Methods for Treating Disease or Disorders

Abstract

Disclosed is a method for the prevention and / or treatment of a disease or disorder associated with a defect in hemoglobin protein activity or expression, or an innate immune response that is a type 1 or type 3 immune related immunodeficiency, comprising administering to a subject in need thereof a therapeutically effective amount of a substance X, or a pharmaceutical composition comprising said substance X, wherein said substance X is a compound of formula I, a pharma- ceutically acceptable salt or solvate thereof. JPEG2024529118000179.jpg2921

Description

[Technical field]

[0001] This application claims priority to PCT Application No. PCT / CN2021 / 112431, filed August 13, 2021, and PCT Application No. PCT / CN2021 / 125764, filed October 22, 2021. This application incorporates the entire text of the above PCT applications.

[0002] The present invention relates to a method for the prevention / treatment of diseases or disorders associated with defects in hemoglobin protein activity or expression, or innate immune response, either type 1 or type 3 immune related immunodeficiency. [Background technology]

[0003] Hemoglobin is a key protein involved in oxygen transport throughout the vertebrate body. Hemoglobin is found in red blood cells and is composed of two α subunits and two β-like subunits. The composition of hemoglobin is developmentally regulated and the human genome encodes various versions of these proteins that are expressed during specific stages of development (Blobel et al, Exp Hematol 2015; Stamatoyannopoulos G, Exp Hematol 2005). In general, fetal hemoglobin (HbF) is composed of two subunits of hemoglobin gamma (HBγ) and two subunits of hemoglobin alpha (HBα), whereas adult hemoglobin (HbA) is composed of two subunits of hemoglobin beta (HBβ) and two subunits of HBα. Thus, the beta-like subunits (HBγ) utilized during the fetal stage of development are switched to hemoglobin beta (HBβ) after birth.

[0004] SCD (Sickle Cell Disease) is a group of inherited red blood cell disorders, an autosomal recessive disease caused by a single homozygous mutation in both copies of the HBB gene (E6V) that results in a variant hemoglobin protein called HbS (https: / / ghr.nlm.nih.gov / condition / sickle-cell-disease). Under deoxygenated conditions, the HbS protein polymerizes, resulting in an abnormal red blood cell morphology. Healthy red blood cells are round and move through small blood vessels, carrying oxygen to all parts of the body. In people with SCD, the red blood cells become stiff and viscous, resembling a crescent-shaped farm tool called a "sickle." Sickle cells die early, causing a constant shortage of red blood cells. Sickle cells also get stuck as they move through small blood vessels, clogging the blood flow. This can cause pain and other serious problems, such as infections, acute chest syndrome, and strokes.

[0005] Beta thalassemia is caused by a mutation in the HBB gene, which results in reduced hemoglobin production (https: / / ghr.nlm.nih.gov / condition / beta-thalassemia). Mutations in the HBB gene normally result in reduced production of adult beta globin protein, leading to reduced amounts of HbA, the adult hemoglobin. This leads to a shortage of red blood cells and less oxygen being delivered throughout the body. Patients with beta thalassemia can become weak, fatigued, and are at risk of developing abnormal blood clots. Thousands of babies with beta thalassemia are born each year, and symptoms are usually detected within the first two years of life.

[0006] Chemotherapy-induced anemia (CIA) is a functional iron deficiency resulting from inflammation and bone marrow infiltration with destruction of erythropoiesis as a result of malignant invasion of normal tissues resulting in blood loss. CIA is a serious consequence of chemotherapy that can delay or limit treatment and, in addition, can contribute to both fatigue and reduced quality of life.

[0007] Anemia is also a common complication in patients with chronic kidney disease (CKD), and it gradually progresses and becomes more severe as the kidney disease progresses. Many factors contribute to the decrease in hemoglobin as CKD progresses, but the failure of erythropoietin production due to kidney failure is the central cause.

[0008] The immune system is composed of two parts: the innate (natural) immune system and the adaptive (acquired) immune system. The innate immune response consists of physical, chemical, and cellular defenses against pathogens. The main purpose of the innate immune response is to immediately prevent the spread and migration of foreign pathogens throughout the body. The innate immune response includes monocytes, NK cells, macrophages, neutrophils, eosinophils, basophils, mast cells, and dendritic cells. The adaptive immune response is carried out by white blood cells called lymphocytes. There are two major categories of such responses - antibody responses and cell-mediated immune responses, which are carried out by different classes of lymphocytes called B cells and T cells, respectively. The innate and adaptive immune systems are grouped together into three main types of cell-mediated effector immunity classified as type 1, type 2, and type 3. Type 1 immunity is characterized by T-bet and T-cell activation. + IFN-γ-producing group 1 ILCs (ILC1 and natural killer cells), CD8 + Cytotoxic T cells (T C 1) CD4 + T h Type 2 immunity is composed of type 1 cells and effector macrophages, which protect against intracellular microorganisms by activating mononuclear phagocytes. + ILC2, T C 2 cells, and T cells that produce IL-4, IL-5, IL-13, etc. h Type 3 immunity is composed of type 2 cells, which protect against helminths and toxins and repair tissue damage by inducing the activation of mast cells, basophils, and eosinophils, as well as the production of IgE antibodies. Type 3 immunity is mediated by the retinoic acid-related orphan receptor γδ. + ILC3, T C 17 cells, and T cells that produce IL-17, IL-22, etc. HIt is mediated by type 17 cells, recruits neutrophils, and induces an epithelial antibacterial response, thereby protecting against extracellular bacteria and fungi (Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity, Journal of Allergy & Clinical Immunology, 2015, 135(3):626-635). Autoimmune diseases are mediated by dysregulation of type 1 and type 3 innate immunity.

[0009] IBD (Inflammatory Bowel Disease), classified by convention as Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic debilitating condition characterized by relapsing and remitting episodes of gastrointestinal (GI) inflammation. UC begins in the rectum, successively affecting the superficial mucosa and is limited to the colon. CD is characterized by transmural inflammation that may affect any part of the GI tract, from the mouth to the anus. The colitis model of acute DSS is mainly caused by the destruction of the epithelium and the activation of macrophages and neutrophils, which may be induced by the absence of adaptive immunity, and is therefore mainly recognized as an induction model of innate immunity. Acute intrarectal administration of TNBS in mice induces a transmural colitis driven primarily by a type 1 immune response and characterized by infiltration of the lamina propria by CD4+ T cells, neutrophils, and macrophages (Kiesler P, Fuss IJ, Strober W. Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol. 2015,1(2):154-170). Selected CD4 + CD45RB highBy injecting T cells into recipient lymphopenic mice, a Th17 cell dominant model can be generated (and combined with Th1 cells). (Cell Mol Gastroenterol Hepatol. 2015,1(2):154-170; Am J Physiol Gastrointest Liver Physiol. 2009 Feb; 296(2):G135-G146). Research is ongoing to find effective, convenient, and tolerable treatments for diseases or disorders associated with defects in hemoglobin protein activity or expression, or innate immune responses, whether type 1 or type 3 immune-related immunodeficiencies. Summary of the Invention

[0010] Contents of the Invention In one aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: (1) a disease or disorder associated with defects in hemoglobin protein activity or expression, (2) Type 1 or type 3 immune-related immunodeficiency, which is an innate immune response (preferably inflammatory bowel disease, including Crohn's disease and ulcerative colitis); A method for preventing and / or treating a disease or disorder selected from the group consisting of: Methods are provided that include administering to a subject in need thereof a therapeutically effective amount of substance X, or a pharmaceutical composition containing substance X.

[0011] In another aspect, the present invention provides a method for producing a composition comprising: (1) a disease or disorder associated with defects in hemoglobin protein activity or expression, (2) Type 1 or type 3 immune-related immunodeficiency, which is an innate immune response (preferably inflammatory bowel disease, including Crohn's disease and ulcerative colitis); The present invention provides the use of a substance X in the manufacture of a medicament for preventing and / or treating a disease or disorder selected from the group consisting of:

[0012] Substance X in the present invention is a compound of formula I, a pharma- ceutically acceptable salt or solvate thereof, [ka] [In the formula, R 1 is aralkyl, R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl; R 3 and R 4 together with the carbon atom to which they are attached form a radical of formula IA, IB, or IC, [ka] X is -C(R 5a )(R 5b )-, -C(=O)-, and -S(=O)-; R 5a and R 5b is independently selected from the group consisting of hydrogen and C1-C4 alkyl; Y is -C(R 6a )(R 6b )-, -S-, -O-, and -N(R 7 )-, or X and Y together form a 5-membered heteroarylenyl ring; Z is -C(R 6c )(R 6d ) m - and R 6a and R 6b is independently selected from the group consisting of hydrogen and C1-C4 alkyl; Each R 6c and R 6d is independently selected from the group consisting of hydrogen and C1-C4 alkyl; m is 0, 1, or 2; R 7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R 8a , R8b , and R 8c is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, carboxamido, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-8 membered heterocyclo, (heterocyclo)C1-C4 alkyl, and alkylsulfonyl; [ka] is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl; [ka] is an optionally substituted fused 3- to 8-membered cycloalkyl or an optionally substituted fused 4- to 8-membered heterocyclo; [ka] is an optionally substituted fused 4- to 8-membered heterocyclo; and " [ka] " is a bond represented by R 3 " * " is a bond represented by R 4 or R 3 is R 3a and R 4 is R 4a and R 3a is selected from the group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 8-membered heterocyclo; and R 4a is hydrogen, halo, C1-C4 haloalkyl, -S(=O)2R 9 , -P(=O)(R 10a )(R 10b ), -C(=O)OR 11a , -C(=O)NR11b R 11c , and -S(=O)(=NR 13a )R 13b is selected from the group consisting of R 9 is selected from the group consisting of C1-C4 alkyl, and C3-C6 cycloalkyl; R 10a and R 10b are independently C1-C4 alkyl; R 11a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 11b and R 11c are independently selected from the group consisting of hydrogen and C1-C4 alkyl; or R 11b and R 11c together with the nitrogen atom to which they are attached form an optionally substituted 4- to 6-membered heterocyclo; R 13a is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and hydroxyalkyl; R 13b is selected from the group consisting of C1-C6 alkyl, and C3-C6 cycloalkyl; or R 13a and R 13b together form a 5- to 7-membered heterocycle, and [ka] is a single bond or a double bond. A compound of formula I, a pharma- ceutically acceptable salt or solvate thereof. [Brief description of the drawings]

[0013] [Figure 1] Compound 73 increased HBG mRNA levels in human CD34+ HSCs. [Diagram 2] Compound 73 increased HbF concentrations in human CD34+ HSCs. [Diagram 3]Compound 73 increased the percentage of HbF+ cells in human CD34+HSCs. [Figure 4A-4B] We show that compound 73 significantly reduced DAI and improved weight loss in a TNBS-induced IBD mouse model. [Figure 5A-5B] Figure 3 shows that compound 73 significantly reduced colon weight and increased colon length in a TNBS-induced IBD mouse model. [Figures 6A-6D] It is shown that compound 73 significantly reduced increased neutrophils and monocytes and improved anemia in peripheral blood in a TNBS-induced IBD mouse model. [Figure 7A-7E] It is shown that compound 73 significantly reduced the increased neutrophils, NK cells, activated NK cells, Th1 (IFN-γ-secreting CD4+T) cells, and macrophage cells in mesenteric lymph nodes in a TNBS-induced IBD mouse model. [Figure 8] Compound 73 significantly reduced the pathological scores in a TNBS-induced IBD mouse model. [Figure 9] Compound 73 significantly reduced fibrosis scores in a TNBS-induced IBD mouse model. [Figure 10A-10B] We show that compound 73 significantly reduced DAI and improved weight loss in a T cell migration-induced IBD mouse model. [Figure 11A-11B] Figure 3 shows that compound 73 significantly reduced colon weight and increased colon length in a T cell migration-induced IBD mouse model. [Figure 12] Compound 73 significantly reduced the pathological scores in a T cell migration-induced IBD mouse model. [Figure 13] Compound 73 significantly increased colon density (colon weight / colon length) in a DSS-induced IBD mouse model. [Figure 14] Compound 73 significantly reduced the pathological scores in a DSS-induced IBD mouse model. [Figure 15]Compound 73 dose-dependently improved body weight in rats with chronic kidney disease-induced anemia. [Figure 16] Compound 73 dose-dependently improved RBC in rats with chronic kidney disease-induced anemia. [Figure 17] Compound 73 dose-dependently improved HGB in rats with chronic kidney disease-induced anemia. [Figure 18] Compound 73 dose-dependently improved HCT in rats with chronic kidney disease-induced anemia. [Figure 19] Compound 73 dose-dependently improved RET in rats with chronic kidney disease-induced anemia. [Figure 20] Combining compound 73 with EPO further improved body weight in rats with chronic kidney disease-induced anemia. [Figure 21] Combining compound 73 with EPO further improved RBC in rats with chronic kidney disease-induced anemia. [Figure 22] Combining compound 73 with EPO further improved HGB in rats with chronic kidney disease-induced anemia. [Diagram 23] Combining compound 73 with EPO further improved HCT in rats with chronic kidney disease-induced anemia. [Figure 24] Combining compound 73 with EPO further improved RET in rats with chronic kidney disease-induced anemia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In some embodiments, the substance X is a compound of formula I, X is -C(R 5a )(R 5b )-, -C(=O)-, and -S(=O)-; Y is -C(R 6a )(R 6b )-, -S-, -O-, and -N(R 7 )-, and R 8a, R 8b , and R 8c is hydrogen, halo, C1-C4 alkyl, C 1- independently selected from the group consisting of C4 haloalkyl, C1-C4 alkoxy, and alkylsulfonyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0015] In some embodiments, the substance X is a compound of formula I, 3 and R 4 together with the carbon atom to which they are attached form a radical of the formula IA, IB, or IC, or a pharma- ceutically acceptable salt or solvate thereof.

