HBF pharmacological inducing compounds for the treatment of sickle cell anemia and beta-thalassemia

Abstract

The present disclosure provides a compound of formula (I). The compounds described in the present disclosure are used to treat diseases related to the expression of endogenous embryonic / fetal globulins (e.g., γ globulins) in red blood cells (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in red blood cells) and / or anemia (β-thalassemia and / or sickle cell anemia). The compounds described in the present disclosure are used to treat, postpone and / or prevent the adverse effects of β-thalassemia and / or sickle cell anemia, induce γ globulin production and / or induce the expression of embryonic / fetal globulin genes in individuals, cells, tissues or biological samples. The present disclosure also provides pharmaceutical compositions, kits and methods for inducing γ globulin production and for treating any target disease using the compounds described in the present disclosure.

Description

Technical Field

[0001] The present disclosure relates to a HBF pharmacological inducing compound for treating sickle cell disease and β-thalassemia. Background Art

[0002] The human α-like globin gene cluster (encoding the ζ (embryonic) and α (fetal / adult) globin chains) and the β-like globin gene cluster (encoding the ε (embryonic), γ (fetal), and β (adult) globin chains) extend over 50,000 bases on chromosomes 16 and 11, respectively. Human hemoglobin is a protein tetramer consisting of two α-like globin chains and two β-like globin chains that serve as oxygen transporters. The expression of the different globin chains is temporally controlled during development. For example, the first switch from embryonic to fetal hemoglobin occurs during pregnancy by silencing embryonic globin genes and activating fetal globin genes. The second switch from fetal to adult hemoglobin occurs approximately 6 months after birth. 1 According to prevalence estimates from the World Health Organization (WHO), at least 5.2% of the world's population suffers from hemoglobin disorders, accounting for approximately 3.4% of deaths in children under the age of 5. 2 These heme disorders are either structural disorders (in which the amino acid sequence is altered to produce abnormal heme) or expressive defects in globin chain synthesis. In both cases, adult functional heme (HbA) deficiencies lead to anemic syndromes such as sickle cell disease (SCD) and beta-thalassemia, the two most common hemoglobinopathies, affecting approximately 4.5% of the world's population. 3 .

[0003] SCD is one of the most common single gene disorders in the world. More than 70% of newborns affected by SCD are born in Africa, and it is estimated that more than 230,000 children with SCD are born in Africa each year. SCD is caused by a point mutation at the 17th nucleotide of the beta globin gene (resulting in a change from glutamic acid to valine). The mutant beta globin chains aggregate under hypoxia, causing the erythrocytes to have a sickle shape. 4 These sickled red blood cells not only lose their ability to transport oxygen, but they also block microvessels, limiting blood flow to organs. As a result, vaso-occlusive crises can lead to pain and organ death (particularly the liver and heart). In addition, these sickled red blood cells lose their elasticity, leading to hemolytic crises and anemia. Due to the high risk of early death, the life expectancy of SCD patients is reported to be shortened to an average of 42-48 years5.

[0004] β-thalassemia is an inherited anemia caused by mutations or deletions within the β-globulin gene that reduce the amount of β-globulin chains expressed. Due to the lack of sufficient β-globulin chains, the excess α-globulin chains form toxic aggregates and bind to the cell membrane, thereby inducing rapid apoptosis of red blood cells during early erythroblast development. 6，7 .

[0005] Three exemplary treatments have been used to regulate anemia and associated symptoms in patients with severe hemochromatosis. The most common treatment is regular blood transfusions throughout life to replenish the functional HbA required for survival. However, chronic transfusions are associated with a high risk of iron overload, which can lead to tissue damage and organ dysfunction. To avoid transfusion-induced iron overload, these chronically transfused patients must undergo expensive iron chelation therapy on a regular basis. Alternatively, bone marrow transplantation represents another treatment option for severe SCD and β-thalassemia. Given the potential for strong immune responses following transplantation, the identification of matched bone marrow donors is a major limitation of this therapy. In addition to these two traditional treatments, pharmacological induction of fetal hemoglobin (HbF) expression is a third approach to regulating hemochromatosis syndrome in patients with hemoglobin disorders. For patients with β-thalassemia, elevated fetal γ-globin chain synthesis can balance excess α-globin chains through the formation of HbF, thereby regulating the severe anemia observed in these patients. 8Furthermore, increased synthesis of γ-globin chains may prevent the formation of sickle heme (HbS), as HbF directly inhibits the polymerization of HbS in SCD patients. 9 . Therefore, drug-induced HbF in patients with hemoglobinopathy is a potentially effective treatment. To date, a variety of chemotherapeutic drugs (e.g., trichostatin A (TSA) (histone deacetylase inhibitor), apicidin (histone deacetylase inhibitor), 5'-aza-cytidine (DNA methyltransferase inhibitor), hydroxyurea (HU) (ribonucleotide reductase inhibitor), sodium butyrate (NaB) and its derivatives (short-chain fatty acids, also known as histone deacetylase inhibitors)) have been shown to stimulate fetal hemoglobin production. 10-15 Among them, HU is the only therapeutic drug approved by the US Food and Drug Administration for the treatment of SCD. It is used to replace the function of HbS in SCD patients to induce the expression of HbF. However, various side effects of HU therapy have been reported, including leucopenia, thrombocytopenia, myelosuppression, and potential reproductive toxicity. 16，17 In addition, at least 25% of SCD patients respond poorly or not at all to HU therapy. 18 Therefore, it is of great clinical significance to study compounds that can induce the expression of endogenous embryonic / fetal globin chains as an alternative treatment for these hemoglobin disorders. Summary of the invention

[0006] The present disclosure provides compounds that induce the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes, such as compounds of formula (I). The compounds described in the present disclosure can be used to treat diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes, including treating anemias such as β-thalassemia and / or sickle cell anemia by at least inducing the expression of globulin genes in erythrocytes. The compounds described in the present disclosure can also be used to treat, delay and / or prevent the adverse effects of β-thalassemia and / or sickle cell anemia. The compounds described in the present disclosure can also be used to induce gamma globulin production and / or induce the expression of embryonic / fetal globulin genes in individuals, cells, tissues or biological samples. The present disclosure also provides pharmaceutical compositions, kits, methods and uses of any compound described in the present disclosure.

[0007] As one aspect of the present disclosure, the present disclosure provides a compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein:

[0010] Each R 1 The embodiments of are each independently halogen, -C(=O)(alkyl), wherein alkyl is optionally substituted with halogen, unsubstituted alkenyl, unsubstituted alkynyl, or is a nitrogen protecting group when attached to a nitrogen atom;

[0011] R 2 is hydrogen, unsubstituted alkyl or a nitrogen protecting group;

[0012] Each R 3 Examples of are each independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR D1 、-N(R D1a ) 2 or -SR D1 ;

[0013] R 4 is hydrogen, unsubstituted alkyl or a nitrogen protecting group;

[0014] Each R 5 Examples of are each independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR D1 、-N(R D1a ) 2 or -SR D1 ;

[0015] R D1is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;

[0016] Each R D1a are each independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group; or optionally two R D1a The examples of and the atoms therebetween form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaromatic ring;

[0017] Y is -O- or -N(R 6 )-;

[0018] R 6 is hydrogen, optionally substituted alkyl or a nitrogen protecting group;

[0019] p is 0, 1, 2, 3, 4 or 5;

[0020] m is 0, 1 or 2;

[0021] n is 0, 1, 2, 3 or 4; and

[0022] x is 0, 1, or 2.

[0023] According to an embodiment of the present disclosure, the present disclosure provides a compound of formula (I):

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, m, n, p and x are as described in the present disclosure.

[0026] According to an embodiment of the present disclosure, the compound of formula (I) is of the formula:

[0027] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or a prodrug thereof, wherein R 1 , R 2, R 4 , R 5 and R 6 As described in this disclosure.

[0028] According to embodiments of the present disclosure, exemplary compounds of formula (I) include, but are not limited to:

[0029] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or a prodrug thereof.

[0030] As a second aspect of the present disclosure, the present disclosure provides a pharmaceutical composition comprising one or more compounds described in the present disclosure and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described in the present disclosure comprises an effective amount of a compound described in the present disclosure for treating diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes, including treating anemias such as β-thalassemia and / or sickle cell anemia by at least inducing the expression of globulin genes in erythrocytes. The pharmaceutical composition described in the present disclosure comprises an effective amount of a compound described in the present disclosure for treating, delaying and / or preventing the adverse effects of β-thalassemia and / or sickle cell anemia. The pharmaceutical composition described in the present disclosure comprises an effective amount of a compound described in the present disclosure for treating anemia in an individual in need (e.g., wherein the individual suffers from or is suspected of suffering from β-thalassemia and / or sickle cell anemia). The pharmaceutical composition described in the present disclosure comprises an effective amount of a compound described in the present disclosure for inducing gamma globulin production and / or inducing the expression of embryonic / fetal globulin genes in an individual, cell, tissue or biological sample. The effective amount described in the present disclosure may be a therapeutically effective amount or a prophylactically effective amount.

[0031] As a third aspect of the present disclosure, the present disclosure provides a method for treating a disease associated with the expression of endogenous embryonic / fetal globulin (e.g., gamma globulin) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing the expression of globulin genes in erythrocytes), for treating, delaying and / or preventing the adverse effects of β-thalassemia and / or sickle cell anemia, for inducing gamma globulin production and / or for inducing the expression of embryonic / fetal globulin genes in an individual, cell, tissue or biological sample, the method comprising administering to an individual in need of treatment, or contacting a cell, tissue or biological sample with an effective amount of a compound or any pharmaceutical composition described in the present disclosure. The present disclosure provides a method for treating an individual suffering from β-thalassemia or sickle cell anemia. The present disclosure provides a method for treating anemia in an individual in need (e.g., wherein the individual suffers from or is suspected of suffering from β-thalassemia or sickle cell anemia).

[0032] According to an embodiment of the present disclosure, the individual being treated is a mammal (eg, a human or a non-human mammal).

[0033] As a fourth aspect of the present disclosure, the present disclosure provides a set, including a container with a compound or pharmaceutical composition described in the present disclosure. The set described in the present disclosure may include a single dose or multiple doses of a compound or pharmaceutical composition. The set can be used in the method of the present disclosure. In certain embodiments, the set also includes instructions for using the compound or pharmaceutical composition. The set may also optionally include a device (e.g., a syringe, such as a pre-filled syringe for parenteral administration) for administering the compound or composition.

[0034] According to an embodiment of the present disclosure, the present disclosure provides compounds and pharmaceutical compositions as described in the present disclosure, for use in treating target diseases as described in the present disclosure (such as diseases related to the expression of endogenous embryonic / fetal globulins (e.g., γ globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in erythrocytes), for treating, delaying and / or preventing adverse effects of β-thalassemia and / or sickle cell anemia, for inducing γ globulin production in individuals, cells, tissues or biological samples, and / or inducing expression of embryonic / fetal globulin genes) and / or for manufacturing a medicament for treating the target disease. According to an embodiment of the present disclosure, the present disclosure provides compounds and pharmaceutical compositions as described in the present disclosure, for use in treating individuals suffering from β-thalassemia and / or sickle cell anemia. According to an embodiment of the present disclosure, the present disclosure provides compounds and pharmaceutical compositions as described in the present disclosure for treating anemia in an individual in need thereof (eg, wherein the individual suffers from or is suspected of suffering from β-thalassemia and / or sickle cell anemia).

[0035] The present disclosure sets forth details of one or more embodiments of the present disclosure. Other features, objectives, and advantages of the present disclosure will become more apparent through detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1A-1B The structures of exemplary compounds II, AS-28, and TN1, and their pharmacokinetic data are shown, wherein the specified compounds were administered to rats by intravenous infusion (IV) or oral administration (PO). Exemplary compound II was administered to rats by intravenous infusion (2.07 mg / kg) and oral administration (19.3 mg / kg). Exemplary compound AS-28 was administered to rats by intravenous infusion (5.0 mg / kg) and oral administration (20.0 mg / kg). Exemplary compound TN1 was administered to rats by intravenous infusion (2.0 mg / kg) and oral administration (10.0 mg / kg). The abbreviations are defined as follows: IV-intravenous; PO-per-os (oral); T 1 / 2 - half-life; CL- clearance; V ss - steady-state distribution volume; AUC(0-inf) - area under the curve; F - bioavailability; ND - not detected. Figure 1A The structures of exemplary Compound II and Compound AS-28 and their pharmacokinetic data are shown. Figure 1B The structure of exemplary compound TN1 and its pharmacokinetic data are shown.

[0037] Figure 2 Shown is a graph showing the dose-dependent effect of the exemplary compound AS-28 on gamma-globulin gene induction by comparing the concentration of AS-28 to the fold increase in gamma-globulin induction and percentage of cell proliferation in primary human erythrocyte cultures.

[0038] Figure 3 is a graph showing that the exemplary compound AS-28 (0.5 μM) induces γ-globin gene expression in hydroxyurea (HU)-resistant primary erythroid cells by comparing the concentration of AS-28 to the fold amount of γ-globin induction and the percentage of cell proliferation in primary human erythroid cultures (e.g., in HU-resistant primary human erythroid cells).

[0039] Figure 4It is a blot of BCL11A protein expression compared with the control group. Primary human erythrocytes were treated with known HbF inducers (HU, NaB and AS-28), and treated with Compound II, SS-2394, Compound 3 and Compound 8. Figure 4 The exemplary compound AS-28 was shown to reduce the expression level of the γ-globin gene repressor BCL11A.

[0040] Figure 5 The dose effect of treating SCD mice (animal model of mouse SCD disease) and control mice with the exemplary compound AS-28 at the indicated doses (50 mg, 75 mg and 100 mg) is illustrated, showing the dose effect under various parameters, including red blood cell (RBC) number, hemoglobin level (hemoglobin levels), reticulocyte (RET), white blood cell (WBC), neutrophil (NEUT) number and fetal hemoglobin (HbF). The abbreviations are defined as follows: RBC-red blood cell; HGB-hemoglobin; RET-reticulocyte; WBC-white blood cell; NEUT-neutrophil; HbF-fetal hemoglobin.

[0041] Figure 6 Shown are the structures of exemplary representative compounds (AS-28, AS-29, and AS-61) provided in the present disclosure.

[0042] Figure 7 RT-qPCR analysis of γ-globin gene transcription regulators in primary human erythrocytes treated with AS-28 (0.5 μM) is shown. Total RNA was isolated from primary human erythrocytes in culture without (mock) and with AS-28 treatment (AS-28) and analyzed by RT-qPCR. N=4 biological experiments, *, p<0.05; ***, p<0.001.

[0043] Figure 8 The overall effect of AS-28 on the gene expression profile of primary human erythrocytes is shown. RNA-seq data were analyzed by Ingenuity Pathways Analysis (IPA). The major cellular pathways in primary erythrocytes affected by AS-28 are listed here. DEGs: fold change ≥ 1.4, p < 0.05.

