Compositions and methods for treating anemia associated with ribosomal disorders - Patents.com

Abstract

The present embodiment is directed to the method of using glycine transporter inhibitors, such as GlyT1 inhibitors, or their pharma- ceutically acceptable salts, hydrates, or prodrugs, or pharmaceutical compositions thereof, to prevent or treat anemia associated with ribosomal disorders and its associated syndromes.In some embodiments, the present disclosure provides a method of treating anemia associated with ribosomal disorders in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or their pharma-ceutically acceptable salts, or one or more prodrugs of GlyT1 inhibitors or their salts.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 160,413, filed March 12, 2022; and No. 63 / 185,466, filed May 7, 2021. The disclosures of the foregoing applications are incorporated herein by reference in their entireties.

[0002] Field Embodiments disclosed herein are directed to methods and uses for preventing or treating anemia associated with ribosomal disorders using a glycine transporter inhibitor, such as, but not limited to, a GlyT1 inhibitor or a pharma- ceutically acceptable salt, hydrate, prodrug, or pharmaceutical composition thereof. [Background technology]

[0003] background Mutations in ribosomal protein (RP) genes or other transcription factors (e.g., GATA1) can result in loss of erythroid precursor cells, causing anemia associated with ribosomal disorders. One example of anemia associated with ribosomal disorders is Diamond-Blackfan anemia (DBA), a rare blood disorder that is almost exclusively associated with RP gene haploinsufficiency. DBA affects approximately 7 per million live births and is usually diagnosed during the first year of life. Classical diagnostic criteria include: (1) macrocytic normochromic anemia; (2) reticulocytopenia; (3) bone marrow erythroid hypoplasia; and (4) early onset of anemia (90% present before 1 year of age).

[0004] In DBA patients, erythrocyte precursors do not mature sufficiently, resulting in congenital erythrocyte aplasia, developmental defects, and increased risk of myelodysplastic syndrome or acute myeloid leukemia. Affected individuals may have physical abnormalities, such as craniofacial malformations, thumb or upper limb abnormalities, cleft palate, and defects of the genitals, urinary tract, eyes, and heart. In some cases, low birth weight and short stature are observed. DBA patients are also at moderate risk of developing leukemia and other malignancies.

[0005] Current treatment options for DBA include corticosteroids, blood transfusions, and bone marrow transplantation. Approximately 80% of DBA patients respond to an initial course of corticosteroids. However, the effectiveness of corticosteroids may wane over time in many patients. These patients and the 20% who do not initially respond to such treatment must be maintained on chronic blood transfusions with iron chelation. Chronic blood transfusions are known to cause iron overload in various organs, including the liver, heart, and endocrine system. Other treatments, such as interleukin-3, high-dose corticosteroids, cyclosporine, antithymocyte globulin, immunoglobulins, and metoclopramide, are unproven and / or appear to benefit relatively few people. Pharmacological doses of erythropoietin (EPO) are also ineffective. Bone marrow transplantation is the only treatment for the hematological manifestations of DBA-associated anemia, but is usually considered only in corticosteroid-resistant individuals due to significant morbidity and mortality. Typically, only transplants from human leukocyte antigen (HLA)-identical siblings have been considered. For many patients, the lack of a suitable donor precludes bone marrow transplantation as a therapeutic option.

[0006] Therefore, there is a high unmet need for effective therapy for treating the anemia associated with ribosomal disorders.Therefore, the objective of the present disclosure is to provide a method for treating, preventing, or reducing the progression rate and / or severity of the anemia associated with ribosomal disorders.The method and use of glycine transporter inhibitors described herein, such as but not limited to GlyT1 inhibitors, meet these needs, as well as others. Summary of the Invention [Means for solving the problem]

[0007] Overview of the Application In some embodiments, the present disclosure provides a method for treating anemia associated with ribosomal disorders in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharma- ceutically acceptable salts thereof, or one or more prodrugs or salts of GlyT1 inhibitors. In some embodiments, the present disclosure provides a method for preventing, treating, or reducing the rate of progression and / or severity of anemia associated with ribosomal disorders in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharma- ceutically acceptable salts thereof, or one or more prodrugs or salts of GlyT1 inhibitors.

[0008] In some embodiments, the present disclosure provides a method for preventing, treating, or reducing the progression rate and / or severity of one or more complications of anemia associated with ribosomal disorders in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more GlyT1 inhibitors or pharma- ceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or pharma-ceutically acceptable salts thereof.In some embodiments, the one or more complications of anemia associated with ribosomal disorders are selected from the group consisting of thrombocytosis, megakaryotypic hyperplasia, infection, bleeding (e.g., from the nose or gums), purpura, splenomegaly, need for more frequent transfusions, need for increased glucocorticoid use, need for allogeneic hematopoietic stem cell transplantation, need for autologous gene therapy, bone marrow failure, MDS, leukemia, and acute myeloid leukemia.

[0009] In some embodiments, the anemia associated with ribosomal disorder is Diamond-Blackfan anemia.In some embodiments, the subject is haploinsufficient for ribosomal protein selected from the group consisting of 40S ribosomal protein S14 (RPS14), 40S ribosomal protein S19 (RPS19), 40S ribosomal protein S24 (RPS24), 40S ribosomal protein S17 (RPS17), 60S ribosomal protein L35a (RPL35a), 60S ribosomal protein L5 (RPL5), 60S ribosomal protein L11 (RPL11) and 40S ribosomal protein S7 (RPS7). In some embodiments, the subject is haploinsufficient for a ribosomal protein selected from the group consisting of 40S ribosomal protein S10 (RPS10), 40S ribosomal protein S26 (RPS26), 60S ribosomal protein L15 (RPL15), 60S ribosomal protein L17 (RPL17), 60S ribosomal protein L19 (RPL19), 60S ribosomal protein L26 (RPL26), 60S ribosomal protein L27 (RPL27), 60S ribosomal protein L31 (RPL31), 40S ribosomal protein S15a (RPS15a), 40S ribosomal protein S20 (RPS20), 40S ribosomal protein S27 (RPS27), 40S ribosomal protein S28 (RPS28) and 40S ribosomal protein S29 (RPS29). In some embodiments, the subject has one or more mutations in ribosomal protein genes.In some embodiments, the subject has one or more mutations in ribosomal protein genes selected from the group consisting of RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28 and RPS29.In some embodiments, the subject has one or more mutations in non-ribosomal protein genes selected from the group consisting of TSR2, GATA1 and EPO.

[0010] In some embodiments, the anemia associated with ribosomal disorder is myelodysplastic syndrome (MDS) associated with isolated del(5q).In some embodiments, the subject has low-risk, intermediate-1, intermediate-2 or high-risk MDS classified by International Prognostic Scoring System (IPSS).In some embodiments, the subject is haploinsufficient for ribosomal protein selected from the group consisting of 40S ribosomal protein S14 (RPS14) and 40S ribosomal protein S19 (RPS19).In some embodiments, the subject has one or more mutations in ribosomal protein genes.In some embodiments, the one or more mutations in ribosomal protein genes are selected from the group consisting of RPS14 or RPS19.

[0011] In some embodiments, the anemia associated with a ribosomal disorder is Shwachman-Diamond syndrome. In some embodiments, the subject has one or more mutations in the SBDS gene. In some embodiments, the subject reduces the need for hematopoietic stem cell transplantation. In some embodiments, the subject reduces neutropenia. In some embodiments, the subject reduces thrombocytopenia. In some embodiments, the subject reduces a risk of developing myelodysplastic syndrome. In some embodiments, the subject reduces a risk of developing leukemia. In some embodiments, the subject reduces a risk of developing an infection. In some embodiments, the subject reduces a risk of developing pneumonia.

[0012] In some embodiments, the anemia associated with ribosomal disorders is dyskeratosis congenita. In some embodiments, the dyskeratosis congenita is x-linked dyskeratosis congenita. In some embodiments, the subject has one or more mutations in the DKC1 gene. In some embodiments, the subject has one or more mutations in a gene selected from the group consisting of TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, PARN, CTC1, and RTEL1. In some embodiments, the method reduces the risk of bone marrow failure in the subject. In some embodiments, the method reduces the risk of pulmonary fibrosis in the subject. In some embodiments, the method reduces the risk of liver fibrosis in the subject. In some embodiments, the anemia associated with ribosomal disorders is cartilage-hair hypoplasia. In some embodiments, the subject has one or more mutations in the RMRP gene.

[0013] In some embodiments, the method reduces the need for bone marrow transplants in the subject. In some embodiments, the subject has elevated heme levels. In some embodiments, the subject has reduced erythroid progenitor survival compared to healthy subjects. In some embodiments, the subject has reduced erythroid progenitor differentiation into mature erythrocytes compared to healthy subjects. In some embodiments, the subject has a low red blood cell count. In some embodiments, the subject has impaired hematopoiesis. In some embodiments, the subject has impaired 40S ribosomal subunit maturation. In some embodiments, the subject has impaired 60S ribosomal subunit maturation. In some embodiments, the subject has reduced hemoglobin levels. In some embodiments, the subject has reduced hematocrit levels. In some embodiments, the subject has a reduced quality of life. In some embodiments, the subject has liver iron overload. In some embodiments, the subject has cardiac iron overload. In some embodiments, the subject has increased spleen size. In some embodiments, the anemia is due to a failure in erythropoiesis. In some embodiments, the subject has elevated red blood cell adenosine deaminase activity. In some embodiments, the subject has increased red blood cell adenosine deaminase activity. In some embodiments, the subject has macrocytic anemia. In some embodiments, the subject has reticulocytopenia. In some embodiments, the subject has a reticulocyte count of less than 1%. In some embodiments, the subject has normal bone marrow cellularity with a deficiency of red cell precursors. In some embodiments, the subject has normal neutrophil and / or platelet counts. In some embodiments, the subject has elevated fetal hemoglobin levels. In some embodiments, the subject has increased fetal hemoglobin content in red cells. In some embodiments, the subject has decreased red cell mass. In some embodiments, the subject has increased mean corpuscular volume of red cells.

[0014] In some embodiments, the subject has a heme level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the method reduces the heme level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces heme synthesis in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces intracellular heme levels. In some embodiments, the method reduces intracellular heme levels in erythroid precursors. In some embodiments, the subject has an red blood cell count that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than the red blood cell count in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the method increases the red blood cell count in the subject. In some embodiments, the method increases the subject's red blood cell count by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0015] In some embodiments, the subject has a hemoglobin level that is at least 10%, 20%, 30%, 40% or 50% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is less than 13 g / dL. In some embodiments, the subject has a hemoglobin level that is less than 11 g / dL. In some embodiments, the method increases the hemoglobin level of the subject. In some embodiments, the method increases the hemoglobin level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the hemoglobin level of the subject to at least 13 g / dL. In some embodiments, the methods increase the subject's hemoglobin level to at least 11 g / dL.

[0016] In some embodiments, the subject has a hematocrit level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the hematocrit level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a hematocrit level that is less than 38%. In some embodiments, the subject has a hematocrit level that is less than 35%. In some embodiments, the method increases the hematocrit level of the subject. In some embodiments, the method increases the hematocrit level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the hematocrit level of the subject to at least 38%. In some embodiments, the method increases the subject's hematocrit level by at least 35%.

[0017] In some embodiments, the method reduces anemia in the subject. In some embodiments, the method reduces anemia in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases reticulocyte count in the subject. In some embodiments, the method increases reticulocyte count in the subject by 1%-2%. In some embodiments, the method increases erythroid progenitor survival in the subject. In some embodiments, the method increases erythroid progenitor survival in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases erythroid progenitor differentiation into mature red blood cells in a subject. In some embodiments, the method increases erythroid progenitor differentiation into mature red blood cells in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0018] In some embodiments, the method reduces the risk of heme toxicity in a subject. In some embodiments, the method reduces the risk of heme toxicity by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the risk of liver iron overload. In some embodiments, the method reduces the level of iron in the liver. In some embodiments, the method reduces the level of iron in the liver by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the risk of cardiac iron overload. In some embodiments, the method reduces the level of iron in the heart. In some embodiments, the method reduces the level of iron in the heart by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0019] In some embodiments, the subject has an increase in spleen size. In some embodiments, the method reduces the spleen size of the subject. In some embodiments, the method reduces the spleen size of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's need for blood transfusion. In some embodiments, the method reduces the subject's need for blood transfusion by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the methods eliminate the subject's need for a blood transfusion.

[0020] In some embodiments, the method increases the subject's quality of life. In some embodiments, the method increases the subject's quality of life by at least 1% (e.g., 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%). In some embodiments, the subject's quality of life is measured using an assessment selected from the group consisting of Functional Assessment of Cancer Therapy Anemia (FACT-An), Functional Assessment of Cancer Therapy Fatigue (FACT-Fatigue), Functional Assessment of Chronic Illness Therapy (FACIT), Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue), Functional Assessment of Chronic Illness Therapy Anemia (FACIT-Anemia), SF-36 Generic PRO Tool, SF-6D Generic PRO Tool and Linear Analog Scale Assessment (LASA).

[0021] In some embodiments, the method reduces the need for corticosteroid treatment in the subject. In some embodiments, the method reduces the dose of corticosteroid treatment required in the subject. In some embodiments, the corticosteroid is a glucocorticoid steroid. In some embodiments, the method increases survival by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method further comprises administering an additional active agent and / or supportive therapy to the subject. In some embodiments, the additional active agent and / or supportive therapy is selected from the group consisting of trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotatercept, luspatercept, iron chelators, blood transfusions, platelet transfusions, allogeneic hematopoietic stem cell transplants, autologous gene therapy, and antibiotics.