[0016] In some embodiments, substance X is a compound of formula II: [ka] [In the formula, R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, Z, [ka] is as defined in Formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0017] In some embodiments, substance X is a compound of formula III, [ka] [In the formula, L is -C(R 8b )= and -N=; R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0018] In some embodiments, substance X is a compound of formula IV: [ka] [In the formula, L is -C(R 8b )= and -N=; R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0019] In some embodiments, the substance X is a compound of formula V: [ka] [In the formula, L is -C(R 8b )= and -N=; R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0020] In some embodiments, the substance X is a compound of formula VI: [ka] [In the formula, L is -C(R 8b )= and -N=; R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0021] In some embodiments, the substance X is a compound of any one of formulas III-VI, 8b)=], or a pharma- ceutically acceptable salt or solvate thereof.

[0022] In some embodiments, substance X is a compound of any one of formulae III-VI, where L is -N=, or a pharma- ceutically acceptable salt or solvate thereof.

[0023] In some embodiments, the substance X is a compound of any one of formulas I-VI, 8a , R 8b , and R 8c is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof. 8a is selected from the group consisting of -CHF2, -CF3, -CH3, -CD3, and cyclopropyl; R 8b and R 8c is hydrogen. 8a is selected from the group consisting of -CF3 or -CH3, R 8b and R 8c is hydrogen.

[0024] In some embodiments, the substance X is a compound of any one of formulas I-VI, 8a is selected from the group consisting of C1-C4 alkyl, 4-8 membered heterocyclo, and (heterocyclo)C1-C4 alkyl; R 8b and R 8c is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof. 8a is C1-C4 alkyl. In another embodiment, R 8a is a 4-8 membered heterocyclo. 8a is (heterocyclo)C1-C4 alkyl. In another embodiment, R 8a is selected from the group consisting of: [ka]

[0025] In some embodiments, the substance X is a compound of formula VII: [ka] [In the formula, L 1 -S-, -O-, and -N(R 8a )-, L 2 is -C(R 8b )= and -N=; L 3 is -C(R 8c )= and -N=; R 8a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8b is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 8c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0026] In some embodiments, the substance X is a compound of formula VIII: [ka] [In the formula, L 1 -S-, -O-, and -N(R 8a )-, L 2 is -C(R 8b )= and -N=; L 3 is -C(R 8c )= and -N=; R8a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8b is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 8c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0027] In some embodiments, the substance X is a compound of formula IX: [ka] [In the formula, L 1 -S-, -O-, and -N(R 8a )-, R 8a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8b is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 8c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0028] In some embodiments, the substance X is a compound of formula X: [ka] [In the formula, R 1 , R 2 , X, Y, Z, [ka] is as defined in Formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0029] In some embodiments, the substance X is a compound of formula XI: [ka] [In the formula, R 8d , R 8e , and R 8f is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl; n is 1, 2, or 3, and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0030] In some embodiments, substance X is a compound of formula XI-A: [ka] [In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , n, X, Y, and Z are as defined in formula XI], or a pharma- ceutically acceptable salt or solvate thereof.

[0031] In some embodiments, substance X is a compound of formula XI-B: [ka] [In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , n, X, Y, and Z are as defined in formula XI], or a pharma- ceutically acceptable salt or solvate thereof.

[0032] In some embodiments, substance X is a compound of formula XII: [ka] [In the formula, L 4 -S-, -O-, and -N(R 8g )-, R 8g is selected from the group consisting of hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 4-8 membered heterocyclo; o is 0, 1, 2, or 3; p is 0, 1, 2, or 3; where the sum of o and p is 1, 2, 3, 4, or 5; and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0033] In some embodiments, substance X is a compound of formula XII-A: [ka] [In the formula, R 1 , R 2 , L 4 , o, p, X, Y, and Z are as defined in formula XII], or a pharma- ceutically acceptable salt or solvate thereof.

[0034] In some embodiments, substance X is a compound of formula XII-B: [ka] [In the formula, R 1 , R 2 , L 4 , o, p, X, Y, and Z are as defined in formula XII], or a pharma- ceutically acceptable salt or solvate thereof.

[0035] In some embodiments, substance X is a compound of formula XIII: [ka] [In the formula, R 1 , R 2 , X, Y, Z, and [ka] is as defined in Formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0036] In some embodiments, the substance X is a compound of formula XIII-A: [ka] [In the formula, R 1 , R 2 , X, Y, Z, and [ka] is as defined in Formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0037] In some embodiments, substance X is a compound of formula XIII-B: [ka] [In the formula, R 1 , R 2 , X, Y, Z, and [ka] is as defined in Formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0038] In some embodiments, the substance X is a compound of formula XIV: [ka] [In the formula, R8d , R 8e , and R 8f is independently selected from the group consisting of hydrogen and C1-C4 alkyl; q is 1, 2, or 3, and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0039] In some embodiments, the substance X is a compound of formula XIV-A: [ka] [In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , q, X, Y, and Z are as defined in formula XIV], or a pharma- ceutically acceptable salt or solvate thereof.

[0040] In some embodiments, the substance X is a compound of formula XIV-B: [ka] [In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , q, X, Y, and Z are as defined in formula XIV], or a pharma- ceutically acceptable salt or solvate thereof.

[0041] In some embodiments, the substance X is a compound of formula XV: [ka] [In the formula, L 5 -S-, -O-, and -N(R 8h )-, R 8his hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-8 membered heterocyclo, -C(=O)R 14a , and -S(=O)R 14b is selected from the group consisting of R 14a and R 14b is independently selected from the group consisting of C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; r is 1, 2, or 3; s is 1, 2, or 3, and R 1 , R 2 , X, Y, and Z are as defined in formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0042] In some embodiments, substance X is a compound of formula XV-A: [ka] [In the formula, R 1 , R 2 , L 5 , r, s, X, Y, and Z are as defined in formula XV], or a pharma- ceutically acceptable salt or solvate thereof.

[0043] In some embodiments, the substance X is a compound of formula XV-B: [ka] [In the formula, R 1 , R 2 , L 5 , r, s, X, Y, and Z are as defined in formula XV], or a pharma- ceutically acceptable salt or solvate thereof.

[0044] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Z is -CH-, or a pharma- ceutically acceptable salt or solvate thereof.

[0045] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where X is -CH-, or a pharma- ceutically acceptable salt or solvate thereof.

[0046] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Z is -C(=O)-, or a pharma- ceutically acceptable salt or solvate thereof.

[0047] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Z is -S(=O)2, or a pharma- ceutically acceptable salt or solvate thereof.

[0048] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Y is -O-, or a pharma- ceutically acceptable salt or solvate thereof.

[0049] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Y is -N(R7)-, or a pharma- ceutically acceptable salt or solvate thereof. 7 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and optionally substituted C3-C8 cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0050] In some embodiments, the substance X is of formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Z is -CH-, X is -C(=O)-, and Y is -N(R 7 )-, or a pharma- ceutically acceptable salt or solvate thereof. 7 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and optionally substituted C3-C8 cycloalkyl. 7 is C1-C4 alkyl. In another embodiment, R 7 is selected from the group consisting of methyl, ethyl, propyl, or isopropyl.

[0051] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where XY together form an optionally substituted fused 5- or 6-membered heteroaryl, or a pharma- ceutically acceptable salt or solvate thereof. In another embodiment, X and Y together form a 5-membered heteroarylenyl ring.

[0052] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where X and Y together form a 5-membered heteroarylenyl of formula ID; [ka] [In the formula, X 1 =CR 15a - and =N-, Y 1 is -O-, -S-, and -NR 15c - selected from the group consisting of Z 1 =CR 15b - and =N-, R 15a and R 15b is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl; R 15c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; and " JPEG2024529118000040.jpg37" is bonded to Z], or a pharma- ceutically acceptable salt or solvate thereof.

[0053] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where X and Y together form a 5-membered heteroarylenyl ring of formula IE; [ka] [In the formula, X 2 =CR 16a- and =N-, Y 2 =CR 16b - and =N-, Z 2 =CR 16b - and =N-, and R 16a , R 16b , and R 16c is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; and " the bond designated "JPEG2024529118000042.jpg37" is bonded to Z], or a pharma- ceutically acceptable salt or solvate thereof.

[0054] In some embodiments, the substance X has formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X and Y are both selected from the following: [ka] forming a 5-membered heteroarylenyl ring selected from the group consisting of [In the formula, “ [ka] " is attached to Z], or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the substance X is a compound of formula XVI: [ka] [In the formula, R 1 , R 2 , R 3a , and R 4a is as defined in Formula I], or a pharma- ceutically acceptable salt or solvate thereof.

[0055] In some embodiments, the substance X is a compound of formula XVI, 3a is optionally substituted phenyl], or a pharma- ceutically acceptable salt or solvate thereof.

[0056] In some embodiments, the substance X is a compound of formula XVI, 3a is an optionally substituted 5-membered heteroaryl], or a pharma- ceutically acceptable salt or solvate thereof.

[0057] In some embodiments, the substance X is a compound of formula XVI, 3a is an optionally substituted 6-membered heteroaryl, or a pharma- ceutically acceptable salt or solvate thereof. 3a is selected from the group consisting of: [ka] .

[0058] In some embodiments, the substance X is a compound of formula XVI, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 3a is selected from the group consisting of: [ka] .

[0059] In some embodiments, the substance X is a compound of formula XVI, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 3a is selected from the group consisting of: [ka] In some embodiments, the substance X is a compound of formula XVI, 3a is an optionally substituted 4- to 6-membered heterocyclo], or a pharma- ceutically acceptable salt or solvate thereof.

[0060] In some embodiments, the substance X is a compound of formula XVI, 4a is C1-C4 haloalkyl], or a pharma- ceutically acceptable salt or solvate thereof.

[0061] In some embodiments, the substance X is a compound of formula XVI, 4a is -S(=O)2R 9 or a pharma- ceutically acceptable salt or solvate thereof.

[0062] In some embodiments, the substance X is a compound of formula XVI, 4a is -P(=O)(R 10a )(R 10b ) or a pharma- ceutically acceptable salt or solvate thereof.

[0063] In some embodiments, the substance X is a compound of formula XVI, 4a is -C(=O)OR 11a or a pharma- ceutically acceptable salt or solvate thereof. 11a is hydrogen.

[0064] In some embodiments, the substance X is a compound of formula XVI, 4a is -C(=O)NR 11b R 11c or a pharma- ceutically acceptable salt or solvate thereof.

[0065] In some embodiments, the substance X is a compound of formula XVI, 4a is -S(=O)(=NR 13a )R 13b or a pharma- ceutically acceptable salt or solvate thereof. 13a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 13b is C1-C4 alkyl. In another embodiment, R 13a and R 13bare both six-membered heterocyclos, e.g. [ka] Form.

[0066] In some embodiments, substance X is of formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 2 is hydrogen], or a pharma- ceutically acceptable salt or solvate thereof.

[0067] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 is R 1 -1, [ka] R 12a , R 12b , and R 12c are hydrogen, halo, C1-C4 alkyl, C1-C 4 independently selected from the group consisting of haloalkyl, and C1-C4 alkoxy; W is selected from the group consisting of -CH2- and -C(=O)-; and and t is 1 or 2], or a pharma- ceutically acceptable salt or solvate thereof.

[0068] In some embodiments, substance X is of formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is R 1 -1, R 12ais fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro, or a pharma- ceutically acceptable salt or solvate thereof. 12a is fluoro and R 12b and R 12c is hydrogen.

[0069] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 is R 1 -2, [ka] R 12a , R 12b , and R 12c are hydrogen, halo, C1-C4 alkyl, C1-C 4 independently selected from the group consisting of haloalkyl, and C1-C4 alkoxy; and t is 1 or 2], or a pharma- ceutically acceptable salt or solvate thereof.

[0070] In some embodiments, substance X is of formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is R 1 -2, R 12a is fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro, or a pharma- ceutically acceptable salt or solvate thereof. 12a is fluoro and R 12b and R 12cis hydrogen.

[0071] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 is R 1 -3, [ka] and R 12a , R 12b , and R 12c each is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, or a pharma- ceutically acceptable salt or solvate thereof.

[0072] In some embodiments, substance X is of formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is R 1 -3, R 12a is fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro, or a pharma- ceutically acceptable salt or solvate thereof. 12a is fluoro and R 12b and R 12c is hydrogen.

[0073] In some embodiments, substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1is R 1 -4, [ka] and R 12a , R 12b , and R 12c each is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, or a pharma- ceutically acceptable salt or solvate thereof.

[0074] In some embodiments, substance X is of formula I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is R 1 -4, R 12a is fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro, or a pharma- ceutically acceptable salt or solvate thereof. 12a is fluoro and R 12b and R 12c is hydrogen.

[0075] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is selected from the group consisting of: [ka] ], or a pharma- ceutically acceptable salt or solvate thereof.

[0076] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is selected from the group consisting of: [ka] ], or a pharma- ceutically acceptable salt or solvate thereof.