[0044] Fig. 9 A graph showing the concentration dependence of the exemplary compound AS-28 on gamma-globin gene induction is shown by comparing the concentration of AS-28 to the fold increase in gamma-globin induction and percentage of cell proliferation in primary human erythrocyte cultures.

[0045] Fig.10 Graph showing induction of γ-globin gene expression in hydroxyurea (HU)-resistant primary erythrocytes by the exemplary compound AS-28 (0.5 μM) by comparing the concentration of AS-28 to the fold induction of γ-globin in primary human erythrocyte cultures and the percentage of cell proliferation (e.g., in HU-resistant primary human erythrocytes).

[0046] Fig.11 It is a blot of the BCL11A protein expression compared with the control group. Primary human erythrocytes were treated with known HbF inducers (HU, NaB) and treated with Compound II, SS-2394, Compound 3 and Compound 8. Fig.11 It was shown that the exemplary compound AS-28 reduced the expression amount of the γ-globin gene inhibitor BCL11A. DETAILED DESCRIPTION

[0047] definition

[0048] The following sections describe in more detail the definitions of specific functional groups and chemical terms. Chemical elements are based on the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are generally defined as described therein. In addition, Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001", "Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989" and "Carruthers, Some Modern Methods of Organic Synthesis, 3 rd General principles of organic chemistry as well as specific functional groups and reactivities are described in Organic Chemistry: ...

[0049] The compounds described in the present disclosure may include one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described in the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods well known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33: 2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure also includes the compounds described herein as individual isomers substantially free of other isomers; or, as a mixture of various isomers.

[0050] When a range of values ​​is listed, it is intended to include every value and sub-range within that range. For example, “C 1-6 "Aims to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4, C 4-6 , C 4-5 and C 5-6 .

[0051] The term "aliphatic" includes saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. Those skilled in the art will understand that "aliphatic" in the present disclosure is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl functional groups. Thus, the term "alkyl" includes straight chain, branched and cyclic alkyl groups. Similar conventions apply to other general terms, such as "alkenyl" and "alkynyl", etc. In addition, the terms "alkyl", "alkenyl" and "alkynyl", etc. include both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to refer to those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

[0052] According to embodiments of the present disclosure, the alkyl, alkenyl and alkynyl groups used in the present disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl and alkynyl groups used in the present disclosure contain 1-10 aliphatic carbon atoms. In another embodiment, the alkyl, alkenyl and alkynyl groups used in the present disclosure contain 1-8 aliphatic carbon atoms. In another embodiment, the alkyl, alkenyl and alkynyl groups used in the present disclosure contain 1-6 aliphatic carbon atoms. In another embodiment, the alkyl, alkenyl and alkynyl groups used in the present disclosure contain 1-4 carbon atoms. Therefore, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl and -CH2-cyclohexyl functional groups, etc., which may also carry one or more substituents. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl and 1-methyl-2-butene-1-yl, etc. Representative alkynyl includes, but is not limited to, ethynyl, 2-propynyl (2-propynyl) (propargyl) and 1-propynyl, etc.

[0053] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C 1 In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butyl, tertiary amyl) and hexyl (C 6 ) (e.g., n-hexyl). Other examples of alkyl groups include n-heptyl (C 7 ) and n-octyl (C 8 ) etc. Unless otherwise indicated, each example of alkyl is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen (e.g., F)) ("substituted alkyl"). In certain embodiments, alkyl is unsubstituted C 1-10 Alkyl (e.g. unsubstituted C 1-6 Alkyl groups, such as -CH 3 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl (e.g. substituted C 1-6 Alkyl, such as -CF 3 ).

[0054] "Alkenyl" refers to a straight or branched chain hydrocarbon group ("C 2-20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ) and butadiene (C 4 ) etc. 2-6 Examples of the alkenyl group include the above-mentioned C 2-4 Alkenyl and pentenyl (C 5 ), pentadienyl (C 5 ) and hexenyl (C 6 ) and the like. Other examples of alkenyl groups include heptenyl (C 7 ), octenyl (C 8 ) and octatrienyl (C 8 ) etc. Unless otherwise specified, each example of alkenyl is independently optionally substituted (i.e., unsubstituted (“unsubstituted alkenyl”)) or substituted with one or more substituents (“substituted alkenyl”). In certain embodiments, alkenyl is unsubstituted C 2-10 In certain embodiments, alkenyl is a substituted C 2-10 In alkenyl, a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH 3 or ) can be an (E)- or (Z)-double bond.

[0055] "Alkynyl" refers to a straight or branched chain hydrocarbon group ("C 2-20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 The carbon-carbon triple bond(s) may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ) and 2-butynyl (C 4 ) etc. 2-6 Examples of the alkenyl group include the above-mentioned C 2-4 Alkynyl and pentynyl (C 5 ) and hexynyl (C 6 ) and the like. Other examples of alkynyl groups include heptynyl (C 7 ) and octynyl (C 8 ) etc. Unless otherwise specified, each alkynyl example is independently optionally substituted (i.e., unsubstituted (“unsubstituted alkynyl”)) or substituted with one or more substituents (“substituted alkynyl”). In certain embodiments, alkynyl is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0056] "Carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclic group"). Exemplary C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ) and cyclohexadienyl (C 6 ) etc. Exemplary C 3-8 Carbocyclic groups include, but are not limited to, the above C 3-6 Carbocyclic and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl(C 7 ) and bicyclo[2.2.2]octyl(C 8 ) etc. Exemplary C 3-10 Carbocyclic groups include, but are not limited to, the above C 3-8 Carbocyclic and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ) and spiro[4.5]decyl(C 10) and the like. As shown in the foregoing embodiments, in certain embodiments, the carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or comprises a fused, bridged or spiroring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which a carbocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, in which case the carbon number continues to represent the number of carbons in the carbocyclic ring system. Unless otherwise stated, each example of a carbocyclyl is independently optionally substituted (i.e., unsubstituted ("unsubstituted carbocyclyl")) or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl is an unsubstituted C 3-10 In certain embodiments, the carbocyclic group is a substituted C 3-10 Carbocyclic group.

[0057] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 (cycloalkyl) 5-6 Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). 3-6 Examples of the cycloalkyl group include the above-mentioned C 5-6 Cycloalkyl and cyclopropyl (C 3 ) and cyclobutyl (C 4 ). 3-8 Examples of the cycloalkyl group include the above-mentioned C 3-6 Cycloalkyl and cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl group”) or substituted with one or more substituents (a “substituted cycloalkyl group”). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0058] "Heterocyclyl" or "heterocycle" refers to a 3- to 10-membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocycle; or a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocycle, and in such cases, the number of ring members continues to represent the number of ring members in the heterocycle system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted (i.e., unsubstituted (“unsubstituted heterocyclyl”)) or substituted (“substituted heterocyclyl”) with one or more substituents. In certain embodiments, heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0059] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In some embodiments, 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen and sulfur.

[0060] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. 6Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclic rings) of an aromatic ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl, etc. Exemplary 6-membered heterocyclic groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aromatic ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0061] "Aryl" refers to a group having 6-14 carbon atoms and zero heteroatoms in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10 or 14 pi electrons in the cyclic array) ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C 6 In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl"; for example, anthracyl). "Aryl" also includes a ring system as defined above fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aromatic ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted (i.e., unsubstituted ("unsubstituted aryl")) or substituted ("substituted aryl") with one or more substituents. In certain embodiments, aryl is unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl.

[0062] "Aralkyl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl substituted with an optionally substituted aryl. In certain embodiments, the aralkyl is an optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is an optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.

[0063] "Heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the ring set) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valency permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the point of attachment is on the heteroaryl ring, in which case the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, in which case the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, and carbazolyl), the point of attachment can be on either ring (i.e., the ring with heteroatoms (e.g., 2-indolyl)) or the ring without heteroatoms (e.g., 5-indolyl).

[0064] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted (i.e., unsubstituted (“unsubstituted heteroaryl”)) or substituted (“substituted heteroaryl”) with one or more substituents. In certain embodiments, heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5-14 membered heteroaryl.

[0065] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoline, quinoxalinyl, phthalazinyl and quinazolinyl.

[0066] "Heteroaralkyl" is a subset of alkyl and heteroaryl, and refers to an optionally substituted alkyl substituted with an optionally substituted heteroaryl.

[0067] "Unsaturated" or "partially unsaturated" refers to a group that includes at least one double or triple bond. "Partially unsaturated" ring systems are further intended to encompass rings with multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl). Likewise, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains only single bonds.

[0068] The alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as divalent bridging groups are further described with the prefix -ene (-ene in English), such as alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene and heteroarylene.

[0069] Unless otherwise specifically stated, atoms, moieties or groups described herein may be unsubstituted or substituted, as valence permits. The term "optionally substituted" refers to substituted or unsubstituted.

[0070] Unless otherwise specified, groups are considered to be optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, whether or not preceded by the term "optionally", the term "substituted" means that at least one hydrogen atom (e.g., a carbon atom or a nitrogen atom) in the group is replaced by an allowed substituent, such as a substituent that results in a stable compound, such as a compound that does not spontaneously convert through rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position of the structure is substituted, the substituents at each position may be the same or different. The term "substituted" is intended to include substitution with all organic compound-allowed substituents, any substituent described in the present disclosure that forms a stable compound. The present disclosure encompasses any and all combinations for achieving a stable compound. For the purposes of the present disclosure, a heteroatom (e.g., a nitrogen atom) as described in the present disclosure may have a hydrogen substituent and / or any suitable substituent provided that the valence of the heteroatom is satisfied and a stable group can be formed. In certain embodiments, the substituent is a substituent on a carbon atom. In certain embodiments, the substituent is a substituent on a nitrogen atom. In certain embodiments, the substituent is a substituent on an oxygen atom. In certain embodiments, the substituent is a substituent on a sulfur atom.

[0071] Exemplary substituents on a carbon atom include, but are not limited to, halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X-, -N(OR cc )R bb , -SH, -SR aa , -SSRcc 、-C(=O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R aa 、-NR bb C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb ) 2 、-OC(=NR bb )N(R bb ) 2 、-NR bb C(=NR bb )N(R bb ) 2 、-C(=O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3 、-OSi(R aa ) 3 、-C(=S)N(R bb ) 2 、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa ) 2 、-P(=O)(OR cc ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O)(N(R bb ) 2 ) 2 、-OP(=O)(N(R bb ) 2 ) 2 、-NR bb P(=O)(R aa ) 2 、-NR bb P(=O)(OR cc ) 2 、-NR bb P(=O)(N(R bb ) 2 ) 2 、-P(R cc ) 2 、-P(OR cc ) 2 、-P(R cc ) 3 + X - 、-P(OR cc ) 3 + X - 、-P(R cc ) 4 、-P(OR cc ) 4 、-OP(R cc ) 2 、-OP(R cc ) 3 + X- 、-OP(OR cc ) 2 、-OP(OR cc ) 3 + X - 、-OP(R cc ) 4 、-OP(OR cc ) 4 ,-B(R aa ) 2 、-B(OR cc ) 2 , -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - It is the counterion;

[0072] Alternatively, the two geminal hydrogen atoms on the carbon atom are represented by the groups =O, =S, =NN (R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb or = NOR cc replaced by;

[0073] Every R aa Examples of each independently selected from C 1-10 Alkyl, C 1-1 0Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aaThe groups are connected to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaromatic ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0074] Every R bb Examples of are each independently selected from hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(=O)R aa 、-C(=O)N(R cc ) 2 , -CO 2 R aa 、-SO 2 R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(=S)N(R cc ) 2 、-C(=O)SR cc 、-C(=S)SR cc ,-P(=O)(R aa ) 2 、-P(=O)(OR cc ) 2 、-P(=O)(N(R cc ) 2 ) 2 , C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the relative ion;

[0075] Every R cc Examples of are each independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-1 membered heteroaryl, or two R cc The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0076] Every R dd Examples of are each independently selected from halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -OH, -OR ee 、-ON(R ff ) 2 、-N(R ff ) 2 、-N(R ff ) 3 + X - 、-N(OR ee )R ff , -SH, -SR ee 、-SSR ee 、-C(=O)R ee , -CO 2 H, -CO 2 R ee 、-OC(=O)R ee 、-OCO 2 R ee 、-C(=O)N(R ff ) 2 、-OC(=O)N(R ff ) 2 、-NR ff C(=O)R ee 、-NR ff CO 2 R ee 、-NR ff C(=O)N(R ff ) 2 、-C(=NR ff )OR ee、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff ) 2 、-OC(=NR ff )N(R ff ) 2 、-NR ff C(=NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R ee 、-S(=O)R ee 、-Si(R ee ) 3 、-OSi(R ee ) 3 、-C(=S)N(R ff ) 2 、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)(OR ee ) 2 ,-P(=O)(R ee ) 2 ,-OP(=O)(R ee ) 2 ,-OP(=O)(OR ee ) 2 , C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two pairs of R dd Substituents may be linked to form =O or =S; where X- is the relative ion;

[0077] Every R ee Examples of are each independently selected from C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0078] Every R ff Examples of are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution; and

[0079] Every R gg Examples of are each independently halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl) 2 、-N(C 1-6 alkyl) 2 、-N(C 1-6 alkyl) 3 + X - 、-NH(C 1-6 alkyl) 2 + X - 、-NH 2 (C 1-6 alkyl) + X - 、-NH 3 + X - 、-N(OC1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 Alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 、-C(=O)N(C 1-6 alkyl) 2 、-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 、-C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl) 2 、-C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 、-OC(=NH)N(C 1-6 alkyl) 2 、-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH 2 、-NHC(NH)N(C 1-6 alkyl) 2 、-NHC(=NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 alkyl) 2 、-SO 2 NH(C 1-6 Alkyl), -SO2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl) 3 、-OSi(C 1-6 alkyl) 3 、-C(=S)N(C 1-6 alkyl) 2 、C(=S)NH(C 1-6 alkyl), C(=S)NH 2 、-C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl) 2 ,-P(=O)(C 1-6 alkyl) 2 ,-OP(=O)(C 1-6 alkyl) 2 ,-OP(=O)(OC 1-6 alkyl) 2 , C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl; or two pairs of R gg Substituents may be linked to form =O or =S; where X - is the relative ion.