[0022] In certain embodiments, the GlyT1 inhibitor has formula I [ka] [wherein Ar is an unsubstituted or substituted aryl or a 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, where the substituted aryl and heteroaryl groups are hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted with halogen, (C1-C6)-alkyl substituted with hydroxy, (CH2)n-(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted with halogen, NR 7 R 8 , C(O)R 9 , SO2R 10 and -C(CH3)=NOR 7 or by a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N and O, optionally substituted by (C1-C6)-alkyl; R 1 is hydrogen or (C1-C6)-alkyl; R 2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or halogen, CH(CH3)-(C3-C7)-cycloalkyl, (CH2) n+1 -C(O)-R 9 , (CH2) n+1 -CN, bicyclo[2.2.1]heptyl, (CH2) n+1 -O-(C1-C6)-alkyl, (CH2) n -heterocycloalkyl, (CH2) n -aryl or (CH2) n - 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen (CH2) n- 5- or 6-membered heteroaryl, where aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy; R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl; R 5 are NO2, CN, and C(O)R 9 or SO2R 10 ;R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR 7 R 8 ;R 10 is (C1-C6)-alkyl optionally substituted with halogen, (CH2) n -(C3-C6)-Cycloalkyl, (CH2) n -(C3-C6)-alkoxy, (CH2) n -heterocycloalkyl or NR 7 R 8 and n is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0023] In certain embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0024] In certain embodiments, the GlyT1 inhibitor has formula II: [ka] [In the formula, R1 represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrrolyl, and thiadiazole, and the heteroaryl is selected from the group consisting of -OH, -NR7R8, halogen, (C1-C8) alkyl, (C3-C 10 ) cycloalkyl, (C1-C8) alkoxy, (C1-C 12 ) alkoxyalkyl, (C1-C8) hydroxyalkyl, (C6-C 14 ) aryl and benzyl; R2, R3 and A independently represent H or (C1-C8)alkoxy, where said alkyl is optionally substituted with one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen; Q is -(CH2) n -(wherein n=1, 2, 3 or 4) or -(CH m -O- (wherein m=2, 3 or 4); Z represents (C 14 R4 and R5 each independently represent H, halogen, (C1-C8) alkyl, (C6-C 14 )Aryl, (C6-C 14 )aryloxy, (C1-C8)alkoxy, (3-10 membered)heterocycloalkyl or (C3-C8)cycloalkoxy; where R4 and R5 are optionally substituted with one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen; Y represents -R6, -(CH2)o-R6, -C(R6)3 or -CH(R6)2, where 0=1, 2 or 3; R6 is H, (C6-C 14 )Aryl, (C1~ 10 ) Alkyl, (C3-C 10 )Cycloalkyl, (C5-C18 ) Bicycloalkyl, (C5-C 18 )tricycloalkyl, (3-10 membered)heterocycloalkyl, (5-10 membered)heteroaryl, -C(=O)NR7R8 or -C(=O)OR7, wherein the R6 groups may be optionally substituted with one or more X groups; X=-OH, (C1-C8)alkoxy, -NR 11 R 12 , -SO2R 10 , -C(=O)R 10 , halogen, cyano, (C1-C8) alkyl, (C1-C 10 )alkoxyalkyl, (5-10 membered)heteroaryl, (C6-C 14 )Aryl, (C6-C 14 )aryloxy, benzyl, or (C1-C8)hydroxyalkyl; R7 and R8 are independently H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10 membered)heterocycloalkyl, (C1-C8)hydroxyalkyl, (5-10 membered)heteroaryl, or (C1-C 10 R7 and R8 may be optionally substituted with one or more X groups; or R7 and R8, together with the nitrogen to which they may be attached, may form a (3-10 membered)heterocycloalkyl group, optionally substituted with one or more X groups; R 10 is (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl; R 11 and R 12 are independently H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) represents alkoxyalkyl] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In other such embodiments, the GlyT1 inhibitor is a compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0025] In certain embodiments, the GlyT1 inhibitor has formula III: [ka] [In the formula, Z 1 is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, HaloC 1~4 Alkyl, phenyl, haloC 1~4 Alkoxy, halophenyl, C 1~4 Alkyl sulfoxy, C 1~4 selected from the group consisting of alkylsulfonyl, bromo and chloro; Z 2 is hydrogen, halogen, cyano, C 1~4 Alkyl, phenyl, haloC 1~4 Alkyl, haloC 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 cycloalkyl; Z 3 is hydrogen, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4Alkylthio, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy and C 3~6 cycloalkyl; Z 4 is hydrogen, halogen, C1-3 alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, Phenyl, HaloC 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 cycloalkyl; Z 5 is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, Phenyl, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 cycloalkyl; 1 ~Z 5 When more than one of Z is methoxy, 1 and Z 5 Only R is methoxy. 3 and R 4 are independently selected from hydrogen and C optionally substituted with one or more groups Y. 1~4 alkyl; or R 3 and R4, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 5-, 6- or 7-membered carbocyclic ring optionally substituted with a group Y'; Y is C 1~4 Alkoxy, Hydroxy, HaloC 1~4 Alkoxy and C 3~5 cycloalkyl; Y' is selected from the group consisting of C 1~4 Alkyl, C 1~4 Alkoxy, halogen, hydroxy, haloC 1~4 Alkoxy, C 3~5 Cycloalkyl and C 5~10aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on A, a 5-, 6- or 7-membered carbocyclic ring; R 5 and R 6 is independently a C optionally substituted with one or more groups X; 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached form a saturated 5- or 6-membered carbocyclic ring optionally substituted with one or more groups X'; R 5 and R6 together with the carbon atom to which they are attached form a 5-membered saturated carbocyclic ring, which ring may optionally further contain a group of additional heteroatoms selected from O, N and S(O)m, where m=0, 1 or 2; X is halogen, hydroxy, C 1~4 Alkoxy, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy and C 5~10 aryl; X' is selected from the group consisting of halogen, hydroxy, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy and C 5~10 aryl; where R 3 , R 4 , R 5 and R 6 are not all simultaneously unsubstituted methyl; however, at the same time, Z 1 is propyloxy, and Z 3 is chloro and Z 2 =Z 4 =Z 5 =H and R 5 and R 6 If both are methyl, R 3 and R 4 do not form a 2-methylpyrrolidine group together with the nitrogen atom to which they are attached; 1 is methyl and Z 3 is methoxy and Z 2= Z4 = Z5 = H, and R 5 and R 6 If both are methyl, R 3 and R 4 do not form, together with the nitrogen atom to which they are attached, a pyrrolidine group. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0026] In certain embodiments, the GlyT1 inhibitor has formula IV: [ka] [Wherein, Z is (CH2) n , O, S, SO, SO2 or N-R5; n is 0, 1 or 2; X is hydrogen, halogen, (C 1~6 ) alkyloxy, (C 3~6 )cycloalkyloxy, (C 6~12 )aryloxy, (C 6~12 )Aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6, and halogens, (C 6~12 ) aryl, (C 1~6 ) alkyloxy or (C 6~12 ) optionally substituted with aryloxy (C 1~4 ) alkyl; or two substituents at adjacent positions together represent a fused (C 5~6 ) aryl group, fused (C 5~6 ) cycloalkyl ring or O-(CH2) m m is 1 or 2; Y is hydrogen, halogen, (C 1~4) alkyloxy, SR6, NR6R6, and halogen optionally substituted (C 1~4 R1 is COOR7 or CONR8R9; R2 and R6 are (C 1~4 R3, R4 and R5 are independently hydrogen or (C 1~4 ) alkyl; R7, R8 and R9 are independently hydrogen, (C 1~4 ) alkyl, (C 6~12 ) aryl or arylalkyl] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0027] In certain embodiments, the GlyT1 inhibitor has formula V: [ka] [In the formula, n is an integer of 1 to 3; R 1 and R 2 is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said rings are independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino; a , R b or R c or R 1 and R 2when attached to the same carbon atom, can be combined to form a cycloalkyl or a monocyclic saturated heterocyclyl to give a spirocycle, where the cycloalkyl or monocyclic saturated heterocyclyl is independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino. d , R c or R f or R 1 and R 2 when attached to the 2- and 5-position or 3- and 6-position carbon atoms of the piperazine ring, they can combine to form a -C1-C3-alkylene chain, in which one of the carbon atoms in the alkylene chain is optionally replaced by -NR-, -O-, -S(O)n- (wherein R is hydrogen or alkyl and n is 0-2), and further, one or two hydrogen atoms in the alkylene chain can be optionally replaced by one or two alkyls; R 3 , R 4 and R 5 are independently hydrogen, alkyl, fluoro or fluoroalkyl; Ar 1 and Ar 2 is independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each of the foregoing rings is selected from R g , R h or R i and R g is alkyl, -C=CR 6 (In the formula, R 6 is aryl or heteroaryl), halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino; R h and R iis independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl, where R g , R h and R i R is independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy(carbpxy), alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino. j , R k or R l with the proviso that the compound of formula V is not 2-(4-benzhydrylpiperazin-l-yl)acetic acid, 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-l-yl)acetic acid, 2-((2R,5S)-4-((R)-(4-(lH-tetrazol-5-yl)phenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-l-yl)acetic acid or 2-((2R,5S)-4-((R)-(4-cyanophenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-l-yl)acetic acid. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0028] In certain embodiments, the GlyT1 inhibitor has formula VI: [ka] [wherein A represents a group of the general formula N-R1, a group of the general formula N+(O-)R1 or a group of the general formula N+(R')R1, where R1 represents either a hydrogen atom, or a linear or branched (C1-C7) alkyl group optionally substituted with one or more fluorine atoms, or a (C4-C7) cycloalkyl group, or a (C3-C7) cycloalkyl(C1-C3) alkyl group, or a phenyl(C1-C3) alkyl group optionally substituted with one or two hydroxyl or methoxy groups, or a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group; R' represents a linear or branched (C1-C7) alkyl group; X represents a hydrogen atom, or a halogen atom and a trialkyl group. R2 represents a hydrogen atom or one or more substituents selected from a halogen atom and a trifluoromethyl, a (C1-C4) alkyl or a (C1-C4) alkoxy group or an amino group of the general formula NR3R4, in which R3 and R4 independently of one another represent a hydrogen atom or a (C1-C4) alkyl group, respectively, or form together with the nitrogen atom carrying them a pyrrolidine, piperidine or morpholine ring, or a phenyl group optionally substituted with atoms or groups as defined above for the symbol X. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0029] In certain embodiments, the GlyT1 inhibitor has formula VII: [ka] [In the formula, R 1 is -(CH2) n -R 1a (In the formula, n is independently 0 to 6; R 1a (1) C which is unsubstituted or substituted with 1 to 6 halogens or hydroxyl 1~6 Alkyl, (2) R 2a , R 2b and R 2c (3) unsubstituted or substituted phenyl 1~6 Alkyl, 1-6 halogens, hydroxy or -NR 10 R 11 C replaced with 3~6 cycloaryl, (4) unsubstituted or substituted with 1 to 6 halogen, hydroxy or -NR 10 R 11 -OC is substituted with 1~6 Alkyl, (5)-COR 9 (wherein R9 is (a) hydrogen, (b) unsubstituted or substituted with 1 to 6 fluoro -C 1~6 (c) alkyl, (d) benzyl, and (e) phenyl; (f) —NR 10 R 11 (In the formula, R 10 and R 11 is (a) hydrogen, (b) unsubstituted or is selected from hydroxy, 1 to 6 fluoro, or -NR 12 R 13 (In the formula, R 12 and R 13 are independently hydrogen and -C 1~6 alkyl) 1~6 alkyl, (c) unsubstituted or selected from hydroxy, 1 to 6 fluoro, or -NR 12 R 13 -C is substituted with 3~6(c) -CH 2 ... 10 R 11 R2 is selected from the group consisting of (1) R 2a , R 2b and R 2c (2) phenyl that is unsubstituted or substituted with 1 to 6 halogen, hydroxy, -NR 10 R 11 , C substituted with phenyl or heterocycle 1~8 Alkyl (wherein phenyl or heterocycle is R 2a , R 2b and R 2c (3) unsubstituted or substituted with 1 to 6 halogen, hydroxy or -NR 10 R 11 C replaced with 3~6 cycloalkyl, and (4) unsubstituted or substituted with 1 to 6 halogen, hydroxy, or -NR 10 R 11 -C is substituted with 1~6 Alkyl-(C 3~6 cycloalkyl); R 2a , R 2b and R 2c is (1) hydrogen, (2) halogen, (3) unsubstituted or (a) 1 to 6 halogens, (b) phenyl, (c) C 3~6 Cycloalkyl, or (d) -NR 10 R 11 -C is substituted with 1~6 alkyl, (4) -OC which is unsubstituted or substituted with 1 to 6 halogens 1~6 Alkyl, (5) Hydroxy, (6) -SCF3, (7) -SCHF2, (8) -SCH3, (9) -CO2R 9 , (10)-CN, (11)-SO2R 9 , (12)-SO2-NR 10 R 11 , (13)-NR 10 R 11 , (14)-CONR 10 R 11(15)-NO2; 3 (1) is unsubstituted or contains 1 to 6 halogen, hydroxyl, or -NR 10 R 11 C replaced with 1~6 (2) unsubstituted or containing 1 to 6 halogens, hydroxyl, or -NR 10 R 11 C replaced with 3~6 cycloalkyl; R 4 and R 5 is (1) hydrogen, and (2) C which is unsubstituted or substituted with halogen or hydroxyl. 1~6 alkyl, or R 4 and R 5 Together, C 3~6 forms a cycloalkyl ring; A is (1) -O-, and (2) -NR 10 - m is zero or 1, where when m is zero, R 2 directly bonds to the carbonyl. and pharma- ceutically acceptable salts thereof, as well as the individual enantiomers and diastereomers thereof or pharma- ceutically acceptable salts thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0030] In certain embodiments, the GlyT1 inhibitor has formula VIII: [ka] [In the formula, R 1 is halogen, C1-C3 alkyl, C3-C6 cycloalkyl, OR 9 or S.R.10 where C1-C3 alkyl and C3-C6 cycloalkyl are each independently selected from R 7 is substituted 1 to 10 times as necessary; R 2 is H;R 3 and R4 are each independently H or CH3; R 5 are (1) hydrogen, (2) R 7 (3) gem-dialkyl, and (4) gem-dihalo; or two R 5 The substituents, together with the carbon atom to which they are attached, form R 7 or two R on adjacent carbons of the ring to which they are attached form a 3-, 4- or 5-membered cycloalkyl optionally substituted 1 to 10 times with 5 The substituents, taken together, are R 7 R 6 teeth, [ka] (wherein E, F, and G are each independently nitrogen or carbon; R 6a is C1-C2 alkyl optionally substituted 1-5 times with halogen or deuterium; R 7 is (1) hydrogen, (2) halogen, (3) deuterium, (4) gem-dialkyl, (5) gem-dihalo, (6) -OR 9 , -NR 11 R 12 , -NR 11 C(O) p R 10 , -S(O) p R 10 , -CN, -NO2, -C(O) p R 10 , -C(O)NR 11 R 12 or NR 11 C(S)R 10 and (7) selected from the group consisting of oxo or thio; R8 is (1) hydrogen, (2) halogen, (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl, where each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is independently selected from R 7 substituted 1 to 11 times as needed), or (4)-OR 9 , -NR 11 R 12 , -NR 11 C(O) p R 10 , -S(O) p R 10 , -CN, -NO2, -C(O) p R 10 , -C(O)NR 11 R 12 Or -NR 11 C(S)R 10 R 9 is hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10 wherein each of C1-C4 alkyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is selected from the group consisting of R 7 substituted 1 to 11 times as necessary; R 10 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, where each of C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted 1 to 11 times with substituents defined in R7, and aryl or heteroaryl is selected from the group consisting of R 8 is substituted 1 to 10 times as necessary; R 11 and R 12are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, where each of C1-C4 alkyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is selected from the group consisting of R 7 and the aryl or heteroaryl is optionally substituted 1 to 11 times with a substituent as defined in 8 or R 11 and R 12 together with the nitrogen to which they are attached, R 7 A forms a saturated or partially saturated monocyclic or fused bicyclic heterocycle optionally substituted 1 to 11 times with [ka] X is N; Y is N; p is 1 or 2; m is 0; provided that R 6 cannot be (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl. or an oxide thereof, a pharma- ceutically acceptable salt of the compound or of the oxide thereof, or an individual enantiomer or diastereomer thereof.