[0077] In some embodiments, the substance X is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, 1 is selected from the group consisting of: [ka] ], or a pharma- ceutically acceptable salt or solvate thereof.

[0078] In some embodiments, substance X is any one or more of the compounds listed in Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0079] [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

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

[0080] In some embodiments, substance X is a compound of formula I selected from the group consisting of: 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, and 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide, or a pharma- ceutically acceptable salt or solvate thereof.

[0081] In some embodiments, substance X is compound 73

[0082] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0083] In some embodiments, the subject may be a mammal.

[0084] In some embodiments, the subject may be a mouse or a human.

[0085] In some embodiments, a pharmaceutical composition may include substance X and an excipient and / or a pharma- ceutically acceptable carrier.

[0086] In some embodiments, the substance X, or the pharmaceutical composition, may be administered orally.

[0087] In some embodiments, the substance X, or pharmaceutical composition, may be administered one or more times per day.

[0088] In some embodiments, the substance X, or pharmaceutical composition, may be administered one or more times per week.

[0089] In some embodiments, substance X may be administered to a subject in need thereof in an amount of 3 mg / kg to 90 mg / kg per dose.

[0090] In some embodiments, substance X may be administered to a subject in need thereof in an amount of 3 mg / kg, 10 mg / kg, 30 mg / kg, or 90 mg / kg per dose.

[0091] In some embodiments, the substance X, or pharmaceutical composition, may be administered continuously for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

[0092] In some embodiments, the disease or disorder associated with defective hemoglobin protein activity or expression is a blood disorder, preferably anemia.

[0093] In some embodiments, the disease or disorder associated with defective hemoglobin protein activity or expression is selected from the group consisting of sickle cell disease, beta thalassemia, beta thalassemia intermedia, beta thalassemia major, beta thalassemia minor, chemotherapy-induced anemia, chronic kidney disease-related anemia, and Cooley anemia. Preferably, the disease or disorder is sickle cell disease or beta thalassemia.

[0094] In another aspect, the present invention provides a method for reducing H3K27me3 levels in erythroid cells or in PBMC monocytes, comprising administering to a subject in need thereof a therapeutically effective amount of a substance X or a pharmaceutical composition comprising said substance X, wherein said substance X is as defined above and said pharmaceutical composition is as defined above.

[0095] In some embodiments, the erythroid cells may be bone marrow-derived erythroid cells.

[0096] In some embodiments, the erythroid cells may be bone marrow-derived TER119+ erythroid cells.

[0097] In some embodiments, the subject may be suffering from a disease or disorder associated with defective hemoglobin protein activity or expression.

[0098] In some embodiments, the disease or disorder associated with defective hemoglobin protein activity or expression is a blood disorder, preferably anemia.

[0099] In some embodiments, the disease or disorder associated with defective hemoglobin protein activity or expression is selected from the group consisting of sickle cell disease, beta thalassemia, beta thalassemia intermedia, beta thalassemia major, beta thalassemia minor, chemotherapy-induced anemia, chronic kidney disease-related anemia, and Cooley anemia. Preferably, the disease or disorder is sickle cell disease or beta thalassemia.

[0100] In some embodiments, the subject may be a mammal.

[0101] In some embodiments, the subject may be a mouse or a human.

[0102] In some embodiments, a pharmaceutical composition may include substance X and an excipient and / or a pharma- ceutically acceptable carrier.

[0103] In some embodiments, the substance X, or the pharmaceutical composition, may be administered orally.

[0104] In some embodiments, the substance X, or pharmaceutical composition, may be administered one or more times per day.

[0105] In some embodiments, the substance X, or pharmaceutical composition, may be administered one or more times per week.

[0106] In some embodiments, substance X may be administered to a subject in need thereof in an amount of 3 mg / kg to 90 mg / kg per dose.

[0107] In some embodiments, substance X may be administered to a subject in need thereof in an amount of 3 mg / kg, 10 mg / kg, 30 mg / kg, or 90 mg / kg per dose.

[0108] In some embodiments, the substance X, or pharmaceutical composition, may be administered continuously for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

[0109] In another aspect, the present invention provides a method for increasing Hbb-bh1 mRNA levels, HBG gene levels (HBG1, HBG2), gamma hemoglobin levels or HbF levels, comprising administering to a subject in need thereof a therapeutically effective amount of substance X or a pharmaceutical composition comprising said substance X, wherein said substance X is as defined above and said pharmaceutical composition is as defined above.

[0110] In some embodiments, the Hbb-bh1 mRNA level may be the Hbb-bh1 mRNA level in blood, for example, peripheral blood.

[0111] In some embodiments, the Hbb-bh1 mRNA level may be the Hbb-bh1 mRNA level in the blood of a CD-1 mouse.

[0112] In some embodiments, the HBG1 gene level may be the HBG1 gene level in blood, for example, peripheral blood.

[0113] In some embodiments, the HBG1 gene level may be the HBG1 gene level in human blood.

[0114] In some embodiments, the HBG2 gene level may be the HBG2 gene level in blood, for example peripheral blood.

[0115] In some embodiments, the HBG2 gene level may be the HBG2 gene level in the human's blood.

[0116] In some embodiments, the gamma hemoglobin level may be the gamma hemoglobin level in blood, for example, peripheral blood.

[0117] In some embodiments, the gamma hemoglobin level may be the gamma hemoglobin level in human blood.

[0118] In some embodiments, the HbF level may be the HbF level in blood, for example, peripheral blood.

[0119] In some embodiments, the HbF level may be the HbF level in human blood.

[0120] In some embodiments, the subject may be suffering from a disease or disorder associated with defective hemoglobin protein activity or expression.

[0121] In some embodiments, the subject may be a mammal.

[0122] In some embodiments, the subject may be a mouse or a human.

[0123] In some embodiments, a pharmaceutical composition may include substance X and an excipient and / or a pharma- ceutically acceptable carrier.

[0124] In some embodiments, the substance X, or the pharmaceutical composition, may be administered orally.

[0125] In some embodiments, the substance X, or pharmaceutical composition, may be administered one or more times per day.

[0126] In some embodiments, the substance X, or pharmaceutical composition, may be administered one or more times per week.

[0127] In some embodiments, substance X may be administered to a subject in need thereof in an amount of 3 mg / kg to 90 mg / kg per dose.

[0128] In some embodiments, substance X may be administered to a subject in need thereof in an amount of 3 mg / kg, 10 mg / kg, 30 mg / kg, or 90 mg / kg per dose.

[0129] In some embodiments, the substance X, or pharmaceutical composition, may be administered continuously for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

[0130] In some embodiments, the disease or disorder associated with defective hemoglobin protein activity or expression is a blood disorder, preferably anemia.

[0131] In some embodiments, the disease or disorder associated with defective hemoglobin protein activity or expression is selected from the group consisting of sickle cell disease, beta thalassemia, beta thalassemia intermedia, beta thalassemia major, beta thalassemia minor, chemotherapy-induced anemia, chronic kidney disease-related anemia, and Cooley anemia. Preferably, the disease or disorder is sickle cell disease or beta thalassemia.

[0132] In some embodiments, the methods include using a second therapeutic agent, preferably erythropoietin (EPO).

[0133] In some embodiments, the innate immune response that is a type 1 or type 3 immune-related immunodeficiency is an inflammatory bowel disease, including Crohn's disease and ulcerative colitis.

[0134] In some embodiments, the innate immune response that is a type 1 or type 3 immune-related immunodeficiency is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APGS), aplastic anemia, autoimmune hemolytic anemia (AIHA), autoimmune hepatitis (AIH), autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune thrombocytopenic purpura (AITP), Behçet's disease, bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Crohn's disease, dermatomyositis, familial dysautonomia, epidermolysis bullosa, pemphigoid in pregnancy, giant cell arteritis, Goodpasture's syndrome, multiple myelopathy, ... The present invention relates to a method for treating ulcerative colitis, granulomatous disease with vasculitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, immunoglobulin A (IgA) neuropathy, ulcerative colitis, interstitial cystitis (IC), Kawasaki disease, Lambert-Eaton myasthenic syndrome (LEMS), chronic Lyme disease, Mooren's ulcer, morphea, myasthenia gravis, neuromyotonia, multiple sclerosis, strabismus clonicus syndrome, optic neuritis, Ordothyroiditis, pemphigus, pernicious anemia, polyarteritis, polyarthritis, polyglandular autoimmune syndrome, primary biliary cirrhosis, psoriasis, Reiter's syndrome, sarcoidosis, rheumatoid arthritis, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu's arthritis, and Vogt-Koyanagi-Harada disease.

[0135] In another aspect, the present invention provides a pharmaceutical composition comprising: (i) substance X; and (ii) erythropoietin.

[0136] In some embodiments, substance X may be administered in an amount of 10-30 mg / kg, preferably 15 mg / kg.

[0137] In some embodiments, erythropoietin (EPO) may be administered in an amount of 10-100 U / kg, preferably 50 U / kg.

[0138] In some embodiments, the innate immune response that is a type 1 or type 3 immune-related immunodeficiency is an inflammatory bowel disease, including Crohn's disease and ulcerative colitis.

[0139] In some embodiments, the innate immune response that is a type 1 or type 3 immune-related immunodeficiency is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APGS), aplastic anemia, autoimmune hemolytic anemia (AIHA), autoimmune hepatitis (AIH), autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune thrombocytopenic purpura (AITP), Behçet's disease, bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Crohn's disease, dermatomyositis, familial dysautonomia, epidermolysis bullosa, pemphigoid in pregnancy, giant cell arteritis, Goodpasture's syndrome, multiple myelopathy, ... The present invention relates to a method for treating ulcerative colitis, granulomatous disease with vasculitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, immunoglobulin A (IgA) neuropathy, ulcerative colitis, interstitial cystitis (IC), Kawasaki disease, Lambert-Eaton myasthenic syndrome (LEMS), chronic Lyme disease, Mooren's ulcer, morphea, myasthenia gravis, neuromyotonia, multiple sclerosis, strabismus clonicus syndrome, optic neuritis, Ordothyroiditis, pemphigus, pernicious anemia, polyarteritis, polyarthritis, polyglandular autoimmune syndrome, primary biliary cirrhosis, psoriasis, Reiter's syndrome, sarcoidosis, rheumatoid arthritis, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu's arthritis, and Vogt-Koyanagi-Harada disease.

[0140] In some embodiments, substance X may be administered in an amount of 10-100 mg / kg, preferably 50 mg / kg or 90 mg / kg.

[0141] The term "preventing" refers to a method of preventing the onset of a disease or condition and / or its associated symptoms or of preventing a subject from contracting a disease. As used herein, "preventing" also includes delaying the onset of a disease and / or its associated symptoms, as well as reducing a subject's risk of contracting a disease. The term "preventing" can include "prophylactic treatment", which refers to reducing the likelihood of a disease or condition reoccurring or a previously controlled disease or condition recurring in a subject who has not experienced, but is at risk of or susceptible to, a reoccurrence of a disease or condition or a recurrence of a disease or condition.

[0142] The term "treating" means to eliminate, reduce, or alleviate a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treating" and synonyms contemplate administering a therapeutically effective amount of a compound to a subject in need of such treatment. Treatment can be symptomatic, e.g., to suppress symptoms. For example, in the context of maintenance therapy, symptomatic treatment can be short-term, medium-term, or long-term treatment.

[0143] The term "subject" means any animal, including a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human. A preferred subject is a human.

[0144] The term "therapeutically effective amount" of a substance or pharmaceutical composition means an amount sufficient to cure, alleviate, or partially arrest the clinical symptoms of a given disease or disorder and its complications. The amount effective for a particular therapeutic purpose will vary depending on the severity of the disease or injury, as well as the weight and general condition of the subject. It is understood that the determination of an appropriate dosage can be accomplished using routine experimentation, by constructing a matrix of values, and testing different points in the matrix, all of which is within the ordinary skill of a trained physician or clinical scientist.

[0145] The term "pharmaceutical acceptable salt" refers to a salt or zwitterionic form of a compound. The salt of a compound can be prepared during the final isolation and purification of the compound or by separately reacting the compound with a suitable acid. The pharmaceutical acceptable salt of a compound can be an acid addition salt formed with a pharmaceutical acceptable acid. Examples of acids that can be used to form pharmaceutical acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Non-limiting examples of salts of the compounds include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate. The salts include, but are not limited to, salts, naphthylenesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, paratoluenesulfonates, undecanoates, lactates, citrates, tartrates, gluconates, methanesulfonates, ethanedisulfonates, benzenesulfonates, and p-toluenesulfonates. Additionally, available amino groups present in the compounds can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl chlorides, bromides, and iodides, lauryl, myristyl, and stearyl; and benzyl and phenethyl bromides.

[0146] The term "solvate" refers to a combination, physical association, and / or solvation of a compound of the present invention with a solvent molecule, e.g., a disolvate, a monosolvate, or a hemisolvate, where the ratio of the solvent molecules to the compound of the present invention is about 2:1, about 1:1, or about 1:2, respectively. This physical association requires varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. The compound can exist in a solvated form with a pharma-ceutically acceptable solvent, such as water, methanol, ethanol, and the like. In some embodiments, the solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates usually function as pharmacological equivalents. Preparation of solvates is known in the art. A typical, non-limiting process for preparing a solvate includes dissolving the compound in a desired solvent (organic, aqueous, or a mixture thereof) at a temperature of at least 20° C. and not more than about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in the solvate crystals.