[0080] Every R gg Examples of are each independently halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl) 2 、-N(C 1-6 alkyl) 2 、-N(C 1-6 alkyl) 3 + X -、-NH(C 1-6 alkyl) 2 + X - 、-NH 2 (C 1-6 alkyl) + X - 、-NH 3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 Alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 、-C(=O)N(C 1-6 alkyl) 2 、-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 、-C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl) 2 、-C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 、-OC(=NH)N(C 1-6 alkyl) 2 、-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH 2 、-NHC(NH)N(C1-6 alkyl) 2 、-NHC(=NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 alkyl) 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl) 3 、-OSi(C 1-6 alkyl) 3 、-C(=S)N(C 1-6 alkyl) 2 、C(=S)NH(C 1-6 alkyl), C(=S)NH 2 、-C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl) 2 ,-P(=O)(C 1-6 alkyl) 2 ,-OP(=O)(C 1-6 alkyl) 2 ,-OP(=O)(OC 1-6 alkyl) 2 , C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl; or two pairs of R gg Substituents may be linked to form =O or =S; where X - is the relative ion.

[0081] A "counterion" or "anionic counterion" is a negatively charged group that is bound to a positively charged group to maintain electrical neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halides (e.g., F - , Cl - Br - ,I - ), NO 3 - , ClO 4 - OH - , H 2 PO 4 - , HSO 4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, and ethane-1-sulfonic acid-2-sulfonate), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, and gluconate), BF 4 - PF 4 - PF 6 - , AsF 6 - , SbF 6 - , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] - BPh 4 - 、A1(OC(CF 3 )3 ) 4 - and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me 5 Br 6 ) - ). Exemplary multivalent counter ions include CO 3 2- , HPO 4 2- ,PO 4 3- , B 4 O 7 2- 、SO 4 2- , S 2 O 3 2- , carboxylate ions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalates, aspartate and glutamate, etc.), and carboranes.

[0082] “Halo” or “halogen” refers to a fluorine atom (F, —F), a chlorine atom (Cl, —Cl), a bromine atom (Br, —Br) or an iodine atom (I, —I).

[0083] "Acyl" refers to a group selected from -C(=O)R aa 、-CHO、-CO 2 R aa 、-C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb ) 2 、-C(=O)NR bb SO 2 Raa 、-C(=S)N(R bb ) 2 、-C(=O)SR aa or -C(=S)SR aa The group composed of R aa and R bb As defined in this disclosure.

[0084] The nitrogen atoms may be substituted or unsubstituted as permitted by valence, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(=O)R aa 、-C(=O)N(R cc ) 2 , -CO 2 R aa 、-SO 2 R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(=S)N(R cc ) 2 、-C(=O)SR cc 、-C(=S)SR cc 、-P(=O)(OR cc ) 2 ,-P(=O)(R aa ) 2 、-P(=O)(N(R cc ) 2 ) 2 , C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups connected to a nitrogen atom ccThe groups are connected to form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaromatic ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution, where R aa , R bb , R cc and R dd As defined in this disclosure.

[0085] In certain embodiments, the substituent on the nitrogen atom is a nitrogen protecting group (also known as an amine protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa 、-N(R cc ) 2 、-C(=O)R aa 、-C(=O)N(R cc ) 2 , -CO 2 R aa 、-SO 2 R aa 、-C(=NR cc )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(=S)N(R cc ) 2 、-C(=O)SR cc 、-C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd substituted with R aa , R bb , R cc and R ddAs defined in the present disclosure. Those skilled in the art are familiar with nitrogen protecting groups, which include "Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999", the detailed description of which is incorporated into the present disclosure as a reference.

[0086] For example, an amide group (eg, -C(=O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, derivative), benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide butanamide), 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetyl methionine derivative, o-nitrobenzamide and o-(benzoyloxy methyl)benzamide.

[0087] Such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate (9-(2-sulfo)fluorenylmethyl carbamate, carbamate), 9-(2,7-dibromo)fluoroenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (2-trimethylsilylethyl carbamate) carbamate, Teoc), 2-phenylethylcarbamate, hZ), 1-(1-adamantyl)-1-methylethylcarbamate, Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate, DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate, TCBOC), 1-methyl-1-(4-biphenylyl)ethylcarbamate, 1-methyl-1-(4-biphenylyl)ethylcarbamate, 1-methyl-2-(4-biphenylyl)ethylcarbamate, 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1,1-dimethyl-2,2-dibromoethylcarbamate, TCBOC, 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate, TCBOC, 1-methyl-1-(4-biphenylyl)ethylcarbamate, 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1,1-dimethyl-2,2,2-dibromoethylcarbamate, TCBOC, 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate, TCBOC, 1-methyl-1-(4-biphenylyl)ethylcarbamate, 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1,1-dimethyl-2,2,2-tribromoethylcarbamate, TCBOC, 1-methyl-2-(2-haloethylcarbamate, DB-t-BOC), 1-methyl-2-(2- carbamate, Bpoc), 1-(3,5-di-t-butyl phenyl)-1-methylethyl carbamate,t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Coc), carbamate, Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate, Cbz, p-methoxy benzyl carbamate, Moz, p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate, Msz, 9-anthrylmethyl carbamate carbamate), diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, carbamate [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate carbamate), 5-benzisoxazolyl methyl carbamate, 2-(trifluoromethyl)-6-chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxy benzylcarbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate.4-dimethoxy-6-nitrobenzyl carbamate), phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinyl carbamate carbamate), o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate,1-dimethylpropynyl carbamate), di(2-pyridyl)methylcarbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methyl cyclohexylcarbamate, 1-methyl-1-cyclopropyl methylcarbamate), 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate carbamate), 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylbenzyl carbamate.

[0088] Such as sulfonamide groups (e.g., -S(=O) 2 R aa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide (benzenesulfonamide), 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (2,3,6,-trimethyl-4-methoxybenzenesulfonamide, Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide ( ...6,-trimethyl-4-methoxybenzenesulfonamide, Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (2,3,6,-trimethyl-4-methoxybenzenesulfonamide, Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (2,3,6,-trimethyl-4-methoxybenzenesulfonamide, Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (2,3,6,-trimethyl-4-methoxybenzenesulfonamide, Mt methyl-4-methoxybenzenesulfonamide, Mte), 4-methoxybenzenesulfonamide (4-methoxybenzenesulfonamide, Mbs), 2,4,6-trimethylbenzenesulfonamide (2,4,6-trimethylbenzenesulfonamide, Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (2,6-dimethoxy-4-methylbenzenesulfonamide, iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (2,2,5,7,8-pentamethylchroman-6-sulfonamide, Pmc), Methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide.

[0089] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, derivative), N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one (5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one), 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine,SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts ammonium salts), N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine, N-[(4-methoxyphenyl)diphenylmethyl]amine, MMTr, N-9-phenylfluorenylamine, N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino, Fcm, N-2-picolylamino N'-oxide N'-oxide), N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylenediamine,N'-isopropylidenediamine), Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chloro salicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-phenyl(pentaacylchromium-or tungsten)acylamine tungsten)acyl]amine), N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide (2,4-dinitrobenzenesulfenamide), pentachlorobenzenesulfonamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfonamide and 3-nitropyridinesulfenamide (Npys).

[0090] Exemplary oxygen atom substituents include, but are not limited to, -R aa 、-C(=O)SR aa 、-C(=O)R aa , -CO 2 R aa 、-C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb ) 2 、-S(=O)R aa 、-SO 2 R aa 、-Si(R aa ) 3 、-P(R cc ) 2 、-P(R cc ) 3 + X - 、-P(OR cc ) 2 、-P(OR cc ) 3 + X - ,-P(=O)(R aa ) 2 、-P(=O)(OR cc ) 2 and -P(=O)(N(R bb ) 2 ) 2 , where X - , R aa , R bb and R ccAs defined in the present disclosure. In certain embodiments, the oxygen atom substituent on the oxygen atom is an oxygen protecting group (also known as a hydroxy protecting group). Oxygen protecting groups well known to those skilled in the art include those described in "Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999", and their detailed descriptions are incorporated into the present disclosure as a reference. Exemplary oxygen protecting groups include, but are not limited to, methyl, tert-butyloxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl ((4-methoxyphenoxy)methyl, p-AOM), guaiacolmethyl (guaiacolmethyl, GUM), tert-butyloxymethyl, 4-pentenyloxymethyl (PO M), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl (3-bromotetrahydropyranyl), tetrahydrothiopyranyl (tetrahydrothiopyranyl), 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide (4-methoxytetrahydrothiopyranyl S, S-dioxide), 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4, 5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido), diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethoxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4" -tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S, S-dioxoS-dioxido), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triphenylmethylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoyl formate, acetate , chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate carbonate, Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzoic carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzoic carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrobenzenesulfonate, sulfate, methanesulfonate (mesylate), phenylmethylsulfonate and toluenesulfonate (Ts).

[0091] Exemplary sulfur atom substituents include, but are not limited to, -R aa 、-C(=O)SR aa 、-C(=O)R aa , -CO 2 R aa 、-C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb ) 2 、-S(=O)R aa 、-SO 2 R aa 、-Si(R aa ) 3 、-P(R cc ) 2 、-P(R cc ) 3 + X - 、-P(OR cc ) 2 、-P(OR cc ) 3 + X - ,-P(=O)(R aa ) 2 、-P(=O)(OR cc ) 2 and -P(=O)(N(R bb ) 2 ) 2 , where R aa , R bb and Rcc As defined in this disclosure.

[0092] A "hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. A hydrocarbon chain comprises (1) one or more carbon atoms directly between two groups of the hydrocarbon chain; (2) one or more hydrogen atoms optionally attached to the carbon atom chain; and (3) one or more substituents ("non-chain substituents" which are not hydrogen) optionally attached to the carbon atom chain. A carbon atom chain is composed of consecutively linked carbon atoms ("chain atoms" or "carbon units") and does not contain hydrogen atoms or heteroatoms. However, a non-chain substituent of a hydrocarbon chain may contain any atom, including hydrogen atoms, carbon atoms, and heteroatoms. For example, a hydrocarbon chain -C A H(C B H2C C H 3 )-contains a chain atom C A , one in C A The hydrogen atoms on the B H 2 C C H 3 ). The term "C x Hydrocarbon chain (C x A hydrocarbon chain (where x is a positive integer) is a hydrocarbon chain containing x atoms between two hydrocarbon chain groups. If there is more than one possible value for x, the hydrocarbon chain is defined by the smallest possible value of x. For example, -CH(C 2 H 5 )-C 1 Hydrocarbon chain, Then C 3 When a range value is used, the meaning of the range is as described in the present disclosure. For example, C 3-10 A hydrocarbon chain is a hydrocarbon chain in which the shortest carbon atom chain directly between two hydrocarbon chain groups has 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The hydrocarbon chain may be saturated (e.g., -(CH 2 ) 4 The hydrocarbon chain may also be unsaturated, containing one or more C=C and / or C≡C bonds at any position of the hydrocarbon chain. For example, -CH=CH-(CH 2 ) 2 -、-CH 2 -C≡C-CH 2 - and -C≡C-CH=CH- are examples of unsubstituted and unsaturated hydrocarbon chains. In certain embodiments, the hydrocarbon chain is unsubstituted (e.g., -C≡C- or -(CH2 ) 4 In certain embodiments, the hydrocarbon chain is substituted (e.g., -CH(C 2 H 5 )- and -CF 2 -). Any two substituents on the hydrocarbon chain may be linked to form an optionally substituted carbocyclic ring, an optionally substituted heterocyclic ring, an optionally substituted aryl group or an optionally substituted heteroaromatic ring. For example, and are all examples of hydrocarbon chains. In contrast, in certain embodiments, and It does not belong to the hydrocarbon chain scope described in the present disclosure. x When the chain atom of a hydrocarbon chain is replaced by a heteroatom, the resulting group is a C x Hydrocarbon chain, not C x-1 Hydrocarbon chains. For example, A C atom is replaced by an oxygen atom 3 Hydrocarbon chain. The term "leaving group" has a general meaning in the field of synthetic organic chemistry, which refers to an atom or group that can be displaced by a nucleophile. For example, see Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of leaving groups include, but are not limited to, halogens (e.g., F, Cl, Br or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxylamino, pixyl and haloformates. In some examples, the leaving group is an activated substituted hydroxyl group (e.g., -OC(=O)SR aa 、-OC(=O)R aa 、-OCO 2 R aa 、-OC(=O)N(R bb ) 2 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-OC(=NR bb)N(R bb ) 2 、-OS(=O)R aa 、-OSO 2 R aa 、-OP(R cc ) 2 、-OP(R cc ) 3 、-OP(=O) 2 R aa ,-OP(=O)(R aa ) 2 ,-OP(=O)(OR cc ) 2 、-OP(=O) 2 N(R bb ) 2 and-OP(=O)(NR bb ) 2 , where R aa , R bb and R cc As defined in the present disclosure). In some examples, the leaving group is a sulfonate, such as tosylate (-OTs), mesylate (-OMs), brosylate (-OBs), -OS (=O) 2 (CF 2 ) 3 CF 3 (nonaflate, -ONf), or triflate, -OTf. In some examples, the leaving group is a bromobenzenesulfonate group (brosylate), such as p-bromobenzenesulfonyloxy. In some examples, the leaving group is a nitrobenzenesulfonyl group (nosylate), such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group, such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether groups, thioether groups, zinc halides, magnesium groups, diazonium salts, and copper groups.

[0093] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without causing undue toxicity, irritation, and allergic reactions, etc., within the scope of sound medical judgment, and are consistent with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known to those skilled in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, and the objects and purposes cited herein are incorporated by reference into the present disclosure. Pharmaceutically acceptable salts of the compounds described in the present disclosure include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amine groups, which are formed by reacting the amine groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods well known in the art, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, sulfate), malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate and valerate, etc. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N- + (C 1-4 alkyl) 4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium salts. In addition, pharmaceutically acceptable salts include, where appropriate, salts formed by non-toxic ammonium, quaternary ammonium and ammonium cations and counter ions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates).

[0094] The term "solvate" refers to a form of a compound that is bound together with a solvent, usually by solvolysis. This physical binding may include hydrogen bonds. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and diethyl ether, etc. The compounds described in the present disclosure can be prepared, for example, in crystalline form, or can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include both stoichiometric solvates and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to separate. "Solvate" covers both solution phase and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0095] The term "hydrate" refers to a compound that is bound to water. Generally speaking, the number of water molecules contained in the hydrate of a compound is in a clear ratio to the number of compound molecules in the hydrate. Thus, for example, the general formula R·xH 2 O represents a hydrate of a compound, where R is the compound and x is a number greater than 0. A given compound may form more than one form of hydrate, including, for example, a monohydrate (x is 1), an oligohydrate (x is greater than 0 and less than 1), such as a hemihydrate (R·0.5H 2 O)), and polyhydrates (x is greater than 1, such as dihydrate (R·2H 2 O) and hexahydrate (R·6H 2 O)).

[0096] The term "tautomers" or "tautomeric" refers to two or more interconvertible compounds formed by at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization can be produced by acid or base catalysis (i.e., the reaction provides a pair of tautomers). Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(another enamine) tautomerization.