[0031] In certain embodiments, the GlyT1 inhibitor is: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0032] In certain embodiments, the GlyT1 inhibitor is represented by formula IX [ka] [In the formula, R 1 represents phenyl or a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N or S, where the phenyl or heteroaryl is optionally joined to one or more R 3 with R being substituted as necessary; 2 represents an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8-10-membered bicyclic heteroaryl, where the monocyclic or bicyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from O, N, or S, and where the aryl or heteroaryl has one or more R 4 with R being substituted as necessary; 3 is a halogen, C 1~4 -Alkyl or C 3~6 -cycloalkyl, where C 1~4 -Alkyl or C 3~6 -cycloalkyl is optionally substituted with one or more halogens; R 4 is halogen, -CN, C 1~4 -Alkyl, C 3~6 -cycloalkyl, -C 1~3 -Alkyl-C 3~6 -Cycloalkyl or -OC 1~6 alkyl, where C 1~4 -Alkyl, C 3~6 -cycloalkyl, -C 1~3 -Alkyl-C 3~6 -Cycloalkyl or -OC 1~6 -alkyl is optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt thereof, or a tautomer or stereoisomer of the compound or a pharma- ceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0033] In certain embodiments, the GlyT1 inhibitor has the formula X [ka] [In the formula, R 1 is a) a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S(O)r; b) a 5- or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from the group consisting of O, N, and S(O)r; and c) a 5- or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from the group consisting of O, N, and S(O)r. r wherein each of said groups a), b) and c) is selected from the group consisting of: C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3~6 -cycloalkyl- and C 3~6 -cycloalkyl-O-, which in the case of a substituent is attached to the nitrogen ring atom, and said substituent is 1~4 -Alkyl-, C 1~4 -Alkyl-CO-, C 3~6 -cycloalkyl- and C 3~6 -cycloalkyl-CO-, wherein C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, C 1~4 -Alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3~6 -cycloalkyl-, C 3~6 -Cycloalkyl-CO- or C 3~6Each of the substituents of -cycloalkyl-O- may be substituted with one or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 2 is hydrogen, C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, -CN and C 3~6 -cycloalkyl-, wherein C 1~4 -Alkyl-, C 1~4 -Alkyl-O- and C 3~6 Each -cycloalkyl- group may be optionally substituted with one, two, three or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 3 is C 1~6 -Alkyl-O-, C 3~6 -cycloalkyl-O-, morpholino, pyrazolyl, and one oxygen atom and optionally O, N and S(O) as ring members s (wherein s=0, 1, or 2), wherein the C 1~6 -alkyl-O- and the C 3~6 -Cycloalkyl-O- is fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -Alkyl-, C 3~6 -cycloalkyl-, C 1~6 -Alkyl-O- and C 3~6 -cycloalkyl-O-, optionally substituted with one, two, three or more substituents independently selected from the group consisting of: R 4 is hydrogen; or R 3 and R 4 together with the ring atoms of the phenyl group to which they are attached, represent 4-, 5-, or 6-membered monocyclic partially saturated heterocycloalkyl, or each of which is O, N, and S(O) s(wherein s=0, 1 or 2), wherein in general formula (I), R 3 There must be one ring oxygen atom directly attached to the ring carbon atom of said phenyl group to which is attached; wherein said heterocycloalkyl group is selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, 1~4 -Alkyl-, C 3~6 -cycloalkyl-, C 1~6 -Alkyl-O-, C 3~6 - optionally substituted with one, two, three or more substituents independently selected from the group consisting of cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-; R 5 is hydrogen; R 6 is hydrogen, C 1~4 -Alkyl-SO2-, C 3~6 -cycloalkyl-SO2 and -CN; R 7 is hydrogen; or a) R 6 and R 7 or b) R 6 and R 5 The first pair of phenyl groups, together with the ring atoms of the phenyl groups to which they are attached, are O, N and S(O) u (wherein u=0, 1 or 2), wherein in general formula (I), R 6 There must be one -SO2- member attached directly to the ring carbon atom of the phenyl group to which is attached, and the heterocycloalkyl group is selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, 1~4 -Alkyl-, C 1~6 -Alkyl-O- and C 3~6-cycloalkyl-O-, optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of: -cycloalkyl-O-, or a pharma- ceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inibitor is of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0034] In some embodiments, the GlyT1 inhibitor is represented by formula XI [ka] Compound [In the formula, R 1 is halogen, -OR 1’ , -SR 1” , cycloalkyl, cyclic amide, heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; R 1’ and R 1” are each independently hydrogen, lower alkyl, lower alkyl substituted with halogen, -(CH2) x -cycloalkyl or -(CH2) x -aryl; R 2 is -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; [ka] teeth, [ka] wherein one of the additional N ring atoms of the aromatic or partially aromatic bicyclic amine is in the form of its oxide. [ka] may be available at 3 ~R 10 are each independently hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO2, NH2, aryl, 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, -NH-lower alkyl, -N(lower alkyl)2, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)2-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH2) y -Lower alkoxy, -O(CH2) y C(O)N(lower alkyl)2, -C(O)-lower alkyl, -O-(CH2) x -aryl, -O-(CH2) x -Cycloalkyl, -O-(CH2) x -heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R, R', R'' and R''' are each independently hydrogen or lower alkyl; or R' and R''' in group e) together with -(CH2)4- form a 6-membered ring; R1, R1', R1'' and R 3 ~R 10 All aryl-, cycloalkyl-, cyclic amido, heterocycloalkyl-, or 5- or 6-membered heteroaryl groups defined for are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen, and lower alkoxy; n, m, o, p, q, r, s, and t are each independently 1 or 2; x is 0, 1, or 2; and y is 1 or 2, or a pharma-ceutically acceptable acid addition salt thereof.

[0035] In certain embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier.

[0036] In certain embodiments, the subject is a subject in need thereof.

[0037] In certain embodiments, the GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof, is administered in a therapeutically effective amount.

[0038] The file of this patent contains at least one drawing / photograph executed in color. Copies of this patent with color drawing / photograph(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0039] [Figure 1] Figure 1A and Figure 1B show RPS19 mRNA levels in TF-1 cell lines transduced with various lentiviruses encoding shRNA targeting RPS19 or a control scrambled shRNA. shRNA expression was inducible with doxycycline treatment. Figure 1A shows RPS19 mRNA expression in TF-1 cells transduced with RPS19-shRNA#a (TF-1 / shRNA#a), RPS19-shRNA#b (TF-1 / shRNA#b) or scrambled shRNA (TF-1 / scrambled) after cells were treated with doxycycline for 2 days. Figure 1B shows RPS19 mRNA expression in TF-1 / shRNA#a, TF-1 / shRNA#b and TF-1 / scrambled cells after cells were treated with doxycycline for 4 days.

[0040] [Diagram 2]Figure 2A and Figure 2B show RPS19 protein levels in TF-1 cell lines transduced with lentivirus encoding shRNA targeting RPS19 or control scrambled shRNA. shRNA expression was inducible with doxycycline treatment. Figure 2A shows Western blots of RPS19 protein levels in TF-1 / shRNA#a cells, TF-1 / shRNA#b cells and TF-1 / scrambled cells after 4 days of treatment with doxycycline. Figure 2B shows quantification of the Western blots described in Figure 2A.

[0041] [Diagram 3] Figures 3A and 3B show the proliferation of TF-1 cells transduced with various lentiviruses encoding shRNAs targeting RPS19 or a control scrambled shRNA, and the cell lines were treated with either erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GMCSF) for 6 days. Figure 3A shows the cell numbers in TF-1 / shRNA#a, TF-1 / shRNA#b or TF-1 / scrambled after cells were treated with EPO for 6 days. Figure 3B shows the cell numbers in TF-1 / shRNA#a, TF-1 / shRNA#b and TF-1 / scrambled after cells were treated with GMCSF for 6 days.

[0042] [Figure 4]Figures 4A and 4B show cell viability measured using CellTiter-Glo® (CTG) of TF-1 cells transduced with various lentiviruses encoding shRNAs targeting RPS19 or a control scrambled shRNA, and the cell lines were treated with either erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GMCSF) for 6 days. Figure 4A shows cell viability of TF-1 cells transduced with either RPS19-shRNA#a, RPS19-shRNA#b or scrambled shRNA after cells were treated with EPO for 6 days. Figure 4B shows cell viability of TF-1 cells transduced with either RPS19-shRNA#a, RPS19-shRNA#b or scrambled shRNA after cells were treated with GMCSF for 6 days.

[0043] [Diagram 5] Figure 5 shows that bitopertin treatment in TF-1 cells with RPS19 knockdown reverses the anti-proliferative effect caused by RPS19 knockdown. Prior to treatment with bitopertin, TF-1 / shRNA#a cells were treated with doxycycline for 4 days to induce RPS19 knockdown by shRNA#a. TF-1 / scrambled shRNA cells were treated similarly as an experimental control. On day 4, both TF-1 / shRNA#a and TF-1 / scrambled shRNA cells were seeded in 12-well cell culture plates at a density of 1×105 cells per well. Bitopertin was added to the cells in the 12-well plates for 48 hours of treatment from day 4 to day 6. Figure 5 shows the cell counts of TF-1 cells transduced with either RPS19-shRNA#a or scrambled shRNA after the cells were treated with either DMSO, 4 nM bitopertin or 37 nM bitopertin for 2 days. Each of the TF-1 cells was also treated with doxycycline to induce shRNA expression and GMCSF to stimulate proliferation throughout the experiment.

[0044] [Figure 6]Figure 6 shows cell viability measured using CellTiter-Glo® (CTG) of TF-1 cells transduced with lentivirus encoding either shRNA targeting RPS19 or control scrambled shRNA. Cells were (1) treated with doxycycline throughout the entire cell culture period to induce shRNA expression; (2) treated with GMCSF throughout the entire 6-day cell culture period to induce proliferation. On day 4 of cell culture, TF-1 cells were seeded into 96-well cell culture plates at a density of 1x104 cells per well and treated with various doses of bitopertin over a 2-day culture period from day 4 to day 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Detailed Description of the Application Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0046] As used herein, the terms "a" or "an" mean "at least one" or "one or more than one," unless the context clearly dictates otherwise.

[0047] As used herein, the term "about" means that the numerical values ​​are approximations and small variations that will not significantly affect the practice of the disclosed embodiments. When numerical limitations are used, unless otherwise indicated by context, "about" means that the numerical values ​​can vary by ±10% and still be within the scope of the disclosed embodiments.

[0048] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0049] As used herein, the term "acylamino" refers to an amino group substituted with an acyl group (e.g., -OC(=O)-H or -OC(=O)-alkyl). Examples of acylamino are -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" refers to a lower acyl group (e.g., -OC(=O)-H or -OC(=O)-C 1~6 An example of a lower acylamino is -NHC(=O)H or -NHC(=O)CH3.

[0050] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0051] As used herein, the term "alkenyl" means a straight or branched alkyl group having one or more double carbon-carbon bonds and 2 to 20 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In some embodiments, the alkenyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0052] The terms "alkoxy", "phenyloxy", "benzoxy" and "pyrimidinyloxy" refer to an optionally substituted alkyl, phenyl, benzyl or pyrimidinyl group, respectively, attached through an oxygen atom. For example, the term "alkoxy" refers to a straight or branched -O-alkyl group of 1-20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain is 1-10 carbon atoms long, 1-8 carbon atoms long, 1-6 carbon atoms long, 1-4 carbon atoms long, 2-10 carbon atoms long, 2-8 carbon atoms long, 2-6 carbon atoms long, or 2-4 carbon atoms long.

