3; n4 is 1, 2, or 3; and m1 is 0 or 1; When n3 is 0 and m1 is 1, then n4 is not 1.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein n3 is 2.

52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein n3 is 1.

53. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 52, wherein n4 is 2.

54. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 52, wherein n4 is 1.

55. The compound according to claim 50, wherein the compound has the structure of formula (II), or a pharmaceutically acceptable salt thereof: Equation (II), in: W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; Each Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently -CH- or -N-; L does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z either does not exist or is -C(O)-; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, C1-C3, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; and m1 is either 0 or 1.

56. The compound according to any one of claims 50 to 55, or a pharmaceutically acceptable salt thereof, wherein Y 4 Y 5 Y 6 and Y 7 Each is -CH-.

57. The compound according to any one of claims 50 to 56, or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 8 Each is -N-.

58. The compound according to claim 50, wherein the compound has the structure of formula (III), or a pharmaceutically acceptable salt thereof: Equation (III), in: W 1 and W 1a Each can be independently hydrogen, halogen, C1-C3 haloalkyl or -NHC(O)CH3; Each Y 2 and Y 3 Independently -CH- or -N-; L 1 It does not exist; it is C1-C. 20 Alkylene or C1-C 20 Heteroalkyl; Z does not exist; R 4 For -CH3, -OR 4a or -NR 4a R 4b ;in R 4a Hydrogen, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Heteroalkyl or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups; Each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted PEG 1-10 Each of them may choose to pass through one or more R X replace; Each R 3a and R 3b Independently hydrogen, C1-C3, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e ,in R 3c and R 3d Each can be independently hydrogen, alkyl, alkyl(phenyl) or PEG; R 3e It is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or phenyl group; Or two Rs 3a The carbon atom or two R atoms it is attached to 3b Together with the carbon atom to which it is attached, it forms C3-C6 cycloalkyl or 3- to 6-membered heterocyclic alkyl; Each R X Independently -CN, -OH, -OR Xa -N3, -NR Xa R Xb -CO(O)R Xc -C(O)OR Xc -C(O)NR Xa R Xb -NHC(O)R Xc -NHC(O)OR Xc -OC(O)NR Xa R Xb Optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; wherein R Xa and R Xb Each can be independently hydrogen, alkyl, or PEG; R Xc It can be alkyl, PEG, cycloalkyl, heterocycloalkyl, or phenyl; n1 is 1, 2, or 3; n2 is either 0 or 1; and m1 is either 0 or 1.

59. The compound according to any one of claims 50 to 58, or a pharmaceutically acceptable salt thereof, wherein each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h Independently for C1-C 10 Alkyl, C1-C 10 Halogenated, or C3-C 10 cycloalkyl or PEG 1-10 Each of them may choose to pass through one or more R X replace.

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, -CH2CF3, cyclohexyl or bicyclo[2.2.1]heptyl.

61. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein each R 2a R 2b R 2c R 2d R 2e R 2f R 2g and R 2h It is a methyl group.

62. The compound according to any one of claims 50 to 60, or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2f R 2g Or R 2h At least one of them is not an unsubstituted C1-C 10 alkyl.

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2d R 2e R 2f R 2g Or R 2h At least one of them is not methyl.

64. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 63, wherein n2 is 0.

65. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 63, wherein n2 is 1.

66. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 63 or 65, wherein Y 2 It is -N-.

67. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 63 or 65, wherein Y 2 It is -CH-.

68. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 67, wherein n1 is 1.

69. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 67, wherein n1 is 2.

70. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 67, wherein n1 is 3.

71. The compound according to any one of claims 50 to 70, or a pharmaceutically acceptable salt thereof, wherein each Y 3 Independently -N-.

72. The compound according to any one of claims 50 to 70, or a pharmaceutically acceptable salt thereof, wherein each Y 3 Independently -CH-.

73. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 72, wherein m1 is 0.

74. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 72, wherein m1 is 1.

75. The compound according to any one of claims 50 to 74, or a pharmaceutically acceptable salt thereof, wherein each R 3b It is hydrogen; and each R 3a Independently hydrogen, -NR 3c R 3d -NHC(O)OR 3c or -NHC(O)R 3e .

76. The compound of claim 75 or a pharmaceutically acceptable salt thereof, wherein each R 3a It can be hydrogen or -NH2 independently.

77. The compound according to any one of claims 50 to 74, or a pharmaceutically acceptable salt thereof, wherein each R 3a and each R 3b It is hydrogen.

78. The compound according to any one of claims 50 to 77, or a pharmaceutically acceptable salt thereof, wherein L is C1-C 20 Alkylene; and R 4 For -NR 4a R 4b ,in R 4a Hydrogen or optionally substituted C1-C 10 alkyl; R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl; Or R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups.

79. The compound of claim 78 or a pharmaceutically acceptable salt thereof, wherein R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Halogenated alkyl groups, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic alkyl.

80. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 4a Hydrogen or optionally substituted C1-C 10 Alkyl; and R 4b C1-C is optionally substituted 10 Alkyl or optionally substituted C1-C 10 Halogenated groups.

81. The compound according to claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein R 4a It is hydrogen.

82. The compound of claim 80 or a pharmaceutically acceptable salt thereof, wherein R 4a For C1-C 10 Alkyl and R 4b For C1-C 10 alkyl.

83. The compound of claim 82 or a pharmaceutically acceptable salt thereof, wherein R 4a It is methyl and R 4b It is a methyl group.

84. The compound of claim 78 or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms optionally substituted 3- to 6-membered heterocyclic alkyl groups.

85. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Together with the nitrogen to which it is attached, it forms an optionally substituted 6-membered heterocyclic alkyl group, which is optionally substituted with one or more halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups.

86. The compound according to any one of claims 50 to 77, or a pharmaceutically acceptable salt thereof, wherein L is C1-C2. 20 Alkylene and R 4 It is -CH3.

87. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 78 to 86, wherein L is a C1-C8 alkylene group.

88. The compound of claim 87 or a pharmaceutically acceptable salt thereof, wherein L is a C1-C6 alkylene group.

89. The compound of claim 88 or a pharmaceutically acceptable salt thereof, wherein L is absent.

90. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 89, wherein Z is absent.

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

92. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 50 to 91, wherein W 1 It is hydrogen and W 1a It is -CF3.

93. The compound according to any one of claims 50 to 91, or a pharmaceutically acceptable salt thereof, wherein W 1 It is hydrogen and W 1a It is hydrogen.

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

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

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