[0097] It is also understood that compounds with the same molecular formula but different properties or atomic bonding order or atomic arrangement in space are called "isomers". When the atomic arrangement in space is different, such isomers are called "stereoisomers".

[0098] Stereoisomers that are not mirror images of each other are called "diastereomers", while those that are nonsuperimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center (for example, bonded to four different groups), a pair of enantiomers may be produced. Enantiomers are characterized by the absolute configuration of their asymmetric center and can be described by the R- and S-ordering of Cahn and Prelog, or designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively) by the way the molecule rotates about the plane of polarization. Chiral compounds can exist as individual enantiomers or as mixtures of them. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0099] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. The crystallization solvent, crystallization rate, storage temperature and other factors may cause one crystal form to become the dominant crystalline form. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0100] The term "prodrug" refers to a compound having a cleavable group that can be converted into a compound described in the present disclosure that is pharmaceutically active in vivo under solvolysis or physiological conditions. Examples include, but are not limited to, choline ester derivatives and N-alkylmorpholine esters. Other derivatives of the compounds described in the present disclosure are active in both their acid and acid derivative forms, but the acid-sensitive form generally has advantages in solubility, tissue compatibility and delayed release in mammals (see Bundgard, H., Design of Prodrugs, pP. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reacting an appropriate alcohol with a parent acid, or amides prepared by reacting a substituted or unsubstituted amine or acid anhydride or mixed anhydride with a parent acidic compound. Simple aliphatic or aromatic esters, amides and anhydrides derived from acid groups pendant to the compounds of the present disclosure may serve as specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Preferred compounds of the present disclosure have C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, aryl, C 7 -C 12 Substituted aryl and C 7 -C 12 Arylalkyl esters.

[0101] The terms "composition" and "formulation" are used interchangeably.

[0102] As used herein, "subject" refers to a human being (i.e., a male or female of any age group, such as a pediatric subject such as an infant, toddler, or adolescent, or an adult subject such as a young, middle-aged, or elderly person). The subject also includes any non-human animal, including, but not limited to, a cynomolgus monkey or rhesus monkey, a cow, a pig, a horse, a sheep, a goat, a cat, a dog, a mouse, a rat, a rabbit, or a bird (commercially relevant birds such as chickens, ducks, geese, or turkeys). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. In certain embodiments, the non-human animal is a mammal, a primate, The non-human animal may be a rodent, poultry, horse, sheep, cattle, goat, cat or canine. The non-human animal may be a male or female individual at any stage of development. The non-human animal may be a transgenic animal or a genetically engineered animal. A "patient" is a human individual in need of treatment for a disease. The individual may also be a plant.

[0103] The term "biological sample" refers to any sample, including tissue samples (e.g., tissue sections and tissue needle aspiration sections), cell samples (e.g., cell smears such as Pap or blood smears or microdissected cell samples), whole biological samples (e.g., samples of yeast or bacteria), or cell parts, fragments, or organelles (e.g., components of cells that have been broken down and separated by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, sliced ​​tissue (e.g., surgical slices or needle aspiration sections), nipple aspirates, breast milk, vaginal fluid, saliva, scrapings (e.g., cheek scrapings), or any material containing biological molecules derived from a first biological sample.

[0104] The terms "administer", "administering", or "administration" refer to implantation, absorption, ingestion, infusion, inhalation, or other means by which a compound or composition described herein or the like can be introduced into a subject.

[0105] The terms "treatment", "treat", and "treating" refer to reversing, slowing down, or delaying the occurrence of a disease described in the present disclosure or inhibiting the progression of the disease. In certain embodiments, medication may be administered after one or more symptoms or signs of the disease occur, or after one or more symptoms or signs of the disease are observed. In other embodiments, medication may be administered when no symptoms or signs of the disease appear. For example, medication may be administered to individuals at risk of developing the disease (e.g., based on a history of symptoms and / or based on exposure to pathogens) before symptoms occur, thereby delaying or preventing the occurrence of the disease. For example, medication may also be continued after symptoms are eliminated, thereby delaying or preventing recurrence.

[0106] The terms "condition," "disease," and "disorder" are used interchangeably.

[0107] An "effective amount" of a compound described in the present disclosure refers to a dose sufficient to produce a desired biological response (i.e., to treat a condition (therapeutic or prophylactic)). As is well known to those skilled in the art, the effective amount of a compound described in the present disclosure may vary depending on factors such as the desired physiological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the individual. In certain embodiments, an effective amount refers to a therapeutically effective amount. In certain embodiments, an effective amount refers to a prophylactic treatment. In certain embodiments, an effective amount refers to a single dose of a compound described in the present disclosure. In certain embodiments, an effective amount is the combined dose of multiple doses of a compound described in the present disclosure.

[0108] A "therapeutically effective amount" of a compound described in the present disclosure refers to a dose sufficient to produce a therapeutic benefit when treating a condition, or delaying, minimizing, or eliminating one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to a dose of a therapeutic agent that provides a therapeutic benefit in treating a condition, either alone or in combination with other treatments. The term "therapeutically effective amount" can encompass a dose that can improve overall treatment, reduce or avoid the signs, symptoms, or causes of the condition, and / or enhance the therapeutic efficacy of another therapeutic agent.

[0109] A "prophylactically effective amount" of a compound disclosed herein refers to a dose sufficient to prevent a condition, or one or more symptoms associated with the condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to a dose of a therapeutic agent that provides a prophylactic benefit in preventing a condition, either alone or in combination with other agents. The term "prophylactically effective amount" may encompass a dose that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0110] The present disclosure provides exemplary endogenous embryonic / fetal globulin chain inducers (inducers) of various preparations for therapeutic administration. According to an embodiment of the present disclosure, the agent is formulated into a pharmaceutical composition by combining with a suitable pharmaceutically acceptable carrier or diluent, which is formulated into a preparation in solid, semi-solid, liquid or gaseous form, such as a tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant, gel, microsphere (microsphere) and aerosol. Therefore, administration is achieved in various ways. In some preparations, the inducer is systemic after administration; in other preparations, the inhibitor (inhibitor) is localized by the dosage form, such as using an implant to keep the active dose at the implantation site.

[0111] In this disclosure, the terms "sickle cell disease" and "sickle cell anemia" are used interchangeably.

[0112] In the present disclosure, the terms "determining", "assessing", "assaying", "measuring" and "detecting" refer to quantitative and qualitative determinations, and therefore, the term "determining" can be used interchangeably with "analyzing" and "measuring" in the present disclosure. When a quantitative determination is performed, descriptions such as "determining an amount" are used to express it. When a qualitative or quantitative determination is performed, "determining a level" or "detecting a level" are used to express it. Specific embodiments

[0114] The present disclosure provides compounds of formula (I) for use in treating target diseases, such as diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by inducing at least globulin gene expression in erythrocytes). The compounds described in the present disclosure can be used to treat, delay and / or prevent the adverse effects of β-thalassemia and / or sickle cell anemia, induce gamma globulin production and / or induce expression of embryonic / fetal globulin genes in individuals, cells, tissues, or biological samples. According to embodiments of the present disclosure, the present disclosure provides compounds for treating anemia in individuals in need thereof (e.g., wherein the individual suffers from or is suspected of suffering from β-thalassemia and / or sickle cell anemia). The present disclosure also provides pharmaceutical compositions, kits, and methods of using the compounds described in the present disclosure to induce gamma globulin production and treat any target disease described in the present disclosure.

[0115] Compounds that inhibit minichromosomes that maintain eukaryotic replication helicase (MCM)

[0116] Embodiments of the present disclosure relate to inducers of gamma globulin production as described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof. These compounds can be used to treat diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by inducing at least globulin gene expression in erythrocytes), treating, delaying and / or preventing adverse effects of β-thalassemia and / or sickle cell anemia, inducing gamma globulin production in an individual, cell, tissue or biological sample, and / or inducing expression of embryonic / fetal globulin genes, and treating anemia in an individual in need thereof (e.g., wherein the individual has or is suspected of having β-thalassemia and / or sickle cell anemia).

[0117] In certain embodiments, the compounds described herein are of formula (I):

[0118]

[0119] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, m, n, p and x are as described in the present disclosure. In certain embodiments, the compound described in the present disclosure is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, Formula (I) includes zero or more substituents R 1 In some embodiments, Formula (I) includes zero substituents R 1 In some embodiments, formula (I) includes one or more substituents R 1 In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, at least one R 1 Examples of are halogens (e.g., F, Cl, Br, or I). In certain embodiments, at least one R 1 An example of is -C(=O)(alkyl). In certain embodiments, at least one R 1 An example of is -C(=O)(optionally substituted alkyl). 1 An example is -C(=O) (optionally substituted C 1 -C 6 In certain embodiments, at least one R 1 Examples of are alkyl groups optionally substituted with halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one R 1 An example of is an optionally substituted alkyl. In certain embodiments, at least one R 1 Examples are C optionally substituted with halogen (eg, F, Cl, Br or I). 1 -C 6 In certain embodiments, at least one R 1 An example is unsubstituted C 1 -C 6In certain embodiments, at least one R 1 An example of is unsubstituted methyl. In certain embodiments, at least one R 1 An example of is unsubstituted ethyl. In certain embodiments, m is 1; at least one R 1 An example of is unsubstituted ethyl. In certain embodiments, at least one R 1 An example is an optionally substituted alkenyl group (e.g., C 2 -C 6 alkenyl).

[0121] In certain embodiments, at least one R 1 An example is an optionally substituted C 2 -C 6 In certain embodiments, at least one R 1 An example of is unsubstituted alkenyl. In certain embodiments, at least one R 1 An example is unsubstituted C 2 -C 6 In certain embodiments, at least one R 1 An example is an optionally substituted alkynyl group (e.g., C 2 -C 10 In certain embodiments, at least one R 1 An example is an optionally substituted C 2 -C 10 In certain embodiments, at least one R 1 Examples are unsubstituted alkynyl (e.g., unsubstituted C 2 -C 10 In certain embodiments, at least one R 1 An example is unsubstituted C 2 -C 10 In certain embodiments, at least one R 1Examples of when attached to a nitrogen atom are nitrogen protecting groups (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzylcarbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0122] Formula (I) includes substituents R 2 In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted alkyl. 2 For the selectively substituted C 1-6 In certain embodiments, R 2 is C optionally substituted with halogen (e.g., F, Cl, Br or I) 1 -C 6 In some embodiments, R 2 In some embodiments, R2 is an unsubstituted C 1 -C 6 In certain embodiments, at least one R 1 An example of is unsubstituted methyl. In certain embodiments, at least one R 1 An example of is unsubstituted ethyl. In some embodiments, R 2 is a nitrogen protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl, trityl, acetyl or p-toluenesulfonamide (Ts)).

[0123] In some embodiments, Formula (I) includes zero or more substituents R 3 In some embodiments, Formula (I) includes zero substituents R 3 In some embodiments, formula (I) includes one or more substituents R 3 In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, at least one R 3Examples of are halogens (e.g., F, Cl, Br, or I). In certain embodiments, at least one R 3 An example of is an optionally substituted acyl group (eg, -C(=O)(alkyl)). In certain embodiments, at least one R 3 Examples are optionally substituted alkyl (e.g., optionally substituted C 1-6 In certain embodiments, at least one R 3 An example is an optionally substituted C 1-6 In certain embodiments, at least one R 3 Examples of optionally substituted alkenyl (eg, optionally substituted C 2 -C 6 In certain embodiments, at least one R 3 Examples are optionally substituted alkynyl (eg, optionally substituted C 2 -C 10 In certain embodiments, at least one R 3 Examples of R3 may be optionally substituted carbocyclyl (e.g., substituted or unsubstituted 3 to 7 membered monocyclic carbocyclyl containing zero, one or two double bonds in the carbocyclic ring system). In some embodiments, examples of at least one R3 may be optionally substituted heterocyclyl (e.g., substituted or unsubstituted 5 to 10 membered monocyclic or bicyclic heterocyclic rings, wherein one or two atoms in the heterocyclic ring are each independently nitrogen, oxygen or sulfur). In some embodiments, at least one R 3 Examples of may be optionally substituted aryl (e.g., phenyl or benzyl). In some embodiments, at least one R 3 Examples of may be optionally substituted heteroaryl (e.g., 5- to 7-membered monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen, or sulfur; or optionally substituted 8- to 10-membered bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen, or sulfur). In some embodiments, at least one R 3 An example of may be -CN. In certain embodiments, at least one R 3 An example of -OR D1 、-N(R D1a ) 2 or -SR D1 , and R D1 As defined in the present disclosure. In some embodiments, at least one R 3 An example of -OR D1 、-N(R D1a ) 2or -SR D1 ; where R D1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; each R D1a are each independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group; or optionally two R D1a The examples of R and the atoms therebetween form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaromatic ring. In some embodiments, at least one R 3 An example of -OR D1 (e.g., -OH or -OMe). In some embodiments, at least one R 3 An example of -N(R D1a ) 2 (e.g., -NH2 or -NMe 2 ). In some embodiments, at least one R 3 An example of -SR D1 (e.g., -SH or -SMe).

[0124] In certain embodiments, R D1 is hydrogen. In certain embodiments, R D1 is an optionally substituted acyl group (eg, -C(=O)Me). In certain embodiments, R D1 is an optionally substituted alkyl group (e.g., a substituted or unsubstituted C 1-6 In certain embodiments, R D1 is a substituted or unsubstituted methyl group. D1 is a substituted or unsubstituted ethyl group. D1 is a substituted or unsubstituted propyl group. In certain embodiments, R D1 is an optionally substituted alkenyl group (e.g., a substituted or unsubstituted C 2-6 In certain embodiments, R D1 is an optionally substituted alkynyl group (e.g., a substituted or unsubstituted C 2-6 In certain embodiments, R D1is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one or two double bonds in the carbocyclic ring system). D1 is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocycle, wherein one or two atoms in the heterocycle are independently nitrogen, oxygen or sulfur). D1 is an optionally substituted aryl group (eg, a substituted or unsubstituted 6- to 10-membered aryl group). D1 In certain embodiments, R D1 is an optionally substituted phenyl group. D1 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl, wherein one, two, three or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl, wherein one, two, three or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen or sulfur). In certain embodiments, R D1 When attached to an oxygen atom, it is an oxygen protecting group. D1 When attached to a sulfur atom, it is a sulfur protecting group.

