Substituted condensed imidazole derivatives and methods for treating sickle cell disease and related complications - Patents.com

Abstract

The present invention provides methods for treating sickle cell disease and related complications using compounds of formula (I) and pharmaceutical compositions thereof, alone or in combination with other active agents.

Description

[Technical field]

[0001] The present invention provides methods of treating sickle cell disease and associated complications using compounds of formula (I) and pharmaceutical compositions thereof, either alone or in combination with other active agents. The present invention also provides compounds and pharmaceutical compositions. [Background technology]

[0002] Sickle cell disease (SCD) is a life-threatening monogenic disorder. SCD is a severe hemoglobinopathy resulting in multiorgan complications due to the expression of abnormal sickle cell hemoglobin (HbS). The most common type of SCD is sickle cell anemia (SCA) (also called HbSS or SS disease or hemoglobin S), in which the patient is homozygous for the mutation that causes HbS. Rare types of SCD in which the patient is heterozygous for the mutation (one copy of the mutation that causes HbS and one copy for another abnormal hemoglobin allele) include sickle cell hemoglobin C (HbSC), sickle cell beta hemoglobin C (HbSC), and sickle cell beta hemoglobin C (HbSC). + Thalassemia (HbS / β + ) and sickle cell disease β0 thalassemia (HbS / β 0 ) are included.

[0003] Sickle cell disease (SCD) results from a point mutation that causes a red blood cell deformity or sickle shape. Sickle cell is associated with the clinical manifestations of SCD, such as anemia, recurrent painful vaso-occlusive attacks, infections, acute chest syndrome, pulmonary hypertension, stroke, priapism, osteonecrosis, renal failure, leg ulcers, retinopathy, and heart disease.

[0004] SCD results from a single point mutation (GAG>GTG) in codon 6 of the HBB globin gene. Deoxygenated venous circulation triggers a process of self-assembly (polymerization) that produces sickle cell hemoglobin molecules (HbS) and damages the red blood cell membrane and cytoskeleton. HbS repeatedly enters into cycles of sickling and unsickling that cause progressively increasing damage to the red blood cell membrane (ischemia-reperfusion (IR) injury) resulting in sickle cells. As a result, these rigid blood cells are unable to deform when passing through small capillaries, leading to vascular occlusion and ischemia. The actual anemia of the disease is caused by hemolysis, which is the destruction of red blood cells caused by deformation of the red blood cells.

[0005] C-reactive protein (CRP) and markers of oxidative stress are significantly increased after IR injury. The subsequent oxidative stress contributes to hemolysis, inactivation of nitric oxide (NO), and adhesive properties of red blood cells, white blood cells, and platelets.

[0006] Sickle red blood cells, together with endothelial cells, activated leukocytes, platelets and plasma proteins, are involved in a multi-step vaso-occlusive process. Heme oxygenase-1 (HO-1) and interleukin-10 (IL-10) are characteristically found to be elevated in SCD patients in an attempt to combat induced inflammation. HO-1 degrades heme released during hemolysis, thereby limiting oxidative stress and inflammation, whereas IL-10 limits the production of pro-inflammatory cytokines.

[0007] Sickle red blood cells stimulate leukocyte recruitment: following an inflammatory stimulus, leukocytes are recruited to the activated endothelium of the venous circulation where they form adhesive interactions with the activated endothelium and sickle red blood cells, leading to reduced blood flow and ultimately vascular occlusion.

[0008] SCD platelets express selectin P (SELP), activated α IIb β 3(GP) and higher concentrations of platelet activation markers show increased surface expression. In healthy individuals, platelet adhesion is inhibited by the antithrombotic factor NO, whereas SCD platelet adhesion is stimulated by activated endothelium. It has been demonstrated that platelets and sickle cells aggregate via the formation of thrombospondin bridges, thereby contributing to vascular occlusion.

[0009] Hydroxyurea (HU) is an approved treatment to modify the disease process of SCD. HU counters the pathophysiology of SCD by increasing the production of fetal hemoglobin (HbF)-containing red blood cells and indirectly altering gene expression and proteins associated with SCD pathophysiology. The increased concentration of HbF-containing red blood cells may dilute the concentration of sickle cells, which in turn may cause reduced hemolysis, increased NO bioavailability, and reduced endothelial activation. However, HU has been demonstrated to reduce the white blood cell count in patients under therapy. Although HU has improved clinical symptoms by reducing pain and vaso-occlusive emergencies, acute chest syndrome, transfusion requirements, and hospitalizations, SCD patients treated with HU have demonstrated side effects such as induction of DNA damage, reduced sperm count, and production of iron nitrosyl Hb.

[0010] Thus, there is a need in the art for new, improved, and / or complimentary therapies for SCD. Summary of the Invention

[0011] PCT Publication No. WO 2011 / 103018 ("WO '018") describes substituted fused imidazole derivatives that upregulate expression of HMOX1 in vitro. PCT Publication No. WO 2012 / 094580 ("WO '580") describes a variety of compounds that modulate cellular oxidative stress, including fused imidazole derivatives having similar or the same structure as the compounds disclosed in WO '018.

[0012] The present invention relates to methods and compositions related to the treatment of one or more blood disorders. In certain embodiments, the blood disorder is SCD, but in specific embodiments, one or more other blood disorders can be treated using the present invention. For example, bleeding disorders (including, for example, coagulation disorders, hypercoagulability, hemophilia, or von Willebrand's disease), platelet disorders (for example, essential or primary thrombocythemia or thrombocytopenia), and / or hemophilia or anemia. In certain embodiments of the present invention, there are methods and compositions for the treatment and / or prevention of sickle cell disease (sometimes referred to as sickle cell anemia (or anemia (SCA)) or sickle cell disease).

[0013] Mammalian and / or non-human mammals or cell lines can be used as sickle cell models. Individuals treated with the methods and / or compositions of the invention may, in specific cases, be experiencing a vaso-occlusive crisis, acute chest crisis, painful chest syndrome, which may or may not require hospitalization. In specific embodiments, the individual may be experiencing or may be experiencing negative side effects of a drug, such as a drug that directly or indirectly results in increased coagulation and / or increased inflammation, in a specific embodiment, the drug is HU.

[0014] In certain embodiments of the present invention, the compound of the present invention is administered alone.In other embodiments, the compound of the present invention is administered together with one or more other drugs (some of which may or may not induce HbF production) for the treatment of SCD.For example, the compound of the present invention can be administered in combination with HU for the treatment of SCD.In another example, the compound of the present invention can be administered in combination with Nrf2 activator, such as fumarate (MMF or DMF) and bardoxolone methyl. The individual to be treated may be known to have SCD, or may be a patient suffering from SCD.

[0015] In an embodiment of the invention, the individual is diagnosed with sickle cell disease prior to receiving the treatment of the invention. The present invention also relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof, as well as pharmaceutical compositions comprising compounds of formula (I) and their pharma- ceutical acceptable salts, and methods for their preparation. [Brief description of the drawings]

[0016] [Figure 1A] 1 shows the relative cell growth and cell viability of KU812 cells in the presence of various concentrations (0, 0.5, 2.5, 5, 10, and 20 μM) of compound 73, compound 134, compound 473, and compound 236, respectively. [Figure 1B] 1 shows the relative cell growth and cell viability of KU812 cells in the presence of various concentrations (0, 0.5, 2.5, 5, 10, and 20 μM) of compound 73, compound 134, compound 473, and compound 236, respectively. [Figure 1C] 1 shows the relative cell growth and cell viability of KU812 cells in the presence of various concentrations (0, 0.5, 2.5, 5, 10, and 20 μM) of compound 73, compound 134, compound 473, and compound 236, respectively. [Figure 1D] Figure 1 shows the relative cell growth and cell viability of KU812 cells in the presence of various concentrations (0, 0.5, 2.5, 5, 10, and 20 μM) of Compound 73, Compound 134, Compound 473, and Compound 236, respectively. Data are presented as mean ± standard deviation (n=3). *, p<0.05 [Figure 1E] Western blots showing the induction levels of HbF after treatment of KU812 cells with various concentrations (0, 0.5, 2.5, 5, 10, and 20 μM) of Compound 73, Compound 134, Compound 473, and Compound 236. Hydroxyurea (HU) and hemin were used as positive controls for HbF induction, and β-actin was used as a protein loading control. [Diagram 2] FIG. 1 shows HbF protein expression levels of KU812 cells obtained by FAC and analyzed as the average concentration of HbF per cell measured by mean fluorescence intensity (MFI). [Figure 3A]Western blots showing the induction levels of HbF and HbS upon treatment of sickle cell progenitor cells with compound 473 (0.5 and 2.5 μM) for 48 hours. Hydroxyurea (HU) and hemin were used as positive controls for HbF induction, and β-actin was used as a protein loading control. [Figure 3B] Sickle cell progenitor cells were treated with compound 473 (0.5 and 2.5 μM) for 48 hours and the percentage of HbF positive cells (F cells) analyzed by flow cytometry is shown. Hydroxyurea (HU) and hemin were used as positive controls for HbF induction. [Figure 4A] Contains images of sickle cell progenitor cells after 10 days of culture and treatment with compound 473 at concentrations of 0.5 μM and 2.5 μM for 48 hours, or with hemin (about 50 μM) or with hydroxyurea (HU) (about 100 μM), and then subjecting the cells to hypoxic conditions (1% O2 and 5% CO2). [Figure 4B] The percentage of sickle cells is shown when sickle cell progenitor cells were cultured for 10 days and treated with compound 473 at concentrations of 0.5 μM and 2.5 μM for 48 hours, or with hemin (about 50 μM) or with hydroxyurea (HU) (about 100 μM), and then subjected to hypoxic conditions (1% O2 and 5% CO2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] I. Definition The following definitions are intended to clarify the terms defined. If a particular term used in this specification is not specifically defined, the term should not be considered indefinite. Rather, such undefined terms should be interpreted according to their plain and ordinary meaning to those of ordinary skill in the art(s) to which the invention is directed.

[0018] As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon having 1 to 10 carbon atoms, optionally substituted as further described herein with a permitted degree of substitution of 2 or more. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, n-hexyl, and 2-ethylhexyl. The number of carbon atoms in an alkyl group is defined herein as "C" which refers to an alkyl group containing carbon atoms from x through y, inclusive. x~y Thus, C 1~6 Alkyl represents an alkyl chain having 1 to 6 carbon atoms, for example, including but not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, and n-hexyl.

[0019] As used herein, the term "alkylene" refers to a straight or branched chain divalent saturated hydrocarbon residue having from 1 to 10 carbon atoms, optionally substituted as further described herein with a permitted degree of substitution of 2 or more. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.

[0020] The number of carbon atoms in an alkylene group is defined herein as "C x~y Similar terminology applies to other terms and ranges as well. Thus, C 1~4Alkylene represents an alkylene chain having 1 to 4 carbon atoms, for example, including, but not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene. As used herein, the term "cycloalkyl" refers to a saturated 3- to 10-membered cyclic hydrocarbon ring, optionally substituted with a permissible degree of substitution of 2 or more, as further described herein. Such "cycloalkyl" groups may be monocyclic, bicyclic, or tricyclic. Examples of "cycloalkyl" groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0021] The number of carbon atoms in a cycloalkyl group is defined herein as "C" which refers to a cycloalkyl group containing x through y carbon atoms, inclusive. x~y Similar terminology applies to other terms and ranges as well. Thus, C 3~10 Cycloalkyl refers to a cycloalkyl group having 3 to 10 carbons, as defined above, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0022] As used herein, the term "heterocycle" or "heterocyclyl" refers to an optionally substituted monocyclic or polycyclic saturated ring system containing one or more heteroatoms. Such "heterocycle" or "heterocyclyl" groups may be substituted with a degree of substitution of 2 or more permitted as further described herein. As used herein, the term "heterocycle" or "heterocyclyl" does not include ring systems containing one or more aromatic rings. Examples of heteroatoms include N-oxides, sulfur oxides, and sulfur dioxides, which include nitrogen, oxygen, or sulfur atoms. Typically, the ring has 3 to 12 members. Such rings may be fused to one or more of another heterocyclic ring(s) or cycloalkyl ring(s). As used herein, examples of "heterocyclic" groups include, but are not limited to, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene, where addition can occur at any point on the ring as long as the addition is chemically feasible. Thus, for example, "morpholine" refers to morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl.

[0023] As used herein, when "heterocycle" or "heterocyclyl" is recited as a possible substituent, the "heterocycle" or "heterocyclyl" group may be attached via either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible. For example, "heterocyclyl" would include pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. When a "heterocycle" or "heterocyclyl" group contains a nitrogen atom in the ring, attachment via the nitrogen atom may alternatively be indicated by using the suffix "-ino" with the ring name. For example, pyrrolidino refers to pyrrolidin-1-yl.

[0024] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein, the term "oxo" refers to a >C=O substituent. When an oxo substituent appears on an otherwise saturated group, such as in an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group.

[0025] As used herein, the term "heteroaryl" refers to an optionally substituted 5-14 membered monocyclic or polycyclic ring system containing at least one aromatic ring and also containing one or more heteroatoms. Such "heteroaryl" groups may be optionally substituted, with a permissible degree of substitution of 2 or more, as further described herein. In polycyclic "heteroaryl" groups containing at least one aromatic ring and at least one non-aromatic ring, the aromatic ring(s) need not contain heteroatoms. Thus, for example, "heteroaryl" as used herein would include indolyl. Furthermore, the point of attachment may be to any ring within the ring system, regardless of whether the ring containing the attachment point is aromatic or contains a heteroatom. Thus, for example, "heteroaryl" as used herein would include indolin-1-yl, indolin-3-yl, and indolin-5-yl. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides, where feasible. Examples of "heteroaryl" groups as used herein include, but are not limited to, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, pteridinyl, and phenazinyl, where the addition can occur at any point on the ring, provided that the addition is chemically feasible. Thus, for example, "thiazolyl" refers to thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl.

[0026] As used herein, when "heteroaryl" is recited as a possible substituent, the "heteroaryl" group can be attached via either a carbon atom or any heteroatom, to the extent attachment at that point is chemically feasible. As used herein, the term "heterocyclylene" refers to an optionally substituted divalent heterocyclyl group (as defined above). The points of attachment can be to the same ring atom or to different ring atoms, so long as the attachment is chemically feasible. The two points of attachment can each independently be to either a carbon atom or a heteroatom, so long as the attachment is chemically feasible. Examples include, but are not limited to,

[0027] [ka] where the * symbol indicates the attachment point.

[0028] As used herein, the term "heteroarylene" refers to a divalent heteroaryl group (as defined above) that may be optionally substituted. The points of attachment may be to the same ring atom or to different ring atoms, so long as the attachment is chemically feasible. The two points of attachment may each independently be to either a carbon atom or a heteroatom, so long as the attachment is chemically feasible. Examples include, but are not limited to, [ka] are listed, and the * marks indicate the addition points.

[0029] Various other chemical terms or abbreviations have their standard meaning to those of ordinary skill in the art. For example: "hydroxyl" refers to -OH; "methoxy" refers to -OCH 3 "Cyano" refers to -CN; "Amino" refers to -NH 2 "Methylamino" refers to -NHCH 3"Sulfonyl" refers to -SO 2 "Carbonyl" refers to -C(O)-; "Carboxy" or "carboxyl" refers to -CO 2 H, etc. Additionally, when a name refers to more than one moiety (e.g., "methylaminocarbonyl-methyl"), the earlier recited moiety is further from the point of attachment than any later recited moiety. Thus, a term such as "methylaminocarbonylmethyl" refers to -CH 2 -C(O)-NH-CH 3 Refers to...

[0030] As used herein, the term "substituted" refers to the replacement of one or more hydrogens of the specified moiety with the enumerated substituent or substituents, with degrees of substitution of 2 or more being permissible, unless otherwise stated, provided that the substitution results in a stable or chemically feasible compound. A stable or chemically feasible compound is one whose chemical structure does not change substantially for at least one week when stored at a temperature of about -80°C to about +40°C in the absence of moisture or other chemically reactive conditions, or a compound that maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a subject. As used herein, the phrase "substituted with one or more ..." or "substituted one or more times with ..." refers to a number of substituents equal to 1 to the maximum number of substituents possible based on the number of available binding sites, provided that the stability and chemical feasibility conditions above are met.