[0053] As used herein, the term "alkyl" refers to a linear or branched saturated hydrocarbon group. The alkyl group can contain 1-20, 2-20, 1-10, 2-10, 1-8, 2-8, 1-6, 2-6, 1-4, 2-4, 1-3, or 2 or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methylpentyl, methyl, ethyl ... 1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and the like.

[0054] As used herein, the term "alkylamino" refers to an amino group substituted with an alkyl group having 1 to 6 carbon atoms. An example of an alkylamino is -NHCH2CH3.

[0055] As used herein, the term "alkylene" or "alkylenyl" refers to a divalent alkyl linking group. Examples of alkylene (or alkylenyl) are methylene or methyleneyl (-CH-).

[0056] As used herein, the term "alkylthio" refers to an -S-alkyl group having 1 to 6 carbon atoms. An example of an alkylthio group is -SCH2CH3.

[0057] As used herein, the term "alkynyl" means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, acetylene, 1-propylene, 2-propylene, etc. In some embodiments, the alkynyl chain is 2-10 carbon atoms in length, 2-8 carbon atoms in length, 2-6 carbon atoms in length, or 2-4 carbon atoms in length.

[0058] The term "amide" as used herein refers to the group [ka] (Wherein, each R 30 independently represent hydrogen or a hydrocarbyl group, or two R 30 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0059] As used herein, the term "amidino" means -C(=NH)NH2.

[0060] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, as well as their salts, e.g., [ka] (Wherein, each R 30 independently represent hydrogen or a hydrocarbyl group, or two R 30 refer to a moiety that can be represented by the formula: (which, together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure).

[0061] As used herein, the term "aminoalkoxy" refers to an alkoxy group substituted with an amino group. An example of an aminoalkoxy is -OCH2CH2NH2.

[0062] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group. An example of an aminoalkyl is -CH2CH2NH2.

[0063] As used herein, the term "aminosulfonyl" means -S(=O)2NH2.

[0064] As used herein, the term "aminoalkylthio" refers to an alkylthio group substituted with an amino group. An example of an aminoalkylthio is -SCH2CH2NH2.

[0065] As used herein, the term "amphiphilic" refers to a three-dimensional structure that has distinct hydrophobic and hydrophilic regions. An amphiphilic compound preferably has the presence of both hydrophobic and hydrophilic elements.

[0066] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrate animals, such as wild animals, domestic animals and farm animals.

[0067] As used herein, the term "aryl" refers to a monocyclic, bicyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon. In some embodiments, an aryl group has 6 to 20 carbon atoms, or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include, but are not limited to, [ka] [ka] Examples include:

[0068] As used herein, the term "arylalkyl" refers to a C substituted with aryl. 1~6 It means alkyl.

[0069] As used herein, the term "arylamino" refers to an amino group substituted with an aryl group. An example of an arylamino is -NH (phenyl).

[0070] As used herein, the term "arylene" refers to an aryl linking group, ie, an aryl group that links one group to another group in a molecule.

[0071] The term "carbamate" is art-recognized and refers to a group [ka] (In the formula, R 29 and R 30 independently represent hydrogen or a hydrocarbyl group, e.g., an alkyl group, or R 29 and R 30 which, together with the intervening atoms, complete a heterocycle having 4 to 8 atoms in the ring structure.

[0072] As used herein, the term "carbamoyl" means -C(=O)NH2.

[0073] As used herein, the term "carbocycle" means a 5- or 6-membered saturated or unsaturated cyclic ring optionally containing an O, S or N atom as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the heterocycles listed above.

[0074] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0075] The term “carbonate” is art-recognized and refers to the group —OCO—R 30 (In the formula, R 30 represents a hydrocarbyl group).

[0076] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0077] As used herein, the term "carrier" refers to a diluent, adjuvant or excipient that is administered with a compound. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants and colorants can be used.

[0078] As used herein, the term "compound" refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0079] As used herein, the terms "comprising" (and any form of comprising, such as "comprise," "comprises," and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0080] As used herein, the term "contacting" refers to bringing two elements together in an in vitro or in vivo system. For example, "contacting" a GlyT1 transporter inhibitor with a GlyT1 transporter in an individual or patient or cell includes not only administration of the compound to an individual or patient, e.g., a human, but also includes introducing the compound into a sample containing a cell preparation or purified preparation that contains the GlyT1 transporter.

[0081] As used herein, the term "cyano" means --CN.

[0082] As used herein, the term "cycloalkyl" means a non-aromatic cyclic hydrocarbon, including cyclized alkyl, alkenyl, and alkynyl groups containing up to 20 ring-forming carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic ring systems, such as fused, bridged, and spiro ring systems. In some embodiments, polycyclic ring systems contain 2, 3, or 4 fused rings. Cycloalkyl groups can contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused (having a bond in common with the cycloalkyl ring) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-on-1-yl).

[0083] As used herein, the term "cycloalkylalkyl" refers to a C substituted with cycloalkyl. 1~6 It means alkyl.

[0084] As used herein, the term "dialkylamino" means an amino group substituted with two alkyl groups each having from 1 to 6 carbon atoms.

[0085] As used herein, the term "diazamino" means -N(NH2)2.

[0086] The term "ester" as used herein refers to the group -C(O)OR 30(In the formula, R 30 represents a hydrocarbyl group).

[0087] The term "ether" as used herein refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0088] As used herein, the term "facially amphiphilic" or "facially amphiphilic" refers to a compound having polar and nonpolar side chains that adopt a conformation that results in the separation of the polar (hydrophilic) and nonpolar (hydrophobic) side chains on opposite faces or separate regions of the structure or molecule.

[0089] As used herein, the term "glycine transporter" or "GlyT" refers to a membrane protein that facilitates the transport of glycine across the plasma membrane of a cell. Non-limiting examples of glycine transporters include glycine transporter 1 (GlyT1) and glycine transporter 2 (GlyT2).

[0090] As used herein, the term "GlyT1" or "GlyT1 transporter" refers to sodium- and chloride-dependent glycine transporter 1, also known as glycine transporter 1, which in humans is a protein encoded by the SLC6A9 gene (Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B (Jun 1994). "Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes". Mol Pharmacol. 45 (4): 608-17;Jones EM, Fernald A, Bell GI, Le Beau MM (Nov 1995). "Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization". Cytogenet Cell Genet. 71 (3): 211), which are incorporated herein by reference in their entireties.

[0091] As used herein, the term "GlyT2" or "GlyT2 transporter" refers to the sodium- and chloride-dependent glycine transporter 2, also known as glycine transporter 2, which in humans is a protein encoded by the SLC6A5 gene (Morrow JA, Collie IT, Dunbar DR, Walker GB, Shahid M, Hill DR (November 1998). "Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome". FEBS Lett. 439 (3): 334-40), which is incorporated herein by reference in its entirety.

[0092] As used herein, the term "GlyT1 inhibitor" refers to a compound that inhibits or blocks the activity of the GlyT1 transporter, including compounds that inhibit the activity of any isoform of GlyT1. Non-limiting examples of GlyT1 inhibitors are provided herein. In some embodiments, the GlyT1 inhibitor is a specific GlyT1 inhibitor, meaning that the inhibitor has a higher inhibitory activity against GlyT1 compared to GlyT2. In some embodiments, the inhibitor inhibits GlyT1 with at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity compared to GlyT2. In some embodiments, the GlyT1 inhibitor inhibits GlyT1 but does not inhibit or does not significantly inhibit the activity of GlyT2. The GlyT1 inhibitor that does not significantly inhibit the activity of GlyT2 then inhibits the activity of GlyT2 by less than 5%, 4%, 3%, 2% or 1%. The selectivity of the GlyT1 inhibitor is determined based on assays known in the art, such as those described in published journal articles (BN Atkinson, SC Bell, M. De Vivo, LR Kowalski, SM Lechner, VI Ognyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and MA Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is incorporated herein in its entirety.

[0093] As used herein, the term "GlyT2 inhibitor" refers to a compound that inhibits or blocks the activity of the GlyT2 transporter, including compounds that inhibit the activity of any isoform of GlyT2. In some embodiments, the GlyT2 inhibitor is a non-specific inhibitor, meaning that it can also inhibit or block the activity of GlyT1. In some embodiments, the GlyT2 inhibitor is a specific GlyT2 inhibitor, meaning that it has a higher inhibitory activity against GlyT2 compared to GlyT1. In some embodiments, the inhibitor inhibits GlyT2 with at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity or with about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity compared to GlyT1. In some embodiments, the GlyT2 inhibitor inhibits GlyT2 activity but does not inhibit or does not significantly inhibit the activity of GlyT1. A GlyT2 inhibitor that does not significantly inhibit the activity of GlyT1 then inhibits the activity of GlyT1 by less than 5%, 4%, 3%, 2% or 1%. The selectivity of GlyT2 inhibitors is determined based on assays known in the art, such as those described in the published journal article (BN Atkinson, SC Bell, M. De Vivo, LR Kowalski, SM Lechner, VI Ognyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and MA Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is incorporated herein in its entirety.

[0094] As used herein, the term "guanidino" means -NH(=NH)NH2.

[0095] As used herein, the term "halo" means a halogen radical, including, but not limited to, fluoro, chloro, bromo and iodo.

[0096] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0097] As used herein, the term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1~6 It refers to an alkyl group. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.

[0098] As used herein, the term "heteroaryl" refers to an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, a heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which is independently sulfur, oxygen, or nitrogen. In some embodiments, a heteroaryl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, 3 to 6 ring-forming atoms, or 3 to 5 ring-forming atoms. In some embodiments, a heteroaryl group contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, a heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidyl, and the like. Examples of such groups include dazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, and phenoxazinyl groups.Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine and 2-aminopyridine.

[0099] As used herein, the term "heteroarylalkyl" refers to a C substituted with a heteroaryl group. 1~6 It means an alkyl group.

[0100] As used herein, the term "heteroarylamino" refers to an amino group substituted with a heteroaryl group. An example of a heteroarylamino is -NH-(2-pyridyl).

[0101] As used herein, the term "heteroarylene" refers to a heteroaryl linking group, ie, a heteroaryl group that links one group to another group in a molecule.

[0102] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0103] As used herein, the term "heterocycle" or "heterocyclic ring" refers to a 5-7 membered monocyclic or bicyclic or 7-10 membered bicyclic heterocyclic ring system, any of whose rings may be saturated or unsaturated, consisting of carbon atoms and 1-3 heteroatoms selected from N, O and S, where the N and S heteroatoms may be optionally oxidized, and the N heteroatom may be optionally quaternized, including any bicyclic group in which any of the heterocyclic rings defined above are fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur in combination with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, and isoxazolyl. , isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl. Morpholino is the same as morpholinyl.

[0104] As used herein, the term "heterocycloalkyl" refers to a non-aromatic heterocycle having up to 20 ring-forming atoms, including cyclized alkyl, alkenyl, and alkynyl groups, in which one or more ring-forming carbon atoms are replaced by a heteroatom, such as an O, N, or S atom. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spiro systems). In some embodiments, heterocycloalkyl groups have 1-20 carbon atoms, or 3-20 carbon atoms. In some embodiments, heterocycloalkyl groups contain 3-14 ring-forming atoms, 3-7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1-4 heteroatoms, 1-3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, heterocycloalkyl groups contain 0-3 double bonds. In some embodiments, heterocycloalkyl groups contain 0-2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, etc. In addition, ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally substituted with oxo or sulfide. For example, ring-forming S atoms can be substituted with one or two oxos (forming S(O) or S(O)2). For another example, ring-forming C atoms can be substituted with oxos (forming carbonyl).Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (having a bond in common with) a non-aromatic heterocyclic ring, including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl and benzo derivatives of heterocycles such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally substituted by oxo or sulfido.

[0105] As used herein, the term "heterocycloalkylalkyl" refers to a C substituted with heterocycloalkyl. 1~6 Refers to alkyl.

[0106] As used herein, the term "hydroxy" or "hydroxyl" means an --OH group. As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl group substituted with a hydroxyl group. Examples of hydroxylalkyl include, but are not limited to, -CHOH and -CHCHOH.

[0107] As used herein, the terms "individual" or "patient", used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, such as humans.

[0108] As used herein, the phrase "inhibitory activity," eg, of an enzyme or transporter activity, means reducing the activity of an enzyme or transporter, eg, a GlyT1 transporter, by any measurable amount.

[0109] As used herein, the phrase "in need thereof" means that an animal or mammal has been identified as having a need for a particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. The animal or mammal may be in need of any of the methods and treatments described herein. In some embodiments, the animal or mammal is in or progressing to an environment where a particular disease, disorder or condition is prevalent.

[0110] As used herein, the phrase "capable of gelling in situ" is meant to encompass not only low viscosity liquids that form gels upon contact with the eye or lacrimal fluid outside the eye, but also more viscous liquids, such as semi-fluids and thixotropic gels, that exhibit a substantial increase in viscosity or gel consistency upon administration to the eye.

[0111] As used herein, the phrase "an integer between X and Y" refers to any integer, including the endpoints. For example, the phrase "an integer between X and Y" refers to 1, 2, 3, 4, or 5.

[0112] The term "lower" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer non-hydrogen atoms, preferably 6 or fewer non-hydrogen atoms, in the substituent. "Lower alkyl" refers, for example, to alkyl groups containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they occur alone or in combination with other substituents, such as hydroxyalkyl and aralkyl (in which case, for example, atoms in aryl groups are not counted when counting carbon atoms in an alkyl substituent) in the description.