[0125] In certain embodiments, at least one R D1a An example of is hydrogen. In certain embodiments, at least one R D1a An example of is an optionally substituted acyl group (eg, -C(=O)Me). In certain embodiments, at least one R D1a is an optionally substituted alkyl group (e.g., a substituted or unsubstituted C 1-6 In certain embodiments, at least one R D1a An example of is substituted or unsubstituted methyl. In certain embodiments, at least one R D1a An example of is substituted or unsubstituted ethyl. In certain embodiments, at least one R D w a An example of is substituted or unsubstituted propyl. In certain embodiments, at least one R D1a Examples are optionally substituted alkenyl (eg, substituted or unsubstituted C 2-6 In certain embodiments, at least one R D1a Examples are optionally substituted alkynyl (eg, substituted or unsubstituted C 2-6 In certain embodiments, at least one R D1aAn example of is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one R D1a Examples of are optionally substituted heterocyclyl (e.g., substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic rings, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). D1a An example of is an optionally substituted aryl group (eg, a substituted or unsubstituted 6- to 10-membered aryl group). In certain embodiments, at least one R D1a An example of is benzyl. In certain embodiments, at least one R D1a An example of is optionally substituted phenyl. In certain embodiments, at least one R D1a Examples of are optionally substituted heteroaryl (e.g., substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one R D1a Examples of are nitrogen protecting groups (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl, trityl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, the two R D1a Examples of are taken together with the atoms therebetween to form a substituted or unsubstituted heterocycle (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocycle in which one or two atoms in the heterocycle are independently nitrogen, oxygen or sulfur) or a substituted or unsubstituted heteroaromatic ring (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl in which one, two, three or four atoms in the heteroaromatic ring system are independently nitrogen, oxygen or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl in which one, two, three or four atoms in the heteroaromatic ring system are independently nitrogen, oxygen or sulfur).

[0126] Formula (I) includes substituents R 4 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted alkyl. 4 For the selectively substituted C 1-6 In certain embodiments, R 4 is C optionally substituted with halogen (e.g., F, Cl, Br or I) 1 -C 6In some embodiments, R 4 is an unsubstituted alkyl group. 4 For unsubstituted C 1 -C 6 In certain embodiments, at least one R 4 An example of is unsubstituted methyl. In certain embodiments, at least one R 4 An example of is unsubstituted ethyl. In some embodiments, R 4 is a nitrogen protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl, trityl, acetyl or p-toluenesulfonamide (Ts)). In some embodiments, R 2 is hydrogen, and R 4 For hydrogen.

[0127] In some embodiments, Formula (I) includes zero or more instances of substituent R3. In some embodiments, Formula (I) includes zero substituent R 5 In some embodiments, formula (I) includes one or more substituents R 5 In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, at least one R 5 Examples of are halogens (e.g., F, Cl, Br, or I). In certain embodiments, at least one R 5 An example of is an optionally substituted acyl group (eg, -C(=O)(alkyl)). In certain embodiments, at least one R 5 Examples are optionally substituted alkyl (e.g., optionally substituted C 1-6 In certain embodiments, at least one R 5 An example is an optionally substituted C 1-6 In certain embodiments, at least one R 5 An example of is unsubstituted alkyl. In certain embodiments, at least one R 5 An example is unsubstituted C 1-6 In some embodiments, at least one R3 is an unsubstituted methyl group. In some embodiments, at least one R3 is an unsubstituted methyl group. 5 An example of is unsubstituted ethyl. In certain embodiments, at least one R5 An example of is unsubstituted propyl. In certain embodiments, at least one R 5 An example of is unsubstituted n-propyl. In certain embodiments, at least one R 5 An example of is unsubstituted isopropyl. In certain embodiments, at least one R 5 Examples of optionally substituted alkenyl (eg, optionally substituted C 2 -C 6 In certain embodiments, at least one R 5 Examples are optionally substituted alkynyl (eg, optionally substituted C 2 -C 10 In certain embodiments, at least one R 5 Examples of may be optionally substituted carbocyclyls (e.g., substituted or unsubstituted 3 to 7 membered monocyclic carbocyclyls containing zero, one or two double bonds in the carbocyclic ring system). In some embodiments, at least one R 5 Examples of may be optionally substituted heterocyclic groups (e.g., substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic rings, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen or sulfur). In some embodiments, at least one R 5 Examples of may be optionally substituted aryl (e.g., phenyl or benzyl). In some embodiments, at least one R 5 Examples of may be optionally substituted heteroaryl (e.g., 5- to 7-membered monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen, or sulfur; or optionally substituted 8- to 10-membered bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are each independently nitrogen, oxygen, or sulfur). In some embodiments, at least one R 5 An example of may be -CN. In certain embodiments, at least one R 5 An example of -OR D1 、-N(R D1a ) 2 or -SR D1 ; and R D1 As defined in the present disclosure. In some embodiments, at least one R 5 An example of -OR D1 、-N(R D1a ) 2 or -SR D1 ; where R D1is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; each R D1a are each independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group; or optionally two R D1a The examples of R and the atoms therebetween form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaromatic ring. In some embodiments, at least one R 5 An example of -OR D1 (e.g., -OH or -OMe). In some embodiments, at least one R 5 An example of -N(R D1a ) 2 (e.g., -NH 2 or -NMe 2 ). In some embodiments, at least one R 5 An example of -SR D1 (e.g. -SH or -SMe).

[0128] In formula (I), Y is part of a six-membered heterocyclic ring. In some embodiments, Y is -O- or -N(R 6 )-; where R 6 is hydrogen, an optionally substituted alkyl or a nitrogen protecting group. In some embodiments, Y is -O- or -N(R 6 )-; where R 6 is an optionally substituted alkyl. In some embodiments, Y is -O-. In some embodiments, Y is -N(R 6 )-, and R 6 is an optionally substituted alkyl. In some embodiments, Y is -N(R 6 )-, and R 6 For the selectively substituted C 1-6 In certain embodiments, Y is -N(R 6 )-, and R 6 For unsubstituted C 1-6 In some embodiments, Y is -N(unsubstituted ethyl)-. In some embodiments, Y is -N(R 6)-, where R 6 The formula is -(CH 2 ) n1 (R 6a ), R 6a is -OH or -O (optionally substituted alkyl), and n1 is 1, 2, 3, 4, 5, 6 or 7. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n1 is 7. In certain embodiments, Y is -N(R 6 )-, where R 6 The formula is -(CH 2 ) n1 (R 6a ), R 6a is -OH or -O (unsubstituted alkyl), and n1 is 1, 2, 3, 4 or 5. In certain embodiments, Y is -N(R 6 )-, and R 6 To selectively replace -OH or -O (unsubstituted C 1 - 6 Alkyl) substituted C 1 - 6 In some embodiments, Y is -N(CH 2 CH 2 OH)-.

[0129] In Formula (I), in some embodiments, x is 0, 1 or 2. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0130] In some embodiments, the compounds described herein are of formula (I):

[0131]

[0132] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or a prodrug thereof, wherein:

[0133] Each R 1 Examples of are each independently halogen, -C(=O)(alkyl), wherein alkyl is optionally substituted with halogen, unsubstituted alkenyl or unsubstituted alkynyl;

[0134] R 2 is hydrogen or unsubstituted alkyl;

[0135] Every R 3Examples of are each independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -OR D1 、-N(R D1a ) 2 or -SR D1 ;

[0136] R 4 is hydrogen or unsubstituted alkyl;

[0137] Every R 5 Examples of are each independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -OR D1 、-N(R D1a ) 2 or -SR D1 ;

[0138] R D1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted carbocyclyl;

[0139] Every R D1a are each independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or optionally two R D1a The examples of and the atoms therebetween form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaromatic ring;

[0140] Y is -O- or -N(R 6 )-;

[0141] R 6 is hydrogen, optionally substituted alkyl or a nitrogen protecting group;

[0142] p is 0, 1, 2 or 3;

[0143] m is 0, 1 or 2;

[0144] n is 0 or 1; and

[0145] x is 0, 1, or 2.

[0146] In some embodiments, the compound of formula (I) may be one of the following formulae:

[0147] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or a prodrug thereof.

[0148] In some embodiments, the compound of formula (I) may be one of the following formulae:

[0149] or a pharmaceutically acceptable salt thereof.

[0150] The present disclosure provides exemplary compounds of formula (I). In some embodiments, the compound of formula (I) may be

[0151] One of the following:

[0152]

[0153] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or a prodrug thereof. In some embodiments, the compound of formula (I) may be one of the following formulae:

[0154]

[0155]

[0156] or a pharmaceutically acceptable salt thereof.

[0157] The compounds described in the present disclosure can be prepared from readily available starting materials using methods well known in the art. It should be understood that, given typical or preferred preparation conditions (i.e., reaction temperature, time, reactant molar ratio, solvent and pressure, etc.), other preparation conditions may also be used unless otherwise specified. The optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by those skilled in the art through conventional optimization procedures. The chemicals used in the above-mentioned synthesis pathways may, for example, include solvents, reagents, catalysts, and protecting groups and deprotecting group reagents. The above method may also include the step of adding or removing suitable protecting groups to finally synthesize compounds before or after the steps specifically described in the present disclosure. In addition, various synthesis steps may be performed in alternating sequence or order to obtain the desired compound. Synthetic chemical transformations and protecting group methods (protection and deprotection) for synthesizing applicable compounds are well known in the art and include, for example, R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TWGreene and PGM Wuts, Protective Groups in Organic Synthesis, 3 rdEd., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof.

[0158] The formula (I) compound provided by the present disclosure can be prepared from easily accessible starting materials using conventional methods and procedures below. An exemplary scheme for synthesizing the disclosed compound is provided in the Examples section below. In the case of typical or preferred preparation conditions (i.e., reaction temperature, time, reactant molar ratio, solvent, pressure, etc.), other preparation conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0159] Pharmaceutical compositions and kits

[0160] The present disclosure provides a pharmaceutical composition comprising a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described in the present disclosure comprises a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition described in the present disclosure can be used to treat a target disease, for example, a disease associated with the expression of endogenous embryonic / fetal globulins (e.g., γ globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in erythrocytes). The pharmaceutical composition described in the present disclosure can be used to treat, delay and / or prevent the adverse effects of β-thalassemia and / or sickle cell anemia, induce γ globulin production and / or induce the expression of embryonic / fetal globulin genes in individuals, cells, tissues or biological samples. The pharmaceutical composition described in the present disclosure is used to treat anemia in an individual in need (e.g., wherein the individual suffers from or is suspected of suffering from β-thalassemia and / or sickle cell anemia).

[0161] In certain embodiments, the subject treated by the present disclosure is an animal. The animal can be of any gender and can be at any stage of development. In certain embodiments, the subject is a human. In certain embodiments, the subject is a mammal (e.g., a non-human mammal). In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject treated by the present disclosure is a companion animal, such as a dog or cat. In certain embodiments, the subject treated by the present disclosure is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject treated by the present disclosure is a zoo animal. In another embodiment, the subject treated by the present disclosure is a research animal, such as In some embodiments, the animal is a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic or genetically engineered animal (e.g., transgenic mouse and transgenic pig). In some embodiments, the subject has or is suspected of having β-thalassemia and / or sickle cell anemia.

[0162] In certain embodiments, the cells contacted with an effective amount of a compound or pharmaceutical composition described herein are in vitro. In certain embodiments, the contacted cells are ex vivo. In certain embodiments, the cells described herein are in vivo.

[0163] In certain embodiments, the compounds described herein are provided in an effective amount in a pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount (e.g., an amount effective to treat a target disease, such as a disease associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in erythrocytes), or treating anemia in an individual in need thereof (e.g., wherein the individual has or is suspected of having β-thalassemia and / or sickle cell anemia). In certain embodiments, the disease is associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes. In certain embodiments, the disease is anemia. In certain embodiments, the disease is β-thalassemia and / or sickle cell disease. In certain embodiments, the disease is β-thalassemia and / or sickle cell disease. anemia). In certain embodiments, the disease is treated by at least inducing globin gene expression in erythrocytes. In certain embodiments, the effective amount is a prophylactic effective amount (e.g., effective to prevent, delay, or prevent the adverse effects of a disease associated with the expression of an endogenous embryonic / fetal globin (e.g., gamma globin) in erythrocytes (e.g., anemia such as β-thalassemia and / or sickle cell anemia). In certain embodiments, the effective amount is a therapeutically effective amount (e.g., effective to treat a disease associated with the expression of an endogenous embryonic / fetal globin (e.g., gamma globin) in erythrocytes (e.g., anemia such as β-thalassemia and / or sickle cell anemia).

[0164] The pharmaceutical compositions disclosed herein can be prepared by any method known in the pharmaceutical field. Generally speaking, such preparation methods include combining the compounds disclosed herein (i.e., "active ingredients") with carriers or excipients and / or one or more other auxiliary ingredients, and if necessary and / or desired, molding and / or packaging the product into a desired single-dose unit or multiple-dose units.

[0165] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to an individual and / or a convenient fraction of such a dose, such as one-half or one-third of the dose.

[0166] The relative amounts of the active ingredient, pharmaceutically acceptable excipients and / or any additional ingredients in the pharmaceutical compositions of the present disclosure will vary depending on the identity, size and / or condition of the individual being treated, and further vary depending on the route of administration of the composition. The composition may contain between 0.1% and 100% (w / w) active ingredient.

[0167] Pharmaceutically acceptable excipients used to make the provided pharmaceutical compositions include inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and fragrances may also be present in the composition.

[0168] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof). In addition to inert diluents, oral compositions may include adjuvants (e.g., wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments of parenteral administration, the conjugates described herein are mixed with solubilizing agents (e.g., In certain embodiments, the composition of the present invention is encapsulated in a carrier, wherein the carrier can be a rigid vesicle, an elastic vesicle, a monolayer vesicle, a multilayer vesicle, a liposome, a niosome, a proniosome, a transfersome Ethosomes, L-595-PEG-8-L vacuoles, nanoemulsions, nanosomes, nanoparticles or a combination thereof.

[0169] Injections can be prepared according to known methods using appropriate dispersants or wetting agents and suspending agents, for example, aqueous or oily suspensions for sterile injections. Sterile injections can be prepared as sterile injection solutions, suspensions or emulsions using non-toxic parenterally acceptable diluents or solvents, for example, solutions of 1,3-butanediol. Acceptable carriers and solvents can be water, Ringer's solution (Ringer's solution, USP) and isotonic sodium chloride solution. In addition, sterile fixed oils can usually be used as solvents or suspension media. Accordingly, any mild fixed oil can be used, including synthetic mono- or di-glycerides. In addition, fatty acids (e.g., oleic acid) can also be used to prepare injections.

[0170] Sterile injectable preparations can be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents into sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0171] In order to prolong the duration of action of a drug, it is often desirable to slow the absorption of a drug via subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material that is poorly water soluble. In this way, the absorption rate of the drug will depend on its dissolution rate, which in turn may depend on the size and crystalline form of the crystals. Alternatively, the absorption of a parenteral dosage form can be slowed by dissolving or suspending the drug in an oily vehicle.