[0031] As used herein, the various functional groups represented may be optionally separated by a hyphen or dash (-) or an * symbol ( * ) is understood to have an attachment point at the functional group having the -CH 2 CH 2 CH 3 In this case, the addition point is the leftmost CH 2 When a group is referred to without an * or dash, the point of attachment is indicated by the plain and ordinary meaning of the referred group.

[0032] Any variable residue may be present in any one component (e.g., R d ) or occurs more than one time in multiple constituents, the definition of the variable residue at each occurrence is independent of its definition at every other occurrence. As used herein, multi-atom divalent species are to be read from left to right. For example, if a specification or claim recites ADE where D is defined as -OC(O)-, the resulting group replacing D is A-OC(O)-E, not AC(O)OE.

[0033] As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur.

[0034] As used herein, "administer" or "administering" means to introduce, such as to introduce a compound or composition into a subject. The term is not limited to any particular form of delivery and can include, for example, intravenous delivery, transdermal delivery, oral delivery, nasal delivery, and rectal delivery. Furthermore, depending on the mode of delivery, administering can be performed by a variety of individuals, including, for example, a medical professional (e.g., doctor, nurse, etc.), a pharmacist, or the subject (i.e., self-administration).

[0035] As used herein, "treat" or "treating" or "treatment" can refer to one or more of slowing the progression of a disease or condition, controlling a disease or condition, slowing the onset of a disease or condition, ameliorating one or more symptoms that characterize a disease or condition, or slowing the recurrence of a disease or condition or its characteristic symptoms, depending on the nature of the disease or condition and the characteristic symptoms of the disease or condition. "Treat" or "treating" or "treatment" can also refer to inhibiting a disease either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both, and inhibiting at least one physical parameter that may or may not be discernible to a subject. In certain aspects, "treat" or "treating" or "treatment" refers to slowing the onset of a disease or at least one symptom thereof in a subject that may be exposed to or susceptible to a disease, even if the subject has not yet experienced or exhibited symptoms of the disease.

[0036] As used herein, "subject" can refer to any mammal, such as, but not limited to, a human. In one embodiment, the subject is a human. In another embodiment, the host is a human exhibiting one or more symptoms that characterize a disease or condition. The term "subject" does not require the subject to have any special status with respect to any hospital, clinic, or research facility (e.g., as an admitted patient, a study participant, etc.). In one embodiment, the subject can be "a subject in need of."

[0037] "Therapeutically effective amount" refers to an amount of a compound that, when administered to a subject for treating a disease or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease or its symptoms. A "therapeutically effective amount" may vary, for example, depending on the compound, the disease and / or symptoms of the disease, the severity of the disease and / or symptoms of the disease or disorder, the age, weight and / or health of the subject being treated, and the judgment of the attending physician. The appropriate amount in any given case may be ascertained by one of ordinary skill in the art or may be determined by routine experimentation.

[0038] As used herein, the term "compound" includes the free acid, free base, and any salts thereof of the compound of formula (I). Thus, phrases such as "a compound of embodiment 1" or "a compound of claim 1" refer to any free acid, free base, and any salts thereof encompassed by embodiment 1 or claim 1, respectively.

[0039] II. Treatment Method A. Treatment of SCD and Related Disorders with Compounds of the Invention In one embodiment, the present invention provides a method of increasing the expression of HbF in a cell by contacting a particular cell, such as a red blood cell or a retinal pigment epithelium (RPE) cell, with a therapeutically effective amount of a compound of the present invention. In another embodiment, the present invention provides a method of increasing the expression of HbF in a cell by administering a compound of the present invention to a subject in need thereof. In an embodiment, the expression of HbF is increased such that HbF is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, or 90% or more of the total hemoglobin in the subject or in a sample taken from the subject. In embodiments, expression of HbF is increased such that HbF is increased by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20% as a percentage of total hemoglobin in the subject or in a sample taken from the subject relative to a baseline sample taken prior to treatment of the subject. In another embodiment, where the subject is a human under the age of 19, expression of HbF is increased such that HbF is greater than or equal to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, or 90% of the total hemoglobin in the subject or in a sample taken from the subject. This method can be used to compensate for a mutation in the human β-globin gene in a cell having one or more mutations in the β-globin gene or its expression control sequences, e.g., a mutation that results in expression of the HbS form of hemoglobin. Compensating for the mutation includes, but is not limited to, increasing the amount of HbF and decreasing the amount of HbS in the subject compared to an untreated subject or before treatment of the subject. In another embodiment, the treatment method results in an increase in the ratio of HbF to HbS expressed in cells of a subject in need thereof.The methods can be used to treat sickle cell disease, eg, sickle cell anemia, and other hemoglobinopathies or thalassemias, as well as complications related to SCD, eg, retinopathy.

[0040] In another aspect, the present invention provides a method of inhibiting polymerization of HbS, increasing dissolved oxygen levels in the blood of a subject, reducing levels of reactive oxygen species (ROS), or any combination thereof, by administering to a subject in need thereof a compound of the present invention.

[0041] In another aspect, the invention provides a method of reducing sickling in response to reduced air pressure, reduced air pressure, reduced oxygen tension, or hypoxia, reducing the incidence or rate of painful crises, reducing the incidence or rate of painful crises requiring hospitalization, reducing the incidence of chest syndromes, reducing the number of transfusion events, reducing the number of units transfused per event, or any combination thereof, by administering a compound of the invention to a subject in need thereof. The reduction in incidence or rate can occur over a period of a week, a month, or a year.

[0042] In another aspect, the invention provides a method of treatment comprising administering to a subject a compound (or salt) according to any one of aspects 1 to 250. In another aspect, the invention provides a method of treatment comprising administering to a subject 0.1 milligrams to 2 grams of a compound (or salt) according to any one of aspects 1 to 250.

[0043] In each of the methods or uses described above, the compound (or salt) of any one of embodiments 1-250 may be administered to a subject as part of a pharmaceutical formulation, as described herein. In each of the methods described herein, the method may further include determining whether the subject has one or more genetic alterations associated with SCD, or initially determining whether the subject has a biochemical or morphological alteration associated with SCD.

[0044] In each of the methods described herein, the method may further include a step of determining whether administration of a compound of the invention has an increased expression of HbF, a decreased biomarker associated with SCD (such ROS), or a reduced symptom associated with SCD. The method may further include a step of administering a higher dose of a compound of the invention to the subject if the expression of HbF is not increased, the biomarker associated with SCD (such ROS) is not decreased, or the symptom associated with SCD is not reduced. B. Treatment in combination with HU or Nrf2 activators The methods of treating SCD or complications thereof described herein may also include administering a compound of the invention in combination or alternation with HU or an Nrf2 activator, which combination may be administered in an amount effective to induce or increase expression of HbF.

[0045] C. The disease being treated The compounds and combinations of the invention described herein can be used to treat subjects with one or more mutations in the beta globin gene (HBB gene). Mutations in the beta globin gene can cause sickle cell disease, beta thalassemia, or related diseases or conditions. As discussed in more detail below, mutations in the beta globin gene can be identified before or after the onset of clinical symptoms of the disease. The compositions can be administered to subjects with one or more mutations in the beta globin gene before or after the onset of clinical symptoms. Thus, in some embodiments, the compositions are administered to subjects who have been diagnosed with one or more mutations in the beta globin gene but have not yet exhibited clinical symptoms. In some embodiments, the compositions are administered to subjects who exhibit one or more symptoms of a disease, condition, or syndrome associated with or caused by one or more mutations in the beta globin gene.

[0046] 1. Sickle cell disease Sickle cell disease (SCD) typically results from a mutation that causes a substitution of thymine for adenine at the sixth codon of the hemoglobin beta chain gene (i.e., GAG to GTG in the HBB gene). This mutation causes a substitution of glutamic acid to valine at position 6 of the Hb beta chain. The resulting Hb, called HbS, has the physical property of forming a polymer under deoxygenated conditions. SCD is typically an autosomal recessive disorder. Thus, in some embodiments, the disclosed compositions and methods are used to treat subjects who are homozygous for an autosomal recessive mutation in the hemoglobin beta chain gene (i.e., homozygous for sickle cell hemoglobin (HbS)). Also referred to as HbSS disease or sickle cell anemia (the most common form), subjects who are homozygous for S globin typically exhibit a severe or moderately severe phenotype and have the shortest survival time for hemoglobinopathies.

[0047] Sickle cell trait or its carrier state is a heterozygous form characterized by the presence of about 40% HbS, the absence of anemia, the inability to concentrate urine (isostenuria), and hematuria. Under conditions that lead to hypoxia, sickle cell trait or its carrier state can be a pathological risk factor. Thus, in some embodiments, the disclosed compositions and methods are used to treat subjects heterozygous for autosomal recessive mutations in the hemoglobin beta chain gene (i.e., heterozygous for HbS).

[0048] 2. Beta-thalassemia Beta thalassemia (β thalassemia) is a group of inherited blood disorders caused by various mutational mechanisms that result in reduced or absent synthesis of β globin, leading to ineffective hematopoiesis, accelerated destruction of red blood cells, and accumulation of aggregates of unpaired insoluble α chains that cause severe anemia. Subjects affected by beta thalassemia exhibit variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The genetic mutations present in β thalassemia are diverse and can be caused by several different mutations. Mutations can include substitutions or deletions or insertions of single bases within, near, or upstream of the β globin gene. For example, mutations occur in the promoter region preceding the beta globin gene or cause the production of abnormal splice variants. Examples of thalassemia include thalassemia minor, thalassemia intermedia, and thalassemia major.

[0049] 3. Sickle cell-related disorders Sickle cell trait carriers do not suffer from SCD, but individuals with one copy of HbS and one copy of the gene encoding another abnormal variant of hemoglobin, such as HbC or Hb beta thalassemia, suffer from less severe disease.Subjects who are double heterozygous for HbS and HbC (HbSC disease) typically feature symptoms of moderate clinical severity.Another common structural variant of beta globin is hemoglobin E or hemoglobin E (HbE).Subjects who are double heterozygous for HbS and HbE suffer from HbS / HbE syndrome, which usually causes a phenotype similar to HbS / b+ thalassemia, which is discussed below. Some mutations in the beta globin gene may cause other structural variations in hemoglobin or may cause a deficiency in the amount of beta globin produced. These types of mutations are called beta thalassemia mutations. Absence of beta globin is called beta zero (beta-0) thalassemia. Subjects who are double heterozygous for HbS and beta-0 thalassemia (i.e., HbS / beta-0 thalassemia) may suffer from symptoms that are clinically indistinguishable from sickle cell anemia. A reduction in the amount of beta globin is called beta plus (beta+) thalassemia. Subjects who are double heterozygous for HbS and beta+ thalassemia (i.e., HbS / beta+ thalassemia) may have mild to moderate severity of clinical symptoms, with variability among different ethnicities. Rare combinations of HbS with other abnormal hemoglobins include HbD Los Angeles, G-Philadelphia, HbO Arab, etc.

[0050] Thus, in some embodiments, the disclosed compositions and methods are used to treat subjects with an HbS / β-0 genotype, an HbS / β+ genotype, an HBSC genotype, an HbS / HbE genotype, an HbD Los Angeles genotype, a G-Philadelphia genotype, or an abHbO Arab genotype. As discussed above, retinopathy due to SCD can also be treated by administering an effective amount of a compound of the invention, optionally in combination or alternation with HU or an Nrf2 activator, in an amount effective to induce expression of HbF in retinal cells, for example, in RPE cells. Administration of a compound of the invention, optionally in combination with HU or an Nrf2 activator, can reduce or inhibit the formation of occlusions in the peripheral retina of sickle cell patients.

[0051] 4. Non-red blood cell related disorders Although red blood cells are the primary producers of hemoglobin, multiple reports have shown that other non-hematopoietic cells, including but not limited to macrophages, retinal pigment cells, and alveolar epithelial cells such as alveolar type II (ATII) cells and Clara cells, also synthesize hemoglobin. In some embodiments, the compositions disclosed herein are used to increase HbF expression in non-erythroid cells, including but not limited to macrophages, retinal pigment cells, and alveolar type II (ATII) cells and Clara cells. In some embodiments, the compositions disclosed herein are used to increase HbF expression in non-erythroid cells at interfaces where oxygen-carbon dioxide diffusion occurs, including but not limited to the eye and lung. In some embodiments, the compositions are used to induce, increase, or enhance hemoglobin synthesis in retinal pigment cells in an amount effective to prevent, reduce, or alleviate one or more symptoms of age-related macular degeneration or diabetic retinopathy.

[0052] D. Symptoms of SCD, Beta Thalassemia, and Related Disorders In some embodiments, the compositions disclosed herein are administered to a subject in an amount effective to treat one or more symptoms of sickle cell disease, beta thalassemia, or a related disorder. Beta thalassemia can include symptoms such as anemia, fatigue and weakness, pale or jaundiced skin, a protruding abdomen with an enlarged spleen and liver, dark urine, abnormalities of the facial bones, poor growth, and loss of appetite.

[0053] In subjects suffering from sickle cell disease or related disorders, physiological changes in RBCs can result in disease manifestations including: (1) hemolytic anemia; (2) vaso-occlusive crisis; and (3) multi-organ damage due to microinfarctions, including the heart, skeleton, spleen, and central nervous system.