[0113] As used herein, the term "mammal" means a rodent (i.e., a mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0114] As used herein, the term "N-alkyl" refers to an alkyl chain substituted with an amine group. Non-limiting examples include, but are not limited to: [ka] and the like. The alkyl chain can be linear, branched, cyclic, or any combination thereof. In some embodiments, the alkyl contains 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 carbons.

[0115] As used herein, the term "nitro" means --NO.

[0116] As used herein, the term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiophene is an example of a 5-membered heteroaryl ring.

[0117] As used herein, the phrase "ophthalmically acceptable" means having no lasting adverse effect on the treated eye or its function, or on the overall health of the treated subject. However, it will be recognized that transient effects, such as mild irritation or a "stinging" sensation, are common with topical administration of drugs, and the presence of such transient effects is not inconsistent with the composition, formulation, or ingredients (e.g., excipients) in the discussion of "ophthalmically acceptable" as defined herein.

[0118] As used herein, the phrase "optionally substituted" means that the substituent is optional, and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the specified atom or moiety can be replaced with a selection from the indicated substituents, provided that the normal valence of the specified atom or moiety is not exceeded and the replacement results in a stable compound. For example, when a methyl group is optionally substituted, three hydrogen atoms on the carbon atom can be replaced with a substituent.

[0119] As used herein, the phrase "pharmacologically acceptable" means compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals. In some embodiments, "pharmacologically acceptable" means approved by a federal or state government regulatory agency or listed by the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0120] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or free base of a compound described herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without undue toxicity, irritation, or allergic reaction. The compounds described herein may have sufficient acidic groups, sufficient basic groups, both types of functional groups, or more than one of each type, and thus react with some inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0121] For compounds described herein that contain a basic group, such as an amine, pharma- ceutically acceptable salts can be prepared by any suitable method available in the art, for example, from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphorous acid, and the like, or from organic acids, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acids, such as glucuronic acid or galacturonic acid, or from carboxylic acids, such as ... They may be prepared by treatment of the free base with an acid, an alpha-hydroxy acid such as mandelic acid, citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, a sulfonic acid such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixtures thereof which are regarded as equivalents or acceptable substitutes given the ordinary level of skill in the art.

[0122] For compounds described herein that contain an acidic group, such as a carboxylic acid group, base addition salts can be prepared by any suitable method available in the art, for example, by treating such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharma-ceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, ammonium, zinc or magnesium salts, or other metal salts; organic amino salts, such as alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts.

[0123] Other examples of pharma- ceutically acceptable salts include, but are not limited to, camsylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diol, tetrahydrofuran ... The salts include ethyl ester, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0124] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this application.

[0125] As used herein, the term "phenyl" means -C6H5. A phenyl group can be unsubstituted or substituted with one, two or three suitable substituents.

[0126] The terms "polycyclic", "polycyclic" and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0127] As used herein, the term "prodrug" refers to a derivative of a known direct-acting drug, which has enhanced delivery properties and therapeutic value compared to the drug, and is converted to an active drug by an enzymatic or chemical process. A common method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to produce the desired molecule. In certain embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, a prodrug with a nitro group on the aromatic ring can be reduced in vivo by a reductase to produce the desired amino group of the corresponding active compound. In another example, functional groups such as hydroxyl, carbonate, or carboxylic acid in the parent compound are present as esters, which can be cleaved by esterases. In addition, amine groups in the parent compound are present in, but not limited to, carbamate, N-alkylated, or N-acylated forms (Simplicio et al, "Prodrugs for Amines," Molecules, (2008), 13:519-547). In certain embodiments, some or all of the compounds described herein in the formulations presented above may be replaced with the corresponding suitable prodrugs.

[0128] As used herein, the term "purified" means that when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of a compound described herein, by weight of the isolate.

[0129] As used herein, the phrase "quaternary ammonium salt" refers to a derivative of the disclosed compounds having one or more tertiary amine moieties, where at least one tertiary amine moiety in the parent compound is alkylated (and the cation is Cl). - , CH3COO - and CF3COO - such as tetrahydrofuran, ...

[0130] As used herein, the term "ribosomal disorder" refers to any disease or dysfunction of ribosomes. It may include diseases or disorders related to mutated and / or abnormal function of ribosomal proteins. It may also include diseases caused by mutations in ribosomal proteins, or diseases caused by reduced levels or partial loss of function of ribosomal proteins, or diseases caused by increased levels of ribosomal proteins, compared to normal healthy control subjects. Ribosomal diseases or dysfunctions include, but are not limited to, (i) diseases of ribosomal biogenesis proteins, (ii) diseases of small nucleolar ribonucleoproteins, and (iii) diseases of ribosomal proteins. Ribosomal disorders include, but are not limited to, Diamond-Blackfan anemia, myelodysplastic syndrome associated (MDS) with isolated del(5q), Shwachman-Diamond syndrome, X-linked dyskeratosis congenita, and cartilage-hair hypoplasia.

[0131] As used herein, the term "semicarbazone" means =NNHC(=O)NH2.

[0132] As used herein, the phrase "solubilizing agent" means an agent that results in the formation of a micellar or true solution of a drug.

[0133] As used herein, the term "solution / suspension" refers to a liquid composition in which a first portion of an active agent is present in solution and a second portion of the active agent is present in a specific form in suspension in a liquid matrix.

[0134] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it is formed or detected. The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" is implicit, provided that such substitution is in accordance with the permitted valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic, substituents of organic compounds. The permissible substituents can be one or more than one and can be the same or different for appropriate organic compounds. For purposes of this application, heteroatoms such as nitrogen can have hydrogen substituents, and / or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatoms.

[0135] The substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the substituents may themselves be substituted, where appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, references to "aryl" groups or moieties implicitly include both substituted and unsubstituted variants.

[0136] The term "sulfate" is art-recognized and refers to the group -OSO3H or a pharma- ceutically acceptable salt thereof.

[0137] The term "sulfonamide" is art-recognized and can be represented by the general formula [ka] (In the formula, R 29 and R 30 independently represent hydrogen or hydrocarbyl, e.g., alkyl, or R 29 and R 30 refers to a group represented by the formula: (which, together with the intervening atoms, completes a heterocycle having 4 to 8 atoms in the ring structure).

[0138] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 30 (In the formula, R 30 represents hydrocarbyl).

[0139] The term "sulfonate" is art-recognized and refers to the group SO3H or a pharma- ceutically acceptable salt thereof.

[0140] The term “sulfone” is art-recognized and refers to the group —S(O)—R 30 (In the formula, R 30 represents hydrocarbyl).

[0141] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that induces a biological or pharmaceutical response desired in a tissue, system, animal, individual or human by a researcher, veterinarian, physician or other clinician. The therapeutic effect depends on the disorder being treated or the biological effect desired. Thus, the therapeutic effect may be a reduction in the severity of symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or may improve the treatment, cure, prevention or elimination of the disorder or side effects. The amount required to induce a therapeutic response can be determined based on the age, health, size and sex of the subject. The optimal amount can also be determined based on monitoring the subject's response to the treatment.

[0142] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0143] The term "thioester" as used herein refers to the group -C(O)SR 30 Or -SC(O)R 30 (In the formula, R 30 represents hydrocarbyl).

[0144] The term "thioether," as used herein, is the equivalent to an ether where the oxygen is replaced with a sulfur.

[0145] As used herein, the terms "treat", "treated" or "treating" refer to both therapeutic treatment and prophylactic measures, where the objective is to delay (reduce) an undesired physiological condition, disorder or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of a condition, disorder or disease; stabilization (i.e., not worsening) of the condition, disorder or disease state; delaying the onset or slowing down the progression of the condition, disorder or disease; amelioration or alleviation (whether partial or total) of the condition, disorder or disease state, whether detectable or undetectable; restoration of at least one measurable physical parameter not necessarily recognized by the patient; or enhancement or amelioration of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. Thus, "treatment of anemia associated with ribosomal disorders" or "treating anemia associated with ribosomal disorders" refers to activities that reduce or ameliorate either the primary phenomena or secondary symptoms associated with anemia associated with ribosomal disorders or other conditions described herein.

[0146] The term "urea" is art-recognized and has the general formula [ka] (In the formula, R 29 and R 30 independently represent hydrogen or hydrocarbyl, e.g., alkyl, or R 29 The appearance of R 30 and together with the intervening atoms complete a heterocycle having 4 to 8 atoms in the ring structure.

[0147] At various places in the present specification, substituents of compounds may be disclosed in groups or in ranges. It is specifically intended that embodiments include each and every individual subcombination of the members of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0148] For compounds in which a variable occurs more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, if a structure is described with two R groups co-occurring in the same compound, the two R groups can represent different moieties selected from the Markush group defined for R. In another example, multiple substituents can be optionally selected, e.g., [ka] When specified in the form: 1 is defined to include hydrogen, e.g., T 1 When is CH2, NH, etc., any H may be replaced with a substituent.

[0149] It will be further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0150] It is understood that the present embodiment encompasses the use of stereoisomers, diastereomers and optical stereoisomers of the compound, as well as mixtures thereof, if applicable.In addition, it is understood that stereoisomers, diastereomers and optical stereoisomers of the compound, as well as mixtures thereof, are within the scope of the embodiment.As a non-limiting example, the mixture may be racemic, or the mixture may contain one particular stereoisomer in an unequal proportion to the other.In addition, the compound may be provided as substantially pure stereoisomers, diastereomers, and optical stereoisomers (such as epimers).

[0151] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, e.g., enantiomers and diastereomers, are intended to be included within the scope of the embodiments, unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, may also exist in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of the compounds are also included within the embodiments, and can be isolated as a mixture of isomers or as separate isomeric forms. When a compound capable of stereoisomerism or geometric isomerism is specified by its structure or name without specifically referring to the R / S or cis / trans configuration, it is intended that all such isomers are contemplated.

[0152] In some embodiments, a composition comprises a compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, that is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure, meaning that the ratio of one enantiomer to the other in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or is entirely in the form of one enantiomer relative to the other. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, for example, in a composition or mixture of compounds, relative to the amount of the other enantiomer. For example, if a composition or mixture of compounds contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[0153] In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% relative to the amount of the other enantiomer in, for example, a composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[0154] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art, including, for example, chiral HPLC, fractional recrystallization using chiral resolving acids, which are organic acids that form optically active salts.Suitable resolving agents for fractional recrystallization include, but are not limited to, optically active acids, such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid.Other resolving agents suitable for fractional crystallization include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of a suitable elution solvent can be determined by one skilled in the art.

[0155] Compounds may also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond together with the migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms when protons can occupy two or more positions of a heterocyclic system, including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0156] Glycine transporter inhibitors, such as GlyT1 inhibitors, including their pharma- ceutically acceptable salts (e.g., GlyT1 inhibitors disclosed herein), can also exist as hydrates and solvates, as well as anhydrous and nonsolvated forms. A "hydrate" is a compound that exists as a composition with water molecules. The composition can contain a stoichiometric amount of water, e.g., a monohydrate or dihydrate, or can contain a random amount of water. A "solvate" is a similar composition, except that a solvent other than water, e.g., methanol, ethanol, dimethylformamide, diethyl ether, etc., is substituted for water. For example, methanol or ethanol can form an "alcoholate," which again can be stoichiometric or nonstoichiometric. Mixtures of such solvates or hydrates can also be prepared. The origin of such solvates or hydrates can be derived from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or associated with such solvent.

[0157] The compounds of the present application, including their pharma- ceutically acceptable salts and prodrugs, may exist as various polymorphs, pseudopolymorphs, or amorphous states. The term "polymorphs" as used herein refers to different crystalline forms of the same compound, and other solid state molecular forms, including pseudopolymorphs such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to different packing of molecules in the lattice as a result of changes in temperature, pressure, or variables in the crystallization process. Polymorphs differ from each other in their physical properties, such as X-ray diffraction properties, stability, melting point, solubility, or rate of dissociation in a certain solvent. Therefore, the form of crystalline polymorphs is an important aspect in the development of suitable dosage forms in the pharmaceutical industry.

[0158] Compounds may also include atoms of all isotopes occurring in intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0159] In some embodiments, the compound or its salt is substantially isolated. Partial separation may include, for example, a composition enriched with the compound. Substantial separation may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound or its salt. Methods for isolating compounds and their salts are routine in the art.

[0160] Although the disclosed compounds are preferred, other functional groups can be introduced into the compounds with the expectation of similar results. In particular, thioamides and thioesters are expected to have very similar properties. The distance between the aromatic rings can affect the geometric pattern of the compounds, and can be substituted as necessary, or this distance can be modified by introducing aliphatic chains of different lengths that can include amino acids, dicarboxylic acids, or diamines. The distance between the monomers in the compounds and their relative orientation can also be modified by replacing the amide bond with a substitute that has an additional atom. Thus, the replacement of the carbonyl group with a dicarbonyl changes the distance between the monomers and the tendency of the dicarbonyl unit to adopt the anti configuration of the two carbonyl moieties, changing the periodicity of the compounds. Pyromellitic anhydride represents yet another alternative to simple amide linkages, which can modify the conformation and physical properties of the compounds. Recent methods of solid phase organic chemistry (E. Atherton and RC Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of homodisperse compounds with molecular weights approaching 5,000 daltons. Other substitution patterns are similarly effective.

[0161] The compounds also include derivatives called prodrugs.

[0162] Compounds containing amine functional groups can also form N-oxides. Reference herein to compounds containing amine functional groups also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Examples of N-oxides include the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or peracid (e.g., peroxycarboxylic acid) (see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).

[0163] This may be claimed according to ranges or in any similar manner, with the right to proviso or exclude any individual member of any such group, including any subrange or combination of subranges within the group, and less than the full scale of the disclosure may be claimed for any reason. Furthermore, this may be claimed according to ranges or in any similar manner, with the right to proviso or exclude any individual substituent, analog, compound, ligand, structure or group of the claimed group, or any member thereof, and less than the full scale of the disclosure may be claimed for any reason. Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications are incorporated by reference in their entirety into this disclosure in order to more fully describe the state of the art as of the date of this disclosure to those skilled in the art. In the event of any inconsistency between the cited patents, patent applications and publications and this disclosure, the present disclosure will control.