[0147] The terms "chronic kidney disease-associated anemia" and "chronic kidney disease-induced anemia" are used interchangeably herein.

[0148] In the context of the present invention (particularly in the context of the claims), use of the terms "a," "an," "the," and similar referents are to be interpreted as covering both the singular and the plural, unless otherwise indicated.

[0149] The term "halo" as used herein, alone or as part of another group, means -Cl, -F, -Br, or -I.

[0150] The term "nitro" as used herein alone or as part of another group means --NO.sub.2.

[0151] The term "cyano" as used herein alone or as part of another group means --CN.

[0152] As used herein, the term "hydroxy" used alone or as part of another group, refers to --OH.

[0153] The term "alkyl" as used herein alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon containing 1 to 12 carbon atoms, i.e., C1-C 12 Alkyl or the number of carbon atoms indicated, for example, C alkyl, such as methyl, C alkyl, such as ethyl, etc. In one embodiment, alkyl is a C-C 10 In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. In another embodiment, one or more hydrogen atoms of an alkyl group are replaced with a deuterium atom, i.e., the alkyl group is isotopically labeled with deuterium. A non-limiting exemplary deuterated alkyl group is -CD3.

[0154] The term "optionally substituted alkyl" as used herein alone or as part of another group means an alkyl group that is unsubstituted or substituted with one, two, or three substituents, where each substituent is independently selected from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl, carboxyalkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , or -S(=O)2R 58 where: R 56a is hydrogen or alkyl, R 56b is an alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C-C 10 aryl, or optionally substituted heteroaryl; R 56c is hydrogen or alkyl, R 56d is an alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C-C 10 aryl, or optionally substituted heteroaryl; R 56eis an alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C-C 10 aryl, or optionally substituted heteroaryl; R 57 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl, and R 58 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl. Non-limiting examples of optionally substituted alkyl include -CH(COMe)CHCOMe, and -CH(CH)CHN(H)C(=O)O(CH).

[0155] The term "alkenyl" as used herein alone or as part of another group refers to an alkyl group containing one, two, or three carbon-carbon double bonds. In one embodiment, an alkenyl group is a C2-C6 alkenyl group. In another embodiment, an alkenyl group is a C2-C4 alkenyl group. In another embodiment, an alkenyl group has one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0156] The term "optionally substituted alkenyl" as used herein alone or as part of another group refers to an alkenyl group that is unsubstituted or substituted with one, two, or three substituents, each of which is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. A non-limiting example of an optionally substituted alkenyl includes --CH=CHPh.

[0157] The term "alkynyl" as used herein alone or as part of another group refers to an alkyl group containing one, two, or three carbon-carbon triple bonds. In one embodiment, an alkynyl is a C2-C6 alkynyl. In another embodiment, an alkynyl is a C2-C4 alkynyl. In another embodiment, an alkynyl has one carbon-carbon triple bond. Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0158] The term "optionally substituted alkynyl" as used herein alone or as part of another group refers to an alkynyl group that is unsubstituted or substituted with one, two, or three substituents, each of which is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting examples of optionally substituted alkynyl include --C≡CPh and --CH(Ph)C≡CH.

[0159] The term "haloalkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted with one, two, or three fluorine atoms. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0160] The term "hydroxyalkyl" or "(hydroxy)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting examples of (hydroxyl)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

[0161] The term "alkoxy" as used herein alone or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C1-C6 alkyl, such that the resulting alkoxy is referred to as a "C1-C6 alkoxy." In another embodiment, the alkyl is a C1-C4 alkyl group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0162] The term "haloalkoxy" as used herein alone or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6 haloalkyl. In another embodiment, the haloalkyl group is a C1-C4 haloalkyl group. Non-limiting examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0163] The term "alkylthio" as used herein alone or as part of another group refers to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting examples of alkylthio groups include -SCH3 and -SCH2CH3.

[0164] The term "alkoxyalkyl" or "(alkoxy)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with an alkoxy group. In one embodiment, an alkoxy is a C1-C6 alkoxy. In another embodiment, an alkoxy is a C1-C4 alkoxy. In another embodiment, an alkyl is a C1-C6 alkyl. In another embodiment, an alkyl is a C1-C4 alkyl. Non-limiting examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0165] The term "heteroalkyl" used alone or as part of another group means an unsubstituted straight or branched chain aliphatic hydrocarbon containing 3 to 20 chain atoms, i.e., a 3- to 20-membered heteroalkyl ring, or the number of carbon atoms indicated, where at least one -CH2- is replaced with one of O-, -N(H)-, -N(C1-C4 alkyl)-, or -S-. The -O-, -N(H)-, -N(C1-C4 alkyl)-, or -S- can be independently located at any interior position of the aliphatic hydrocarbon chain, provided that each -O-, -N(H)-, -N(C1-C4 alkyl)-, and -S- group is separated by at least two -CH2- groups. In one embodiment, one -CH2- group is replaced with one -O- group. In another embodiment, two -CH2- groups are replaced with two -O- groups. In another embodiment, three -CH2- groups are replaced with three -O- groups. In another embodiment, four -CH2- groups are replaced with four -O- groups. Non-limiting examples of heteroalkyl groups include -CH2OCH3, -CH2OCH2CH2CH3, -CH2CH2CH2OCH3, --CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3.

[0166] The term "cycloalkyl" as used herein alone or as part of another group refers to saturated and partially unsaturated monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing, for example, 3 to 12 carbon atoms, i.e., C3- 12 Cycloalkyl refers to cycloalkyl or the indicated number of carbons, e.g., C3 cycloalkyl, such as cyclopropyl, C4 cycloalkyl, such as cyclobutyl, etc. In one embodiment, cycloalkyl is bicyclic, i.e., has two rings. In another embodiment, cycloalkyl is monocyclic, i.e., has one ring. In another embodiment, cycloalkyl is C3-8 cycloalkyl. In another embodiment, cycloalkyl is C 3-6In another embodiment, the cycloalkyl is a C5 cycloalkyl, i.e., cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C6 cycloalkyl, i.e., cyclohexyl. C3- 12 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0167] The term "optionally substituted cycloalkyl," as used herein alone or as part of another group, means a cycloalkyl group that is unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from halo, nitro, cyano, hydroxy, amino (e.g., -NH, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, aryl ... alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 -OR 59 where R 56a , R56b , R 56c , R 56d , R 56e , R 57 , and R 58 is as defined under the term "optionally substituted alkyl" and R 59 is (hydroxy)alkyl or (amino)alkyl. The term "optionally substituted cycloalkyl" further includes cycloalkyl groups having a fused optionally substituted aryl or optionally substituted heteroaryl, such as:

[0168] [ka]

[0169] Non-limiting examples of optionally substituted cycloalkyls include:

[0170] [ka]

[0171] The term "heterocyclo" as used herein alone or as part of another group refers to saturated and partially unsaturated monocyclic, bicyclic, or tricyclic groups containing from 3 to 14 ring members, i.e., heterocyclos with 1, 2, 3, or 4 heteroatoms, e.g., containing one or two double bonds. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to a sulfoxide, i.e., S(=O), or a sulfone, i.e., S(=O)2.

[0172] The term "heterocyclo" includes groups in which one or more -CH groups are replaced with one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one.

[0173] The term "heterocyclo" further includes groups having a fused optionally substituted aryl or an optionally substituted heteroaryl, such as indoline, indolin-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0174] In one embodiment, the heterocyclo group is a 4-8 membered ring containing one ring and one or two oxygen atoms, such as tetrahydrofuran or tetrahydropyran, or a 4-8 membered ring containing one or two nitrogen atoms, such as pyrrolidine, piperidine, or piperazine, or a 4-8 membered ring containing one oxygen and one nitrogen atom, such as morpholine, optionally with one -CH2- group substituted with one -C(=O)- group, i.e., pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5-8 membered ring containing one ring and one or two nitrogen atoms, optionally with one -CH2- group substituted with a -C(=O) group. In another embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally one -CH2- group is replaced with a -C(=O) group. In another embodiment, the heterocyclo group is an 8-12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be attached to the remainder of the molecule through any available carbon or nitrogen atom. Non-limiting examples of heterocyclo groups include the following:

[0175] [ka]

[0176] The term "optionally substituted heterocyclo" as used herein alone or as part of another group means a heterocyclo group that is unsubstituted or substituted with 1 to 4 substituents, each of which is independently selected from halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, aryloxy ... , carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 -OR 59 where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , and R 59 is as defined in the term "optionally substituted cycloalkyl". The substitution can occur on any available carbon or nitrogen atom of the heterocyclo group. Non-limiting examples of optionally substituted heterocyclos include: [ka]

[0177] The term "aryl" as used herein alone or as part of another group refers to an aromatic ring system having 6 to 14 carbon atoms, i.e., C6-C 14 means aryl. Non-limiting examples of aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0178] The term "optionally substituted aryl" as used herein alone or as part of another group means aryl that is unsubstituted or substituted with 1 to 5 substituents, each of which is independently selected from halo, nitro, cyano, hydroxy, amino (e.g., -NH, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 -OR 59 where R 56a , R 56b , R 56c , R56d , R 56e , R 57 , R 58 , and R 59 is as defined for the term "optionally substituted cycloalkyl."

[0179] In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-limiting examples of optionally substituted aryl include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term "optionally substituted aryl" includes aryl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo groups. Non-limiting examples include 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and 2-oxo, 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl.

[0180] The term "heteroaryl" as used herein alone or as part of another group refers to monocyclic and bicyclic aromatic ring systems having 5-14 ring members, i.e., 5-14 membered heteroaryls, containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has 3 heteroatoms. In another embodiment, the heteroaryl has 2 heteroatoms. In another embodiment, the heteroaryl has 1 heteroatom. In another embodiment, the heteroaryl is a 5-10 membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, which is a 5 membered heteroaryl having 4 carbon atoms and 1 sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, which is a 6 membered heteroaryl having 5 carbon atoms and 1 nitrogen atom. Non-limiting examples of heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthronyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl.In one embodiment, heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., For example, pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term "heteroaryl" further includes N-oxides. A non-limiting example of an N-oxide is pyridyl N-oxide.

[0181] The term "optionally substituted heteroaryl" as used herein alone or as part of another group means heteroaryl that is unsubstituted or substituted with one to four substituents, the substituents being independently selected from halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, aryloxy ... , carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 -OR 59 where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , and R 59 is as defined for the term "optionally substituted cycloalkyl."

[0182] In one embodiment, the optionally substituted heteroaryl has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

[0183] The term "5-membered heteroarylenyl" as used herein alone or as part of another group refers to the divalent form of an optionally substituted 5-membered heteroaryl. In one embodiment, the heteroarylenyl is a substituted 5-membered heteroarylenyl. In one embodiment, the heteroarylenyl is an unsubstituted 5-membered heteroarylenyl. Non-limiting examples of 5-membered heteroarylenyls include the following: [ka]

[0184] The term "aryloxy" as used herein alone or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting example of an aryloxy group is PhO-.

[0185] The term "heteroaryloxy" as used herein alone or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom. A non-limiting example of an aryloxy group is -O-.

[0186] The term "aralkyloxy" as used herein alone or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting example of an aralkyloxy group is PhCH2O-.

[0187] The term "(cyano)alkyl" as used herein alone or as part of another group refers to an alkyl substituted with one, two, or three cyano groups. In one embodiment, the alkyl is substituted with one cyano group. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting examples of (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0188] The term "(cycloalkyl)alkyl" as used herein alone or as part of another group refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting examples of (cycloalkyl)alkyl groups include: [ka]

[0189] The term "sulfonamide" as used herein alone or as part of another group refers to a group of the formula -SONR 50a R 50b where R 50a and R 50b are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R 50a and R 50b together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. Non-limiting examples of sulfonamide groups include --SO2NH2, --SO2N(H)CH3, and --SO2N(H)Ph.

[0190] The term "carboxamide" as used herein alone or as part of another group refers to a group of the formula -C(=O)NR 50c R 50d where R 50c and R 50dare each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R 50c and R 50d together with the nitrogen to which they are attached form a 3- to 8-membered, optionally substituted heterocyclo group. Non-limiting examples of carboxamide groups include -C(=O)NH2, -C(=O)(H)CH3, and -C(=O)N(CH3)2.

[0191] The term "alkylcarbonyl" as used herein alone or as part of another group refers to a carbonyl group substituted with an alkyl group, i.e., -C(=O)-. In one embodiment, the alkyl is a C1-C4 alkyl. A non-limiting example of an alkylcarbonyl group is -COCH3.

[0192] The term "arylcarbonyl" as used herein alone or as part of another group refers to a carbonyl group substituted with an optionally substituted aryl, i.e., -C(=O)-. A non-limiting example of an arylcarbonyl group is -COPh.

[0193] The term "alkylsulfonyl" as used herein alone or as part of another group refers to a sulfonyl group substituted with an alkyl group, i.e., -SO2-. A non-limiting example of an alkylsulfonyl group is -SO2CH3.

[0194] The term "arylsulfonyl" as used herein alone or as part of another group refers to a sulfonyl group substituted with a substituted aryl group, i.e., -SO2-. A non-limiting example of an arylsulfonyl group is -SO2Ph.

[0195] The term "mercaptoalkyl" as used herein alone or as part of another group refers to an alkyl substituted with an --SH group.

[0196] The term "carboxy" used alone or as part of another group means a radical of the formula -C(=O)OH.