[0054] III. Compositions for Use in Treating SCD and Related Disorders A. Compounds of the Invention (Compounds of Formula (I)) The compound of formula (I) has the structure shown below: [ka] wherein X 1 is =N- or =CH-, X 2 is =C(R 1 )- and X 3 is =C(-LG)-, or X 2 is =C(-LG)- and X 3 is =C(R 1 )-and G is hydrogen, -C 1~8 Alkyl, -C 3~10 Cycloalkyl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkylene-C 3~10 Heterocyclyl, phenyl, heteroaryl, or NR h R k wherein the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are R c or G is -CH 2 Y 3 , -CH 2 CH 2 Y 3 , -CH 2 CH 2 CH 2 Y 3 , -CH(CH 3 )CH 2 Y 3 , -CH 2 CH(Y 3 )CH 3 , -CH(Y 3 )CH 3 , -CH 2 C(Y 3 )(CH 3 ) 2 , -C(Y 3 )(CH 3 ) 2 or [ka] {In the formula, Y 3 is cyclopropyl, -CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CH 3 , -F, -Cl, -OH, -O(CH 2 ) 2 -OH, -O(CH 2 ) 2 -F, -SCH 3 , -S(O) 2 -CH 3 , -SCH 2 CH 3 , -S(O) 2 CH 2 CH 3 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, -NH-C(O)-CH 3 , -NH-C(O)-CH 2 CH 3 , tetrahydrofuran-2-yl-methyloxy, or -C(O)-Y 4 where Y 4 -OH, -OCH 3 , -OCH 2 CH 3 , -OC(CH 3 ) 3 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl; L is -CH 2 -C(O)N(R 6 )-, -C(O)N(R 6 )-, -C(O)-O-, -SO 2 -, -C(O)-, R x or R x is a heterocyclylene optionally substituted one or more times with more independently selected substituents; or the group -LG is -cyano; R 1 is hydrogen, R a , phenyl, or heteroaryl, where the phenyl and heteroaryl groups are R x optionally substituted one or more times with more independently selected substituents; R 2 is R b and; R 3 is hydrogen, -C 1~6 Alkyl or -C 1~6 Alkylene-C 3~10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are R z optionally substituted one or more times with more independently selected substituents; R 4 -C 1~6 Alkyl or -C 1~6 Alkylene-C 3~10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are R y optionally substituted one or more times with more independently selected substituents; R 6 is hydrogen, -C 1~6 Alkyl, -C 1~6 Alkylene-C 3~10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are R x optionally substituted one or more times with more independently selected substituents; R a teeth, a)-Halogen, b)-C 1~6 Alkyl, c)-C 3~10 Cycloalkyl, d)-heterocyclyl, e)-Cyano, f)-CF 3 , g)-OCF 3 , h)-OR d , i)-S(O) w -R d , j)-S(O) 2 OR d , k)-NR d R e , l)-C(O)-R d , m)-C(O)-OR d , n)-OC(O)-R d , o)-C(O)NR d R e , p) -C(O)-heterocyclyl, q)-NR d C(O)R e , r)-OC(O)NR d R e , s)-NR d C(O)OR d or t)-NR d C(O)NR d R e where the alkyl, cycloalkyl, and heterocyclyl groups are R y optionally substituted one or more times with more independently selected substituents; R b teeth, a)-Halogen, b)-C 1~6 Alkyl, c)-C 3~10 Cycloalkyl, d)-heterocyclyl, e)-phenyl, f)-heteroaryl, g)-Cyano, h)-CF 3 , i)-OCF 3 , j)-OR f , k)-S(O) w -R f , l)-S(O) 2 OR f , m)-NR f R g , n)-C(O)-R f , o)-C(O)-OR f , p)-OC(O)-R f , q) -C(O)NR f R g , r) -C(O)-heterocyclyl, s)-NR f C(O)R g , t)-OC(O)NR f R g , u)-NR f C(O)OR f or v)-NR f C(O)NR f R g wherein the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are R z optionally substituted one or more times with more independently selected substituents; R c teeth, a)-Halogen, b)-C 1~6 Alkyl, c)-C 3~10 Cycloalkyl, d)-heterocyclyl, e)-Cyano, f)-CF 3 , g)-OCF 3 , h)-OR h , i)-S(O) w -R h , j)-S(O) 2 OR h , k)-NR h R k , l)-C(O)-R h , m)-C(O)-OR h , n)-OC(O)-R h , o)-C(O)NR h R k , p) -C(O)-heterocyclyl, q)-NR h C(O)R k , r)-OC(O)NR h R k , s)-NR h C(O)OR k , t)-NR h C(O)NR h R k , u)-NR h S(O) w R k , v) -phenyl, w) -heteroaryl, or x)-O-(C 1~4 alkylene)-O-(C 1~4 alkylene)-N(R h )C(O)-OR k wherein the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are R x optionally substituted one or more times with more independently selected substituents; R d and R e are independently hydrogen, C 1~6 Alkyl or C 3~10cycloalkyl, where the alkyl and cycloalkyl groups are R y or R d and R e and R may be joined together with the nitrogen atom to form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is selected from the group consisting of R y optionally substituted one or more times with more independently selected substituents; R f and R g are independently hydrogen, C 1~6 Alkyl, C 3~10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are each independently selected from R z or R f and R g and R may be joined together with the nitrogen atom to form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is selected from the group consisting of R z optionally substituted one or more times with more independently selected substituents; R h and R k are independently hydrogen, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are each independently selected from R x or R h and R kand R may be joined together with the nitrogen atom to form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is selected from the group consisting of R x optionally substituted one or more times with more independently selected substituents; R y teeth, a)-Halogen, b) -NH 2 , c)-Cyano, d)-Carboxy, e)-hydroxy, f)-thiols, g)-CF 3 , h)-OCF 3 , i) -C(O)-NH 2 , j)-S(O) 2 -NH 2 , k) oxo, l) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -C 1~6 Alkyl, m) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -heterocyclyl, optionally substituted one or more times with substituents independently selected from the group consisting of n) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl)2 -C 3~10 Cycloalkyl, o) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -OC 1~6 Alkyl, p) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -OC 3~10 Cycloalkyl, q) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -NH-C 1~6 Alkyl, r) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -N(C 1~6 Alkyl) 2 , s) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -C(O)-C 1~6 Alkyl, t) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -C(O)-OC, optionally substituted one or more times with substituents independently selected from the group consisting of 1~6 Alkyl, u) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -SC 1~6 Alkyl, v) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -S(O) 2 -C 1~6 Alkyl, w) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -C(O)-NH-C 1~6 Alkyl, x) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -C(O)-N(C 1~6 Alkyl) 2 , y) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -S(O) 2 -NH-C 1~6 Alkyl, z) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -S(O) 2 -N(C 1~6 Alkyl) 2 , aa) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -NH-C(O)-C 1~6 Alkyl, or bb) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -NH-S(O) 2 -C 1~6 is alkyl; R x teeth, a)-R y b) Halogen, -OH, -OC 1~6 Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -phenyl, optionally substituted one or more times with substituents independently selected from the group consisting of: c) Halogens, -OH, -OC 1~6Alkyl, -NH 2 , -NH-C 1~6 Alkyl, and -N(C 1~6 Alkyl) 2 -heteroaryl, optionally substituted one or more times with substituents independently selected from the group consisting of: d) -O-phenyl, e) -O-heteroaryl, f) -C(O)-phenyl, g) —C(O)-heteroaryl, h) —C(O)—O-phenyl, or i) -C(O)-O-heteroaryl; R z teeth, a)-R y ; b) -phenyl, c)-heteroaryl; d) -O-phenyl, e) -O-heteroaryl, f) -C(O)-phenyl, g) —C(O)-heteroaryl, h) —C(O)—O-phenyl, or i) -C(O)-O-heteroaryl; v is an integer from 0 to 4, and and w is an integer of 0 to 2.

[0055] Aspect 2: G is hydrogen, -C 1~8 Alkyl, -C 3~10 Cycloalkyl, -C 1~6 Alkylene-C 3~10 cycloalkyl, heterocyclyl, phenyl, heteroaryl, or NR h R k wherein the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are R c or G is -CH 2 Y 3 , -CH 2 CH 2 Y 3 , -CH 2CH 2 CH 2 Y 3 , -CH(CH 3 )CH 2 Y 3 , -CH 2 CH(Y 3 )CH 3 , -CH(Y 3 )CH 3 , -CH 2 C(Y 3 )(CH 3 ) 2 , -C(Y 3 )(CH 3 ) 2 or [ka] {In the formula, Y 3 is -cyclopropyl, -CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CH 3 , -F, -Cl, -OH, -O(CH 2 ) 2 -OH, -O(CH 2 ) 2 -F, -SCH 3 , -S(O) 2 -CH 3 , -SCH 2 CH 3 , -S(O) 2 CH 2 CH 3 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, -NH-C(O)-CH 3 , -NH-C(O)-CH 2 CH 3 , tetrahydrofuran-2-yl-methyloxy, or -C(O)-Y4 where Y 4 -OH, -OCH 3 , -OCH 2 CH 3 , -OC(CH 3 ) 3 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl; R c teeth, a)-Halogen, b)-C 1~6 Alkyl, c)-C 3~10 Cycloalkyl, d)-heterocyclyl, e)-Cyano, f)-CF 3 , g)-OCF 3 , h)-OR h , i)-S(O) w -R h , j)-S(O) 2 OR h , k)-NR h R k , l)-C(O)-R h , m)-C(O)-OR h , n)-OC(O)-R h , o)-C(O)NR h R k , p) -C(O)-heterocyclyl, q)-NR h C(O)R k , r)-OC(O)NR h R k , s)-NR h C(O)OR k , t)-NR h C(O)NR h R k , u)-phenyl, v)-heteroaryl, or w)-O-(C 1~4 alkylene)-O-(C 1~4 alkylene)-N(R h )C(O)-OR k wherein the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are R x optionally substituted one or more times with more independently selected substituents; R h and R k are independently hydrogen, C 1~6 Alkyl, C 3~10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are each independently selected from R x or R h and R k and R may be joined together with the nitrogen atom to form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is selected from the group consisting of R x and R y teeth, a)-Halogen, b) -NH 2 , c)-Cyano, d)-Carboxy, e) -C, which may be substituted one or more times with halogen; 1~6Alkyl, f) -heterocyclyl, optionally substituted one or more times with halogen; g) -C, which may be substituted one or more times with halogen; 3~10 Cycloalkyl, h) -OC, which may be substituted one or more times with halogen; 1~6 Alkyl, i) -OC, which may be substituted one or more times with halogen; 3~10 Cycloalkyl, j)-Hydroxy, k)-thiol, l)-CF 3 , m)-OCF 3 , n) -C(O)-C, optionally substituted one or more times with halogen 1~6 Alkyl, o) -C(O)-OC, optionally substituted one or more times with halogen. 1~6 Alkyl, p) optionally substituted one or more times with halogen, -SC 1~6 Alkyl, or q) -S(O) optionally substituted one or more times with halogen 2 -C 1~6 The compound according to embodiment 1, wherein the aryl group is alkyl.

[0056] Aspect 3: R 3 The compound according to embodiment 2, wherein is hydrogen. Aspect 4: R 3 The compound according to embodiment 2, wherein is methyl. Aspect 5: X 1 A compound according to any one of embodiments 2 to 4, wherein is =N-. Aspect 6: X 1 The compound according to any one of embodiments 2 to 4, wherein is =CH-. Embodiment 7: A compound according to any one of embodiments 2 to 6, wherein v is an integer from 0 to 2. Embodiment 8: A compound according to any one of embodiments 2 to 6, wherein v is 0 or 1. Embodiment 9: A compound according to any one of embodiments 2 to 6, wherein v is 1. Aspect 10: v is 1 and R 2 A compound according to any one of embodiments 2 to 6, wherein is attached to either the 5- or 6-position of the benzothiazole ring. Aspect 11: v is 1 and R 2 A compound according to any one of embodiments 2 to 6, wherein is attached to the 6-position of the benzothiazole ring. Aspect 12: v is 2 and R 2 A compound according to any one of embodiments 2 to 68, wherein is attached to the 6-position of the benzothiazole ring. Aspect 13: v is 2 and R 2 A compound according to any one of embodiments 2 to 6, wherein is attached to the 5- and 6-positions of the benzothiazole ring. Aspect 14: R 2 But, -halogen, -C 1~6 Alkyl, -CF 3 , -OCF 3 , -OR f , or -S(O) w -R f where the alkyl group is R z A compound according to any one of aspects 2 to 13, optionally substituted one or more times with more independently selected substituents. Aspect 15: R 2 -Halogen, -Methyl, -CF 3 , -OCF 3 , -SCF 3 , -O-heteroaryl, or -S(O) 2 -CH 3 The compound according to any one of embodiments 2 to 13, wherein Aspect 16: R 2 -Cl, -F, -CF 3 , and -OCF 3 14. The compound according to any one of embodiments 2 to 13, selected from: Aspect 17: R 2 Ga-OCF 3 The compound according to any one of embodiments 2 to 13, wherein Aspect 18: R 2 Ga-CF 3 The compound according to any one of embodiments 2 to 13, wherein Aspect 19: R 2The compound according to any one of embodiments 2 to 13, wherein is -F. Aspect 20: R 2 A compound according to any one of embodiments 2-13, wherein is -Cl. Aspect 21: R 4 -Methyl, -ethyl, -n-propyl, -isopropyl, -n-butyl, -sec-butyl, -isobutyl, -tert-butyl, -(CH 2 ) 1~2 -OCH 3 , -(CH 2 ) 1~2 -F, -(CH 2 ) 1~2 -Cl, -(CH 2 ) 1~2 -OCF 3 , -(CH 2 ) 1~2 -NH 2 , -(CH 2 ) 1~2 -CN, -(CH 2 ) 1~2 -OH, -(CH 2 ) 1~2 -CF 3 , -(CH 2 ) 1~2 -CO 2 H, -(CH 2 ) 1~2 -SH, -(CH 2 ) 1~2 -SCH 3 , -(CH 2 ) 1~2 -S(O) 2 CH 3 , -(CH 2 ) 1~2 -OCH 2 CH 3 , -(CH 2 ) 1~2 -SCH 2 CH 3 , -(CH 2 ) 1~2 -S(O) 2 CH 2 CH 3 , -(CH 2 ) 1~2 -NH-CH 3 , or -(CH 2 ) 1~2-N(CH 3 ) 2 The compound according to any one of embodiments 2 to 20, wherein Aspect 22: R 4 -Methyl, -ethyl, -isopropyl, -isobutyl, -CH 2 CH 2 -OCH 3 , -CH 2 CH 2 -F or -CH 2 CH 2 -NH 2 The compound according to any one of embodiments 2 to 21, wherein Aspect 23: R 4 A compound according to any one of embodiments 2 to 22, wherein is -methyl, -ethyl, -isopropyl, or -isobutyl. Aspect 24: R 4 A compound according to any one of embodiments 2 to 23, wherein is -methyl. Aspect 25: R 4 A compound according to any one of embodiments 2 to 23, wherein is -ethyl. Aspect 26: R 4 But -(CH 2 ) 2 -OCH 3 , -(CH 2 ) 2 -F, -(CH 2 ) 2 -Cl, -(CH 2 ) 2 -OCF 3 , -(CH 2 ) 2 -NH 2 , -(CH 2 ) 2 -CN, -(CH 2 ) 2 -OH, -(CH 2 ) 2 -CF 3 , -(CH 2 ) 2 -CO 2 H, -(CH 2 ) 2 -SH, -(CH 2 ) 2 -SCH 3 , or -(CH 2 )2 -S(O) 2 CH 3 The compound according to any one of embodiments 2 to 21, wherein Aspect 27: R 1 But hydrogen, -OCH 3 , -F, -Cl, -NH 2 , -cyano, -OH, -CF 3 , -OCF 3 , -SH, -SC 1~6 Alkyl, -S(O) 2 -C 1~6 Alkyl, -CO 2 H, -NH-C 1~6 Alkyl, -N(C 1~6 Alkyl) 2 , and -NH-C 1~6 The compound according to any one of embodiments 2 to 26, wherein: Aspect 28: R 1 But, -OCH 3 , -F, -CF 3 , -OCF 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , and -N(CH 3 )(CH 2 CH 3 27. The compound according to any one of embodiments 2 to 26, independently selected from: Aspect 29: R 1 But hydrogen, -OCH 3 The compound according to any one of embodiments 2 to 26, independently selected from: Aspect 30: R 1 A compound according to any one of embodiments 2-26, wherein is hydrogen.

[0057] Embodiment 31: G is hydrogen, -C 1~8 Alkyl, -C 3~10 Cycloalkyl, -C 1~6 Alkylene-C 3~8 Cycloalkyl, heterocyclyl, or NR h R kwherein the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are R c or G is -CH 2 Y 3 , -CH 2 CH 2 Y 3 , -CH 2 CH 2 CH 2 Y 3 , -CH(CH 3 )CH 2 Y 3 , -CH 2 CH(Y 3 )CH 3 , -CH(Y 3 )CH 3 , -CH 2 C(Y 3 )(CH 3 ) 2 , -C(Y 3 )(CH 3 ) 2 or [ka] {In the formula, Y 3 is -cyclopropyl, -CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CH 3 , -F, -Cl, -OH, -O(CH 2 ) 2 -OH, -O(CH 2 ) 2 -F, -SCH 3 , -S(O) 2 -CH 3 , -SCH 2 CH 3 , -S(O) 2 CH 2 CH 3 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, -NH-C(O)-CH 3 , -NH-C(O)-CH 2 CH 3 , tetrahydrofuran-2-yl-methyloxy, or -C(O)-Y 4 where Y 4 -OH, -OCH 3 , -OCH 2 CH 3 , -OC(CH 3 ) 3 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl; L is -CH 2 -C(O)N(R 6 )-, -C(O)N(R 6 )-, -C(O)-O-, -SO 2 -, -C(O)-, or R x is a heterocyclylene optionally substituted one or more times with more independently selected substituents; or the group -LG is -cyano; R 1 is hydrogen or R a and; R c teeth, a)-Halogen, b)-C 1~6 Alkyl, c)-C 3~10 Cycloalkyl, d)-heterocyclyl, e)-Cyano, f)-CF 3 , g)-OCF3 , h)-OR h , i)-S(O) w -R h , j)-S(O) 2 OR h , k)-NR h R k , l)-C(O)-R h , m)-C(O)-OR h , n)-OC(O)-R h , o)-C(O)NR h R k , p) -C(O)-heterocyclyl, q)-NR h C(O)R k , r)-OC(O)NR h R k , s)-NR h C(O)OR k , t)-NR h C(O)NR h R k or u)-O-(C 1~4 alkylene)-O-(C 1~4 alkylene)-N(R h )C(O)-OR k wherein the alkylene, alkyl, cycloalkyl, and heterocyclyl groups are R x optionally substituted one or more times with more independently selected substituents; R h and R k are independently hydrogen, C 1~6 Alkyl or C 3~10 cycloalkyl, where the alkyl and cycloalkyl groups are R x or R h and R kand R may be joined together with the nitrogen atom to form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is selected from the group consisting of R x and R x is R y The compound according to any one of embodiments 2 to 30, wherein

[0058] Embodiment 32: A compound according to any one of embodiments 2 to 31, wherein -LG is not -cyano. Aspect 33: -LG is -C(O)NR h R k The compound according to any one of embodiments 2 to 32, wherein Aspect 34: L is -C(O)N(R 6 33. A compound according to any one of embodiments 2 to 32, wherein the R is —C(O)—O—. Aspect 35: L is -C(O)N(R 6 33. The compound according to any one of embodiments 2 to 32, wherein Aspect 36: L is -CH 2 -C(O)N(R 6 )-, wherein the compound is not Embodiment 37: A compound according to any one of embodiments 2 to 32, wherein L is -C(O)-O-. Embodiment 38: A compound according to any one of embodiments 2 to 32, wherein L is -C(O)-. Aspect 39: L is -S(O) 2 -. Aspect 40: L is R x The compound according to any one of embodiments 2 to 30, which is heteroarylene optionally substituted one or more times with substituents independently selected from: Aspect 41: R 6 A compound according to any one of embodiments 2 to 40, wherein is hydrogen. Aspect 42: R6 A compound according to any one of embodiments 2 to 40, wherein is hydrogen or -methyl. Embodiment 43: G is hydrogen, -C 1~8 Alkyl, -C 3~10 Cycloalkyl or -C 1~6 Alkylene-C 3~8 cycloalkyl, where the alkyl, cycloalkyl, and alkylene groups are R x A compound according to any one of embodiments 2 to 42, optionally substituted one or more times with more independently selected substituents.