[0172] Compositions for rectal or vaginal administration are generally suppositories, which can be prepared by mixing the conjugate described in the present disclosure with an appropriate non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ingredient).

[0173] Solid dosage forms suitable for oral administration include capsules, tablets, pills, powders and granules. Solid dosage forms are prepared by mixing the active ingredient with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dibasic calcium phosphate and / or (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retarding agents, such as paraffin, (f) absorption promoters, such as quaternary ammonium compounds, (g) wetting agents, such as cetyl alcohol and glyceryl monostearate, (h) absorbents, such as kaolin and bentonite, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may contain buffering agents.

[0174] Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells (e.g., enteric coatings and other coatings known in the pharmaceutical art). They may optionally contain an opacifying agent and may be a composition that releases the active ingredient only or preferably in certain parts of the digestive tract (optionally in a delayed manner). Examples of coating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.

[0175] The active ingredient can be formulated in a micro-encapsulated form with one or more of the above excipients. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills and granules can be prepared with coatings and shells (e.g., enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical field). In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can contain additional substances other than inert diluents according to conventional practices, such as tablet lubricants and other tablet auxiliary substances such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may contain a buffer. It may optionally contain an emulsifier and may be a composition that releases the active ingredient only in or preferably in certain parts of the digestive tract (optionally in a delayed manner). Examples of coating agents that can be used include polymeric substances and waxes.

[0176] The dosage form of the compound of the present disclosure for topical and / or transdermal administration may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. In general, the active ingredient is mixed with a pharmaceutically acceptable carrier or excipient and / or any required preservative and / or required buffer under aseptic conditions. In addition, the present disclosure may use a transdermal patch, which generally has the additional advantage of delivering the active ingredient to an individual in a controllable manner. This dosage form may be prepared, for example, by dissolving and / or dispersing the active ingredient in an appropriate medium. Alternatively or even more, a rate-controlled membrane may be provided and / or the active ingredient may be dispersed in a polymer matrix and / or a gel to regulate the rate.

[0177] Suitable devices for delivering the intradermal pharmaceutical compositions disclosed herein include short needle devices. The intradermal composition can be administered by a device that limits the effective penetration length of the needle into the skin. Alternatively or more, a conventional syringe can be used for intradermal administration in the classic mantoux method. A rapid injection device can be used, which delivers the liquid formulation to the dermis by a liquid jet injector and / or by piercing the stratum corneum to produce a jet that reaches the dermis. A ballistic powder / particle delivery device can be used, which uses compressed gas to accelerate the compound in powder form through the outer layer of the skin to reach the dermis.

[0178] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid formulations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions (e.g., creams, ointments and / or pastes) and / or solutions and / or suspensions. Topical formulations may, for example, contain from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may also contain one or more additional ingredients described herein.

[0179] The pharmaceutical compositions disclosed herein may be formulated, packaged, and / or marketed as formulations suitable for oral administration to the lungs. Such formulations may include dry particles of the active ingredient having a diameter of between about 0.5 and about 7 nanometers, or between about 1 and about 6 nanometers. Such compositions are dry powders and are therefore easily administered using a device comprising a dry powder reservoir that directs a stream of propellant into the dry powder reservoir to disperse the powder, and / or using a self-propelling solvent / powder dispensing container, such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% (by weight) of the particles have a diameter greater than 0.5 nanometers and at least 95% (by number) of the particles have a diameter less than 7 nanometers. Alternatively, at least 95% (by weight) of the particles have a diameter greater than 1 nanometer and at least 90% (by number) of the particles have a diameter less than 6 nanometers. The dry powder composition may include a solid fine powder diluent (e.g., sugar) and be in a unit dosage form for ease of provision.

[0180] Low boiling point propellants typically include liquid propellants having a boiling point below 65°F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may also include additional ingredients, such as liquid nonionic and / or solid anionic surfactants and / or solid diluents (which may have a particle size of the same order as the particles containing the active ingredient).

[0181] The pharmaceutical composition for pulmonary administration described in the present disclosure can provide active ingredients in the form of droplets of solutions and / or suspensions. Such preparations can be prepared, packaged and / or sold including aqueous and / or dilute alcohol solutions and / or suspensions (optionally sterile) of active ingredients, and any atomization and / or atomization device can be used for easy administration. Such preparations may also include one or more additional ingredients, including, but not limited to, flavorings (e.g., saccharin sodium), volatile oils, buffers, surfactants and / or preservatives (e.g., methylhydroxybenzoate). The droplets provided by this route of administration can have an average diameter of about 0.1 to about 200 nanometers.

[0182] The formulations for pulmonary administration described in the present disclosure can be used for intranasal delivery of the pharmaceutical compositions described in the present disclosure. Another formulation suitable for intranasal administration is a coarse powder containing an active ingredient and having an average particle size of about 0.2 to 500 microns. This formulation is administered by rapid inhalation through the nasal passages from a powder container placed near the nasal cavity.

[0183] Formulations for nasal administration may, for example, contain from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may contain one or more additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold as formulations for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges prepared by known methods, and may, for example, contain 0.1 to 20% (w / w) of the active ingredient, with the remainder comprising an orally dissolvable and / or degradable composition, and optionally one or more additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension of the active ingredient. Such powdered, aerosolized and / or misted formulations may have an average particle and / or droplet size of about 0.1 to about 200 nanometers when dispersed, and may further comprise one or more additional ingredients described herein.

[0184] The pharmaceutical compositions disclosed herein can be prepared, packaged, and / or sold as preparations for intraocular administration. Such preparations can be, for example, in the form of eye drops, which contain, for example, 0.1-1.0% (w / w) of a solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may also contain buffers, salts, and / or one or more other additional ingredients described herein. Other useful ocular administration preparations include preparations containing the active ingredient in microcrystalline form and / or liposomal preparations. The scope of the present disclosure also includes ear drops and / or eye drops.

[0185] Although the description of the pharmaceutical compositions provided in the present disclosure is mainly about pharmaceutical compositions suitable for human administration, such compositions are generally also suitable for administration to various animals. It is fully understood that pharmaceutical compositions suitable for humans can be modified so that the compositions are suitable for administration to different animals, and veterinary pharmacologists with ordinary knowledge can simply experimentally design and / or perform these modifications.

[0186] The compounds provided by the present disclosure are usually formulated into dosage unit forms, so as to facilitate administration and make the dosage consistent. However, it is understood that medical staff can determine the total daily dosage of the compositions described in the present disclosure within the scope of reasonable medical judgment. The specific therapeutic effective amount for any particular individual or organism will be adjusted according to different factors, including the disease to be treated, the severity of the disease, the activity of the specific active ingredient used, the specific composition used, the age / weight / general health status / sex / and dietary habits of the individual, the administration time, the route of administration, and the discharge rate of the specific active ingredient used, the duration of treatment, the medicine combined or used in conjunction with the specific active ingredient used, and other factors known to the medical field.

[0187] The present disclosure also encompasses kits (e.g., pharmaceutical packaging). The provided kits may include pharmaceutical compositions or compounds described herein, and containers (e.g., vials, ampules, bottles, syringes and / or dispenser packaging, or other suitable containers). In some embodiments, the provided kits may optionally further include a second container, which contains a pharmaceutical excipient for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein provided in the first container and the second container may be combined to form a unit dosage form.

[0188] In certain embodiments, the kits described herein include a first container, the first container containing a compound or pharmaceutical composition described herein. In certain embodiments, the kits described herein can be used to treat diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing the expression of globulin genes in erythrocytes) and / or anemia (e.g., β-thalassemia and / or sickle cell anemia). In certain embodiments, the disease is anemia (e.g., β-thalassemia and / or sickle cell anemia) in an individual in need thereof. In some embodiments, the compounds described herein can be used to treat, delay and / or prevent the adverse effects of β-thalassemia and / or sickle cell anemia, induce gamma globulin production and / or induce the expression of embryonic / fetal globulin genes in an individual, cell, tissue or biological sample.

[0189] In certain embodiments, the kits described in the present disclosure also include instructions for use of the compounds or pharmaceutical compositions contained in the kits. The kits described in the present disclosure may also include information required by regulatory agencies (e.g., the U.S. Food and Drug Administration (FDA)). In certain embodiments, the information contained in the kit is prescribing information. In certain embodiments, these kits and instructions are provided for treating diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing the expression of globulin genes in erythrocytes), and / or anemia in individuals in need (e.g., β-thalassemia and / or sickle cell anemia), and / or treating, delaying and / or preventing the adverse effects of β-thalassemia and / or sickle cell anemia, inducing gamma globulin production and / or inducing the expression of embryonic / fetal globulin genes in individuals, cells, tissues or biological samples. The kits described in the present disclosure may include one or more additional agents described in the present disclosure as separate compositions.

[0190] Treatment

[0191] As shown in the examples below, the exemplary compounds described in the present disclosure successfully induce γ-globulin gene expression (e.g., inducing γ-globulin gene expression in hydroxyurea (HU)-resistant primary erythrocytes), reduce the expression level of the exemplary γ-globulin gene repressor BCL11A, can achieve the goal of producing γ-globulin, and help induce γ-globulin production in cells such as erythrocytes (e.g., primary erythrocytes).

[0192] Thus, the present disclosure provides methods for treating diseases associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes in an individual in need thereof (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in erythrocytes), the method comprising administering to the individual an effective amount (e.g., a therapeutically effective amount) of a compound described herein or a pharmaceutical composition thereof. The present disclosure provides methods for treating anemia in an individual in need thereof (e.g., wherein the individual has or is suspected of having β-thalassemia or sickle cell anemia).

[0193] Another embodiment of the present disclosure is a method for preventing a proliferative disease and / or an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount (eg, a prophylactically effective amount) of a compound described herein or a pharmaceutical composition thereof.

[0194] The compounds and pharmaceutical compositions disclosed herein can be used to treat, delay and / or prevent the adverse effects of β-thalassemia and / or sickle cell anemia, induce gamma globulin production and / or induce expression of embryonic / fetal globulin genes in an individual, cell, tissue or biological sample. In certain embodiments, the disease is anemia. In certain embodiments, the disease is β-thalassemia and / or sickle cell disease. In certain embodiments, the disease is β-thalassemia and / or sickle cell anemia. In certain embodiments, the disease is treated by inducing globulin gene expression in at least red blood cells.

[0195] In certain embodiments, the methods described herein further comprise administering an additional agent to an individual. In certain embodiments, the methods described herein further comprise contacting a biological sample with an additional agent. In certain embodiments, the methods described herein further comprise contacting a tissue with an additional agent. In certain embodiments, the methods described herein further comprise contacting a cell with an additional agent. In certain embodiments, the methods described herein further comprise a therapeutic agent for treating anemia (e.g., beta-thalassemia and / or sickle cell anemia).

[0196] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intracranial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, interdermal, rectal, intravaginal, intraperitoneal, topical (e.g., by powders, ointments, creams, and / or drops), by any means that facilitates the transport of the compounds or compositions described herein into or through the tissues / skin of a subject in vivo or ex vivo (e.g., iontophoresis), mucosa, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In some embodiments, the pharmaceutical composition is administered orally or parenterally. In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition is administered parenterally. Specifically, the intended route is oral administration, intravenous administration (e.g., systemic intravenous injection), transfusion, infusion, topical administration via blood and / or lymphatic supply, and / or direct administration to the affected site, such as a tumor. In general, the most suitable route of administration varies with various factors, including the characteristics of the medicament (e.g., its stability in the gastrointestinal tract) and / or the condition of the individual (e.g., whether the individual can accept oral administration). In certain embodiments, the compounds or pharmaceutical compositions described in the present disclosure are suitable for topical administration to the eye of an individual.

[0197] The exact amount of the compound that can achieve an effective amount will vary from individual to individual, depending on, for example, the species, age and general condition of the individual, the severity of the side effects or symptoms, the characteristics of the specific compound and the mode of administration. The effective amount can be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to an individual or applied to a biological sample, tissue or cell, any two of the multiple doses may contain different or substantially the same doses of the compound described in the present disclosure. In certain embodiments, when multiple doses are administered to an individual or applied to a biological sample, tissue or cell, the frequency of multiple doses administered to an individual or multiple doses administered to a tissue or cell can be 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every 1 day, 1 dose every 3 days, 1 dose per week, 1 dose every 2 weeks, 1 dose every 3 weeks, or 1 dose every 4 weeks. In certain embodiments, the frequency of multiple doses administered to an individual or multiple doses administered to a tissue or cell is 1 dose per day. In certain embodiments, the frequency of multiple doses administered to an individual or multiple doses administered to a tissue or cell is 2 doses per day. In certain embodiments, the frequency of multiple doses administered to an individual or multiple doses administered to a tissue or cell is 3 doses per day. In certain embodiments, when multiple doses are administered to an individual or administered to a biological sample, tissue or cell, the duration between the first dose of multiple doses and the last dose is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years or the survival of an individual, biological sample, tissue or cell. In certain embodiments, the duration between the first dose of multiple doses and the last dose is 3 months, 6 months or 1 year. In certain embodiments, the duration between the first dose of multiple doses and the last dose is the survival of an individual, biological sample, tissue or cell. In certain embodiments, a dose (e.g., a single dose or any of multiple doses) described in the present disclosure may include between 0.1 micrograms (μg) and 1 microgram, between 0.001 milligrams (mg) and 0.01 milligrams, between 0.01 milligrams and 0.1 milligrams, between 0.1 milligrams and 1 milligram, between 1 milligram and 3 milligrams, between 3 milligrams and 10 milligrams, between 10 milligrams and 30 milligrams, between 30 milligrams and 100 milligrams, between 100 milligrams and 300 milligrams, between 300 milligrams and 1,000 milligrams, or between 1 gram and 10 grams (including each value itself). In certain embodiments, a dose described in the present disclosure may include between 1 milligram and 3 milligrams (including each value itself) of the compound described in the present disclosure. In certain embodiments, a dose described in the present disclosure may include between 3 milligrams and 10 milligrams (including each value itself) of the compound described in the present disclosure. In certain embodiments, a dose described herein may contain between 10 mg and 30 mg (inclusive) of a compound described herein.In certain embodiments, a dose described herein may contain between 30 mg and 100 mg (inclusive) of a compound described herein.

[0198] The dosage ranges described in the present disclosure relate to guidance for the administration of pharmaceutical compositions provided for adults. For example, a medical practitioner or a person skilled in the art may determine that the dosage to be administered to a child or adolescent may be lower, higher, or the same as the dosage to be administered to an adult.