[0197] The term "ureido" as used herein alone or as part of another group refers to a group of the formula -NR 51a -C(=O)-NR 51b R 51c where R 51a is hydrogen or alkyl; R 51b and R 51c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R 51b and R 51c together with the nitrogen to which they are attached form a 4-8 membered optionally substituted heterocyclo group. Non-limiting examples of ureido groups include -NH-C(C=O)-NH2 and -NH-C(C=O)-NHCH3.

[0198] The term "guanidino" as used herein alone or as part of another group refers to a group of the formula -NR 52a -C(NR 53 )-NR 52b R 52c where R 52a is hydrogen or alkyl; R 52b and R 52c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R 52b and R 52c together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclic ring; R 53 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamide, or sulfonamide. Non-limiting examples of guanidino groups include -NH-C(C=NH)-NH2, NHC(C=NCN)-NH2, and NH-C(C=NH)-NHCH3.

[0199] The term "(heterocyclo)alkyl" as used herein alone or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the alkyl is substituted with one optionally substituted 5-8 membered heterocyclo group. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. The heterocyclo group can be attached to the alkyl group via a carbon or nitrogen atom. Non-limiting examples of (heterocyclo)alkyl groups include: [ka]

[0200] The term "carbamate" as used herein alone or as part of another group refers to a group of the formula -NR 54a -C(=O)-OR 54b where R 54a is hydrogen or alkyl; R 54b is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting example of a carbamate group is -NH-(C=O)-OtBu.

[0201] The term "(heteroaryl)alkyl" as used herein alone or as part of another group refers to an alkyl substituted with one or two optionally substituted heteroaryl groups. In one embodiment, an alkyl group is substituted with one optionally substituted 5-14 membered heteroaryl group. In another embodiment, an alkyl group is substituted with two optionally substituted 5-14 membered heteroaryl groups. In another embodiment, an alkyl group is substituted with one optionally substituted 5-9 membered heteroaryl group. In another embodiment, an alkyl group is substituted with two optionally substituted 5-9 membered heteroaryl groups. In another embodiment, an alkyl group is substituted with one optionally substituted 5- or 6 membered heteroaryl group. In another embodiment, an alkyl group is substituted with two optionally substituted 5- or 6 membered heteroaryl groups. In one embodiment, an alkyl group is a C1-C6 alkyl. In another embodiment, an alkyl group is a C1-C4 alkyl. In another embodiment, an alkyl group is a C1 or C2 alkyl. Non-limiting examples of (heteroaryl)alkyl groups include: [ka]

[0202] The term "aralkyl" or "(aryl)alkyl" as used herein alone or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or an optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting examples of (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0203] The term "amide" as used herein alone or as part of another group refers to a group of the formula --C(=O)NR 60a R 60b where R 60a and R 60b are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl; 60a and R 60b together with the nitrogen to which they are attached form a 4-8 membered optionally substituted heterocyclo group. 60a and R 60b are each independently hydrogen or C1-C6 alkyl.

[0204] The term "amino" used alone or as part of another group refers to a group of the formula -NR55a R 55b where R 55a and R 55b is independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl.

[0205] In one embodiment, amino is -NH2.

[0206] In another embodiment, amino is “alkylamino”, i.e., R 55a C 1-6 is alkyl, R 55b is an amino group where R 55a is C1-C4 alkyl. Non-limiting examples of alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0207] In another embodiment, amino is “dialkylamino”, i.e., R 55a and R 55b are each independently, C 16 In one embodiment, R 55a and R 55b is each independently C1-C4 alkyl. Non-limiting examples of dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0208] In another embodiment, amino is “hydroxyalkylamino”, i.e., R 55a is (hydroxyl)alkyl, and R 55b is an amino group where R is hydrogen or C1-C4 alkyl.

[0209] In another embodiment, amino is "cycloalkylamino", i.e., R 55a is optionally substituted cycloalkyl; R 55b is an amino group where R is hydrogen or C1-C4 alkyl.

[0210] In another embodiment, amino is an "aralkylamino", i.e., R 55a is aralkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting examples of aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0211] In another embodiment, amino is “(cycloalkyl)alkylamino”, i.e., R 55a is (cycloalkyl)alkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting examples of (cycloalkyl)alkylamino include: [ka]

[0212] In another embodiment, amino is “(heterocyclo)alkylamino”, i.e., R 55a is (heterocyclo)alkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting examples of (heterocyclo)alkylamino include: [ka]

[0213] The term "(amino)alkyl" as used herein alone or as part of another group refers to an alkyl substituted with an amino group. In one embodiment, the amino group is -NH2. In one embodiment, the amino group is an alkylamino. In another embodiment, the amino group is a dialkylamino. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting examples of (amino)alkyl groups include -CH2NH2, CH2CH2N(H)CH3, -CH2CH2N(CH3)2, CH2N(H)cyclopropyl, -CH2N(H)cyclobutyl, and -CH2N(H)cyclohexyl, and -CH2CH2CH2N(H)CH2Ph, and -CH2CH2CH2N(H)2(4-CF3-Ph).

[0214] The present disclosure encompasses any of the compounds of formula I that are isotopically labeled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, for example, 2 H (or deuterium (D)), 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl, e.g. 3 H, 11 C, and 14C. In one embodiment, a compound is provided in which substantially all atoms at positions in substance X are replaced by atoms having a different atomic mass or mass number. In another embodiment, a compound is provided in which substantially all atoms at positions in substance X are replaced by deuterium atoms, e.g., all hydrogen atoms of -CH3 groups are replaced by deuterium atoms to form -CD3 groups. In another embodiment, a compound is provided in which a portion of atoms at positions in substance X are replaced, i.e., substance X is enriched at the positions of atoms having different atomic masses or mass numbers. In another embodiment, a compound is provided in which none of the atoms of substance X are replaced by atoms having different atomic masses or mass numbers. Isotopically labeled compounds of formula I can be prepared by methods known in the art-.

[0215] The compounds of formula I may contain one or more asymmetric centers, and therefore may give rise to enantiomers, diastereomers, and other stereoisomers. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms, and mixtures thereof. In view of the present disclosure, individual enantiomers can be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, it is intended to include both E and Z geometric isomers, unless otherwise indicated. All tautomers are also encompassed by the present disclosure.

[0216] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. "Stereoisomers" includes enantiomers and isomers of compounds with two or more chiral centers that are not mirror images of one another (diastereomers).

[0217] The term "chiral center" or "asymmetric carbon atom" means a carbon atom to which four different groups are attached.

[0218] The terms "enantiomer" and "enantiomeric" refer to molecules that are not superimposable in their mirror images; therefore, when an enantiomer rotates the plane of polarized light in one direction, its mirror image has optical activity that rotates the plane of polarized light in the opposite direction.

[0219] The term "racemate" refers to a mixture of equal parts of enantiomers, said mixture being optically inactive. In one embodiment, the compound of formula I is racemic.

[0220] The term "absolute configuration" refers to the arrangement in space of the atoms of a chiral molecular entity (or group) and its stereochemical designation, e.g., R or S.

[0221] Stereochemical terms and conventions used herein have the meanings consistent with those disclosed in Pure & Appl. Chem 68:2193 (1996), unless otherwise specified.

[0222] The term "enantiomeric excess", or "ee", refers to a measure of how much more of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the enantiomeric excess is defined as |RS|*100, where R and S are the mole or weight fractions of each of the enantiomers in the mixture, and R+S=1. With knowledge of the optical rotation of a chiral substance, the enantiomeric excess can be calculated by the ratio ([α] obs / [α] max )*100, where [α] obs is the optical rotation of the mixture of enantiomers, [α] max is the optical rotation of the pure enantiomer. Enantiomeric excess can be measured using a variety of analytical techniques, including NMR spectroscopy, column chromatography, or polarimetry.

[0223] As used herein, the term "about" includes the recited number plus or minus 10%. Thus, "about 10" means 9 to 11.

[0224] The pharmaceutical composition can be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Suitable formulations vary according to the route of administration selected. The pharmaceutical composition is usually in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the pharmaceutical composition can further contain a solid carrier such as gelatin or an adjuvant. The tablets, capsules, and powders contain about 0.01% to about 95%, and preferably about 1% to about 50%, of substance X. When administered in liquid form, a liquid carrier such as water, petroleum, or oil of animal or vegetable origin can be added. The pharmaceutical composition in liquid form can further contain saline, dextrose or other sugar solution, or glycol. When administered in liquid form, the pharmaceutical composition contains about 0.1% to about 90% by weight, and preferably about 1% to about 50% by weight of substance X.

[0225] When the pharmaceutical composition is administered by intravenous, cutaneous or subcutaneous injection, the pharmaceutical composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking into consideration pH, isotonicity, stability, etc., is within the skill of the art. Pharmaceutical compositions suitable for intravenous, cutaneous or subcutaneous injection usually contain an isotonic carrier.

[0226] Substance X can be easily combined with pharma- ceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers allow the active agent to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Medicaments for oral use can be obtained by adding substance X to a solid excipient, optionally grinding the resulting mixture, processing the granulated mixture, and obtaining tablets or dragee cores after adding suitable auxiliary agents, if necessary. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, disintegrants can be added.

[0227] The pharmaceutical composition can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.The preparation for injection can be in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives.The pharmaceutical composition can take the form of a suspension, solution, or emulsion in an oily or aqueous carrier, and can contain formulating agents such as suspending, stabilizing, and / or dispersing agents.

[0228] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Furthermore, the suspension of substance X can be prepared as a suitable oily injection suspension. Suitable lipophilic solvents or carriers include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can further contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the pharmaceutical composition can be in powder form for constitution with a suitable carrier, for example, sterile pyrogen-free water, before use.

[0229] The pharmaceutical composition can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases. In addition to the above-mentioned formulations, the pharmaceutical composition can also be formulated as a depot preparation. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, substance X can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or with an ion exchange resin.

[0230] Specifically, the pharmaceutical composition can be administered orally, bucally, or sublingually, alone or in a mixture with excipients, in the form of tablets, capsules, or avules containing excipients such as starch or lactose, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid formulations can be prepared with pharma- ceutically acceptable additives, such as suspending agents. Substance X can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the substance is usually used in the form of a sterile aqueous solution, which can contain other substances, such as salts or monosaccharides (e.g., mannitol or glucose), to make the solution isotonic with blood.

[0231] The use of any and all examples or exemplary language (e.g., "in some embodiments") provided herein is intended to better describe the invention and does not limit the scope of the invention, unless otherwise stated in the claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. EXAMPLES

[0232] The present invention is further described in the following non-limiting examples.

[0233] Compound 73 used in the following embodiments is [ka] It is.

[0234] EMBODIMENT 1 1.Animals

[0235] Female CD-1 mice (8 weeks old) were housed and handled in a temperature-controlled environment with a 12-hour light / 12-hour dark cycle. A total of 25 mice were randomly assigned into five groups based on body weight and then treated with vehicle (po, qd), 3 mg / kg compound 73 (po, qd), 10 mg / kg compound 73 (po, qd), 30 mg / kg compound 73 (po, qd), or 90 mg / kg compound 73 (po, qd) for 5 days. The protocols and procedures for the care and use of animals were approved by the Institutional Animal Care and Use Committee (IACUC) of WuXiAppTec(Shanghai) Co.,Ltd.(Shanghai,China).

[0236] 2. Measurement of H3K27me3 levels in bone marrow cells and PBMC monocytes Mice were euthanized 4 hours after the last dose. Whole blood and bone marrow were collected. Bone marrow cells were flushed from femurs and tibias with IMDM+ / + (IMDM, 10% heat-inactivated FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin). Aggregates were removed through a 40 μm cell strainer. Cells were pelleted using 5 mL of DPBS after centrifugation and the number of cells was counted. 1X RBC cell lysis buffer was added to whole blood to remove RBCs (whole blood:1X RBC cell lysis buffer=1:9), and mononuclear cells were collected by centrifugation. After centrifugation, cells were washed once with 1X DPBS and resuspended in 3 mL of DPBS, and then the number of cells was counted.

[0237] Bone marrow cells were stained with FITC-conjugated anti-mouse TER-119 antibody (Thermo Fisher, 11-5921-82) and eFluor 506-conjugated anti-mouse CD45 antibody (Thermo Fisher, 69-0451-82). TER-119+ cells were erythroid cells. PBMCs were stained with eFlour 450-conjugated anti-mouse CD11b antibody (Invitrogen, 48-0112-82), PerCP-eFluor710-conjugated anti-mouse CD3 antibody (Invitrogen, 46-0032-82), and eFluor 506-conjugated CD45 antibody (Thermo Fisher, 69-0451-82). CD45+CD3+CD11b+ cells were monocytes derived from PBMC.

[0238] After washing, centrifugation, and fixation, the cells were permeabilized and further incubated with antibodies against H3K27m3 (tri-methyl-histone H3 (Lys27) (C36B11), rabbit mAb (PE Conjugate), CST, 40724S) and H3 (Histone H3 (D1H2) XP® rabbit mAb (Alexa Fluor® 647 Conjugate), CST, 12230S), and the mean fluorescence intensity of the target cells was quantified by FACS analysis. The ratio of the fluorescence intensity of H3K27me3 to that of H3 was used to reflect the level of H3K27me3 in the cells.