[0059] Embodiment 44: G is -H, -methyl, -ethyl, -n-propyl, -isopropyl, -isobutyl, -CH 2 Y 3 , -CH 2 CH 2 Y 3 , -CH 2 CH 2 CH 2 Y 3 , -CH(CH 3 )CH 2 Y 3 , -CH 2 CH(Y 3 )CH 3 , -CH(Y 3 )CH 3 , -CH 2 C(Y 3 )(CH 3 ) 2 , or -C(Y 3 )(CH 3 ) 2 where Y 3 is -cyclopropyl, -CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CH 3 , -F, -OH, -O(CH 2 ) 2 -OH, -O(CH 2 ) 2 -F, -SCH 3 , -S(O) 2 -CH 3 , -SCH 2 CH 3, -S(O) 2 CH 2 CH 3 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -NH-C(O)-CH 3 , -NH-C(O)-CH 2 CH 3 , or C(O)-Y 4 where Y 4 -OH, -OCH 3 , -OCH 2 CH 3 , -OC(CH 3 ) 3 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , or -N(CH 2 CH 3 ) 2 The compound according to any one of embodiments 2 to 42, wherein Embodiment 45: G is -methyl, -ethyl, -n-propyl, -isopropyl, or -isobutyl, each of which is -CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CH 3 , -F, -OH, -O(CH 2 ) 2 -OH, -O(CH 2 ) 2 -F, -SCH 3 , -SCH 2 CH 3 , -NH-CH 3 , -NH-CH 2 CH 3 , and -N(CH 3 ) 2 A compound according to any one of embodiments 2 to 42, optionally substituted one or more times with more independently selected substituents.

[0060] Embodiment 46: A compound according to any one of embodiments 2 to 42, wherein G is H. Embodiment 47: G is a C optionally substituted one or more times with halogen 1~8 The compound according to any one of embodiments 2 to 42, wherein is alkyl. Embodiment 48: G is a C optionally substituted one or more times with halogen 3~10 The compound according to any one of embodiments 2 to 42, which is cycloalkyl. Embodiment 49: A compound according to any one of embodiments 2 to 42, wherein G is heterocyclyl optionally substituted one or more times with halogen. Embodiment 50: G is -C optionally substituted one or more times with halogen 1~6 Alkylene-C 3~10 The compound according to any one of embodiments 2 to 42, which is cycloalkyl. Aspect 51: G is NR h R k The compound according to any one of embodiments 2 to 42, wherein Aspect 52: G is -CH 2 -R c The compound according to any one of embodiments 2 to 42, wherein Aspect 53: G is -CH 2 CH 2 -R c The compound according to any one of embodiments 2 to 42, wherein Aspect 54: G is -CH 2 CH 2 CH 2 -R c The compound according to any one of embodiments 2 to 42, wherein Aspect 55: G is -CH(CH 3 )CH 2 R c The compound according to any one of embodiments 2 to 42, wherein Aspect 56: G is -CH 2 CH(R c )CH 3 The compound according to any one of embodiments 2 to 42, wherein Aspect 57: G is -CH(R c )CH 3 The compound according to any one of embodiments 2 to 42, wherein Aspect 58: G is -CH 2 C(R c )(CH 3 ) 2 The compound according to any one of embodiments 2 to 42, wherein Aspect 59: G is -C(R c )(CH 3 ) 2 The compound according to any one of embodiments 2 to 42, wherein

[0061] Embodiment 60: G is imidazol-2-yl, thiazol-2-yl, oxazol-2-yl, pyrazol-1-yl, furan-2-yl, thiophen-2-yl, pyrrol-1-yl, 1H-1,2,4-triazolyl-3-yl, 5-methyl-1H-1,2,4-triazolyl-3-yl, -(CH 2 ) 1~3 -(imidazol-2-yl), -(CH 2 ) 1~3 -(thiazol-2-yl), -(CH 2 ) 1~3 -(Oxazol-2-yl), -(CH 2 ) 1~3 -(pyrazol-1-yl), -(CH 2 ) 1~3 -(Furan-2-yl), -(CH 2 ) 1~3 -(thiophen-2-yl), -(CH 2 ) 1~3 -(pyrrol-1-yl), -(CH 2 ) 1~3 -(1H-1,2,4-triazolyl-3-yl), or -(CH 2 ) 1~3 -(5-methyl-1H-1,2,4-triazolyl-3-yl). Embodiment 61: A compound according to any one of embodiments 2 to 60, in its free (non-salt) form. Embodiment 62: A compound according to any one of embodiments 2 to 60, in the form of a pharma- ceutically acceptable salt.

[0062] Embodiment 63: Any "heterocyclyl" group present therein may be selected from the group consisting of azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, imidazolidin-1-yl, imidazolidin-2-yl, Imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4 ...5-yl Lysin-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, 1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl, 1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, 1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, thian-2-yl, thian-3-yl, thian-4-yl, piperazin-1-yl, piperazin-2-yl, morpholinyl and wherein each of these enumerated rings is selected from the group consisting of halogen, —NH 2 , cyano, carboxy, C 1~4 Alkyl, C 3~10 Cycloalkyl, hydroxyl, thiol, -CF 3 , -OCF 3 , -OC 1~4 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl) 2 , -SC 1~4 Alkyl, -S(O) 2 -C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, -C(O)NH 2 , -C(O)NH-C 1~4 Alkyl, and -C(O)N(C 1~4 Alkyl) 2A compound according to any one of embodiments 1-62, wherein any nitrogen atom in any of these recited rings may be optionally oxidized one or more times with more independently selected substituents, and wherein any sulfur atom in any of these recited rings may be optionally oxidized once or twice, if chemically feasible.

[0063] Embodiment 64: Any "heteroaryl" group present therein may be selected from the group consisting of 1H-pyrrol-1-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, oxazole- 2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H -1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, furazan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 2H-isoindol-1-yl, 2H-isoindol and each of the rings enumerated herein is selected from the group consisting of halogen, -NH, -phenyl-2-yl, -quinolin-2-yl, -quinolin-3-yl, -quinolin-4-yl, -isoquinolin-1-yl, -isoquinolin-3-yl, -isoquinolin-4-yl, -benzoxazol-2-yl, -benzothiazol-2-yl, -1H-benzimidazol-1-yl, -1H-benzimidazol-2-yl, -benzofuran-2-yl, -benzofuran-3-yl, -benzothiophen-2-yl, and -benzothiophen-3-yl, wherein each of these enumerated rings is selected from the group consisting of halogen, -NH 2 , cyano, carboxy, C 1~4 Alkyl, C 3~10 Cycloalkyl, hydroxyl, thiol, -CF3 , -OCF 3 , -OC 1~4 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl) 2 , -SC 1~4 Alkyl, -S(O) 2 -C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, -C(O)NH 2 , -C(O)NH-C 1~4 Alkyl, -C(O)N(C 1~4 Alkyl) 2 A compound according to any one of the preceding embodiments, optionally substituted one or more times with substituents independently selected from:

[0064] Aspect 65: Any "heteroarylene" group present therein is selected from the group consisting of 1H-pyrrole-2,5-diyl, furan-2,5-diyl, thiophene-2,5-diyl, 1H-imidazole-2,4-diyl, 1H-imidazole-2,5-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, thiazole-2,4-diyl, thiazole-2,5-diyl, 1H-1,2,4-triazole-3,5-diyl, and 2H-isoindole-1,3-diyl, wherein each of these enumerated rings is selected from the group consisting of halogen, -NH 2 , cyano, carboxy, -C 1~4 Alkyl, -C 3~10 Cycloalkyl, hydroxyl, thiol, -CF 3 , -OCF 3 , -OC 1~4 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl) 2 , -SC 1~4 Alkyl, -S(O) 2 -C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, -C(O)NH 2 , -C(O)NH-C 1~4Alkyl, -C(O)N(C 1~4 Alkyl) 2 A compound according to any one of the preceding embodiments, optionally substituted one or more times with substituents independently selected from:

[0065] Embodiment 66: A compound according to embodiment 1. Aspect 67: R 3 The compound according to embodiment 66, wherein is hydrogen. Aspect 68: R 3 The compound according to embodiment 66, wherein is methyl. Aspect 69: R 3 The compound according to embodiment 66, wherein is ethyl. Aspect 70:R 3 The compound according to embodiment 66, wherein is isopropyl. Aspect 71:X 1 The compound according to any one of embodiments 66 to 70, wherein is =N-. Aspect 72:X 1 The compound according to any one of embodiments 66-70, wherein is =CH-. Embodiment 73: A compound according to any one of embodiments 66 to 72, wherein v is 0, 1 or 2. Embodiment 74: A compound according to any one of embodiments 66 to 72, wherein v is 1 or 2. Embodiment 75: A compound according to any one of embodiments 66 to 72, wherein v is 1. Aspect 76: v is 1 and R 2 A compound according to any one of embodiments 66-72, wherein is attached to either the 5- or 6-position of the benzothiazole ring. Aspect 77: v is 1 and R 2 A compound according to any one of embodiments 66-72, wherein is attached to the 6-position of the benzothiazole ring. Aspect 78: v is 2 and R 2 A compound according to any one of embodiments 66-72, wherein is attached to the 6-position of the benzothiazole ring. Aspect 79: v is 2 and R 2 A compound according to any one of embodiments 66-72, wherein is attached to the 5- and 6-positions of the benzothiazole ring.

[0066] Aspect 80:R 2 But, -halogen, -C 1~6 Alkyl, -CF 3 , -OCF 3 , -OR f , or -S(O) w -R f where the alkyl group is R z A compound according to any one of embodiments 66 to 79, optionally substituted one or more times with more independently selected substituents. Aspect 81:R 2 -Halogen, -Methyl, Ethyl, Isopropyl, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 , -SCF 3 , -S(O) 2 -CH 3 80. A compound according to any one of embodiments 66-79, wherein R is -O-phenyl, -O-(2-pyridyl), -O-(3-pyridyl), or -O-(4-pyridyl). Aspect 82:R 2 -Halogen, -Methyl, Ethyl, Isopropyl, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 , -SCF 3 , -S(O) 2 -CH 3 or -O-(3-pyridyl). Aspect 83:R 2 -Cl, -F, -CF 3 , or -OCF 3 The compound according to any one of embodiments 66 to 79, wherein Aspect 84:R 2 Ga-OCF 3 The compound according to any one of embodiments 66 to 79, wherein Aspect 85:R 2 Ga-CF3 The compound according to any one of embodiments 66 to 79, wherein Aspect 86:R 2 The compound according to any one of embodiments 66-79, wherein is -F. Aspect 87:R 2 The compound according to any one of embodiments 66-79, wherein is -Cl. Aspect 88:R 2 -SO 2 CH 3 The compound according to any one of embodiments 66 to 79, wherein Aspect 89:R 2 The compound according to any one of embodiments 66-79, wherein is methyl, ethyl, or isopropyl. Aspect 90:R 2 The compound according to any one of embodiments 66-79, wherein is methyl. Aspect 91:R 2 -OCH 2 CH 3 The compound according to any one of embodiments 66 to 79, wherein Aspect 92:R 2 The compound according to any one of embodiments 66-79, wherein is -O-phenyl. Aspect 93:R 2 The compound according to any one of embodiments 66-79, wherein is -O-(2-pyridyl), -O-(3-pyridyl), or -O-(4-pyridyl). Aspect 94:R 2 The compound according to any one of embodiments 66-79, wherein is -O-(3-pyridyl).

[0067] Aspect 95:R 4 -Methyl, -ethyl, -n-propyl, -isopropyl, -n-butyl, -sec-butyl, -isobutyl, -tert-butyl, -(CH 2 ) 1~2 -OCH 3 , -(CH 2 ) 1~2 -F, -(CH 2 ) 1~2 -Cl, -(CH 2 ) 1~2 -OCF 3 , -(CH2 ) 1~2 -NH 2 , -(CH 2 ) 1~2 -CN, -(CH 2 ) 1~2 -OH, -(CH 2 ) 1~2 -CF 3 , -(CH 2 ) 1~2 -CO 2 H, -(CH 2 ) 1~2 -SH, -(CH 2 ) 1~2 -SCH 3 , -(CH 2 ) 1~2 -S(O) 2 CH 3 , -(CH 2 ) 1~2 -OCH 2 CH 3 , -(CH 2 ) 1~2 -SCH 2 CH 3 , -(CH 2 ) 1~2 -S(O) 2 CH 2 CH 3 , -(CH 2 ) 1~2 -NH-CH 3 , or -(CH 2 ) 1~2 -N(CH 3 ) 2 The compound according to any one of embodiments 66 to 94, wherein

[0068] Aspect 96:R 4 -Methyl, -ethyl, -isopropyl, -isobutyl, -CH 2 CH 2 -OCH 3 , -CH 2 CH 2 -F, -CH 2 CH 2 -NH 2 , or -CH 2 CH 2 -NH-CH 3 The compound according to any one of embodiments 66 to 94, wherein Aspect 97:R 4 A compound according to any one of embodiments 66-94, wherein is -methyl, -ethyl, -isopropyl, or -isobutyl. Aspect 98:R 4 The compound according to any one of embodiments 66-94, wherein is -methyl. Aspect 99:R 4 The compound according to any one of embodiments 66-94, wherein is -ethyl. Aspect 100:R 4 The compound according to any one of embodiments 66-94, wherein is -isopropyl. Aspect 101: R 4 The compound according to any one of embodiments 66-94, wherein is -isobutyl. Aspect 102: R 4 Ga-CH 2 CH 2 -OCH 3 The compound according to any one of embodiments 66 to 94, wherein Aspect 103: R 4 Ga-CH 2 CH 2 -F. Aspect 104: R 4 Ga-CH 2 CH 2 -NH 2 The compound according to any one of embodiments 66 to 94, wherein Aspect 105:R 4 Ga-CH 2 CH 2 -NH-CH 3 The compound according to any one of embodiments 66 to 94, wherein