[0199] The compounds or compositions as described herein can be administered in combination with one or more additional agents (e.g., therapeutic and / or prophylactic agents) for treating a disease associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in erythrocytes) in an individual in need thereof, and / or treating, delaying, and / or preventing adverse effects of a disease associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing globulin gene expression in erythrocytes) and / or anemia (e.g., β-thalassemia and / or sickle cell anemia) in an individual in need thereof. The compounds or compositions can be administered in combination with additional agents that improve their activity (e.g., activity of potency and / or efficacy) in treating a disease associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes of a subject in need thereof (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing expression of globulin genes in erythrocytes), and / or treating, delaying and / or preventing adverse effects of a disease associated with expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in erythrocytes (e.g., treating β-thalassemia and / or sickle cell anemia by at least inducing expression of globulin genes in erythrocytes) and / or anemia (e.g., β-thalassemia and / or sickle cell anemia) in a subject in need thereof, improving bioavailability, improving safety, reducing drug resistance, reducing and / or altering metabolism, inhibiting excretion, and / or altering distribution in a subject, biological sample, tissue, or cell. It should also be understood that the therapy used can achieve the desired effect for the same condition, for different conditions, and / or achieve different effects. In certain embodiments, the pharmaceutical composition described in the present disclosure comprising the compounds described in the present disclosure is administered to a patient in need, thereby advantageously treating one or more diseases. In certain embodiments, the one or more diseases are diseases associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in red blood cells (e.g., β-thalassemia and / or sickle cell anemia), anemia (e.g., β-thalassemia and / or sickle cell anemia), or a combination thereof. In a preferred embodiment, the one or more diseases are β-thalassemia, anemia, or a combination thereof.

[0200] The compound or composition can be administered simultaneously, before or after one or more additional agents, which can be used, for example, as a combination therapy for treating, delaying and / or preventing the adverse effects of the disease. Wherein the disease is a disease associated with the expression of endogenous embryonic / fetal globulins (e.g., gamma globulins) in red blood cells (e.g., β-thalassemia and / or sickle cell anemia). In certain embodiments, the compound or composition described in the present disclosure can be administered to a patient in need, wherein the patient's anemia (e.g., β-thalassemia and / or sickle cell anemia) is resistant to at least one agent. In certain embodiments, the disease is anemia (e.g., β-thalassemia and / or sickle cell anemia), and the anemia (e.g., β-thalassemia and / or sickle cell anemia) is resistant to one or more anemia therapeutic agents, including, but not limited to, hydroxyurea (HU). The agent includes a therapeutic active agent. The agent also includes a preventive active agent. Pharmaceutical agents include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or animal use as defined in the U.S. Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional agent is an agent for treating a disease associated with the expression of an endogenous embryonic / fetal globulin (e.g., gamma globulin) in red blood cells and / or anemia (e.g., beta-thalassemia and / or sickle cell anemia). In certain embodiments, the additional agent is an agent for preventing a disease associated with the expression of an endogenous embryonic / fetal globulin (e.g., gamma globulin) in red blood cells. In certain embodiments, the additional agent is an agent for treating anemia (e.g., β-thalassemia and / or sickle cell anemia). In certain embodiments, the additional agent is an agent approved by a regulatory agency (e.g., the U.S. FDA) for the treatment and / or prevention of diseases and / or anemia (e.g., β-thalassemia and / or sickle cell anemia) associated with the expression of endogenous embryonic / fetal globulins (e.g., γ globulins) in red blood cells. In certain embodiments, the additional agent is an agent approved by a regulatory agency (e.g., the U.S. FDA) for the treatment and / or prevention of anemia (e.g., β-thalassemia and / or sickle cell anemia). Each additional agent can be administered according to a dose and / or schedule determined for the agent. The additional agents can also be administered separately in a single dose or different doses together with each other and / or with the compounds or compositions described in the present disclosure. The specific combination used in the course of treatment will take into account the compatibility of the compounds described in the present disclosure with the additional agent and / or the desired therapeutic and / or preventive efficacy to be achieved.Generally, it is expected that the dosage of the additional agent used in combination therapy will not exceed the dosage when it is used alone. In some embodiments, the dosage used in combination is lower than the dosage when used alone.

[0201] In certain embodiments, the additional agent is an anti-angiogenesis agent, an anti-inflammatory agent, an immunosuppressant, an antibacterial agent, an antiviral agent, a cardiovascular agent, a cholesterol-lowering agent, an antidiabetic agent, an antiallergic agent, an analgesic agent, or a combination thereof. In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with an anemia therapy.

[0202] Analytical methods

[0203] Exemplary synthetic schemes for preparing the compounds described in the present disclosure are described above. (See Nam TG et al., Identification and Characterization of Small-Molecule Inducers of Fetal Hemoglobin. Chem Med Chem. 2011; 6(5): 777-780; and Imbach P et al., PCT File: WO / 2000 / 049018A1, 2000; Publication No.: EP1153024B1, 2004; US6767906B2, 2004). In one embodiment, the present disclosure provides a method for preparing a compound of formula (I).

[0204] Example

[0205] The present disclosure will be more fully understood through the following examples. The synthetic and biological examples described in this disclosure are provided to illustrate the compounds, pharmaceutical compositions and methods provided by the disclosure and are not intended to limit the scope in any way.

[0206] Example 1: Preparation of Exemplary Compounds

[0207] In the present study, six asymmetric heterocyclic compounds that effectively induced the expression of gamma-globulin in primary human erythrocytes were investigated. These compounds share a common pharmacophore, which is described as a yellow dye. 19,20 . Given its high efficiency and specificity in inducing γ-globulin chains, compound II has the potential to be developed into a new generation of therapy for SCD and β-thalassemia. However, the solubility of asymmetric heterocyclic compound II is poor and it can only be dissolved in DMSO. In addition, pharmacokinetic data showed that the oral bioavailability of compound II was only 2.34% ( Figure 1A-1B ). Considering the disadvantages of compound II in further drug development, compound TN1, which induces HbF, was used to induce HbF. 21The pharmacophore of AS-28 was used as a reference for designing a new compound (AS-28). Pharmacokinetic studies showed that TNI was not orally bioavailable in rats. Unexpectedly, it was found that the exemplary compound AS-28 was an orally active compound with an oral bioavailability of about 25% in rats ( Figure 1A-1B ). In this study, the HbF-inducing efficacy and therapeutic potential of AS-28 were established by using primary human erythrocyte cultures and SCD mouse models. The possible biological mechanism of AS-28-mediated reactivation of γ-globin gene expression was also revealed.

[0208] Materials and methods

[0209] Synthetic compounds

[0210] Figure 6 The 2-amino-6-anilino-purine compound described in the invention can be prepared according to the above method. 21，25 The analytical data of the compounds are shown below.

[0211] 3-p-Tolyl-propynoic acid {3-[9-ethyl-2-(4-ethylpiperazin-1-yl)-9H-purin-6-ylamino]phenyl}amide hydrochloride (AS-28). 1 H NMR (300MHz, DMSO-d6): δ10.92(s, 1H), 10.77(s, 1H), 10.39(s, 1H), 8.83(s, 1H), 8.56 (s, 1H), 7.56 (d, J = 8.1Hz, 2H), 7.44 (d, J = 8.1Hz, 1H), 7.35-7.30 (m, 3H), 7.1 6(d, J=8.4Hz, 1H), 4.82-4.77(m, 2H), 4.21(q, J=7.2Hz, 2H), 3.56-3.38(m, 4H), 3 .19-2.98 (m, 4H), 2.37 (s, 3H), 1.46 (t, J=7.4Hz, 3H), 1.27 (t, J=7.2Hz, 3H); MS (ES + )m / z C 29 H 32 N 8 O theoretical value: 508.27; experimental value: 509.4 (M+H + ).

[0212] 3-p-Tolyl-propynoic acid (3-{9-ethyl-2-[4-(2-hydroxyethyl)-piperazin-1-yl]-9H-purin-6-ylamino}phenyl)amide HCl salt (AS-061; AS-61). 1 HNMR (400MHz, DMSO-d6): δ11.02(s, 1H), 10.77(bs, 2H), 9.28(s, 1H), 8.59(s, 1H), 7.56 (d, J=8.0Hz, 2H), 7.43 (d, J=8.8Hz, 1H), 7.36-7.29 (m, 3H), 7.20 (d, J =8.0Hz, 1H), 4.79-4.75 (m, 2H), 4.24 (q, J = 7.2Hz, 2H), 3.82 (t, J = 5.0Hz, 2H), 3 .63-3.48 (m, 4H), 3.24-3.15 (m, 4H), 2.36 (s, 3H), 1.47 (t, J=7.2Hz, 3H); MS (ES + )m / z C 29 H 32 N 8 O 2 Theoretical value: 524.26; Found value: 525.2 (M+H+).

[0213] 3-p-Tolyl-propynoic acid {3-[9-ethyl-2-(2-morpholin-4-yl-ethoxy)-9H-purin-6-ylamino]phennyl}amide (AS-29). 1 H NMR (300 MHz, DMSO-d 6): 10.87 (s, 1H), 9.97 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.59 (d, J=7.5Hz, 2H), 7. 63 (d, J=7.8Hz, 2H), 7.32 (d, J=6.6Hz, 1H), 4.47 (t, J=6.0, 5.9Hz, 2H), 4.18 (q, J= 14.4, 7.2Hz, 2H), 3.60 (t, J=4.4, 4.2Hz, 4H), 3.39 (s, 4H), 2.72 (t, J=5.9, 5.7Hz, 2H), 2.54 (d, J=6.6Hz, 2H), 2.42 (s, 3H), 1.46 (t, J=7.4, 7.2Hz, 3H); MS (ES+) m / zC 29 H 31 N 7 O 3 Theoretical value: 525.25; Found value: 526.3 (M+H+).

[0214] Example 2: Bioassays of Exemplary Compounds

[0215] Cultivation of primary erythroid cells

[0216] Peripheral blood samples were purchased from Taipei Blood Center. The concentrated blood was diluted 1:5 (volume percentage concentration (V / V)) in phosphate-buffered saline (PBS) and distributed in a thin layer on Ficoll-paquePLUS (d=1.007 g / ml) (GE Healthcare) in a SepMate column (STEMCELL). After centrifugation at 1200g for 10 minutes, the cells in the interphase region were collected. The collected cells were washed with PBS and centrifuged three times at low speed. The remaining mononuclear cells were incubated in phase I medium containing 1X SFEM (STEMCELL), 100ng / ml SCF, 20ng / ml IL-3, 20ng / ml IL-6 and 100ng / ml Flt3-L at 37°C, 5% CO 2 The expanded monocytes were further differentiated for 7 days in a phase II medium containing 1X SFEM (StemSpan), 20 ng / ml SCF, 5 ng / ml IL-3, and 1 U / ml EPO. Differentiated erythrocytes were treated with different doses of the indicated compounds at 5x10 5 The cells were seeded at a density of 50 cells / ml and treated for 3 days.

[0217] Quantitative RT-PCR

[0218] After 3 days of compound treatment, total RNA was extracted by Quick-RNA Miniprep Kit (Zymo) and reverse transcribed using Maxima H Minus Reverse Transcriptase (ThermoFisher Scientific) according to the manufacturer's instructions. Quantitative PCR was performed on a LightCycler system with SYBR green master mix according to the manufacturer's instructions (Roche). Relative quantitative RT-PCR data were normalized to the Cq number of β-actin and compared with the mock control group.

[0219] Cell viability analysis

[0220] Cell viability was assessed using AlamarBlue reagent (Invitrogen). After the third day of treatment, 100 μl of treated cell culture was transferred to a 96-well plate, 1 / 10 volume of AlamarBlue reagent was added, and the cell culture was cultured overnight at 37° C. Cell viability was assessed using a multi-label counter (Ex 530-560 nanometers, Em 590 nanometers) (PerkinElmer).

[0221] Western blotting analysis

[0222] After the third day of treatment, the cells were lysed by modified RIPA (50 mM Tris-HCl pH 7.8, 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, 1 mM EGTA, 5 mM EDTA, 10 mM NaF, 1 mM NaV 3 O 4 Total proteins were extracted with 1x complete EDTA-free protease inhibitor cocktail. 30 μg of protein extracts were separated by 10% SDS-PAGE, and the resulting gel was blotted onto a PVDF membrane. After blotting on TBST containing 5% skim milk, the membrane was incubated with primary antibodies against BCL11A or β-actin overnight at 4°C. After incubation with horseradish peroxidase-conjugated secondary antibodies and washing of the blots, the signals of the indicated proteins were visualized by ECL (PerkinElmer) according to the manufacturer's protocol.

[0223] Mouse

[0224] Sickle cell anemia mice (B6; 129-Hbatm1(HBA)Tow 、Hbb tm2(HBG1，HBB*)Tow / J) was purchased from Jackson Laboratory and bred at AS Core, Academia Sinica. Mice aged 6-8 weeks were used for the experiment. The treatment group received vehicle [20% (2-hydroxypropyl)-β-cyclodextrin] plus AS-28 (50 mg / kg, 75 mg / kg, or 100 mg / kg) by oral gavage twice a day, 5 days a week, for 4 weeks.

[0225] Complete red blood cell count analysis

[0226] Blood was collected by submandibular bleeding and analyzed using the ProCyte Dx automated analyzer.

[0227] Quantification of F-cells

[0228] 10 μl of whole blood was washed twice with PBS and then fixed with 0.05% glutaraldehyde for 10 minutes. After fixation, cells were washed twice with PBS and then permeabilized by adding cold 0.1% Triton X-100 for 5 minutes. Cells were washed twice with 0.1% BSA / PBS and stained with PE-HbF antibody (BD) for 40 minutes at room temperature (protected from light). Finally, cells were washed 3 times with 0.1% BSA / PBS and passed through a 0.3 μM cell strainer (Falcon). F-cell % was analyzed by flow cytometry (LSRII-18P, BD).

[0229] Hemoglobin high-performance liquid chromatography (HPLC)

[0230] Dissolve 50 μl of whole blood in 200 μl of ddHO 2 O and centrifuged at 13,000 rpm for 5 minutes to extract the hemolysate. HPLC was performed according to the previously described procedure. 22 conduct.

[0231] Blood smear

[0232] For hypoxia treatment, whole blood was placed in a hypoxic incubator (3% O 2 ) for 30 minutes. 2 μl of whole blood (with or without hypoxia) was used to prepare blood smears on slides. Before quantifying the percentage of sickle cells, the slides were air-dried and stained with Liu-stain.

[0233] Exemplary efficacy of exemplary compound AS-28 in red blood cells

[0234] AS-28 can induce γ-globulin expression in primary human erythrocyte cultures

[0235] Compound AS-28 was designed based on the pharmacophore of HbF-inducing compound TN1 ( Figure 1A-1B The efficacy of AS-28 treatment to induce γ-globin genes was evaluated using a primary human erythroid culture system. After two weeks of in vitro erythroid differentiation, cells were treated with AS-28 for three days and then used for quantitative RT-PCR analysis and cell viability assays. Treatment with AS-28 significantly increased the fold change of γ-globin mRNA expression in primary human erythroid cultures in a dose-dependent manner, with working concentrations ranging from 0.06 μM to 0.5 μM ( Figure 2 and Fig. 9 , black bars). AS-28 treatment at higher concentrations (1 μM and 2 μM) resulted in cytotoxicity, thereby reducing γ-globulin induction. Importantly, primary human erythrocytes treated with 0.5 μM AS-28 activated γ-globulin mRNA expression 3.5-fold without causing significant cytotoxicity.