[0164] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0165] Various embodiments of the compounds and salts thereof are provided. If a variable is not specifically recited, the variable may be any of the options described herein unless otherwise stated or indicated by context.

[0166] In some embodiments, the compound is as set forth in the accompanying non-limiting exemplary claims, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0167] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor has formula I: [ka] [In the formula, Ar is an unsubstituted or substituted aryl or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, where the substituted aryl and heteroaryl groups are hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR 7 R 8 , C(O)R 9 , SO2R 10 and -C(CH3)=NOR 7 or by a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N and O, optionally substituted by (C1-C6)-alkyl; R 1is hydrogen or (C1-C6)-alkyl; R 2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or halogen, CH(CH3)-(C3-C7)-cycloalkyl, (CH2) n+1 -C(O)-R 9 , (CH2) n+1 -CN, bicyclo[2.2.1]heptyl, (CH2) n+1 -O-(C1-C6)-alkyl, (CH2) n -heterocycloalkyl, (CH2) n -aryl or (CH2) n - 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen (CH2) n - 5- or 6-membered heteroaryl, where aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy; R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl; R 5 are NO2, CN, and C(O)R 9 or SO2R 10 and; R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR 7 R 8and; R 10 is (C1-C6)-alkyl optionally substituted with halogen, (CH2) n -(C3-C6)-Cycloalkyl, (CH2) n -(C3-C6)-alkoxy, (CH2) n -heterocycloalkyl or NR 7 R 8 and; n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0168] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor has formula II: [ka] [In the formula, R1 represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrrolyl, and thiadiazole, wherein the heteroaryl is -OH, -NR7R8, halogen, (C1-C8) alkyl, (C3-C 10 ) cycloalkyl, (C1-C8) alkoxy, (C1-C 12 ) alkoxyalkyl, (C1-C8) hydroxyalkyl, (C6-C 14 ) optionally substituted with one or more substituents selected from aryl and benzyl; R2, R3 and A independently represent H or (C1-C8)alkoxy, where said alkyl is optionally substituted with one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen; Q is -(CH2) n -(wherein n=1, 2, 3 or 4) or -(CH m -O- (wherein m=2, 3 or 4); Z is (C6~C 14 ) aryl, (C1-C8) alkyl or (C3-C8) cycloalkyl; R4 and R5 are each independently H, halogen, (C1-C8) alkyl, (C6-C 14 )Aryl, (C6-C 14 )aryloxy, (C1-C8)alkoxy, (3-10 membered)heterocycloalkyl or (C3-C8)cycloalkoxy; where R4 and R5 are optionally substituted with one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen; Y represents -R6, -(CH2)o-R6, -C(R6)3 or -CH(R6)2 (wherein 0=1, 2 or 3); R6 is H, (C6~C 14 ) aryl, (C 1~10 ) Alkyl, (C3-C 10 )Cycloalkyl, (C5-C 18 ) Bicycloalkyl, (C5-C 18 )tricycloalkyl, (3-10 membered)heterocycloalkyl, (5-10 membered)heteroaryl, -C(=O)NR7R8, or -C(=O)OR7, wherein the R6 groups can be optionally substituted with one or more X groups; X = -OH, (C1-C8)alkoxy, -NR 11 R 12 , -SO2R 10 , -C(=O)R 10 , halogen, cyano, (C1-C8) alkyl, (C1-C 10)alkoxyalkyl, (5-10 membered)heteroaryl, (C6-C 14 )Aryl, (C6-C 14 ) aryloxy, benzyl or (C1-C8) hydroxyalkyl; R7 and R8 are independently H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl; R7 and R8 may be optionally substituted with one or more X groups; Alternatively, R7 and R8, together with the nitrogen to which they may be attached, may form a (3-10 membered) heterocycloalkyl group optionally substituted with one or more X groups; R 10 is (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl; R 11 and R 12 are independently H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) represents alkoxyalkyl] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0170] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0171] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0172] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor has formula III: [ka] [In the formula, Z 1 is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, HaloC 1~4 Alkyl, phenyl, haloC 1~4 Alkoxy, halophenyl, C 1~4 Alkyl sulfoxy, C 1~4 Selected from the group consisting of alkylsulfonyl, bromo and chloro; Z 2 is hydrogen, halogen, cyano, C 1~4 Alkyl, phenyl, haloC 1~4 Alkyl, haloC 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 cycloalkyl; Z 3 is hydrogen, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy and C 3~6 cycloalkyl; Z 4 is hydrogen, halogen, C1-3 alkyl, haloC 1~4 Alkyl, C1~4 Alkoxy, C 1~4 Alkylthio, Phenyl, HaloC 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 cycloalkyl; Z 5 is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, Phenyl, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 cycloalkyl; Here, Z 1 ~Z 5 When more than one of Z is methoxy, 1 and Z 5 Only R is methoxy. 3 and R 4 are independently selected from hydrogen and C optionally substituted with one or more groups Y. 1~4 alkyl; or R 3 and R4 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated A, 5-, 6- or 7-membered carbocyclic ring optionally substituted with a group Y'; Y is C 1~4 Alkoxy, Hydroxy, HaloC 1~4 Alkoxy and C 3~5 cycloalkyl; Y' is C 1~4 Alkyl, C 1~4 Alkoxy, halogen, hydroxy, haloC 1~4 Alkoxy, C 3~5 Cycloalkyl and C 5~10 aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on A, a 5-, 6- or 7-membered carbocyclic ring; R 5 and R6 is independently a C optionally substituted with one or more groups X; 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached form a saturated 5- or 6-membered carbocyclic ring optionally substituted with one or more groups X'; R 5 and when R6 together with the carbon atom to which they are attached form a 5-membered saturated carbocyclic ring, the ring may optionally further contain an additional group of heteroatoms selected from O, N and S(O)m, where m=0, 1 or 2; X is halogen, hydroxy, C 1~4 Alkoxy, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy and C 5~10 aryl; X' is selected from the group consisting of halogen, hydroxy, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl, haloC 1~4 Alkoxy and C 5~10 aryl; where R 3 , R 4 , R 5 and R 6 are not all simultaneously unsubstituted methyl; However, at the same time, Z 1 is propyloxy, and Z 3 is chloro and Z 2 =Z 4 =Z 5 =H and R 5 and R 6 If both are methyl, R 3 and R 4 do not form a 2-methylpyrrolidine group together with the nitrogen atom to which they are attached; 1 is methyl and Z 3 is methoxy and Z 2 = Z4 = Z5 = H, and R 5 and R 6 If both are methyl, R 3and R 4 do not form, together with the nitrogen atom to which they are attached, a pyrrolidine group. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0173] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0174] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula IV: [ka] [In the formula, Z is (CH2) n , O, S, SO, SO2 or N-R5; n is 0, 1 or 2; X is hydrogen, halogen, (C 1~6 ) alkyloxy, (C 3~6 )cycloalkyloxy, (C 6~12 )aryloxy, (C 6~12 )Aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6, and halogens, (C 6~12 ) aryl, (C 1~6 ) alkyloxy or (C 6~12 ) optionally substituted with aryloxy (C 1~4 ) alkyl; or two substituents at adjacent positions together represent a fused (C 5~6 ) aryl group, fused (C 5~6 ) cycloalkyl ring or O-(CH2) m -O; m is 1 or 2; Y is hydrogen, halogen, (C 1~4 ) alkyloxy, SR6, NR6R6, and halogen optionally substituted (C 1~4 ) represents 1 to 3 substituents independently selected from alkyl; R1 is COOR7 or CONR8R9; R2 and R6 are (C 1~4 R3, R4 and R5 are independently hydrogen or (C 1~4 ) alkyl; R7, R8 and R9 are independently hydrogen, (C 1~4 ) alkyl, (C 6~12 ) aryl or arylalkyl] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0175] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0176] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula V: [ka] [In the formula, n is an integer from 1 to 3; R 1 and R 2 is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said rings are independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino; a , Rb or R c with R 1 and R 2 when attached to the same carbon atom, can be combined to form a cycloalkyl or a monocyclic saturated heterocyclyl to give a spirocycle, where the cycloalkyl or monocyclic saturated heterocyclyl is independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino. d , R c or R f or R 1 and R 2 when attached to the 2- and 5-position or 3- and 6-position carbon atoms of the piperazine ring, they can combine to form a -C1-C3-alkylene chain, in which one of the carbon atoms in the alkylene chain is optionally replaced by -NR-, -O-, -S(O)n- (wherein R is hydrogen or alkyl and n is 0-2), and further, one or two hydrogen atoms in the alkylene chain can be optionally replaced by one or two alkyl; R 3 , R 4 and R 5 are independently hydrogen, alkyl, fluoro or fluoroalkyl; Ar 1 and Ar 2 is independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each of the foregoing rings is selected from R g , R h or R i and R g is alkyl, -C=CR 6 (In the formula, R 6is aryl or heteroaryl), halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino; R h and R i is independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl, where R g , R h and R i R is independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino. j , R k or R l with the proviso that the compound of formula V is not 2-(4-benzhydrylpiperazin-l-yl)acetic acid, 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-l-yl)acetic acid, 2-((2R,5S)-4-((R)-(4-(lH-tetrazol-5-yl)phenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-l-yl)acetic acid or 2-((2R,5S)-4-((R)-(4-cyanophenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-l-yl)acetic acid. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0177] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0178] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula VI: [ka] [In the formula, A represents a radical of the general formula N-R1, a radical of the general formula N+(O-)R1 or a radical of the general formula N+(R')R1, where R1 represents either a hydrogen atom or a linear or branched (C1-C7) alkyl radical optionally substituted with one or more fluorine atoms, or a (C4-C7) cycloalkyl radical, or a (C3-C7) cycloalkyl(C1-C3) alkyl radical, or a phenyl(C1-C3) alkyl radical optionally substituted with one or two hydroxyl or methoxy groups, or a (C2-C4) alkenyl radical, or a (C2-C4) alkynyl radical; R' represents a linear or branched (C1-C7) alkyl group; X represents a hydrogen atom or one or more substituents selected from halogen atoms and trifluoromethyl, linear or branched (C1-C4) alkyl and (C1-C4) alkoxy groups; R2 represents either a hydrogen atom or a halogen atom and one or more substituents selected from trifluoromethyl, a (C1-C4) alkyl group or a (C1-C4) alkoxy group or an amino group of general formula NR3R4, in which R3 and R4, independently of one another, represent a hydrogen atom or a (C1-C4) alkyl group, respectively, or, together with the nitrogen atom they carry, form a pyrrolidine, piperidine or morpholine ring, or a phenyl group optionally substituted with atoms or groups as defined above for the symbol X. or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0179] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0180] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula VII [ka] [In the formula, R 1 is -(CH2) n -R 1a (In the formula, n is independently 0 to 6; R 1a teeth, (1) C unsubstituted or substituted with 1 to 6 halogen or hydroxyl 1~6 Alkyl, (2)R 2a , R 2b and R 2c (3) unsubstituted or substituted phenyl 1~6 Alkyl, 1-6 halogens, hydroxy or -NR 10 R11 C replaced with 3~6 Cycloaryl, (4) unsubstituted or substituted with 1 to 6 halogen, hydroxy or -NR 10 R 11 -OC is substituted with 1~6 Alkyl, (5)-CO2R 9 (Wherein, R9 is (a) hydrogen, (b) -C which is unsubstituted or substituted with 1 to 6 fluoro. 1~6 Alkyl, (c) benzyl, and (d) Phenyl ), (6)-NR 10 R 11 (In the formula, R 10 and R 11 teeth, (a) hydrogen, (b) is unsubstituted or is hydroxy, 1 to 6 fluoro, or -NR 12 R 13 (In the formula, R 12 and R 13 is hydrogen and -C 1~6 substituted with -C 1~6 Alkyl, (c) is unsubstituted or is hydroxy, 1 to 6 fluoro, or -NR 12 R 13 -C is substituted with 3~6 Cycloalkyl, (d) benzyl, (e) Phenyl (independently selected from (7)-CONR 10 R 11 is selected from the group consisting of R 2 teeth, (1)R 2a , R 2b and R 2cphenyl substituted with (2) unsubstituted or substituted with 1 to 6 halogen, hydroxy, -NR 10 R 11 , C substituted with phenyl or heterocycle 1~8 Alkyl (wherein phenyl or heterocycle is R 2a , R 2b and R 2c ), (3) unsubstituted or substituted with 1 to 6 halogen, hydroxy or -NR 10 R 11 C replaced with 3~6 cycloalkyl, and (4) unsubstituted or substituted with 1 to 6 halogen, hydroxy or -NR 10 R 11 -C is substituted with 1~6 Alkyl-(C 3~6 Cycloalkyl) selected from the group consisting of; R 2a , R 2b and R 2c teeth, (1) Hydrogen, (2) halogens, (3) unsubstituted, or (a) 1 to 6 halogens, (b) phenyl, (c)C 3~6 cycloalkyl, or (d)-NR 10 R 11 -C is substituted with 1~6 Alkyl, (4) -OC, which is unsubstituted or substituted with 1 to 6 halogens 1~6 Alkyl, (5) Hydroxy, (6)-SCF3, (7)-SCHF2, (8)-SCH3, (9)-CO2R 9 , (10)-CN, (11)-SO2R 9 , (12)-SO2-NR 10 R 11 , (13)-NR 10 R 11 , (14)-CONR 10 R 11 , and (15)-NO2 independently selected from the group consisting of: R 3 teeth, (1) unsubstituted or substituted with 1 to 6 halogen, hydroxyl or -NR 10 R 11 C replaced with 1~6 Alkyl, (2) unsubstituted or substituted with 1 to 6 halogen, hydroxyl or -NR 10 R 11 C replaced with 3~6 Cycloalkyl is selected from the group consisting of R 4 and R 5 teeth, (1) Hydrogen, and (2) C which is unsubstituted or substituted with halogen or hydroxyl 1~6 Alkyl or R 4 and R 5 Together, C 3~6 forming a cycloalkyl ring; A is, (1)-O-, and (2)-NR 10 - selected from the group consisting of; m is zero or one, where, when m is zero, R 2 directly bonds to the carbonyl. and pharma- ceutically acceptable salts thereof, as well as the individual enantiomers and diastereomers thereof or pharma- ceutically acceptable salts thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0182] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula VIII: [ka] [In the formula, R 1 is halogen, C1-C3 alkyl, C3-C6 cycloalkyl, OR 9 or S.R. 10 where C1-C3 alkyl and C3-C6 cycloalkyl are each independently selected from R 7 is substituted 1 to 10 times as necessary; R 2 is H; R 3 and R4 are each independently H or CH3; R 5 teeth, (1) Hydrogen, (2)R 7 C1-C6 alkyl optionally substituted 1 to 11 times with (3) gem-dialkyl, and (4) gem-dihalogen or Two R on the same carbon 5 The substituents, together with the carbon atom to which they are attached, form R 7 or forming a 3-, 4- or 5-membered cycloalkyl optionally substituted 1 to 10 times with Two R on adjacent carbons of the ring to which they are attached 5 The substituents, taken together, are R 7may form a 3-, 4-, 5- or 6-membered cycloalkyl optionally substituted 1 to 10 times with R 6 teeth, [ka] (wherein E, F, and G are each independently nitrogen or carbon; R 6a is C1-C2 alkyl optionally substituted 1 to 5 times with halogen or deuterium; R 7 teeth, (1) Hydrogen, (2) halogens, (3) Deuterium, (4) gem-dialkyl, (5) gem-dihalogen, (6)-OR 9 , -NR 11 R 12 , -NR 11 C(O) p R 10 , -S(O) p R 10 , -CN, -NO2, -C(O) p R 10 , -C(O)NR 11 R 12 or NR 11 C(S)R 10 , and (7) oxo or thio selected from the group consisting of; R 8 (1) Hydrogen, (2) halogens, (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C4-C7 cycloalkylalkyl (wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is independently selected from R 7 substituted 1 to 11 times as necessary), or (4)-OR 9 , -NR 11R 12 , -NR 11 C(O) p R 10 , -S(O) p R 10 , -CN, -NO2, -C(O) p R 10 , -C(O)NR 11 R 12 Or -NR 11 C(S)R 10 selected from the group consisting of; R 9 is hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10 wherein each of C1-C4 alkyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is selected from the group consisting of R 7 with 1 to 11 optional substitutions; R 10 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, where each of C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted 1 to 11 times with substituents defined in R7, and aryl or heteroaryl is selected from the group consisting of R 8 is substituted 1 to 10 times as necessary; R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, where each of C1-C4 alkyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl is selected from the group consisting of R 7 and the aryl or heteroaryl is optionally substituted 1 to 11 times with a substituent as defined in 8 or R 11 and R12 together with the nitrogen to which they are attached, R 7 forming a saturated or partially saturated monocyclic or fused bicyclic heterocycle optionally substituted 1 to 11 times with; A is, [ka] and; X is N; Y is N; p is 1 or 2; m is 0; However, R 6 cannot be (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl. or an oxide thereof, a pharma- ceutically acceptable salt of the compound or of the oxide thereof, or an individual enantiomer or diastereomer thereof.