[0069] Aspect 106:R 1 But hydrogen, -OCH 3 , -F, -Cl, -NH 2 , -cyano, -OH, -CF 3 , -OCF 3 , -SH, -SC 1~6 Alkyl, -S(O) 2 -C 1~6 Alkyl, -CO 2 H, -NH-C 1~6Alkyl, -N(C 1~6 Alkyl) 2 , or -NH-C 1~6 The compound according to any one of embodiments 66-105, wherein is alkyl. Aspect 107: R 1 But, -OCH 3 , -F, -CF 3 , -OCF 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 The compound according to any one of embodiments 66 to 105, wherein Aspect 108: R 1 is hydrogen, -OCH 3 or F. Aspect 109:R 1 The compound according to any one of embodiments 66-105, wherein is hydrogen. Aspect 110:R 1 The compound according to any one of embodiments 66 to 105, wherein is -F. Aspect 111:R 1 -OCH 3 The compound according to any one of embodiments 66 to 105, wherein Aspect 112:R 1 -N(CH 2 CH 3 ) 2 The compound according to any one of embodiments 66 to 105, wherein

[0070] Embodiment 113: G is hydrogen, -C 1~8 Alkyl, -C 3~10 Cycloalkyl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkylene-C 3~10 Heterocyclyl or NR h R k wherein the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are Rc or G is -CH 2 Y 3 , -CH 2 CH 2 Y 3 , -CH 2 CH 2 CH 2 Y 3 , -CH(CH 3 )CH 2 Y 3 , -CH 2 CH(Y 3 )CH 3 , -CH(Y 3 )CH 3 , -CH 2 C(Y 3 )(CH 3 ) 2 , -C(Y 3 )(CH 3 ) 2 or [ka] {In the formula, Y 3 is -cyclopropyl, -CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CH 3 , -F, -Cl, -OH, -O(CH 2 ) 2 -OH, -O(CH 2 ) 2 -F, -SCH 3 , -S(O) 2 -CH 3 , -SCH 2 CH 3 , -S(O) 2 CH 2 CH 3 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, -NH-C(O)-CH 3 , -NH-C(O)-CH 2 CH 3 , tetrahydrofuran-2-yl-methyloxy, or -C(O)-Y 4 where Y 4 -OH, -OCH 3 , -OCH 2 CH 3 , -OC(CH 3 ) 3 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl; L is -CH 2 -C(O)N(R 6 )-, -C(O)N(R 6 )-, -C(O)-O-, -SO 2 -, -C(O)-, or R x is a heterocyclylene optionally substituted one or more times with more independently selected substituents; or the group -LG is -cyano; R 1 is hydrogen or R a and; R c teeth, a)-Halogen, b)-C 1~6 Alkyl, c)-C 3~10 Cycloalkyl, d)-heterocyclyl, e)-Cyano, f)-CF 3 , g)-OCF3 , h)-OR h , i)-S(O) w -R h , j)-S(O) 2 OR h , k)-NR h R k , l)-C(O)-R h , m)-C(O)-OR h , n)-OC(O)-R h , o)-C(O)NR h R k , p) -C(O)-heterocyclyl, q)-NR h C(O)R k , r)-OC(O)NR h R k , s)-NR h C(O)OR k , t)-NR h C(O)NR h R k , u)-NR h S(O) w R k or v)-O-(C 1~4 alkylene)-O-(C 1~4 alkylene)-N(R h )C(O)-OR k wherein the alkylene, alkyl, cycloalkyl, and heterocyclyl groups are R x optionally substituted one or more times with more independently selected substituents; R h and R k are independently hydrogen, C 1~6 Alkyl or C 3~10 cycloalkyl, where the alkyl and cycloalkyl groups are R xor R h and R k and R may be joined together with the nitrogen atom to form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is selected from the group consisting of R x and R x is R y The compound according to any one of embodiments 66 to 112, wherein

[0071] Embodiment 114: A compound according to any one of embodiments 66 to 112, wherein -LG is not -cyano. Aspect 115: L is -C(O)N(R 6 113. The compound according to any one of embodiments 66 to 112, wherein Aspect 116:R 6 The compound according to embodiment 115, wherein is hydrogen. Aspect 117: R 6 The compound according to embodiment 115, wherein is methyl. Aspect 118: G is -N(CH 3 ) 2 The compound according to embodiment 117, wherein Aspect 119: -LG is -C(O)NR h R k The compound according to any one of embodiments 66 to 112, wherein Aspect 120: NR h R k is pyrrolidino, piperidino, piperazino, 4-methyl-piperazino, or morpholino, each of the above being -(CH 2 ) 1~3 A compound according to embodiment 119, optionally substituted once with -OH. Aspect 121: NR h R kThe compound according to embodiment 120, wherein is pyrrolidino, 4-(2-hydroxyethyl)-piperazino, or 4-(3-hydroxypropyl)-piperidino. Aspect 122: NR h R k N[(CH 2 ) 2 -OH] 2 The compound according to embodiment 119, wherein Aspect 123: L is -CH 2 -C(O)N(R 6 )-, wherein the compound is not Embodiment 124: A compound according to any one of embodiments 66 to 123, wherein L is not heterocyclylene. Aspect 125: L is -S(O) 2 - . The compound according to any one of embodiments 66 to 112, Embodiment 126: G is methyl or -CF 3 The compound according to embodiment 125, wherein Aspect 127: L is R x The compound according to any one of embodiments 66 to 112, which is heteroarylene optionally substituted one or more times with more independently selected substituents. Embodiment 128: A compound according to embodiment 127, wherein -LG is imidazol-2-yl, 1,2,4-triazol-3-yl, or 5-methyl-1,2,4-triazol-3-yl. Embodiment 129: A compound according to any one of embodiments 66 to 112, wherein L is -C(O)-O-.

[0072] Embodiment 130: G is hydrogen or -C 1~8 alkyl, where the alkyl group is R c The compound according to embodiment 129, optionally substituted one or more times with more independently selected substituents. Embodiment 131: A compound according to embodiment 130, wherein G is methyl or ethyl. Embodiment 132: A compound according to embodiment 130, wherein G is hydrogen. Aspect 133: G is -C 1~8 Alkyl, -C 3~10 Cycloalkyl, -C 1~6Alkylene-C 3~10 Cycloalkyl, heterocyclyl, or -C 1~6 Alkylene-C 3~10 heterocyclyl, where the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are R c A compound according to any one of embodiments 66 to 116, optionally substituted one or more times with more independently selected substituents. Aspect 134: G is R c -C may be substituted one or more times with independently selected substituents 1~8 The compound according to embodiment 133, wherein the is alkyl. Embodiment 135: A compound according to embodiment 134, wherein G is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or isobutyl. Embodiment 136: A compound according to embodiment 134, wherein G is methyl, ethyl, or n-propyl. Embodiment 137: A compound according to embodiment 134, wherein G is 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl. Embodiment 138: A compound according to embodiment 134, wherein G is 2-cyanoethyl. Embodiment 139: G is -C(O)-OR h -C substituted once by 1~8 The compound according to embodiment 134, wherein the is alkyl.

[0073] Aspect 140: G is -CH 2 -C(O)-OR h The compound according to embodiment 139, wherein Aspect 141:R h The compound according to embodiment 140, wherein is hydrogen or methyl. Aspect 142: G is -CH 2 CH 2 -C(O)-OR h The compound according to embodiment 139, wherein Aspect 143:R h The compound according to embodiment 142, wherein is hydrogen or methyl. Aspect 144: G is -C(CH 3 ) 2 -C(O)-ORh The compound according to embodiment 139, wherein Aspect 145:R h The compound according to embodiment 144, wherein is hydrogen or methyl. Aspect 146: G is -CH(CH 3 )-C(O)-OR h The compound according to embodiment 139, wherein Aspect 147:R h The compound according to embodiment 146, wherein is hydrogen or methyl. Embodiment 148: G is -C(O)NR h R k -C substituted once by 1~8 The compound according to embodiment 134, wherein the is alkyl. Aspect 149: G is CH 2 -C(O)-O-NR h R k The compound according to embodiment 148, wherein

[0074] Aspect 150:NR h R k The compound according to embodiment 149, wherein is methylamino, dimethylamino, or diethylamino. Aspect 151: NR h R k The compound according to embodiment 149, wherein is thiomorpholino or 1,1-dioxothiomorpholino. Aspect 152: NR h R k The compound according to embodiment 149, wherein is morpholino, pyrrolidino, piperidino, piperazino, or 4-methylpiperazino. Aspect 153: NR h R k The compound according to embodiment 149, wherein is pyrrolidino, 3-hydroxy-pyrrolidino, 3-methoxy-pyrrolidino, 3-amino-pyrrolidino, 3-(methylamino)-pyrrolidino, 3-(dimethylamino)-pyrrolidino, 2-(hydroxymethyl)-pyrrolidino, 2-(dimethylaminocarbonyl)-pyrrolidino, or 3,4-dihydroxy-pyrrolidino. Aspect 154: NR h R kThe compound according to embodiment 149, wherein is piperazino, 4-methylpiperazino, 4-(methylsulfonyl)-piperazino, or 4-(dimethylaminosulfonyl)-piperazino. Aspect 155: NR h R k is piperidino, 3-hydroxypiperidino, 4-hydroxypiperidino, 2-(hydroxymethyl)-piperidino, 3-(hydroxymethyl)-piperidino, 4-(hydroxymethyl)-piperidino, 3-methoxy-piperidino, 4-(methoxymethyl)-piperidino, 4-(fluoromethyl)-piperidino, 4-(trifluoromethyl)-piperidino, 4-cyano-piperidino, 4-carbamoyl-piperidino, 4-(methylamino)-piperidino, 4-(dimethylamino)-piperidino, 4-(methylaminomethyl)-piperidino, or 4-(dimethylaminomethyl)-piperidino. Aspect 156: NR h R k NHR k where R k The compound according to embodiment 149, wherein is 2-hydroxypropyl, 2-(methylsulfonyl)-ethyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl, piperidin-3-yl, or 1-methylpiperidin-3-yl. Aspect 157: NR h R k N(CH 3 )R k where R k The compound according to embodiment 149, wherein is 2-hydroxyethyl, tetrahydropyran-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, or piperazin-3-yl. Aspect 158: NR h R k N(CH 2 CH 2 OH] 2 The compound according to embodiment 149, wherein Aspect 159: G is -(CH 2 ) 2~3 -C(O)-N(CH 3 ) 2The compound according to embodiment 148, wherein

[0075] Aspect 160: G is -(CH 2 ) 3 The compound according to embodiment 148, wherein the compound is -C(O)-(4-methylpiperazino). Aspect 161: G is -CH(CH 3 )-C(O)-NR h R k where NR h R k The compound according to embodiment 148, wherein is methylamino, dimethylamino, 4-methylpiperazino, or morpholino. Aspect 162: G is -C(CH 3 ) 2 -C(O)-N(CH 3 ) 2 The compound according to embodiment 148, wherein Embodiment 163: G is -CH-[C(O)-N(CH 3 ) 2 ]-[CH 2 OH], -CH-[C(O)-N(CH 3 ) 2 ]-[(CH 2 ) 4 -NH 2 ], or -CH-[C(O)-N(CH 3 ) 2 ]-[(CH 2 ) 4 -N(CH 3 ) 2 The compound according to embodiment 134, wherein Aspect 164: G is -OR h -C substituted once by 1~8 The compound according to embodiment 134, wherein the is alkyl. Aspect 165: G is -(CH 2 ) 2 -OR h The compound according to embodiment 164, wherein Aspect 166:R h The compound according to embodiment 165, wherein is hydrogen, methyl, or ethyl. Aspect 167:R hThe compound according to embodiment 165, wherein is trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, or 2,2-difluoroethyl. Aspect 168:R h The compound according to embodiment 165, wherein is tetrahydrofuran-2-ylmethyl. Aspect 169:R h The compound according to embodiment 165, wherein is 2-hydroxyethyl.

[0076] Aspect 170:R h The compound according to embodiment 165, wherein is 3-hydroxypropyl. Aspect 171:R h The compound according to embodiment 165, wherein is 2-methoxyethyl. Aspect 172:R h The compound according to embodiment 165, wherein is 2-(2-hydroxyethoxy)-ethyl. Aspect 173:R h The compound according to embodiment 165, wherein is 2-hydroxypropyl or 1-hydroxyprop-2-yl. Aspect 174:R h The compound according to embodiment 165, wherein is 2-cyanoethyl, 2-(methylcarbonylamino)-ethyl, or 2-(methylsulfonylamino)-ethyl. Aspect 175:R h The compound according to embodiment 165, wherein is 2-aminoethyl, 2-(methylamino)-ethyl, or 2-(dimethylamino)-ethyl. Aspect 176:R h The compound according to embodiment 165, wherein is carbamoylmethyl. Aspect 177: G is -(CH 2 ) 3 -OR h The compound according to embodiment 164, wherein Aspect 178:R h The compound according to embodiment 177, wherein is hydrogen, methyl, or ethyl. Aspect 179:R h The compound according to embodiment 177, wherein is 2-hydroxyethyl.

[0077] Embodiment 180: G is -(CH)4 -OH, -(CH2) 5 -OH, -CH 2 C(CH 3 ) 2 -OH, -CH 2 C(CH 3 ) 2 -OCH 3 , -CH 2 C(CH 3 ) 2 -CH 2 -OH, -CH(CH 3 )-CH 2 -OCH 3 , -(CH 2 ) 3 C(CH 3 ) 2 -CH 2 -OH, -(CH 2 ) 2 CH(CH 3 )-CH 2 -OH or -(CH 2 ) 2 CH(CH 3 ) —OH. Aspect 181: G is -CH 2 CH(CH 3 )-OR h The compound according to embodiment 164, wherein Aspect 182:R h The compound according to embodiment 181, wherein is hydrogen, methyl, or ethyl. Aspect 183: G is -CH 2 -CH(OH)-CH 2 The compound according to embodiment 134, wherein said compound is -OH. Embodiment 184: G is -NR h R k -C substituted once by 1~8 The compound according to embodiment 134, wherein the is alkyl. Aspect 185: G is -(CH 2 ) 2 -NR h R k The compound according to embodiment 184, wherein Aspect 186: NR h R kThe compound according to embodiment 185, wherein is amino, methylamino, or dimethylamino. Aspect 187: NR h R k The compound according to embodiment 185, wherein is methylcarbonylamino. Aspect 188: NR h R k The compound according to embodiment 185, wherein is (dimethylamino)methylcarbonylamino, hydroxymethylcarbonylamino, or 1-hydroxyethylcarbonylamino. Aspect 189: NR h R k The compound according to embodiment 185, wherein is methylsulfonylamino.

[0078] Aspect 190: NR h R k The compound according to embodiment 185, wherein is piperidino, 4-hydroxypiperidino, or 3-hydroxypiperidino. Aspect 191: NR h R k The compound according to embodiment 185, wherein is piperidino, 4,4-difluoropiperidino, or 3,3-difluoropiperidino. Aspect 192: NR h R k The compound according to embodiment 185, wherein is 2-oxo-pyrrolidino, 2-oxo-imidazolidino, or 3-oxo-piperazino. Aspect 193: NR h R k The compound according to embodiment 185, wherein is piperazino, 4-methylpiperazino, morpholino, or 1,1-dioxo-thiomorpholino. Aspect 194: G is -(CH 2 ) 3 -NR h R k The compound according to embodiment 184, wherein Aspect 195: NR h R k The compound according to embodiment 194, wherein is amino, dimethylamino, or diethylamino. Aspect 196: NR h R kThe compound according to embodiment 194, wherein is piperidino, 4-methylpiperazino, or morpholino. Aspect 197: G is -(CH 2 ) 4 -NR h R k The compound according to embodiment 184, wherein Aspect 198: NR h R k The compound according to embodiment 197, wherein is amino, dimethylamino, or diethylamino. Aspect 199: G is -C 1~6 alkylene-heterocyclyl, where the alkylene and heterocyclyl groups are R c The compound according to embodiment 133, optionally substituted one or more times with more independently selected substituents.