[0236] AS-28 activates gamma-globin expression in hydroxyurea-resistant primary human erythrocytes

[0237] Since there are currently limited treatment options for SCD patients who do not respond well or do not respond to HU, we next examined the HbF-inducing capacity of AS-28 in primary human erythrocytes that do not respond to HU treatment. Figure 3 and Fig.10 As shown, AS-28 treatment (0.5 μM) increased γ-globin mRNA expression in HU-resistant cells by at least 2-fold with only mild cytotoxicity. This result demonstrates the advantage of using AS-28 to develop a new generation of therapeutic drugs that can be used for a wide range of hemepathic patients, whether they are HU-responsive or HU-resistant.

[0238] BCL11A protein level is downregulated by AS-28 treatment

[0239] BCL11A has been reported as a key negative regulator of γ-globin gene expression 23. The reduction of BCL11A significantly increased the expression of γ-globulin genes. To investigate whether HbF inducers activate γ-globulin gene expression by regulating the amount of BCL11A protein, primary human erythrocytes were treated with known HbF inducers (HU, NaB, and AS-28 (0.5 μM and 1 μM)) and compound II, SS-2394, compound 3, and compound 8, and the resulting cells were then used for Western blotting ( Figure 4 ; Fig.11 After the cells were treated with these HbF inducers (HU, NaB and AS-28) and two of Compound II, SS-2394, Compound 3, Compound 8 and AS-28, the expression of BCL11A protein was significantly reduced, reducing the amount of BCL11A protein by 50% ( Figure 4 ) and reduced the amount of BCL11A protein by 60% ( Fig.11 ). This result suggests that AS-28 activates γ-globulin gene expression at least in part by downregulating the expression of BCL11A, a negative regulator of γ-globulin. There was no detectable change in the amount of BCL11A in HU-treated red blood cells, suggesting that HU may activate γ-globulin gene expression through another mechanism.

[0240] Oral administration of AS-28 significantly alleviated the signs of anemia in SCD mice.

[0241] To further evaluate the therapeutic potential of AS-28 in treating hemoglobin diseases, SCD mice (an animal model of SCD disease generated by Professor Tim Townes' laboratory at the University of Alabama) were used to examine whether AS-28 treatment could alleviate anemia in SCD mice. Different doses of AS-28 were administered to 6-8 week old SCD mice over 4 weeks. After 4 weeks of oral gavage, blood samples from treated SCD mice were collected for a variety of biochemical analyses ( Figure 5 ). Complete blood cell evaluation showed that AS-28 treatment slightly increased the number of red blood cells (RBC) and the amount of hemoglobin (HGB) in peripheral blood samples of SCD mice compared to mock-treated control mice. Reticulocyte (RET), white blood cell (WBC), and neutrophil (NEUT) values ​​were equal between AS-28-treated and mock-treated SCD mice. HPLC analysis showed that AS-28 significantly increased the percentage of HbF in SCD mice, which is consistent with the finding of increased percentage of F-cells in these mice detected by flow cytometry. The diagnostic indicator of SCD is the characteristic sickle morphology of red blood cells under hypoxic conditions. Existing studies have shown that overexpression of gamma-globulin can reduce the percentage of sickled red blood cells in the peripheral blood of SCD patients. 24The percentage of sickle cells in blood smears of SCD mice under hypoxic conditions was evaluated, and it was found that this parameter was significantly reduced after AS-28 treatment, indicating that AS-28 treatment may reduce the risk of vaso-occlusive crisis in SCD mice. In summary, the in vivo experiments in SCD mice showed that AS-28 has the potential to be developed into a new drug for the treatment of SCD and β-thalassemia.

[0242] Analysis of AS-28 and cytotoxicity

[0243] To examine whether AS-28 causes cytotoxicity, the gene expression profiles of cultured primary human erythrocytes were compared by RNA-seq analysis. Several candidate genes known to encode gamma globin gene regulators were selected from the gene list of RNA-seq data (fold change > 1.4) for validation by RT-qPCR ( Figure 7 ). The results showed that AS-28 induced the expression of γ-globin activators GATA1 (1.5-fold) and NFE2L2 (1.5-fold). In addition, AS-28 inhibited the expression of γ-globin inhibitory factor c-MYB (0.5-fold). Figure 7 The data suggest that AS-28 activates γ-globulin gene expression in part by modulating the expression of transcriptional regulators of these three γ-globulin genes.

[0244] To show the overall efficacy of AS-28 on primary human erythrocytes, differentially expressed genes (DEGs) were selected from RNA-seq data (fold change ≥ 1.4 and p < 0.05) for Ingenuity Pathways Analysis (IPA). Figure 8 As shown, the top five canonical pathways affected by AS-28-treated primary human erythrocytes do not include cytotoxicity-related pathways, such as cell cycle arrest, DNA repair, DNA damage, etc.

[0245] Derivatives of AS-28

[0246] The invention described in this disclosure is based on the unexpected discovery that certain 2-amino-6-anilinopurine compounds are effective in inducing gamma-globulin expression. Figure 6 Exemplary representative compounds from the present disclosure are listed, each compound having been assigned a unique compound number.

[0247] Combined with a variety of pharmacophores to design a new exemplary compound AS-28. AS-28 exhibits improved water solubility and bioavailability. In vitro experiments confirmed that AS-28 can effectively induce γ-globulin expression at non-toxic concentrations in primary red blood cells. It was also found that AS-28 can induce γ-globulin expression in HU-resistant cells. These findings support that AS-28 can be a good candidate for the development of new therapeutic compounds. The molecular mechanism of AS-28 inducing γ-globulin expression was identified. According to Western blot, AS-28 reduced the expression of BCL11A, a key inhibitor of γ-globulin. In order to test the γ-globulin induction efficacy of AS-28 in vivo, SCD mice were used as an animal model, and AS-28 was designed as an orally administered compound for drug development purposes. AS-28 was administered to SCD mice by oral gastric tube gavage for 4 weeks. The results showed that AS-28 improved multiple blood parameters in SCD mice. Therefore, AS-28 is an exemplary compound as a candidate for the treatment of SCD and β-thalassemia.

[0248] References

[0249] 1. Weatherall DJ. Phenotype[mdash]genotype relationships in monogenicdisease: lessons from the thalassaemias. Nat Rev Genet. 2001; 2(4): 245-255.

[0250] 2. Modell B. Global epidemiology of haemoglobin disorders and derived service indicators. Bulletin of the World Health Organization. 2008; 2008(6): 480-487.

[0251] 3. Patrinos GP, Grosveld FG. Pharmacogenomics and therapeutics of hemoglobinopathies. Hemoglobin. 2008; 32(1-2): 229-236.

[0252] 4. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood. 2008; 112(10): 3927-3938.

[0253] 5.Platt OS,Brambilla DJ,Rosse WF,et a1.Mortality in sickle celldisease.Life expectancy and risk factors for early death.N Engl J Med.1994;330(23):1639-1644。

[0254] 6.Scott MD,van den Berg JJ,Repka T,et al.Effect of excess alpha-hemoglobin chains on cellular and membrane oxidation in model beta-thalassemic erythrocytes.J Clin Invest.1993;91(4):1706-1712。

[0255] 7.Aljurf M,Ma L,Angelucci E,et al.Abnormal assembly of membraneproteins in erythroid progenitors of patients with beta-thalassemiamajor.B1ood.1996;87(5):2049-2056。

[0256] 8.Natta CL,Niazi GA,Ford S,Bank A.Balanced g1obin chain synthesis inhereditary persistence offetal hemoglobin.J Clin Invest.1974;54(2):433-438。

[0257] 9.Noguchi CT,Rodgers GP,Serjeant G,Schechter AN.Levels of fetalhemoglobin necessary for treatment of sickle cell disease.N Engl J Med.1988;318(2):96-99。

[0258] 10.Ley TJ,Nienhuis AW.Induction of hemoglobin F synthesis in patientswith beta thalassemia.Annu Rev Med.1985;36:485-498。

[0259] 11.Humphries RK,Dover G,Young NS,et al.5-Azacytidine acts directly onboth erythroid precursors and progenitors to increase production of fetalhemoglobin.J Clin Invest.1985;75(2):547-557。

[0260] 12.Olivieri NF,Weatherall DJ.The therapeutic reactivation of fetalhaemoglobin.Hum Mol Genet.1998;7(10):1655-1658。

[0261] 13.McCaffrey PG,Newsome DA,Fibach E,Yoshida M,Su MS.Induction ofgamma-globin by histone deacetylase inhibitors.Blood.1997;90(5):2075-2083。

[0262] 14.Witt O,Monkemeyer S,Ronndahl G,et al.Induction of fetal hemoglobinexpression by the histone deacetylase inhibitor apicidin.Blood.2003;101(5):2001-2007。

[0263] 15.Constantoulakis P,Knitter G,Stamatoyannopoulos G.On the inductionof fetal hemoglobin by butyrates:in viVo and in vitro studies with sodiumbutyrate and comparison of combination treatments with 5-AzaC andAraC.Blood.1989;74(6):1963-1971。

[0264] 16.Grigg A.Effect of hydroXyurea on sperm count,motility andmorphology in adult men with sickle cell or myeloproliferative disease.InternMedJ.2007;37(3):190-192。

[0265] 17.Kinney TR,Helms RW,O′Branski EE,et al.Safety of hydroxyurea inchildren with sickle cell anemia:results of the HUG-KIDS study,a phase I / IItrial.Pediatric Hydroxyurea Group.Blood.1999;94(5):1550-1554。

[0266] 18.Steinberg MH,Lu ZH,Barton FB,Terrin ML,Charache S,Dover GJ.Fetalhemoglobin in sickle cell anemia:determinants of response tohydroxyurea.Multicenter Study of Hydroxyurea.Blood.1997;89(3):1078-1088。

[0267] 19.Rule HG,Thompson SB.Acenaphthenone and acenaphthenequtnone.Journalofthe Chemical Society.1937:1761-1763。

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[0269] 21.Nam T-g,Lee J,Walker JR,Brinker A,Cho CY,Schultz PG.Identificationand Characterization of Small-Molecule Inducers of FetalHemoglobin.ChemMedChem.2011;6(5):777-780。

[0270] 22.Fibach E,Prus E.Differentiation of Human Erythroid Cells inCulture.Current Protocols in Immunology.2005;69(1):22F.27.21-22F.27.10。

[0271] 23.Basak A,Sankaran VG.Regulation of the fetal hemoglobin silencingfactor BCL11A.Annals of the New York Academy of Sciences.2016;1368(1):25-30。

[0272] 24.Akinsheye I,Alsultan A,Solovieff N,et al.Fetal hemoglobin insickle cell anemia.Blood.2011;118:19-27。

[0273] 25.ImbachP, Capraro HG, Zimmermann J, Caravatti G, FuretP, Brill W, (Novartis-Erfindungen; Vienna, Austria), PCT document: WO / 2000 / 049018A1, 2000; Published patents: EP1153024B1, 2004; US6767906B2, 2004.

[0274] Equivalent terms and scope

[0275] Unless otherwise specified or obvious from the context, in the claims, articles such as "a," "an," and "the" may mean one or more. When the term "or" is included between one or more elements of a group described in the claims and specification of this application, unless otherwise specified or obvious from the context, it is deemed that one, more than one, or all of the elements of the group are included in, used in, or related to a given product or process. The present disclosure includes embodiments in which specific elements of the group are included in, used in, or related to a given product or process. The present disclosure includes embodiments in which more than one group element or all group elements are included in, used in, or related to a given product or process.

[0276] In addition, the present disclosure encompasses all variations, combinations and permutations, wherein one or more limitations, elements, words (clauses) and descriptive words from one or more claims can be cited in another claim. For example, any claim attached to another claim can be modified to include one or more restrictions described in any other claim attached to the same reference basis. When elements are listed in a Markush group format, for example, each group of elements is also included, and any element can be removed from the group. It should be understood that, in general, when the present disclosure or examples of the present disclosure refer to the inclusion of specific elements and / or features, certain embodiments or examples of the present disclosure are composed of these elements and / or features, or are substantially composed of these elements and / or features. For the sake of brevity, the present disclosure will no longer specifically describe these embodiments. It should also be noted that the terms "include" and "contain" are open and allow the inclusion of additional elements or steps. In the case of a given range, the range is inclusive of its endpoint values. In addition, unless otherwise indicated or apparent from the context and understanding of one skilled in the art, numerical values ​​expressed as ranges in various embodiments of the present disclosure may be any specific value or sub-range within the range, to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0277] The present disclosure includes various granted patents, published patents, journal articles and other public documents, which are hereby incorporated in their entirety for reference. If there is a conflict between any incorporated reference and this specification, the disclosure of the specification shall prevail. In addition, if any specific embodiment of the present disclosure falls within the disclosure scope of the prior art, such content may be explicitly excluded by any one or more claims. Since these embodiments are considered to be well known to those skilled in the art, these contents may be excluded even if the present disclosure does not explicitly exclude them. Regardless of whether they are related to the prior art, any claim of the present disclosure may exclude any specific embodiment of the present disclosure for any reason.

[0278] Those skilled in the art will understand or ascertain many equivalents to the specific embodiments described in the present disclosure without undue experimentation. The scope of the embodiments described in the present disclosure is not intended to be limited to the specific embodiments described above, but is as set forth in the appended claims. It should be understood by those skilled in the art that various changes and modifications may be made to the description without departing from the spirit or scope of the present disclosure as defined in the claims.

Claims

1. A compound, wherein the compound is of the formula: (AS-28), or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for treating a disease in a subject in need thereof. The pharmaceutical composition according to claim 3 , wherein the disease is anemia.

5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 4, in the preparation of a medicament for treating anemia.

6. The use according to claim 5, wherein the anemia is β-thalassemia.

7. The use according to claim 5, wherein the anemia is sickle cell anemia.

8. The use according to any one of claims 5 to 7, wherein the pharmaceutical composition is administered orally.

9. The use according to any one of claims 5 to 7, wherein the pharmaceutical composition is administered parenterally.

10. The use according to any one of claims 5 to 7, wherein the pharmaceutical composition is administered in combination with an additional therapeutic agent.

11. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 4, in the preparation of a drug for inducing the production of gamma globulin.

12. The use according to claim 11, wherein the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 4 is used in combination with an additional therapeutic agent.

13. A kit comprising: The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 4; as well as Instructions for administering to an individual or contacting a biological sample with the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 4.

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