[0183] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is one of the following: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0184] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0185] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula IX: [ka] [In the formula, R 1 represents phenyl or a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N or S, where the phenyl or heteroaryl is optionally joined to one or more R 3 with substitutions as necessary; R 2 represents an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8-10-membered bicyclic heteroaryl, where the monocyclic or bicyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from O, N, or S, and where the aryl or heteroaryl has one or more R 4 with substitutions as necessary; R 3 is a halogen, C 1~4 -Alkyl or C 3~6 -cycloalkyl, where C 1~4 -Alkyl or C 3~6 -cycloalkyl is optionally substituted with one or more halogens; R 4 is halogen, -CN, C 1~4 -Alkyl, C 3~6 -cycloalkyl, -C 1~3 -Alkyl-C 3~6 -Cycloalkyl or -OC 1~6 alkyl, where C 1~4 -Alkyl, C 3~6 -cycloalkyl, -C 1~3 -Alkyl-C 3~6-Cycloalkyl or -OC 1~6 -alkyl is optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt thereof, or a tautomer or stereoisomer of the compound or a pharma- ceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0186] In certain embodiments, the compound of formula IX has formula IX(a): [ka] or a pharma- ceutically acceptable salt thereof, or a tautomeric compound or a pharma- ceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0187] In certain embodiments, the compound of formula IX has formula IX(b): [ka] or a pharma- ceutically acceptable salt thereof, or a tautomeric compound or a pharma- ceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0188] In certain embodiments, the compound of formula IX is a compound selected from any of the following, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0189] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula X: [ka] [In the formula, R 1 teeth, a) a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S(O)r; b) 5- or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from the group consisting of O, N, and S(O)r; and c) O, N and S(O) r A 9- or 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from the group consisting of wherein r is 0, 1 or 2; wherein each of the groups a), b) and c) is C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3~6 -cycloalkyl- and C 3~6 -cycloalkyl-O-, which in the case of a substituent is attached to the nitrogen ring atom, and said substituent is 1~4 -Alkyl-, C 1~4 -Alkyl-CO-, C 3~6 -cycloalkyl- and C 3~6 -cycloalkyl-CO-, Here, the C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, C 1~4 -Alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3~6 -cycloalkyl-, C 3~6 -Cycloalkyl-CO- or C 3~6 Each of the substituents of -cycloalkyl-O- is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 2 is hydrogen, C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, -CN and C 3~6 -cycloalkyl-, Here, the C 1~4 -Alkyl-, C 1~4 -Alkyl-O- and C 3~6-each cycloalkyl group is optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 3 is C 1~6 -Alkyl-O-, C 3~6 -cycloalkyl-O-, morpholino, pyrazolyl, and one oxygen atom and optionally O, N and S(O) as ring members s (wherein s=0, 1, or 2), Here, the C 1~6 -alkyl-O- and the C 3~6 -Cycloalkyl-O- is fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -Alkyl-, C 3~6 -cycloalkyl-, C 1~6 -Alkyl-O- and C 3~6 -cycloalkyl-O-; R 4 is hydrogen; or R 3 and R 4 together with the ring atoms of the phenyl group to which they are attached, represent 4-, 5-, or 6-membered monocyclic partially saturated heterocycloalkyl, or each of which is O, N, and S(O) s (wherein s=0, 1 or 2), wherein in general formula (I), R 3 there must be one ring oxygen atom directly attached to a ring carbon atom of said phenyl group to which is attached; wherein the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, 1~4 -Alkyl-, C 3~6 -cycloalkyl-, C 1~6-Alkyl-O-, C 3~6 -optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, and tetrahydropyranyl-O-; R 5 is hydrogen; R 6 is hydrogen, C 1~4 -Alkyl-SO2-, C 3~6 -cycloalkyl selected from the group consisting of -SO2 and -CN; R 7 is hydrogen; or a)R 6 and R 7 or b) R 6 and R 5 The first pair of phenyl groups, together with the ring atoms of the phenyl groups to which they are attached, are O, N and S(O) u (wherein u=0, 1 or 2), wherein in general formula (I), R 6 There must be one -SO2- member attached directly to a ring carbon atom of the phenyl group to which is attached; wherein the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, 1~4 -Alkyl-, C 1~6 -Alkyl-O- and C 3~6 -cycloalkyl-O-, optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of: or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0190] In certain embodiments, the compound of formula X is a compound selected from any of the following, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0191] For example, the compound of formula X can be any diastereomeric mixture or single diastereomer of the following, or a pharma- ceutically acceptable salt thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0192] In certain embodiments, the compound of formula X has the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0193] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula XI [ka] Compound [In the formula, R 1 is halogen, -OR 1’ , -SR 1” , cycloalkyl, cyclic amide, heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; R 1’ and R 1” are each independently hydrogen, lower alkyl, lower alkyl substituted with halogen, -(CH2) x -cycloalkyl or -(CH2) x -aryl; R 2is -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; [ka] teeth, [ka] [ka] wherein one of the additional N ring atoms of the aromatic or partially aromatic bicyclic amine is in the form of its oxide. [ka] may be available at; R 3 ~R 10 are each independently hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO2, NH2, aryl, 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, -NH-lower alkyl, -N(lower alkyl)2, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)2-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH2) y -Lower alkoxy, -O(CH2) y C(O)N(lower alkyl)2, -C(O)-lower alkyl, -O-(CH2) x -aryl, -O-(CH2) x -Cycloalkyl, -O-(CH2) x -heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R, R', R'' and R''' are each independently hydrogen or lower alkyl; or In group e), R' and R''' together with -(CH2)4- form a 6-membered ring; R1, R1', R1" and R 3 ~R 10 All aryl-, cycloalkyl-, cyclic amido, heterocycloalkyl- or 5- or 6-membered heteroaryl groups defined for are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen, and lower alkoxy; n, m, o, p, q, r, s and t are each independently 1 or 2; x is 0, 1 or 2; and y is 1 or 2] or a pharma- ceutically acceptable acid addition salt thereof.

[0194] In certain embodiments, the compound of formula XI or a pharma- ceutically acceptable salt thereof is represented by formula XI(a): [ka] or a pharma- ceutically acceptable salt thereof, [ka] or a pharma- ceutically acceptable salt thereof, a compound of formula XI(c): [ka] or a pharma- ceutically acceptable salt thereof, a compound of formula XI(d): [ka] or a pharma- ceutically acceptable salt thereof, a compound of formula XI(e): [ka] or a pharma- ceutically acceptable salt thereof, a compound of formula XI(f): [ka] or a pharma- ceutically acceptable salt thereof, a compound of formula XI(g): [ka] or a pharma- ceutically acceptable salt thereof, or a compound of formula XI(h): [ka] or a pharma- ceutically acceptable salt thereof.

[0195] In certain embodiments, the compound of formula XI is a compound selected from any of the following, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka]

[0196] In certain methods and uses disclosed herein, the subject is a subject in need thereof.

[0197] In some embodiments of the uses and methods disclosed herein, the glycine transporter inhibitor, e.g., a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharma- ceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, e.g., a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharma- ceutically acceptable salt thereof, is administered in a therapeutically effective amount.

[0198] In some embodiments, the compound or its pharma- ceutically acceptable salt, solvate or prodrug is selected from the compounds described herein. Any of the compounds provided herein can be prepared as a pharma- ceutically acceptable salt, solvate or prodrug, and / or as part of a pharmaceutical composition described in the patents or patent application publications cited herein.

[0199] The compounds described herein may exhibit a specific stereochemistry around a certain atom, for example, cis or trans, but the compounds can also be made in the reverse orientation or in racemic mixtures.Such isomers or racemic mixtures are encompassed in the present disclosure.In addition, the compounds are summarized in the table, but any compound, or its pharmaceutically acceptable salt, solvate or prodrug, can be selected from the table and used in the embodiments provided herein.

[0200] The compounds described herein can be made according to the methods described in the patents or published patent applications cited herein.

[0201] The compounds can be used to inhibit the GlyT1 transporter, and therefore, in some embodiments, the compounds can be referred to as compounds that inhibit the GlyT1 transporter or GlyT1 inhibitors.

[0202] The compounds described herein can be administered in any conventional manner by any route in which they are active.Administration can be systemic, local, or oral.For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ophthalmic, or vaginal, by inhalation, by depot injection, or by implant.The method of administration can depend on the condition or disease that is targeted or treated.The selection of the specific route of administration can be selected or adjusted by the clinician according to the method known to the clinician to obtain the desired clinical response.

[0203] In some embodiments, it may be desirable to administer one or more compounds, or its pharma-ceutically acceptable salt, solvate or prodrug locally to the area that needs treatment.This can be achieved, for example, but not limited to, by local injection during surgery, local application, for example, in conjunction with wound dressing after surgery, by injection, by means of catheter, by means of suppository, or by means of implant, where implant is of porous, non-porous or gelatinous material, including membrane such as silastic membrane, or fiber.

[0204] The compounds described herein can be administered alone or in combination with other pharmaceuticals (together or sequentially).For example, the compounds can be administered in combination with other drugs, such as for the treatment of anemia associated with ribosomal disorders.Examples of other pharmaceuticals or drugs are known to those skilled in the art and include, but are not limited to, those described herein.

[0205] Means and methods for administration are known in the art, and the skilled artisan can refer to various pharmacology references for guidance (see, e.g., Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980)).

[0206] The amount of compound administered is a therapeutically effective amount.The dosage administered depends on the characteristics of the subject to be treated, such as the specific animal to be treated, age, weight, health, type of concomitant treatment if any, and frequency of treatment, and can be easily determined by those skilled in the art (e.g., by clinicians).Standard dosages for protamine can be used and adjusted (i.e., increased or decreased) according to the above factors.The selection of specific dosage regimen can be selected or adjusted or titrated by clinicians according to methods known to clinicians to obtain desired clinical response.

[0207] The amount of the compounds described herein that is effective in treating and / or preventing a particular disease, condition, or disorder will depend on the nature and extent of the disease, condition, or disorder, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may be used as necessary to help identify optimal dosage ranges. The precise dose to be used in the compositions will also depend on the route of administration and the severity of the disorder, and should be determined according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for oral administration are generally about 0.001 milligrams to about 200 milligrams per kilogram of body weight, about 0.01 milligrams to about 100 milligrams per kilogram of body weight, about 0.01 milligrams to about 70 milligrams per kilogram of body weight, about 0.1 milligrams to about 50 milligrams per kilogram of body weight, 0.5 milligrams to about 20 milligrams per kilogram of body weight, or about 1 milligram to about 10 milligrams per kilogram of body weight. In some embodiments, the oral dose is about 5 milligrams per kilogram of body weight.