[0079] Aspect 200: G is -CH 2 -heterocyclyl, where the heterocyclyl group is R c The compound according to embodiment 199, optionally substituted once with a substituent selected from: Embodiment 201: A compound according to embodiment 200, wherein the heterocyclyl group is tetrahydropyran-4-yl, tetrahydrofuran-2-yl, 1,4-dioxan-2-yl, morpholin-2-yl, tetrahydropyran-2-yl, piperidin-4-yl, 1-(2-hydroxyethyl)-piperidin-4-yl, 1-(dimethylaminomethylcarbonyl)-piperidin-4-yl, piperazin-2-yl, or 1-methyl-piperazin-2-yl. Aspect 202: G is R c C may be substituted one or more times with a substituent independently selected from 3~10 The compound according to embodiment 133, wherein the compound is cycloalkyl. Embodiment 203: A compound according to embodiment 202, wherein G is 4-hydroxy-cyclohexyl, 4-carboxy-cyclohexyl, or 4-(dimethylaminocarbonyl)-cyclohexyl. Embodiment 204: A compound according to embodiment 202, wherein G is 1-carboxy-cyclopropyl, 1-(ethoxycarbonyl)-cyclopropyl, or 1-(dimethylamino-carbonyl)-cyclopropyl. Aspect 205: G is C 1~6 Alkylene-C 3~10 cycloalkyl, where the alkylene and cycloalkyl groups are R c The compound according to embodiment 133, optionally substituted one or more times with more independently selected substituents. Aspect 206: G is -CH 2 The compound according to embodiment 205, wherein the compound is -(4-hydroxy-cyclohexyl). Aspect 207: G is -(CH 2 ) 2 The compound according to embodiment 205, wherein the compound is -(4-hydroxy-cyclohexyl). Aspect 208: G is -CH 2 The compound according to embodiment 205, wherein the compound is -[4-(hydroxymethyl)-cyclohexyl]. Aspect 209: G is R c The compound according to embodiment 133, which is heterocyclyl optionally substituted one or more times with more independently selected substituents.

[0080] Embodiment 210: A compound according to embodiment 209, wherein G is piperidin-4-yl, 1-methyl-piperidin-4-yl, 1-carboxy-piperidin-4-yl, 1-(methylsulfonyl)-piperidin-4-yl, 1-(2-hydroxyethyl)-piperidin-4-yl, 1-(dimethyl-aminocarbonyl)-piperidin-4-yl, or 1-(dimethylaminomethylcarbonyl)-piperidin-4-yl. Embodiment 211: A compound according to embodiment 209, wherein G is piperidin-3-yl or 1-(dimethylaminomethylcarbonyl)-piperidin-3-yl. Embodiment 212: A compound according to embodiment 209, wherein G is 1,1-dioxo-tetrahydrothiophen-3-yl. Embodiment 213: A compound according to embodiment 209, wherein G is pyrrolidin-3-yl, 1-methyl-pyrrolidin-3-yl, 1-(2-hydroxyethyl)-pyrrolidin-3-yl, 1-(2-hydroxypropyl)-pyrrolidin-3-yl, 1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-yl, 1-(1-hydroxyethylcarbonyl)-pyrrolidin-3-yl, 1-(2-carboxyethyl)-pyrrolidin-3-yl, or 1-(2-methylsulfonylamino-ethyl)-pyrrolidin-3-yl. Aspect 214: G is -SR h -C substituted once by 1~8 The compound according to embodiment 134, wherein the is alkyl. Aspect 215: G is -(CH 2 ) 2 -SR h The compound according to embodiment 214, wherein Aspect 216:R h The compound according to embodiment 215, wherein is methyl or ethyl. Aspect 217:R h The compound according to embodiment 215, wherein is 2-hydroxyethyl. Aspect 218: G is -(CH 2 ) 3 -SR h The compound according to embodiment 214, wherein Aspect 219:R h The compound according to embodiment 218, wherein is methyl.

[0081] Aspect 220: G is -SO 2 -R h -C substituted once by 1~8 The compound according to embodiment 134, wherein the is alkyl. Aspect 221: G is -(CH 2 ) 2 -SO 2 -R h The compound according to embodiment 220, wherein Aspect 222:R h The compound according to embodiment 221, wherein is methyl or ethyl. Aspect 223:R h The compound according to embodiment 221, wherein is 2-hydroxyethyl. Aspect 224: G is -(CH 2 ) 3 -SO 2 -R h The compound according to embodiment 220, wherein Aspect 225:R h The compound according to embodiment 224, wherein is methyl. Aspect 226: G is -CH(CH 3 )-NR h R k where NR h R k The compound according to embodiment 133, wherein is pyrrolidino, piperidino, 4-methyl-piperazino, morpholino, or dimethylamino. Embodiment 227: A compound according to embodiment 133, wherein G is 1-(2-hydroxypropyl)-pyrrolidin-3-yl or 1-(1-hydroxyethylcarbonyl)-pyrrolidin-3-yl. Embodiment 228: A compound according to embodiment 133, wherein G is 1-(dimethylaminomethylcarbonyl)-piperidin-4-yl. Aspect 229: G is -(CH 2 ) 3~5 The compound according to embodiment 133, wherein said compound is -OH.

[0082] Embodiment 230: A compound according to embodiment 133, wherein G is 4-hydroxy-cyclohexylmethyl. Aspect 231: G is -(CH 2 ) 2 -NHC(O)-CH 2 -N(CH 3 ) 2 The compound according to embodiment 133, wherein Embodiment 232: A compound according to embodiment 133, wherein G is 4-hydroxy-cyclohexylmethyl. Aspect 233: G is -CH 2 -C(O)-NR h R k where NR h R k The compound according to embodiment 133, wherein is 3-hydroxy-pyrrolidino or 3-(dimethyl-amino)-pyrrolidino. Aspect 234: G is -CH 2-C(O)-NR h R k where NR h R k The compound according to embodiment 133, wherein is morpholino. Aspect 235: G is -CH 2 -C(O)-NR h R k where NR h R k The compound according to embodiment 133, wherein is 4-hydroxy-piperidino, 4-methoxy-piperidino, 4-(hydroxymethyl)-piperidino, 3-hydroxy-piperidino, 3-methoxy-piperidino, 3-(hydroxymethyl)-piperidino, or 4,4-difluoropiperidino. Aspect 236: G is -CH 2 -C(O)-NR h R k where NR h R k The compound according to embodiment 133, wherein is dimethylamino. Aspect 237: G is -(CH 2 ) 2 -O-(CH 2 ) 2 The compound according to embodiment 133, wherein said compound is -OH. Aspect 238: G is -(CH 2 ) 2 -O-(CH 2 ) 2 -OCH 3 The compound according to embodiment 133, wherein Aspect 239: G is -CH 2 -CH(CH 3 ) —OH.

[0083] Embodiment 240: L is C(O)NH and G is a C(O)NH substituted once by a heteroaryl group. 1~8 alkyl, where the heteroaryl group is R x A compound according to any one of embodiments 66 to 112, optionally substituted one or more times with more independently selected substituents. Embodiment 241: G is -CH 2 -(2-furyl), -CH 2-(2-thienyl), -CH 2 -(2-oxazolyl) or -CH 2 The compound according to embodiment 240, wherein the compound is -(2-thiazolyl). Aspect 242: G is -(CH 2 ) 2~3 -(1-pyrrolyl), -(CH 2 ) 2~3 -(1-pyrazolyl), or -(CH 2 ) 2~3 The compound according to embodiment 240, wherein the compound is -(1-imidazolyl). Embodiment 243: L is C(O)NH and G is a C(O)NH substituted once by a phenyl group. 1~8 alkyl, where the phenyl group is R x A compound according to any one of embodiments 66 to 112, optionally substituted one or more times with more independently selected substituents. Aspect 244: G is -(-CH 2 ) 1~2 -(4-hydroxyphenyl) or -(-CH 2 ) 1~2 -(4-methoxy-3-hydroxyphenyl). Embodiment 245: L is C(O)NH and G is -CH 2 -C(O)NH-CH 2 The compound according to any one of embodiments 66-112, wherein R is -(4-hydroxyphenyl). Embodiment 246: L is C(O)NH and G is -CH 2 The compound according to any one of embodiments 66 to 112, wherein the compound is -C(O)-[4-(pyrimidin-2-yloxy)-piperidino]. Aspect 247:X 2 = C(R 1 )- and X 3 A compound according to any one of the preceding embodiments, wherein is =C(-LG)-. Embodiment 248: A compound according to any one of embodiments 1 to 247, in the form of a free acid or a free base. Embodiment 249: A compound according to any one of embodiments 1 to 247, in the form of a pharma- ceutically acceptable salt.

[0084] Embodiment 250: A compound according to embodiment 1, which is a compound of Table A or a pharma- ceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17]

[0085] Compounds 1-474 of Table A can be prepared as described in WO '018, or by other methods apparent to one of skill in the art. For example, compounds 473 and 474 of Table A can be prepared as described in the Examples section below.

[0086] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof for use in treating sickle cell disease or a related disorder. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound (or salt) of any one of the embodiments 1-250 (recited above) and a pharmaceutical carrier. In another embodiment, the pharmaceutical composition comprises a compound (or salt) of any one of the embodiments and a pharma- ceutical acceptable carrier.

[0087] Thus, in another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In another aspect, the invention provides a pharmaceutical composition comprising a compound (or salt) of any one of aspects 1 to 250 and a pharma- ceutically acceptable carrier.

[0088] In another aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in medicine. In another aspect, the present invention provides a compound (or salt) of any one of aspects 1 to 250 for use in medicine.

[0089] B. Coadministration The present invention further provides for the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with one or more active compounds for simultaneous, sequential or sequential administration. The present invention also provides for the use of a compound (or salt) of any one of embodiments 1-250 in combination with one or more medically effective active compounds for simultaneous, sequential or sequential administration. Examples of such active ingredients include, but are not limited to, HU, Nrf2 activators, antioxidants, antidotes, and anti-inflammatory agents. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound (or salt) of any one of embodiments 1-250 and at least one other medically effective active ingredient selected from HU, Nrf2 activators, antioxidants, antidotes, and anti-inflammatory agents. In another aspect, the present invention provides for the use of a compound (or salt) of any one of aspects 1 to 250 in combination with at least one other medically effective active ingredient selected from Nrf2 activators, antioxidants, antidotes, and anti-inflammatory agents, for simultaneous, sequential, or sequential administration.

[0090] The Nrf2 activator may include a Michael addition acceptor, one or more fumarate esters, i.e., monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, further ethacrynic acid, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate), isothiocyanates such as sulforaphane, 1,2-dithiol-3-thiones such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, or pharmacologically active derivatives or analogues of the above-mentioned agents. In one embodiment, the Nrt2 activator for use in combination with the compounds of the present invention is bardoxolone methyl and a fumarate ester.

[0091] Nrf2 activator compounds can be classified based on their chemical structure: diphenols, Michael reaction acceptors, isothiocyanates, thiocarbamates, trivalent arsenicals, 1,2-dithiole-3-thiones, hydroperoxides, vicinal dimercaptans, heavy metals, and polyenes. In general, Nrf2 activators are chemically reactive in that they can be electrophiles that are substrates for glutathione transferases, and / or can modify sulfhydryl groups by alkylation, oxidation, or reduction.

[0092] In another embodiment, the Nrf2 activators are bardoxolone methyl and dialkyl fumarates, such as dimethyl fumarate and diethyl fumarate. In another embodiment, the Nrf2 activator is selected from the group consisting of chalcone derivatives such as 2-trifluoromethyl-2'-methoxychalcone, auranofin, ebselen, 1,2-naphthoquinone, cinnamaldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, and tert-butylquinone, (tBHQ, tBQ), vitamins K1, K2 and K3, menadione, fumarate esters, i.e., fumarate monoesters and / or fumarate diesters, which may be selected from the group consisting of monoalkyl hydrogen fumarates and dialkyl fumarates, such as monomethyl hydrogen fumarate, dimethyl fumarate (DMF), monoethyl hydrogen fumarate, and diethyl fumarate; 2-Cyclopentenone, ethacrynic acid and its alkyl esters, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate) (CDDO-Me, RTA-402), ethyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), (2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), isothiocyanates such as sulforaphane, 1,2-dithiole-3-thiones such as oltipraz, 3,5-Di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allyl isothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, corticosteroids such as dexamethasone, 8-isoprostaglandin A2, alkyl pyruvates such as methyl pyruvate and ethyl pyruvate. , diethyl oxalopropionate or dimethyl oxalopropionate, 2-acetamidoacrylate, methyl-2-acetamidoacrylate or ethyl-2-acetamidoacrylate, hypestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[10] -shogaol, eugenol, 1'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, Phenethyl isothiocyanate, 4-(methylthio)-3-butenyl isothiocyanate and 6-methylsulfinylhexyl isothiocyanate, ferulic acid and its esters such as ferulic acid ethyl ester and ferulic acid methyl ester, sofalcone, 4-methyldaphnetin, imperatorin, auraptene, poncimarin, bis[2-hydroxybenzylidene]acetone, alicylcurcuminoids, 4-bromoflavone, beta-naphthoflavone, sappanone A, aurone and benzylidene-indoline. and their corresponding indole derivatives such as benzoyl-2-one, perillaldehyde, quercetin, fisetin, copalin, genistein, tanshinone HA, BHA, BHT, PMX-290, AL-1, avicin D, gedunin, fisetin, andrographolide, as well as the tricyclic bis(cyanoenone) TBE-31 [(±)-(4bS,8aR,10aS)-10a-ethynyl-4-b,8,8-trimethyl-3,7-dioxo-3,4-b,7,8,-8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile]. In another embodiment, the Nrf2 activator is selected from the group consisting of carnosic acid, 2-naphthoquinone, cinnamaldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, vitamins K1, K2 and K3, fumarate esters, i.e., monoalkyl fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate and diethyl fumarate. Esters and / or fumaric acid diesters, isothiocyanates such as sulforaphane, 1,2-dithiole-3-thiones such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allyl isothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate , sulforaphane, 8-methylthiooctyl isothiocyanate, 8-isoprostaglandin A2, alkyl pyruvates such as methyl pyruvate and ethyl pyruvate, diethyl or dimethyl oxalopropionate, 2-acetamidoacrylate, methyl-2-acetamidoacrylate or ethyl-2-acetamidoacrylate, hypestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal isothiocyanate, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[10] -shogaol, eugenol, 1'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(methylthio)-3-butenyl isothiocyanate and 6-methylsulfinylhexyl isothiocyanate, as well as the quinone or hydroquinone forms of each of the quinone and hydroquinone derivatives mentioned above. In another embodiment, the Nrf2 activator can be a Michael reaction acceptor such as dimethyl fumarate isothiocyanate, monomethyl hydrogen fumarate isothiocyanate, and 1,2-dithiole-3-thione. In another embodiment, the Nrf2 activator is selected from monomethyl hydrogen fumarate, dimethyl fumarate, oltipraz, 1,2-naphthoquinone, tert-butylhydroquinone, methyl or ethyl pyruvate, 3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyl oxalopropionate, hypestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[10] -shogaol, eugenol, 1'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(methylthio)-3-butenyl isothiocyanate, and 6-methylsulfnylhexyl isothiocyanate.

[0093] Examples of antioxidants include vitamin C, vitamin E, carotenoids, retinoids, polyphenols, flavonoids, lignans, selenium, butylated hydroxyanisole, ethylenediaminetetraacetate, disodium calcium, acetylcysteine, probucol, and tempo. Examples of antidotes include dimethylcaprol, glutathione, acetylcysteine, methionine, sodium bicarbonate, deferoxamine mesylate, calcium disodium edetate, trientine hydrochloride, penicillamine, and pharmaceutical charcoal.