[0239] Compound 73 appeared to inhibit H3K27me3 in erythroid cells in bone marrow. Compared to the vehicle group, treatment with compound 73 reduced H3K27me3 levels in TER119+ erythroid cells derived from bone marrow of CD-1 mice. When mice were treated with 3 mg / kg, 10 mg / kg, and 30 mg / kg (qd×5 days), respectively, a 21.2%, 18.7%, and 21.6% reduction in H3K27me3 levels was observed, and at 90 mg / kg (qd×5 days), a more significant inhibition was observed, with a 39.7% reduction in H3K27me3 levels (p<0.01 vs. vehicle).

[0240] H3K27me3 levels in PBMC monocytes were used as another PD marker. Compared with the vehicle group, treatment with Compound 73 reduced H3K27me3 levels in PBMC monocytes. The reduction rates were 17.9%, 40.5%, 8.8%, and 41.2% when Compound 73 was administered at 3 mg / kg, 10 mg / kg, 30 mg / kg, and 90 mg / kg, respectively.

[0241] 3. Measurement of Hbb-bh1 mRNA levels in whole blood The mouse Hbb-bh1 gene, a homolog of the human HBG1 gene encoding gamma hemoglobin, is used as an efficacy biomarker in wild-type CD-1 mice. 120 μL of whole blood was collected for RNA isolation according to the instructions for Trizol LS reagent (Invitrogen, 10296028). The overall expression of Hbb-bh1 mRNA relative to GAPDH mRNA was quantified by qPCR. The overall expression of Hbb-bh1 mRNA in whole blood of CD-1 mice increased with increasing doses of Compound 73 from 3 mg / kg (qd×5 days) to 90 mg / kg (qd×5 days). When compound 73 was administered at 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, Hbb-bh1 mRNA levels were 82.2%, 114.6%, and 178.3% of the vehicle control group, and a 3.04-fold increase was observed with compound 73 at 90 mg / kg (p<0.05 vs. vehicle). Increased expression of Hbb-bh1 mRNA may lead to increased expression of mouse βh1 hemoglobin. In humans, a similar increase in expression of the HBG1 and HBG2 genes is expected, ultimately resulting in a therapeutic effect in SCD patients by increasing the proportion of HbF in peripheral blood.

[0242] 4. Measurement of HBG mRNA levels, HbF concentration, and percentage of HbF+ cells in human CD34+ HSCs Cell culture and drug treatment First, human umbilical cord blood CD34+ hematopoietic stem cells (HSCs) were expanded in expansion medium (StemSpan SFEM II + StemSpan CD34 Expansion Supplement) to reach the desired cell number and then differentiated in differentiation medium (StemSpan SFEM II + StemSpan Erythroid Expansion Supplement (100x)) for 3 days without drug treatment. Various concentrations of Compound 73 were added on day 4 of differentiation and cells were cultured for an additional 7 days. 33 mM hydroxyurea was used as a control.

[0243] 4.1 Measurement of HBG mRNA levels On the seventh day of treatment, cells were harvested. Total RNA was isolated using Trizol LS reagent (Invitrogen-10296028), and 1 μg of RNA from each sample was reverse transcribed into cDNA using the High Capacity cDNA Reverse Transcription Kit (AB(Applied Biosystems)-4374966) according to the manufacturer's instructions. Quantitative RT-PCR (qRT-PCR) was performed using an Applied Biosystems QuantStudio 7 Flex system with the following primer pairs: hHBG-mRNA-F1 (5'-TGGCAAGAAGGTGCTGACTTC-3'), and hHBG-mRNA-R1 (5'-TCACTCAGCTGGGCAAAGG-3'). As shown in Figure 1, compound 73 showed a concentration-dependent induction effect on HBG mRNA in human CD34+HSCs. When cells were treated with 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, and 1.0 μM of compound 73, HBG mRNA levels were 1.09, 2.49, 7.84, 9.69, and 12.2-fold higher than the vehicle group. The maximal effect was observed with 1.0 μM of compound 73, where HBG mRNA increased 12.2-fold (p<0.0001 vs. vehicle). HBG mRNA levels in cells treated with 33 mM hydroxyurea, an approved drug for SCD, were 6.46-fold higher than the vehicle group.

[0244] 4.2 Measurement of HbF concentration by ELISA After 7 days of treatment, cells were harvested and lysed. The concentration of HbF in cell lysates was measured using a human fetal hemoglobin (HBF) ELISA kit (MyBioSource, MBS2024474). As shown in Figure 2, compound 73 showed a concentration-dependent induction effect on HbF production in human CD34+HSCs. When cells were treated with 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, and 1.0 μM compound 73, respectively, the cellular HbF concentrations were 1.27, 1.39, 1.52, 1.58, and 1.69 times that of the vehicle group. The maximum effect was observed with 1.0 μM compound 73, at which the cellular HbF concentration was 1.69 times that of the vehicle group (p<0.01). The HbF concentration of cells treated with 33 mM hydroxyurea was 1.18 times that of the vehicle group. Clinically, small increases in HbF concentration (1–5%) may result in clinical benefit in any patient with SCD.

[0245] 4.3 Measurement of HbF+ cell percentage by FACS After 7 days of treatment, cells were harvested and stained with PE-labeled mouse anti-human fetal hemoglobin (BD, 560041). The percentage of HbF+ cells was quantified by FACS. As shown in Figure 3, when cells were treated with 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, and 1.0 μM of compound 73, the percentage of HbF+ cells was 0.73, 0.86, 1.50, 1.73, and 2.58 times that of the vehicle group, respectively. The maximum effect was observed with 1.0 μM of compound 73, where the percentage of HbF+ cells was 2.58 times that of the vehicle group (p<0.0001). When cells were treated with 33 mM hydroxyurea, the percentage of HbF+ cells was 1.82 times that of the vehicle group.

[0246] EMBODIMENT 2 Example of TNBS-induced IBD model 1. Experimental protocol for TNBS-induced inflammatory bowel disease (IBD) model in Balb / c mice

[0247] There are two types of IBD: Crohn's disease (CD) and ulcerative colitis (UC). Acute TNBS administration provides a preclinical type 1 immune-induced mouse model that recapitulates clinical Crohn's disease.

[0248] Female Balb / c mice (8 weeks old) were obtained from Beijing Vital River Laboratory Animal Co. Ltd. Animals were housed and handled in a temperature-controlled environment with a 12-hour light / 12-hour dark cycle. A total of 30 mice were randomized based on weight and assigned to three groups.

[0249] On day 0, mice weighing 18-20 g were euthanized with avidin (Easycheck, M2910), and then further injected intrarectally with 100 μL of 1.5% TNBS solution (final concentration in 50% ethanol) in the vehicle and treatment groups. For the sham group, mice were intrarectally administered with the same volume of 50% ethanol.

[0250] Mice in groups 1 and 2 were treated with vehicle for 8 days (po, qd, days -1 to 6). Mice in group 3 were treated with 90 mg / kg compound 73 for 8 days (po, qd, days -1 to 6). The protocols and procedures for the care and use of animals were approved by the Institutional Animal Care and Use Committee (IACUC) of Wuxi Apptec (Shanghai, China). The groupings are shown in Table 2.

[0251] [Table 2]

[0252] 2. Clinical scores Clinical signs of IBD were assessed daily based on the Disease Activity Index (DAI) score, which was assessed using a scoring system of 0 to 4 based on three parameters: stool consistency (0, normal stool; 1, soft but formed stool; 2, soft but not formed stool; 3, very soft and wet stool; 4, watery diarrhea), bleeding score (0, negative occult blood; 1, weak positive occult blood; 2, positive occult blood; 3, visible blood stains in stool; 4, total rectal bleeding), and weight loss (0, no weight loss; 1, 1-5% weight loss; 2, 6-10% weight loss; 3, 11-20% weight loss; 4, more than 20% weight loss).

[0253] [Table 3]

[0254] As shown in Figures 4A-4B, mice in group 1 (sham control) showed almost no symptoms of DAI (DAI score less than 2 throughout the entire study period). Compared with the G1 sham control group, the G2 group had a higher DAI score after rectal introduction of TNBS, reaching a maximum clinical score of 10.70 ± 0.14 on day 1. Compound 73 demonstrated efficacy by significantly reducing the DAI score of IBD and improving body weight loss. These results indicated that treatment with Compound 73 could alleviate the progression of TNBS-induced IBD in mice.

[0255] 3. Measurement of colon weight and colon length At the end of the experiment (day 7), the animals were euthanized, dissected, the entire colon was quickly removed, and the feces was gently removed.

[0256] Whole colons were weighed and their total length was measured. Colon weight increase and shortening are indirect markers of inflammation. As expected, TNBS induced a significant increase in colon weight of 336.8 ± 26.68 mg. Treatment with compound 73 significantly reduced the TNBS-induced increase in colon weight to 213.8 ± 6.08 mg (Figure 5A).

[0257] TNBS induced a significant decrease in colon length to 6.26±0.17 cm. Treatment with 90 mg / kg compound 73 significantly improved colon length to 8.79±0.22 cm (FIG. 5B).

[0258] These results indirectly demonstrated that treatment with compound 73 improved colonic inflammation in TNBS-induced colitis mice.

[0259] 4. Whole Blood Cell Counting At the end of the experiment, the animals were euthanized and blood was immediately collected by cardiac puncture for complete blood cell analysis.

[0260] Neutrophils and monocytes, as important components of the innate immune response, are key regulators of gut microenvironment homeostasis, which promote the development of IBD. Most intestinal macrophages originate from monocytes in peripheral blood. As shown in Figures 6A-6B, TNBS induced a significant increase in neutrophils and monocytes in peripheral blood compared with sham controls. Treatment with Compound 73 significantly reduced the increase in neutrophil and monocyte cell counts in peripheral blood. Anemia is the most common extraintestinal manifestation of IBD. TNBS induction led to a decrease in red blood cells and hemoglobin in peripheral blood, and treatment with Compound 73 improved anemia in the TNBS-induced IBD mouse model (Figures 6C-6D).

[0261] 5. Analysis of MLN cell populations by flow cytometry At the end of the study (day 7), cell suspensions from the sham control, model control, and Compound 73 treatment groups were obtained from mesenteric lymph nodes (MLNs). Cells were stained with the following fluorescently labeled antibodies: APC-Cy7-labeled anti-mouse CD45, BV510-labeled anti-mouse CD3e, AF700-labeled anti-mouse CD8a, BUV395-labeled anti-mouse CD4, BV421-labeled anti-mouse CD25, FITC-labeled anti-mouse Foxp3, BV650-labeled anti-mouse IFN-γ, APC-labeled anti-mouse B220, BV395-labeled anti-mouse CD3e, BV605-labeled anti-mouse CD11b, BB700-labeled anti-mouse CD11c, AF488-labeled anti-mouse MHCII, BV421-labeled anti-mouse NK1.1, BV510-labeled anti-mouse Ly6G, PE-Cy7-labeled anti-mouse CD107a, and PE-CF594-labeled anti-mouse F4 / 80. All cells were primarily gated on single and live lymphocytes based on forward scatter (FCS), side scatter (SSC), and live / dead staining buffer. Cells were analyzed by flow cytometer (BD LSRFortessa) to determine the percentage of each lymphocyte subtype. As shown in Figures 7A-7E, after treatment with 90 mg / kg of compound 73, neutrophils (CD45 + CD3 - B220 - CD11B + LY6G + ), NK cells (CD45 + CD3 - B220 - NK1.1 + ), activated NK cells (CD45 + CD3 - B220 - NK1.1 + CD107a + ), IFN-γ secreted CD4 + T cells (CD45 + CD3 + CD8 + , Th1 cells), and macrophages (CD45 + CD3 - B220 - CD11b + F4 / 80 + ) was significantly reduced when compared to the vehicle control.

[0262] 6. Histopathological Evaluation At the end of the study (day 7), all animals were sacrificed with CO2. Colons were rolled and fixed with neutralized PFA, followed by H&E staining. A pathologist from the WuXi clinical pathology analysis platform (blind to animal ID) then reviewed and scored the H&E staining. Pathology scoring criteria were as follows: crypt structure (normal, 0; severe crypt distortion with loss of entire crypts, 3), degree of inflammatory cell infiltration (normal, 0; dense inflammatory infiltration, 3), muscle hypertrophy (normal, 0; significant muscle hypertrophy present, 3), goblet cell depletion (absent, 0; present, 1), and crypt abscess (absent, 0; present, 1).

[0263] As shown in FIG. 8, mice in the vehicle group (G2) exhibited a pathological score of 10.33±0.35, indicating extensive inflammatory cell infiltration in the colon, while treatment with compound 73 significantly reduced this score to 1.70±0.37, which was consistent with the alleviation of clinical symptoms as indicated by the clinical score.

[0264] 7. Masson's Trichrome Staining Fixed colons were stained with Masson's trichrome to investigate collagen fibers in colonic tissue. The procedure of Masson's trichrome staining followed standard protocols. Then, a pathologist from WuXi clinical pathology analysis platform, blinded to the animal information, reviewed and scored the entire slice. The pathology scoring criteria were as follows: no increase - 0, increase in submucosa - 1; increase in mucosa - 2; increase in muscularis mucosa with hypertrophy / disorganization of muscularis mucosa - 3; increase in muscularis propria (visible increase in collagen fibrils relative to Sirius red) - 4; disorganization throughout muscularis propria - 5. As shown in Figure 9, the results of Masson's trichrome staining showed significant evidence of fibrosis (4.33 ± 0.30) in the carrier control group compared to the G1 sham control. Treatment with Compound 73 significantly reduced the fibrosis score to 1.10 ± 0.17.