[0094] Anti-inflammatory agents include steroidal anti-inflammatory agents and non-steroidal anti-inflammatory agents. Examples of steroidal anti-inflammatory agents include cortisone acetate, hydrocortisone, paramethasone acetate, prednisolone, methylprednisolone, dexamethasone, triamcinolone, and betamethasone. Examples of non-steroidal anti-inflammatory agents include salicylic acid non-steroidal anti-inflammatory agents such as aspirin, difiunisal, aspirin plus ascorbic acid, and aspirin dialuminate; aryl acid non-steroidal anti-inflammatory agents such as diclofenac sodium, sulindac, fenbufen, indomethacin, indomethacin farnesyl, acemetacin, proglumetacin maleate, amfenac sodium, nabumetone, mofezolac, and etodorag; mefenamic acid, flufenamic acid aluminum, tolfenamic acid, and floctafenine. These include fenamic acid nonsteroidal anti-inflammatory agents; propionic acid nonsteroidal anti-inflammatory agents such as ibuprofen, flurbiprofen, ketoprofen, naproxen, pranoprofen, fenoprofen calcium, tiaprofen, oxaprozin, loxoprofen sodium, alminoprofen, and zaltoprofen; oxicam nonsteroidal anti-inflammatory agents such as piroxicam, ampiroxicam, tenoxicam, lornoxicam, and meloxicam; and basic nonsteroidal anti-inflammatory agents such as tiaramide hydrochloride, epirizole, and emorfazone.

[0095] The appropriate time course for sequential administration can be selected by the physician depending on factors such as the nature of the patient's illness and the patient's condition for administration of the individual active agents, hi certain embodiments, sequential administration involves co-administration of one or more additional active agents within a period of one week, 72 hours, 48 ​​hours, 24 hours, or 12 hours. In some embodiments, the compositions disclosed herein are co-administered in combination with one or more additional active agents for the treatment of sickle cell disease, beta thalassemia, or related disorders. Such additional active agents may include, but are not limited to, folic acid, penicillin or another antibiotic, preferably a quinolone or macrolide, an antiviral agent, an antimalarial prophylactic, and an analgesic to control pain crises. In some embodiments, the composition is co-administered with one or more additional agents that increase expression of HbF, such as hydroxyurea (HU). In some embodiments, the compositions are administered in conjunction with one or more additional treatment protocols, such as blood transfusion therapy, stem cell therapy, gene therapy, bone marrow transplant, dialysis or kidney transplant for kidney disease, cholecystectomy in people suffering from cholelithiasis, hip replacement surgery for avascular necrosis of the hip joint, surgery for eye problems, and wound care for leg ulcers.

[0096] C. Effective Dose In some embodiments, the composition is administered in an amount effective to induce a pharmacological, physiological, or molecular effect compared to a control to which the composition is not administered, hi some embodiments, the composition is administered to a subject in need thereof to increase expression of HbF in the subject. Suitable controls are known in the art and can be determined based on the disease being treated. Suitable controls include, but are not limited to, one or more subjects that are not afflicted with sickle cell disease, beta thalassemia, or a sickle cell-related disorder; or that are free of the condition or state of a subject afflicted with the disease or disorder prior to the initiation of treatment.

[0097] D. Dosage and Dosage Regimens The selected dosage depends on the desired therapeutic effect, the route of administration, and the desired duration of treatment. In general, a dosage level of 0.001 to 100 mg / kg body weight per day is administered to a mammal. In general, the dosage may be lower when administered by intravenous injection or infusion. The suitable dose of the compound of formula (I) or its pharma-ceutically acceptable salt for use in the present invention can be determined by any one of several well-established protocols.For example, animal tests such as tests using mice, rats, dogs and / or monkeys can be used to determine the suitable dose of pharmaceutical compound.The results from animal tests can be extrapolated to determine the dose for use in other species, such as humans. The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered in a daily dosage of 0.1 mg to 15 mg per kg. In another embodiment, when the subject is a human, the daily dosage may be 1 mg to 1000 mg. In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of 10 mg / day to 1000 mg / day, or 25 mg / day to 800 mg / day, or 37 mg / day to 750 mg / day, or 75 mg / day to 700 mg / day, or 100 mg / day to 600 mg / day, or 150 mg / day to 500 mg / day, or 200 mg / day to 400 mg / day. In other embodiments, the previous daily administration period of the amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be changed to a period of 6 hours, 12 hours, 48 ​​hours, 72 hours, 96 hours, one week, or every two weeks.

[0098] In some embodiments, the daily dosage for a fumarate ester in a human, which is a composition comprising a fumarate ester, such as DMF, MMF, or a combination thereof, can range from about 1 mg to about 5,000 mg, about 10 mg to about 2,500 grams, or about 50 mg to about 2,000 grams of the fumarate ester or a pharmacologically active salt thereof. In another embodiment, the effective amount of DMF or MMF administered to a subject can be, for example, orally, from about 0.1 g to about 1 g or more per day, from about 200 mg to about 800 mg per day, from about 240 mg to about 720 mg per day, from about 480 mg to about 720 mg per day, or about 720 mg per day. The daily dosage can be administered in two, three, four, or six equal separate administrations. In some embodiments, one or more fumarate esters or pharmacologically active salts, derivatives, analogs, or prodrugs thereof are present in a pharmaceutical formulation. In some embodiments, the composition is administered to the patient three times a day (TID). In some embodiments, the pharmaceutical formulation is administered to the patient twice a day (BID). In some embodiments, the composition is administered at least 1 hour before or after food is consumed by the patient.

[0099] In some embodiments, the composition is administered as part of a dosage regimen.For example, a patient can be administered a first dose of the composition over a first dosage period, a second dose of the composition over a second dosage period, and then one or more additional doses over one or more additional dosage periods.The first dosage period can be less than one week, one week, or more than one week.

[0100] In some embodiments, the dosage regimen is an escalating dose regimen: the first dose can be a low dose, followed by measuring HbF expression levels, then decreasing, maintaining or increasing the dose. Current labeled dosing of hydroxyurea for sickle cell disease requires administration of an initial dose of 15 mg / kg / day in the form of a single dose, with monitoring of the patient's blood counts every two weeks. If the blood counts are within acceptable limits, the dose may be increased by 5 mg / kg / day every 12 weeks until the MTD of 35 mg / kg / day is reached. The pharmaceutical composition may contain 1 mg / kg to 50 mg / kg of a fumarate ester, such as MMF, in combination with 1 mg / kg to 35 mg / kg of HU. The combination formulation may contain 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / kg of HU.

[0101] E. Preparation Pharmaceutical compositions comprising the compounds of the present invention are disclosed.The pharmaceutical compositions may be for administration by oral, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), transdermal (passively or using iontophoresis or electroporation), or transmucosal (nasal, vaginal, rectal, or sublingual) administration route or by using biodegradable inserts, and can be formulated in unit dosage forms suitable for each administration route. Red blood cells, which are cells of the erythroid lineage, are the major producers of hemoglobin. Therefore, in one embodiment, the compound or pharmaceutical composition of the present invention is administered to a subject in an effective amount to induce HbF in hematopoietic stem cells. Therefore, in some embodiments, the compound or pharmaceutical composition of the present invention is administered to a subject in an effective amount to induce HbF expression in cells of the erythroid lineage in bone marrow (i.e., red bone marrow), liver, spleen, or a combination thereof.

[0102] In further embodiments, the compounds or pharmaceutical compositions of the present invention induce HbF in cells that synthesize or are committed to synthesize hemoglobin. For example, in preferred embodiments, the compounds of the present invention induce HbF in basophilic normoblasts / early normoblasts, also commonly referred to as normoblasts, polychromatic normoblasts / intermediate normoblasts, normochromatic normoblasts / late normoblasts, or combinations thereof. In some embodiments, the compound or pharmaceutical composition of the present invention is administered locally to the site requiring therapy. Although red blood cells are the major producers of hemoglobin, other non-hematopoietic cells, including macrophages, retinal pigment cells, and alveolar epithelial cells such as alveolar type II (ATII) cells and Clara cells, can also synthesize hemoglobin. Thus, in some embodiments, the compound or pharmaceutical composition of the present invention is administered locally to interfaces where oxygen-carbon dioxide diffusion occurs, including but not limited to the eye or lung.

[0103] In some embodiments, a compound or pharmaceutical composition of the invention is administered topically to the eye to treat retinopathy or another ocular manifestation associated with sickle cell disease or a related disorder. In one embodiment, the pharmaceutical composition is formulated for oral delivery. Oral solid dosage forms are generally described in Chapter 45 of Remington's Pharmaceutical Sciences, 21st Ed. 2005. Solid dosage forms include tablets, capsules, pills, troches or lozenges, sachets, pellets, powders or granules, or the incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes. Such compositions can affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the disclosed. The composition can be prepared in liquid form or in dry powder (e.g., lyophilized) form. Another embodiment provides liquid dosage forms for oral administration, including pharma- ceutically acceptable emulsions, solutions, suspensions, and syrups, which can contain inert diluents; adjuvants such as wetting agents, emulsifying agents, and suspending agents; and other components including sweeteners, flavoring agents, and perfumes. A controlled release oral formulation may be desired. The compounds of the present invention can be incorporated into an inert matrix, such as a gum, that allows release by either diffusion or leaching mechanisms. Slowly degenerating matrices can also be incorporated into the formulation. For oral formulations, the location of release may be the stomach, the small intestine (the duodenum, jejunum, or ileum), or the large intestine.

[0104] IV. Diagnostic Methods The treatment methods disclosed herein may include a first step of selecting a subject for treatment. In some embodiments, a subject is selected for treatment when the subject exhibits one or more of the clinical symptoms of sickle cell disease, beta thalassemia, or related disorders, such as those discussed above. In some embodiments, a subject is selected for treatment when the subject exhibits genetic or biochemical indicators of sickle cell disease, beta thalassemia, or related disorders. For example, a subject can be selected for treatment based on the identification of genetic alterations, defects, or mutations in the beta globin gene or its expression control sequences, due to biochemical or morphological changes in hemoglobin or hemoglobin-synthesizing cells, or a combination thereof.

[0105] In some embodiments, the subject is selected when a combination of clinical symptoms and genetic or biochemical changes is identified. In some embodiments, the subject is selected based on one or more clinical symptoms, or one or more genetic or biochemical changes. For example, the subject can be selected for treatment based on the identification of genetic changes, biochemical or morphological changes, or a combination thereof, before the subject exhibits clinical symptoms of sickle cell disease, beta thalassemia, or related disorders.

[0106] In some embodiments, the method of treatment may further include obtaining or obtaining a biological sample from the subject to determine whether the subject is at risk for or afflicted with sickle cell disease, beta thalassemia, or a related disorder, and performing or having performed bodily fluid testing on the biological sample to determine whether the subject has a biomarker or genetic mutation associated with sickle cell disease, beta thalassemia, or a related disorder. If the subject is determined to be at risk for or afflicted with sickle cell disease, beta thalassemia, or a related disorder, the method further includes administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0107] In any of the preceding methods, the method may further comprise obtaining or obtaining biological samples from the subject over a period of time, and performing or performing bodily fluid tests on the biological samples to determine whether the level of one or more biochemical markers is increasing or decreasing, and administering a higher dose of the compound of formula (I) or its pharmaceutically acceptable salt if the level of one or more biochemical markers is not trending in a desired direction.For example, the ratio of HbF to HbS in the sample may be measured, and a significant increase in the amount of HbF to HbS in the second sample of the subject relative to the first sample indicates that the dosage of formula (I) or its pharmaceutically acceptable salt is a therapeutically effective dosage.Conversely, no change or no significant change in the amount of HbF to HbS in the second sample of the subject relative to the first sample may indicate that the dosage of formula (I) or its pharmaceutically acceptable salt is not a therapeutically effective dosage, and the dosage may need to be increased.

[0108] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a subject in need thereof in an amount that reduces a marker level of one or more biomarkers, such as CRP or ROS. The period between collection of biological samples may be 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 6 months, 9 months, or 12 months, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered during this period.

[0109] A. Identification of genetic alterations In some embodiments, subjects are selected for treatment based on the identification of one or more genetic alterations in one or more alleles of the human beta globin gene or its expression control sequence. Genetic alterations indicative of sickle cell disease, beta thalassemia, or related disorders include the exemplary mutations discussed above, or other mutations that lead to reduced synthesis, structure, or function of human beta globin protein. The method for selecting a subject having one or more genetic changes in one or more alleles of the beta globin gene or its expression control sequence includes obtaining a biological sample and detecting the presence or absence of one or more genetic changes. In one embodiment, the obtained biological sample contains nucleic acid from the subject, and the detecting step detects the presence or absence of one or more genetic changes in one or more alleles of the beta globin gene or its expression control sequence in the biological sample. Any biological sample containing the DNA of the subject to be diagnosed can be used, including tissue samples and blood samples, with nucleated blood cells being a particularly convenient source. DNA can be isolated from the biological sample prior to testing the DNA for the presence or absence of genetic changes. The detecting step may include determining whether the subject is heterozygous or homozygous for the genetic variation. The detecting step of the presence or absence of the genetic variation may include detecting the presence or absence of the variation in any chromosome of the subject (i.e., detecting the presence or absence of one or two alleles containing the marker or functional polymorphism). Two or more copies of the genetic variation (i.e., a subject homozygous for the genetic marker) may indicate a higher risk of developing sickle cell disease, beta thalassemia, or related disorders. In some embodiments, the subject is heterozygous for two or more genetic variations in the beta-globin gene (also referred to herein as double heterozygotes, triple heterozygotes, etc.). One copy of two or more genetic variations in the beta-globin gene may indicate a higher risk of developing sickle cell disease, beta thalassemia, or related disorders.

[0110] The process of determining the gene sequence of human beta globin gene is called genotyping.In some embodiments, human beta globin gene is sequenced.The method of amplifying DNA fragments and sequencing them is well known in the art.For example, the automated sequencing procedures that can be used to sequence beta globin gene include, but are not limited to, mass spectrometry single molecule real-time sequencing, ion semiconductor (ion torrent sequencing), pyrosequencing (454), sequencing by synthesis, sequencing by ligation, and sequencing by chain termination reaction (Sanger sequencing).

[0111] In some embodiments, the subject's genotype is determined by identifying the presence of one or more single nucleotide polymorphisms (SNPs) associated with sickle cell disease, beta thalassemia, or related disorders. Methods for SNP genotyping are generally known in the art. SNP genotyping can include collecting a biological sample (e.g., a tissue, cell, fluid, secretion, etc. sample) from a subject, isolating genomic DNA from the cells of the sample, contacting the nucleic acid with one or more primers that specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions that allow hybridization and amplification of the target nucleic acid region, and determining the nucleotide present at the SNP position of interest, or in some assays, detecting the presence or absence of an amplification product (assays can be designed such that hybridization and / or amplification occurs only when a particular SNP allele is present or absent). In some assays, the size of the amplification product is detected and compared to that of a control sample; for example, deletions and insertions can be detected by a change in size of the amplification product compared to a normal genotype. The flanking sequences can be used to design SNP detection reagents such as oligonucleotide probes and primers. Common SNP genotyping methods include, but are not limited to, TaqMan assay, molecular beacon assay, nucleic acid array, allele-specific primer extension, allele-specific PCR, sequence primer extension, homogeneous primer extension assay, primer extension with mass spectrometry detection, pyrosequencing, multiplex primer extension screened on gene array, ligation with rolling circle amplification, homogeneous ligation, multiplex ligation reaction screened on gene array, restriction-fragment length polymorphism, single base extension-tag assay, and Invader assay. Such methods can be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.

[0112] Other suitable methods for detecting polymorphisms include using protection from cleavage agents to detect mismatched bases in RNA / RNA or RNA / DNA duplexes, comparing the electrophoretic mobility of mutant and wild-type nucleic acid molecules, and using denaturing gradient gel electrophoresis (DGGE) to assay the migration of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturing agents. Sequence variations at specific positions can also be assessed by nuclease protection assays, such as Rnase and S1 protection, or chemical cleavage methods. Another method for genotyping SNPs is the use of two oligonucleotide probes in an oligonucleotide ligation assay (OLA). Other methods that can be used to genotype SNPs include single-strand conformation polymorphism (SSCP).