[0265] Example in T cell migration-induced IBD model 1. Experimental protocol for T cell migration-induced inflammatory bowel disease (IBD) model in CB17 mice

[0266] The T cell migration model of colitis recapitulates the clinical pathology (colitis and small intestinal inflammation) observed in human intestinal inflammatory diseases.

[0267] Female CB17 mice (8 weeks old) were obtained from Zhejiang Vital River Laboratory Animal Co. Ltd. Animals and were housed and handled in a temperature-controlled environment with a 12-hour light / 12-hour dark cycle. A total of 30 mice were randomized based on weight and assigned to three groups.

[0268] To produce T cell transfer-induced colitis, 95 female Balb / c mice (8–10 weeks old) were used to culture naïve CD4 + CD45RB high T, and CD4 + CD45RB low T cells were prepared. The spleens of the mice were harvested in pre-cooled DPBS, ground into a cell suspension, and passed through a 70 μm cell filter after lysis of red blood cells with ACK. The cells were collected and counted by centrifugation. CD4 positive T cells were then isolated using a negative magnetic bead separation kit. CD4 + CD45RB high Naive T cells were selected by flow cytometry and used for model construction. On day 0, 20 CB17 model mice were inoculated with 5 × 10 5 Naive CD4 + CD45RB high T cells were injected intraperitoneally, respectively. On day 0, 10 mice in the negative control group were injected with 5 × 10 5 CD4 + CD45RB low T cells were injected.

[0269] Mice in group 2 were treated with vehicle for 28 days (po, qd, days 14-41). Mice in group 3 were treated with 90 mg / kg compound 73 for 28 days (treatment, po, qd, days 14-41). The protocols and procedures for the care and use of animals were approved by the Institutional Animal Care and Use Committee (IACUC) of Wuxi Apptec (Shanghai, China). The groupings are shown in Table 4.

[0270] [Table 4]

[0271] 2. Clinical scores Clinical signs of IBD were assessed daily based on the Disease Activity Index (DAI) score, which was assessed using a scoring system of 0 to 4 based on two parameters: stool consistency (0, normal stool; 1, soft but formed stool; 2, soft but not formed stool; 3, very soft and wet stool; 4, watery diarrhea) and weight loss (0, no weight loss; 1, 1-5% weight loss; 2, 6-10% weight loss; 3, 11-20% weight loss; 4, more than 20% weight loss).

[0272] [Table 5]

[0273] As shown in Figures 10A-10B, group 1 (CD45RB low ) mice showed little to no symptoms of DAI changes (DAI score of less than 1 throughout the study). low Compared with the control group, the DAI score increased in the G2 group, reaching a maximum DAI score of 4.90 ± 0.41 on day 42. Treatment with Compound 73 significantly reduced the DAI to 1.4 ± 0.27 on day 42 and improved the weight loss. These results suggest that treatment with Compound 73 significantly reduced the CD4 + CD45RB highIt has been shown that it can alleviate the progression of T cell migration-induced IBD.

[0274] 3. Colon weight and colon length At the end of the study (day 42), animals were euthanized, dissected, and the entire colon was rapidly removed and the feces gently removed.

[0275] The whole colon was weighed and its length was measured. Increased colon weight and shortening are indirect markers of inflammation. As expected, CD4 + CD45RB high T cell migration induced a significant increase in colon weight to 439.10±25.46 mg. Treatment with compound 73 significantly reduced colon weight gain to 323.40±16.06 mg (FIG. 11A).

[0276] CD4 + CD45RB high T cell migration induced a significant decrease in colon length to 7.72±0.18 cm. Treatment with 90 mg / kg compound 73 significantly improved colon length to 10.26±0.22 cm (FIG. 11B).

[0277] These results suggest that treatment with compound 73 significantly increased the CD4 + CD45RB high This indirectly indicates that colonic inflammation was ameliorated in mice with T cell migration-induced colitis.

[0278] 4. Histopathological Evaluation At the end of the study (day 42), all animals were sacrificed with CO2. Colons were rolled and fixed with neutralized PFA, followed by H&E staining. A pathologist from the WuXi clinical pathology analysis platform (blind to animal ID) then reviewed and scored the H&E staining. Pathology scoring criteria were as follows: crypt structure (normal, 0; severe crypt distortion with loss of entire crypts, 3), degree of inflammatory cell infiltration (normal, 0; dense inflammatory infiltration, 3), muscle hypertrophy (normal, 0; significant muscle hypertrophy present, 3), goblet cell depletion (absent, 0; present, 1), and crypt abscess (absent, 0; present, 1).

[0279] As shown in FIG. 12, mice in the vehicle group (G2) exhibited a pathological score of 9.00±0.47, indicating extensive inflammatory cell infiltration in the colon, while treatment with compound 73 significantly reduced this score to 3.70±0.37, which was consistent with an alleviation of clinical symptoms as indicated by the clinical score.

[0280] Example of DSS-induced inflammatory bowel disease (IBD) model 1. Experimental protocol for DSS-induced inflammatory bowel disease (IBD) model in C57BL / 6 mice

[0281] DSS-induced colitis shows clinical and histological similarities to ulcerative colitis.

[0282] Female C57BL / 6 mice (8 weeks old) were obtained from Beijing Vital River Laboratory Animal Co. Ltd. Animals and were housed and handled in a temperature-controlled environment with a 12-hour light / 12-hour dark cycle. A total of 30 mice were randomized based on weight and assigned to three groups.

[0283] On day 0, colitis was induced by administering 3% DSS (dextran sulfate sodium salt, molecular weight: 36,000-50,000) with free access to water for 8 days. Eight-week-old mice were divided into three groups: group 2, DSS-treated group (vehicle, po, qd, day 0 to day 7); group 3, 90 mg / kg Compound 73 plus DSS (po, qd, day 0 to day 7); and group 1 (G1), naive group, and mice were provided with drinking water without DSS. The protocols and procedures for animal care and use were approved by the Institutional Animal Care and Use Committee (IACUC) of Wuxi Apptec (Shanghai, China). The groupings are shown in Table 6.

[0284] [Table 6]

[0285] 2. Colon weight and colon length At the end of the study, the animals were euthanized, dissected, the entire colon rapidly removed, and the feces gently removed.

[0286] Whole colons were weighed and their total length was measured. An increase in colon density (colon weight / colon length) is an indirect marker of inflammation. As expected, DSS induced an increase in colon density to 50.88±2.53. Treatment with compound 73 significantly reduced colon density to 41.86±2.57 (FIG. 13).

[0287] This result indirectly indicates that treatment with compound 73 improved colon inflammation in DSS-induced colitis mice.

[0288] 3. Histopathological Evaluation At the end of the study (day 8), all animals were sacrificed with CO2. Colons were rolled and fixed with neutralized PFA, followed by H&E staining. A pathologist from the WuXi clinical pathology analysis platform (blind to animal ID) then reviewed and scored the H&E staining. Pathology scoring criteria were as follows: crypt structure (normal, 0; severe crypt distortion with loss of entire crypts, 3), degree of inflammatory cell infiltration (normal, 0; dense inflammatory infiltration, 3), muscle hypertrophy (normal, 0; significant muscle hypertrophy present, 3), goblet cell depletion (absent, 0; present, 1), and crypt abscess (absent, 0; present, 1).

[0289] As shown in FIG. 14, mice in the vehicle group (G2) showed an increase in pathology score to 10.10±0.18, while treatment with 90 mg / kg of compound 73 significantly reduced the score to 8.30±0.54.

[0290] These results indicated that treatment with compound 73 plays a therapeutic role in DSS-induced IBD in mice.

[0291] EMBODIMENT 3 1. Materials and Methods

[0292] SPF grade male SD rats (200±20g, 8 weeks old) were purchased from Zhejiang Vital River Laboratory Animal Technology Co.,Ltd. After 1 week of acclimation, blood samples were collected and analyzed to exclude abnormal animals. Normal animals were randomized and 10 animals were assigned to the control group that remained untreated until the end of the study, and the remaining animals received 300mg / kg adenine by oral gavage (QD x 6 weeks). Compared with the rats in the control group, the adenine-treated rats showed a significant increase in serum creatine and BUN levels and a significant decrease in HGB levels, indicating that the model was successfully established. Then, 60 adenine-treated rats that successfully established the model were further randomized into the following six groups: model group (treated with vehicle), EPO group (50U / kg), compound 73 5mg / kg group, compound 73 15mg / kg group, compound 73 45mg / kg group, and compound 73+EPO group (15mg / kg+50U / kg).Each group contained 10 animals.Compound 73 was administered to rats by oral gavage (QD x 4 weeks), while EPO was administered subcutaneously (TIW x 4 weeks).

[0293] The weight, mortality, and health status of the rats were recorded twice a week. After the model was established, blood samples were taken from the orbit to measure several parameters, including RBC, HGB, HCT, RET, BUN, and creatine. During drug treatment, blood samples were taken once a week to analyze RBC, HGB, HCT, and RET.

[0294] 2. Compound 73 significantly improved body weight, RBC, HGB, HCT, and RET in rats with chronic kidney disease-induced anemia

[0295] As shown in FIG. 15, at the end of the study, the body weight of SD rats in the model group (6 weeks adenine + 4 weeks vehicle) was significantly lower than that of the control group (untreated) SD rats (p<0.001). Treatment with 50U / kg EPO (TIW x 4 weeks) significantly improved the body weight of the rats (p<0.001 vs. model). Treatment with Compound 73 improved the body weight of the adenine-treated rats in a dose-dependent manner, and a significant difference was observed at the end of the study (p<0.001, or 0.01 vs. model). It should be noted that Compound 73 at 45mg / kg improved the body weight of the rats to the same extent as EPO at 50U / kg. Overall, Compound 73 was effective in improving body weight in a rat model of chronic kidney disease-induced anemia.

[0296] As shown in Figure 16, Figure 17, Figure 8, and Figure 19, at the end of the study, the RBC, HGB, HCT, and RET values ​​of SD rats in the model group (6 weeks adenine + 4 weeks vehicle) were significantly lower than those of SD rats in the control group (untreated) (p<0.001). Treatment with 50U / kg EPO (TIW x 4 weeks) significantly improved these parameters (p<0.001 vs. model), suggesting the therapeutic effect of EPO in the rat model of chronic kidney disease-induced anemia. Treatment with Compound 73 improved these parameters in adenine-treated rats in a dose-dependent manner, and significant differences were observed at the end of the study (p<0.001, or 0.05 vs. model). It should be noted that 45mg / kg Compound 73 improved these parameters to the same extent as 50U / kg EPO. Overall, compound 73 demonstrated dose-dependent therapeutic effects in a rat model of chronic kidney disease-induced anemia.

[0297] 3. Combined treatment of compound 73 and EPO further improved body weight, RBC, HGB, HCT, and RET in rats with chronic kidney disease-induced anemia.

[0298] As shown in Figure 20, the combination of 15 mg / kg compound 73 and EPO further improved the body weight of adenine-treated rats, reaching a significant difference at the end of the study when compared with each single agent. As shown in Figures 21, 22, 23, and 24, the combination of 15 mg / kg compound 73 and EPO further increased the values ​​of RBC, HGB, HCT, and RET. At the end of the study, all parameters returned to normal levels and were higher than each single agent. Significant differences were observed in all parameters when compared with the 15 mg / kg compound 73 single agent group, and significant differences were observed in RBC and RET when compared with the EPO single agent group. Overall, the combination treatment of compound 73 and EPO showed improved therapeutic effects in a rat model of chronic kidney disease-induced anemia.

[0299] It should be understood that the description of the foregoing embodiments is not a complete description of the principles of the present invention, but is intended to merely illustrate the principles of the present invention, modifications and variations being apparent to those skilled in the art, and the present invention is not intended to be limited except as expressly set forth in the following claims.