[0113] B. Identification of Biochemical and Morphological Changes In some embodiments, subjects are selected for treatment based on the identification of biochemical or morphological changes or abnormalities in hemoglobin or hemoglobin-synthesizing cells such as hematopoietic stem cells, erythroid progenitor cells, erythrocytes, macrophages, retinal pigment epithelial cells, alveolar type II (ATII) cells, etc. The method typically involves identifying one or more biochemical or morphological changes that are associated with genetic alterations in the human beta globin gene or are otherwise associated with a diagnosis of sickle cell disease, beta thalassemia, or related disorders. Methods for diagnosing sickle cell disease, beta thalassemia, or related disorders by biochemical or morphological changes in hemoglobin or hemoglobin-synthesizing cells are known in the art and include, but are not limited to, analysis of red blood cell morphology, osmotic fragility, hemoglobin composition, globin synthesis rate, and red blood cell indices.

[0114] In some embodiments, the method includes first testing the subject's blood for HbS and selecting the subject for treatment if HbS is present. Methods for testing the subject's blood for the presence of HbS include solubility tests (e.g., SICKLEDEX) and sickling tests. In the SICKLEDEX test, if HbS is present in the sample, it becomes insoluble and forms a turbid suspension. Other hemoglobins are more soluble and form a clear solution. The sickling test can be used to determine whether red blood cells become sickled after mixing the blood sample with a reducing agent by identifying morphological changes to the shape of the red blood cells (i.e., "sickling") by microscopic examination. The shape change of red blood cells can also be analyzed for shape change using a flow cytometer such as the Amnis ImageStreamX Mark II Imaging Flow Cytometer (MilliporeSigma). Erythrocyte shape change may be quantified using software programs such as the IDEAS application software (MilliporeSigma) I using modified protocols as described in "Imaging flow cytometry for automated detection of hypoxia-induced erythrocyte shape change in sickle cell disease." van Beers EJ, et al. Am J Hematol. 2014; 89(6):598-603; or "Sickle Cell Imaging Flow Cytometry Assay (SIFCA)." Fertrin KY, et al. Methods Mol Biol. 2016; 1389:279-292.

[0115] Other suitable tests include hemoglobin electrophoresis, which employs gel electrophoresis techniques to separate different types of hemoglobin from a blood sample obtained from a subject. This test can detect abnormal levels of HbS and other abnormal hemoglobins, such as hemoglobin C. This test can also be used to determine whether there is a deficiency in any normal form of hemoglobin, as in the case of various thalassemias. Alternatives to electrophoresis techniques include isoelectric focusing and chromatographic techniques. Other tests that can be used to select subjects for treatment using the compositions and methods disclosed herein include tests typically employed as part of hemoglobinopathy screening, such as a complete blood count (CBC) or iron tests (ferritin). For example, a blood count can be used to detect anemia and blood smears, and a blood count can be used to identify sickle cell. EXAMPLES

[0116] General Procedure A: Ipso Substitution of 6-Chloro-5-nitro-nicotinic Acid Methyl Ester To a solution of 6-chloro-5-nitro-nicotinic acid methyl ester in DMF or THF, 2M methylamine in THF is added and the reaction mixture is stirred at room temperature for 16 hours. The resulting mixture is poured into water to precipitate the product. The precipitate may be filtered and dried to give the product, which may not need further purification before being used in the next step.

[0117] General Procedure B: Reduction of a Nitro Group to an Amine To the methanol solution of this nitro compound, add 10% Pd / C. The resulting mixture is heated to 100°C. 2 Stir at room temperature under atmospheric pressure for 16 hours. The contents can then be filtered through a pad of Celite or silica gel and the solids washed with a small amount of methanol. The combined filtrate and washings are evaporated to give the corresponding amine, which can be used in the next step without further purification.

[0118] General Procedure C: Thiourea formation and its conversion to 2-amino-imidazopyridines 1,1'-Thiocarbonylimidazole is added to a solution of the amine containing triethylamine (1 eq.) in acetonitrile (10 mL). The reaction mixture is stirred at room temperature (1-24 h). The solvent is then evaporated and the product is suspended in acetonitrile. The solvent is then evaporated to yield the product as a precipitate. The precipitate is filtered, washed with acetonitrile and dried. The product may be used directly in the next step without further purification. To the product obtained immediately above, EDAC is added at room temperature followed by a substituted diaminopyridine, and the reaction mixture is stirred at 90° C. for 16 hours. The reaction mixture is then cooled to room temperature, poured into cold water, and the solid is collected by filtration. The crude product thus obtained may be purified by trituration with methanol.

[0119] General Procedure D: Hydrolysis of Esters To a solution of the ester in THF / MeOH (1:1) is added an aqueous solution of NaOH, and the resulting mixture is stirred at 60° C. for 16 h. After completion of the reaction, the mixture is concentrated under vacuum. The pH of the resulting suspension is adjusted to pH 3 by dropwise addition of 6N HCl, and the precipitate may be collected by filtration, washed with water, and dried under vacuum. The desired carboxylic acid may be used without purification.

[0120] General Procedure F: Amide formation using HBTU as coupling reagent To a solution of the carboxylic acid in anhydrous DMF, DIEA is added followed by HBTU and the reaction mixture is stirred at room temperature for 30 minutes. An appropriate amount of amine is then added and the reaction is stirred at room temperature for 16 hours. The contents may be diluted with ice water to precipitate the product. The pure product may be isolated after filtration either with subsequent washes with water and DCM / methanol or via silica gel chromatography using hexane / ethyl acetate (80:20 to 60:40) as the eluent system.

[0121] Compound 473 N-[2-(2-hydroxyethoxy)ethyl]-3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxamide [ka] 6-Methylamino-5-nitro-nicotinic acid methyl ester (5.0 g) was prepared by starting with 6-chloro-5-nitro-nicotinic acid methyl ester (5.0 g) and methylamine (33% in EtOH, 24 mL) in THF (150 mL) and following general procedure A. The crude product was used in the next step without further purification. Starting from 6-methylamino-5-nitro-nicotinic acid methyl ester (5.0 g) and Pd / C (20 wt %, 1.0 g) in methanol:THF (1:1, 50 mL) and following general procedure B, 5-amino-6-methylamino-nicotinic acid methyl ester (4.8 g) was prepared. The crude product was used in the next step without further purification. Starting from 6-(trifluoromethyl)-1,3-benzothiazol-2-amine (5.0 g), 5-amino-6-methylamino-nicotinic acid methyl ester (5.0 g), 1,1'-thiocarbonyl-diimidazole (5.0 g), and EDAC (4.5 g), methyl 3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylate (5.0 g) was prepared by following general procedure C. The crude product was used in the next step without further purification. Starting with methyl 3-methyl-2-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylate (5.0 g) and a solution of NaOH (2N, 25 mL) in methanol:THF (2:1, 50 mL) and following general procedure D, 3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylic acid (4.2 g) was prepared. The crude product was used in the next step without further purification.

[0122] By following general procedure E starting from 3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylic acid (100 mg), 2-(2-aminoethoxy)ethanol (100 mg), HBTU (200 mg) and DIEA (0.2 mL) in DMF (2.0 mL), N-[2-(2-hydroxyethoxy)ethyl]-3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxamide (40 mg) was prepared. LC / MS: m / z 481.7. 1 H NMR (DMSO-d 6 ,400MHz):δ 8.67-8.59(m,2H),8.29-8.23(d,2H),7.71-7.69(d,1H),4.61(s,1H),3.68(br s,3H),3.57-3.44(m,8H),3.32(br s,2H).

[0123] Compound 474 1-Ethyl-N-[2-(2-hydroxyethoxy)ethyl]-2-[[5-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]benzimidazole-5-carboxamide [ka] Starting with 3-ethyl-2-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylic acid (100 mg) (see WO '018), 2-(2-aminoethoxy)ethanol (100 mg), HBTU (200 mg) and DIEA (0.2 mL) in DMF (2.0 mL) and following general procedure E, 1-ethyl-N-[2-(2-hydroxyethoxy)ethyl]-2-[[5-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]benzimidazole-5-carboxamide (40 mg) was prepared. LC / MS: m / z 510.7.

[0124] Common Assay Methods Western blot assay Approximately 20-50 μg of protein is separated by SDS-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. The membrane is incubated with HbF or actin antibodies for 30 min in 5% milk powder containing TBS-T followed by blocking for 1 h. After several washes, the membrane is incubated with a 1:10000 diluted HRP-conjugated secondary antibody (Thermo Scientific) and developed using ECL Prime reagent (GE Healthcare Bio-sciences). Images are captured on a Bio-Rad Chemi-Doc MP Imaging System and protein bands may be quantified by densitometry. Flow cytometry assay After compound treatment, approximately 5×105 cells are harvested, washed twice with ice-cold phosphate-buffered saline, and resuspended in 4% paraformaldehyde for 40 min at 37° C. Fixed cells are permeabilized with ice-cold acetone / methanol (4:1), washed with phosphate-buffered saline, and then incubated with FITC-conjugated anti-HbF antibody (1:1000, Abcam) for 20 min. Labeled cells may be analyzed using a Becton Dickerson LSR-II flow cytometer (BD Bioscience, San Jose, Calif., USA) and FlowJo version 0.9 software.

[0125] Example 1 KU812, a human leukemia cell line expressing fetal gamma globin and adult beta globin genes, was used as a system for screening. KU812 cells have a globin gene response pattern similar to primary erythrocytes after treatment with potential HbF inducers. (See Zein S, Lou RF, Sivanand S, Ramakrishnan V, Mackie A, Li W, Pace BS. KU812 Cell Line: model for identifying fetal hemoglobin inducing drugs. Exp Biol Med (Maywood) 235: 1385-94, 2010.) KU812 cells were grown to log phase growth in Iscove's modified Dulbecco's medium (IMDM) and 10% fetal bovine serum.

[0126] Logarithmic growth phase KU812 cells were treated with 0.5, 2.5, 5.0 and 20 μM doses of compounds 73, 134, 473 and 236 (see Table A) for 48 hours. Upon harvest, cell number and viability were measured by 0.4% trypan blue exclusion. See Figures 1A-1D. Compounds 134 and 473 had minimal effects on cell growth rate, with viability remaining >90% over the widest range of drug concentrations (see Figures 1B and 1C, respectively).

[0127] Western blot analysis was also performed to determine the induction level of HbF in KU812 cells by compounds 73, 134, 473, and 236. Hydroxyurea and hemin were used as positive controls, and β-actin was used as a protein loading control. Compounds 73, 134, and 473 each showed HbF induction, while compounds 134 and 473 increased HbF at concentrations between 0.5 and 5 μM (Figure 1E). Compound 236 did not show significant induction of HbF by Western blot analysis at the concentrations tested. Flow cytometry was performed on KU812 cells after treatment with various concentrations (0.5, 2.5, 5, 10, and 20 μM) of compound 473 and compound 236. For compound 473, an increase in the number of HbF positive cells (F cells) and an increase in mean fluorescence intensity (MFI) were observed ( FIG. 2 ). In contrast, compound 236 did not significantly increase F cells at these concentrations, although some increase in MFI was observed (data not shown). Compounds 73 and 134 were not analyzed by flow cytometry.

[0128] Example 2 To test the compounds under conditions that more closely model the physiological conditions for those suffering from SCD, sickle cell progenitors were cultured for 10 days and then treated with compound 473 at concentrations of 0.5 μM and 2.5 μM for 48 hours. Treated cells were analyzed by Western blot for expression levels of HbF, HbS, and β-actin compared to cells treated with DMSO, hemin, or HU. The same treated cells were also analyzed by flow cytometry for gamma globin gene expression compared to cells treated with DMSO, hemin, or HU. Compound 473 (0.5 μM and 2.5 μM) induced gamma globin gene expression by 1.6-fold and 1.9-fold, respectively, without affecting HbS protein levels. See Figure 3A. Increased levels of F cells were observed by flow cytometry. See Figure 3B.

[0129] Anti-sickling activity was observed in cells treated under hypoxic conditions. Sickle cell progenitor cells were cultured for 10 days as described above and then treated with Compound 473 at concentrations of 0.5 μM and 2.5 μM or hemin (~50 μM) or HU (~100 μM) for 48 hours. The treated cells were then placed under hypoxic conditions (1% O 2 and 5% CO 2 ) Cells treated with compound 473 at concentrations of 0.5 μM and 2.5 μM significantly reduced the percentage of sickle cells compared to the DMSO control. See Figures 4A and 4B.

Claims

1. Combination of a compound of formula (I) in the manufacture of a medicament for treating sickle cell disorder or complications thereof Use of the compound or a pharma- ceutical acceptable salt thereof, The compound of formula (I) has the structure shown below: 【Chemistry 1】 wherein X １ is ═N— or ═CH—, X ２ is = C(R １ )- and X ３ is =C(-L-G)-, where G is - CH ２ Y ３ , -CH ２ CH ２ Y ３ , or -CH ２ CH ２ CH ２ Y ３ and In the formula, Y ３ is -OCF ３ , -OCH ３ , -OCH ２ CH ３ , -O(CH ２ ) ２ -OH or -C(O)-Y ４ where Y ４ is -NH-CH ３ , —NH—CH ２ CH ３ , -N(CH ３ ) ２ , or -N(CH ２ CH ３ ) ２ and L is -C(O)N(R ６ ) - and R １ is hydrogen, R ２ is —CF 3 or —OCF 3 , R ３ is hydrogen, R ４ is methyl or ethyl, R ６ is hydrogen, and v is 1, use.

2. The use according to claim 1, wherein the compound is 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide or a pharma- ceutically acceptable salt thereof.

3. The use according to claim 1, wherein the compound is 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide or a pharma- ceutically acceptable salt thereof.

4. The use according to claim 1, wherein the compound is 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide or a pharma- ceutically acceptable salt thereof.

5. The use according to claim 1, wherein the compound is N-[2-(2-hydroxyethoxy)ethyl]-3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxamide or a pharma- ceutically acceptable salt thereof.

6. The use according to claim 1, wherein the compound is 1-ethyl-N-[2-(2-hydroxyethoxy)ethyl]-2-[[5-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]benzimidazole-5-carboxamide or a pharma- ceutically acceptable salt thereof.

7. The therapeutically effective amount is an amount sufficient to increase expression of fetal hemoglobin expression (HbF) in a subject. The use according to any one of claims 1 to 6.

8. A therapeutically effective amount, Inhibits the polymerization of HbS, Increase the level of dissolved oxygen in the subject's blood, or reducing levels of reactive oxygen species (ROS); is sufficient for The use according to any one of claims 1 to 6.

9. A therapeutically effective amount, Reducing sickling of blood cells in response to reduced air pressure, reduced atmospheric pressure, reduced oxygen tension, or hypoxia; is sufficient for The use according to any one of claims 1 to 6.

10. A therapeutically effective amount of Reduce the incidence or rate of painful attacks; Reduce the incidence or proportion of painful attacks requiring hospitalization; Reduce the incidence of chest syndrome, Reduce the number of transfusion events, or Reduce the number of units of blood transfused per event; is sufficient for Use according to any one of claims 2 to 8.

11. The therapeutically effective amount is an amount sufficient to treat hemolytic anemia, vaso-occlusive crisis, or multiple organ damage due to microinfarction. The use according to any one of claims 1 to 6.

12. The use described in any one of claims 1 to 6, wherein the subject is selected for treatment when the subject exhibits one or more clinical symptoms of sickle cell disease, beta thalassemia, or a related disorder.

13. The use described in any one of claims 1 to 6, wherein the subject is selected for treatment when the subject exhibits genetic or biochemical indicators of sickle cell disease, beta thalassemia, or a related disorder.

14. The use according to any one of claims 1 to 6, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with another active compound, wherein the other active compound is selected from the group consisting of hydroxyurea, dimethyl fumarate, monomethyl fumarate, and bardoxolone methyl.

15. A compound which is N-[2-(2-hydroxyethoxy)ethyl]-3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxamide, or a pharma- ceutically acceptable salt thereof.

16. The compound which is 1-ethyl-N-[2-(2-hydroxyethoxy)ethyl]-2-[[5-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]benzimidazole-5-carboxamide, or a pharma- ceutically acceptable salt thereof.

17. 17. A pharmaceutical composition comprising a compound of claim 15 or 16 and a pharma- ceutically acceptable carrier.

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