Claims

1. A substance X or pharmaceutical composition for the prevention and / or treatment of a disease or disorder associated with a defective hemoglobin protein activity or expression, or an innate immune response that is a type 1 or type 3 immune-related immunodeficiency, in a subject in need thereof, and comprising a therapeutically effective amount of an active ingredient, substance X, wherein: The substance X is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: 【Chemical 1】 [In the formula, R １ is aralkyl, R ２ is hydrogen and C １ -C ４ alkyl; R ３ and R ４ together with the carbon atom to which they are attached form a radical of formula IA, IB, or IC, 【Chemistry 2】 X is -C(R ５ａ ) (R ５ｂ )-, -C(=O)-, and -S(=O) ２ - selected from the group consisting of R ５ａ and R ５ｂ is hydrogen and C １ -C ４ alkyl; Y is -C(R ６ａ ) (R ６ｂ )-, -S-, -O-, and -N(R ７ )-; or X and Y together form a 5-membered heteroarylenyl ring; Z is -C(R ６ｃ ) (R ６ｄ ) ｍ - and R ６ａ and R ６ｂ is hydrogen and C １ -C ４ alkyl; Each R ６ｃ and R ６ｄ is hydrogen and C １ -C ４ alkyl; m is 0, 1, or 2; R ７ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ４ -C ８ selected from the group consisting of heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R ８ａ , R ８ｂ , and R ８ｃ is hydrogen, halo, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, carboxamido, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, (heterocyclo)C １ -C ４ independently selected from the group consisting of alkyl, and alkylsulfonyl; 【Chemistry 3】 is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl; 【Chemistry 4】 is an optionally substituted fused 3- to 8-membered cycloalkyl or an optionally substituted fused 4- to 8-membered heterocyclo; 【Chemistry 5】 is an optionally substituted fused 4- to 8-membered heterocyclo; and 「 【Chemistry 6】 " is a bond represented by R ３ and " ＊ " is a bond represented by R ４ or R ３ is R ３ａ and R ４ is R ４ａ and R ３ａ is selected from the group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 8-membered heterocyclo; and R ４ａ is hydrogen, halo, C １ -C ４ Haloalkyl, —S(═O) ２ R ９ , -P(=O)(R １０ａ ) (R １０ｂ ), -C(=O)OR １１ａ , —C(═O)NR １１ｂ R １１ｃ , and -S(=O)(=NR １３ａ ) R １３ｂ is selected from the group consisting of R ９ is C １ -C ４ Alkyl, and C ３ -C ６ cycloalkyl; R １０ａ and R １０ｂ is independent, C １ -C ４ is alkyl, R １１ａ is hydrogen and C １ -C ４ alkyl; R １１ｂ and R １１ｃ is hydrogen and C １ -C ４ alkyl; R １１ｂ and R １１ｃ together with the nitrogen atom to which they are attached form a 4- to 6-membered optionally substituted heterocyclo; R １３ａ is C １ -C ６ Alkyl, C ３ -C ６ selected from the group consisting of cycloalkyl, and hydroxyalkyl; R １３ｂ is C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; or R １３ａ and R １３ｂ together form a 5- to 7-membered heterocycle, and 【Chemistry 7】 is a single bond or a double bond. Substance X or a pharmaceutical composition.

2. R ３ and R ４ together with the carbon atom to which they are attached form a radical of formula IA, and said substance X is a compound of formula II: 【Chemistry 8】 or a pharmaceutically acceptable salt or solvate thereof; For example, the substance X is a compound of formula III, IV, V, or VI: 【Chemistry 9】 wherein L is selected from the group consisting of -C(R 8b )=, and -N=; For example, L is -C(R 8b )=, or L is -N=; and / or R 8a , R 8b , and R 8c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, optionally substituted 4-8 membered heterocyclo, and (heterocyclo)C 1 -C 4 alkyl; For example, R 8a is selected from the group consisting of —CF 3 , —CH 3 , —CHF 2 , —CD 3 , and cyclopropyl, and R 8b and R 8c are hydrogen; or, The substance X is a compound of formula VII, VIII, or IX: 【Chemistry 10】 [In the formula, L 1 is selected from the group consisting of —S—, —O—, and —N(R 8a )—; L 2 is selected from the group consisting of -C(R 8b )= and -N=; L 3 is selected from the group consisting of -C(R 8c )= and -N=; R 8a is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; R 8b is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl; and R 8c is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl. or a pharmaceutically acceptable salt or solvate thereof; or, R 3 and R 4 together with the carbon atom to which they are attached form a radical of formula IB, and said substance X is a compound of formula X: 【Chemistry 11】 For example, a compound of formula XI: 【Chemistry 12】 [In the formula, R 8d , R 8e , and R 8f are independently selected from the group consisting of hydrogen, halo, and C 1 -C 4 alkyl; and n is 1, 2, or 3; or Compound of Formula XII: 【Chemistry 13】 [In the formula, L 4 is selected from the group consisting of —S—, —O—, and —N(R 8g )—; R 8g is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and optionally substituted 4- to 8-membered heterocyclo; o is 0, 1, 2, or 3, and p is 0, 1, 2, or 3; where the sum of o and p is 1, 2, 3, 4, or 5. or a pharmaceutically acceptable salt or solvate thereof; or, R 3 and R 4 together with the carbon atom to which they are attached form a radical of formula IC, and said substance X is a compound of formula XIII: 【Chemistry 14】 For example, a compound of formula XIV: 【Chemistry 15】 [In the formula, R 8d , R 8e , and R 8f are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and q is 1, 2, or 3; or Compound of Formula XV: 【Chemistry 16】 [In the formula, L 5 is selected from the group consisting of —S—, —O—, and —N(R 8h )—; R 8h is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-8 membered heterocyclo, —C(═O)R 14a , and —S(═O) 2 R 14b ; R 14a and R 14b are independently selected from the group consisting of C 1 -C 6 alkyl, and optionally substituted C 3 -C 8 cycloalkyl; r is 1, 2, or 3, and s is 1, 2, or 3. or a pharmaceutically acceptable salt or solvate thereof; or The substance X is a compound of formula XVI: 【Chemistry 17】 wherein R 2 is hydrogen. or a pharmaceutically acceptable salt or solvate thereof; 2. Substance X or pharmaceutical composition according to claim 1.

3. Z is -CH ２ - is; and / or X is selected from the group consisting of —C(R 5a )(R 5b )—, —C(═O)—, and —S(═O) 2 —, and Y is selected from the group consisting of —C(R 6a )(R 6b )—, —S—, —O—, and —N(R 7 )—; for example, X is —CH 2 —, or X is —C(═O)—, or X is —S(═O) 2 —; and / or Y is —O—, or Y is —N(R 7 )—; for example, R 7 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and optionally substituted C 3 -C 8 cycloalkyl; and / or X and Y together form a 5-membered heteroarylenyl ring; or a pharmaceutically acceptable salt or solvate thereof; 2. Substance X or pharmaceutical composition according to claim 1.

4. R １ is R １ -1, 【Chemistry 18】 R １２ａ , R １２ｂ , and R １２ｃ are hydrogen, halo, and C, respectively. １ -C ４ Alkyl, C １ -C ４ Haloalkyl, and C １ -C ４ independently selected from the group consisting of alkoxy; for example, R 12a is fluoro, and R 12b and R 12c are independently selected from the group consisting of hydrogen and fluoro; or R 12a is fluoro and R 12b and R 12c are hydrogen; W is -CH ２ - and -C(=O)-, and t is 1 or 2; for example, W is —C(═O)— and t is 1; or W is —CH 2 — and t is 2; or W is —CH 2 — and t is 1; or a pharmaceutically acceptable salt or solvate thereof; 2. Substance X or pharmaceutical composition according to claim 1.

5. 2. The substance X or pharmaceutical composition according to claim 1, wherein the substance X is selected from the group consisting of: 【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】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】 【Table 1-38】 【Table 1-39】 【Table 1-40】 for example, The substance X is selected from the group consisting of: 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, and 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide, Selected from: for example, The substance X is compound 73 【Chemistry 19】 or a pharmaceutically acceptable salt or solvate thereof; 2. Substance X or pharmaceutical composition according to claim 1.

6. the subject is a mammal, preferably a mouse or a human; or the pharmaceutical composition comprises substance X and an excipient and / or a pharmaceutically acceptable carrier; or said substance X or said pharmaceutical composition is administered orally; or said substance X or said pharmaceutical composition is administered one or more times daily or one or more times weekly; or or wherein the substance X is administered to the subject in need thereof in an amount of 3 mg / kg to 90 mg / kg per dose, preferably 3 mg / kg, 10 mg / kg, 30 mg / kg, or 90 mg / kg per dose to the subject in need thereof; or The substance X or the pharmaceutical composition is administered continuously for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

2. Substance X or pharmaceutical composition according to claim 1.

7. A substance X or a pharmaceutical composition, said pharmaceutical composition for use in reducing H3K27me3 levels in erythroid cells or in PBMC monocytes in a subject in need thereof, and comprising a therapeutically effective amount of an active ingredient substance X, wherein said substance X is as defined in any one of claims 1 to 6 and said pharmaceutical composition is as defined in any one of claims 1 to 6. Substance X or a pharmaceutical composition.

8. The erythroid cells are bone marrow-derived erythroid cells, preferably bone marrow-derived TER119+ erythroid cells; or the subject suffers from a disease or disorder associated with defective hemoglobin protein activity or expression; or the subject is a mammal, preferably a mouse or a human; or the pharmaceutical composition comprises substance X and an excipient and / or a pharmaceutically acceptable carrier; or said substance X or said pharmaceutical composition is administered orally; or said substance X or said pharmaceutical composition is administered one or more times daily or one or more times weekly; or or wherein the substance X is administered to the subject in need thereof in an amount of 3 mg / kg to 90 mg / kg per dose, preferably 3 mg / kg, 10 mg / kg, 30 mg / kg, or 90 mg / kg per dose to the subject in need thereof; or The substance X or the pharmaceutical composition is administered continuously for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks. Substance X or pharmaceutical composition according to claim 7.

9. A substance X or pharmaceutical composition, said pharmaceutical composition for use in increasing Hbb-bh1 mRNA levels, HBG gene levels (HBG1 gene levels, HBG2 gene levels), gamma hemoglobin levels or HbF levels in a subject in need thereof, and comprising a therapeutically effective amount of an active ingredient substance X, wherein said substance X is as defined in any one of claims 1 to 6 and said pharmaceutical composition is as defined in any one of claims 1 to 6. Substance X or a pharmaceutical composition.

10. The Hbb-bh1 mRNA level is the Hbb-bh1 mRNA level in blood, preferably peripheral blood, or the Hbb-bh1 mRNA level is the Hbb-bh1 mRNA level in the blood of a CD-1 mouse; The HBG1 gene level is the HBG1 gene level in blood, preferably peripheral blood, or the HBG1 gene level is the HBG1 gene level in human blood; The HBG2 gene level is the HBG2 gene level in blood, preferably peripheral blood, or the HBG2 gene level is the HBG2 gene level in human blood; The gamma hemoglobin level is the gamma hemoglobin level in blood, preferably peripheral blood, or the gamma hemoglobin level is the gamma hemoglobin level in human blood; or The HbF level is the HbF level in blood, preferably peripheral blood, or the HbF level is the HbF level in human blood; 10. Substance X or pharmaceutical composition according to claim 9.

11. the subject suffers from a disease or disorder associated with defective hemoglobin protein activity or expression; or the subject is a mammal, preferably a mouse or a human; or the pharmaceutical composition comprises substance X and an excipient and / or a pharmaceutically acceptable carrier; or said substance X or said pharmaceutical composition is administered orally; or said substance X or said pharmaceutical composition is administered one or more times daily or one or more times weekly; or or wherein the substance X is administered to the subject in need thereof in an amount of 3 mg / kg to 90 mg / kg per dose, preferably 3 mg / kg, 10 mg / kg, 30 mg / kg, or 90 mg / kg per dose to the subject in need thereof; or The substance X or the pharmaceutical composition is administered continuously for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

10. Substance X or pharmaceutical composition according to claim 9.

12. the disease or disorder is a blood disorder; For example, the disease or disorder is anemia. For example, the disease or disorder is selected from the group consisting of sickle cell disease, beta thalassemia, beta thalassemia intermedia, beta thalassemia major, beta thalassemia minor, chemotherapy-induced anemia, chronic kidney disease-related anemia, and Cooley anemia; For example, the disease or disorder is sickle cell disease, the disease or disorder is beta thalassemia, the disease or disorder is chemotherapy-induced anemia, or the disease or disorder is chronic kidney disease-related anemia. A substance X or a pharmaceutical composition according to any one of claims 1 to 11.

13. The substance X or pharmaceutical composition according to any one of claims 1 to 11, which is used in combination with a second therapeutic agent, For example, the second therapeutic agent is erythropoietin (EPO); For example, the dosage of substance X is 10-30 mg / kg, preferably 15 mg / kg; and / or The dosage of erythropoietin (EPO) is 10-100 U / kg, preferably 50 U / kg. Substance X or a pharmaceutical composition.

14. the innate immune response is type 1 or type 3 immune-related immunodeficiency, and the innate immune response is inflammatory bowel disease; For example, the innate immune response, which is a type 1 or type 3 immune-related immunodeficiency, is Crohn's disease, or ulcerative colitis; or The innate immune response, which is a type 1 or type 3 immune-related immunodeficiency, is a non-organ-specific systemic autoimmune disease: acute disseminated encephalomyelitis (ADEM), Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APGS), aplastic anemia, autoimmune hemolytic anemia (AIHA), autoimmune hepatitis (AIH), autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune thrombocytopenic purpura (AITP), Behçet's disease, bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Crohn's disease, dermatomyositis, familial dysautonomia, epidermolysis bullosa, pemphigoid in pregnancy, giant cell arteritis, Goodpasture's syndrome, multiple sclerosis, psoriasis, psoriasis of the genitals, schizophrenia ... and / or granulomatous disease with vasculitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, immunoglobulin A (IgA) neuropathy, ulcerative colitis, interstitial cystitis (IC), Kawasaki disease, Lambert-Eaton myasthenic syndrome (LEMS), chronic Lyme disease, Mooren's ulcer, morphea, myasthenia gravis, neuromyotonia, multiple sclerosis, strabismus clonicus syndrome, optic neuritis, Ordo's thyroiditis, pemphigus, pernicious anemia, polyarteritis, polyarthritis, autoimmune polyglandular syndrome, primary biliary cirrhosis, psoriasis, Reiter's syndrome, sarcoidosis, rheumatoid arthritis, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu's arthritis, and Vogt-Koyanagi-Harada disease; and / or the dosage of substance X is 10-100 mg / kg, preferably 50 mg / kg or 90 mg / kg; A substance X or a pharmaceutical composition according to any one of claims 1 to 6.

15. A pharmaceutical composition comprising (i) a substance X according to any one of claims 1 to 5, and (ii) erythropoietin.

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