[0208] In some embodiments, suitable dosage ranges for intravenous (iv) administration are about 0.01 mg to about 500 mg per kg of body weight, about 0.1 mg to about 100 mg per kg of body weight, about 1 mg to about 50 mg per kg of body weight, or about 10 mg to about 35 mg per kg of body weight. Suitable dosage ranges for other methods of administration can be calculated based on the aforementioned dosages, as known to those of skill in the art. For example, recommended dosages for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal, or inhalation administration are within the range of about 0.001 mg to about 200 mg per kg of body weight, about 0.01 mg to about 100 mg per kg of body weight, about 0.1 mg to about 50 mg per kg of body weight, or about 1 mg to about 20 mg per kg of body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.

[0209] In certain embodiments, the glycine transporter inhibitor administered is a GlyT1 inhibitor, such as a GlyT1 inhibitor disclosed herein. In some embodiments, a suitable dosage range for a GlyT1 inhibitor is about 5 mg / day to 200 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 5 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 10 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 15 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 20 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 25 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 30 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 35 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 40 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 45 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 50 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 55 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 60 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 65 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 70 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 75 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 80 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 85 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 90 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 95 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 100 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 105 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 110 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 115 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 120 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 125 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 130 mg / day.In some embodiments, the GlyT1 inhibitor is administered at 135 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 140 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 145 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 150 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 155 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 160 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 165 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 170 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 175 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 180 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 185 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 190 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 195 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 200 mg / day.

[0210] In certain embodiments, the glycine transporter inhibitor administered is a GlyT1 inhibitor, such as bitopertin, a pharma- ceutically acceptable salt thereof, or a prodrug of bitopertin or a pharma- ceutically acceptable salt thereof. In some embodiments, the GlyT1 inhibitor is bitopertin. In some embodiments, a suitable dosage range for bitopertin is about 5 mg / day to 200 mg / day. In some embodiments, bitopertin is administered at 5 mg / day. In some embodiments, bitopertin is administered at 10 mg / day. In some embodiments, bitopertin is administered at 15 mg / day. In some embodiments, bitopertin is administered at 20 mg / day. In some embodiments, bitopertin is administered at 25 mg / day. In some embodiments, bitopertin is administered at 30 mg / day. In some embodiments, bitopertin is administered at 35 mg / day. In some embodiments, bitopertin is administered at 40 mg / day. In some embodiments, bitopertin is administered at 45 mg / day. In some embodiments, bitopertin is administered at 50 mg / day. In some embodiments, bitopertin is administered at 55 mg / day. In some embodiments, bitopertin is administered at 60 mg / day. In some embodiments, bitopertin is administered at 65 mg / day. In some embodiments, bitopertin is administered at 70 mg / day. In some embodiments, bitopertin is administered at 75 mg / day. In some embodiments, bitopertin is administered at 80 mg / day. In some embodiments, bitopertin is administered at 85 mg / day. In some embodiments, bitopertin is administered at 90 mg / day. In some embodiments, bitopertin is administered at 95 mg / day. In some embodiments, bitopertin is administered at 100 mg / day. In some embodiments, bitopertin is administered at 105 mg / day. In some embodiments, bitopertin is administered at 110 mg / day. In some embodiments, bitopertin is administered at 115 mg / day. In some embodiments, bitopertin is administered at 120 mg / day. In some embodiments, bitopertin is administered at 125 mg / day. In some embodiments, bitopertin is administered at 130 mg / day.In some embodiments, bitopertin is administered at 135 mg / day. In some embodiments, bitopertin is administered at 140 mg / day. In some embodiments, bitopertin is administered at 145 mg / day. In some embodiments, bitopertin is administered at 150 mg / day. In some embodiments, bitopertin is administered at 155 mg / day. In some embodiments, bitopertin is administered at 160 mg / day. In some embodiments, bitopertin is administered at 165 mg / day. In some embodiments, bitopertin is administered at 170 mg / day. In some embodiments, bitopertin is administered at 175 mg / day. In some embodiments, bitopertin is administered at 180 mg / day. In some embodiments, bitopertin is administered at 185 mg / day. In some embodiments, bitopertin is administered at 190 mg / day. In some embodiments, bitopertin is administered at 195 mg / day. In some embodiments, bitopertin is administered at 200 mg / day.

[0211] The compounds described herein can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. In some embodiments, the compounds can be administered by continuous subcutaneous infusion over a period of about 15 minutes to about 24 hours. The formulations for injection can be in unit dosage form, e.g., in ampoules or multi-dose containers, with preservatives added as needed. The compositions can take the form of suspensions, solutions or emulsions in oil or aqueous media, and can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents. In some embodiments, the injectables are in the form of short-acting, depot, or implants, and pellets that are injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is in the form of a solution, suspension, emulsion, or dry powder.

[0212] For oral administration, the compounds described herein can be formulated by combining the compounds with pharma- ceutically acceptable carriers known in the art.Such carriers allow the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, cachets, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, etc., for oral ingestion by the patient to be treated.The pharmaceutical preparations for oral use can be obtained, for example, by adding solid excipients, grinding the mixture obtained as necessary, and processing the mixture of granules after adding suitable auxiliary agents as required to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, bulking agents, such as, but are not limited to, sugars, including lactose, sucrose, mannitol and sorbitol; cellulose preparations, such as, but are not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP).If desired, disintegrating agents can be added, such as, but are not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.

[0213] Orally administered compositions can contain one or more optional agents, such as sweeteners, such as fructose, aspartame or saccharin; flavorings, such as peppermint, oil of wintergreen, or cherry; colorings; and preservatives, to provide pharmacologic palatable preparations.Also, when in tablet or pill form, the composition can be coated to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a long period of time.Selectively permeable membranes surrounding the osmotically active driving compound are also suitable for orally administered compounds.Oral compositions can contain standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.Such vehicles are preferably of pharmaceutical grade.

[0214] Dragee core can be provided with suitable coating.For this purpose, concentrated sugar solution can be used, which can contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixture as required.Dyes or pigments can be added to tablet or dragee coating to identify or characterize different combinations of active compound doses.

[0215] Pharmaceutical preparations that can be used orally include, but are not limited to, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers, such as glycerol or sorbitol. Push-fit capsules can contain active ingredients in a mixture with fillers, such as lactose, binders, such as starch, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added.

[0216] For buccal administration, the compositions may take the form of, for example, tablets or lozenges formulated in conventional manner.

[0217] For administration by inhalation, the compounds described herein can be delivered in the form of aerosol spray presentation from pressurized pack or nebulizer by using suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.In the case of pressurized aerosol, dosage unit can be determined by providing a valve to deliver a measured amount.Capsules and cartridges of, for example, gelatin for use in inhaler or inhaler can be formulated to contain a powder mix of the compound and suitable powder base, for example, lactose or starch.

[0218] The compounds described herein can also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter or other glycerides.The compounds described herein can also be formulated in vaginal compositions, such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine devices.

[0219] For transdermal administration, the compound can be applied to a plaster or by a transdermal therapeutic system that is then delivered to the organism. In some embodiments, the compound is present in a cream, a solution, a powder, a liquid emulsion, a liquid suspension, a semisolid, an ointment, a paste, a gel, a jelly, and a foam, or in a patch containing any of the above.

[0220] The compounds described herein can be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months, or longer. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts.

[0221] In some embodiments, the compound can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J. Med., 1989, 321, 574). In some embodiments, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, the controlled release system can be placed in close proximity to the target of the compounds described herein, such as the liver, and thus require only a small amount of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533 may also be used.

[0222] It is also known in the art that the compound may be included in such formulations with pharma- ceutically acceptable diluents, bulking agents, disintegrants, binders, lubricants, surfactants, hydrophobic media, aqueous media, emulsifiers, buffers, humectants, solubilizers, preservatives, etc. The pharmaceutical composition may also include suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In some embodiments, the compounds described herein may be used with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair) or rinses (e.g., Caphosol).

[0223] In some embodiments, the compounds described herein can be delivered in a vehicle, in particular a liposome (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid, pp. 317-327; see generally, ibid.).

[0224] Suitable compositions include, but are not limited to, oral non-absorbable compositions. Suitable compositions also include, but are not limited to, saline, water, cyclodextrin solutions, and buffers with a pH of 3-9.

[0225] The compounds described herein, or their pharma- ceutically acceptable salts, solvates or prodrugs, can be formulated with a number of excipients, including, but not limited to, purified water, propylene glycol, PEG400, glycerin, DMA, ethanol, benzyl alcohol, citric acid / sodium citrate (pH 3), citric acid / sodium citrate (pH 5), tris(hydroxymethyl)aminomethane HCl (pH 7.0), 0.9% saline, and 1.2% saline, and any combination thereof.In some embodiments, the excipient is selected from propylene glycol, purified water and glycerin.

[0226] In some embodiments, the formulation can be lyophilized to a solid and reconstituted, for example, with water prior to use.

[0227] When administered to mammals (eg, animals for veterinary use or humans for clinical use), the compounds can be administered in isolated form.

[0228] When administered to humans, the compound can be sterile. When the compound of formula I-VIII is administered intravenously, water is a suitable carrier. Saline solution and aqueous dextrose and glycerol solutions can also be used as liquid carriers, especially for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

[0229] The compositions described herein can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing liquid, powder, sustained release formulation, suppository, aerosol, spray, or any other form suitable for use.Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, AR Gennaro (Editor) Mack Publishing Co.

[0230] In some embodiments, the compound is formulated according to routine procedures as a pharmaceutical composition suitable for administration to humans. Typically, the compound is a solution in a sterile isotonic aqueous buffer. If necessary, the composition can also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic, such as lidocaine, to ease pain at the site of injection. Generally, the ingredients are supplied in unit dosage form, either separately or mixed together, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampoule or sachet indicating the amount of active agent. If the compound is administered by injection, it can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or saline. If the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0231] Pharmaceutical composition can be in unit dosage form.In such form, composition can be divided into unit doses containing appropriate amount of active components.Unit dosage form can be packaged preparation, package containing discrete amount of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.Unit dosage form can also be capsules, cachets or tablets themselves, or it can be any of these packaged forms in appropriate number.

[0232] In some embodiments, the composition is in the form of a liquid, where the active agent (i.e., one of the facially amphiphilic polymers or oligomers disclosed herein) is present in a solution, in a suspension, as an emulsion, or as a solution / suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

[0233] In some embodiments, the composition is in the form of a solid article.For example, in some embodiments, the ophthalmic composition is a solid article, which can be inserted into a suitable location in the eye, for example between the eye and the eyelid or the conjunctival sac, and releases active agent there, for example, as described in U.S. Pat. No. 3,863,633; U.S. Pat. No. 3,867,519; U.S. Pat. No. 3,868,445; U.S. Pat. No. 3,960,150; U.S. Pat. No. 3,963,025; U.S. Pat. No. 4,186,184; U.S. Pat. No. 4,303,637; U.S. Pat. No. 5,443,505; and U.S. Pat. No. 5,869,079.The release from such an article is usually to the cornea, either through the tear fluid that bathes the surface of the cornea, or directly to the cornea itself, and the solid article is generally in intimate contact.The solid article suitable for implantation into the eye in such a way is generally composed mainly of polymers, and can be biodegradable or non-biodegradable. Biodegradable polymers that can be used in the preparation of ocular implants carrying one or more compounds include, but are not limited to, aliphatic polyesters such as poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate) and poly(hydroxyvalerate) polymers and copolymers, polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates, and polyether lactones. Suitable non-biodegradable polymers include silicone elastomers.

[0234] The compositions described herein can contain preservative.Suitable preservative includes, but is not limited to, mercury-containing substances, such as phenylmercury salts (such as phenylmercuric acetate, phenylmercuric borate and phenylmercuric nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride; imidazolidinyl urea; parabens, such as methylparaben, ethylparaben, propylparaben and butylparaben, and their salts; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDTA; and sorbic acid and its salts.

[0235] Optionally, one or more stabilizers may be included in the composition to enhance chemical stability, if necessary. Suitable stabilizers include, but are not limited to, chelating or complexing agents, such as the calcium complexing agent ethylenediaminetetraacetic acid (EDTA). For example, a suitable amount of EDTA, or a salt thereof, such as the disodium salt, may be included in the composition to complex excess calcium ions and prevent gel formation during storage. EDTA or a salt thereof may be suitably included in an amount of about 0.01% to about 0.5%. In those embodiments containing a preservative other than EDTA, EDTA or a salt thereof, more specifically, disodium EDTA, may be present in an amount of about 0.025% to about 0.1% by weight.

[0236] One or more antioxidants may also be included in the composition.Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art.Such preservatives are typically used at a level of about 0.001% to about 1.0% by weight.

[0237] In some embodiments, the compound is solubilized, at least in part, by an acceptable solubilizing agent. Certain acceptable non-ionic surfactants, such as polysorbate 80, can be useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400 (PEG-400), and glycol ethers.

[0238] Suitable solubilizers for solution and solution / suspension compositions are cyclodextrins.Suitable cyclodextrins can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, alkyl cyclodextrins (e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin), hydroxyalkyl cyclodextrins (e.g., hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), carboxy-alkyl cyclodextrins (e.g., carboxymethyl-β-cyclodextrin), sulfoalkyl ether cyclodextrins (e.g., sulfobutyl ether-β-cyclodextrin), etc. The ophthalmic application of cyclodextrins is reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.

[0239] In some embodiments, the composition optionally contains a suspending agent.For example, in those embodiments where the composition is an aqueous suspension or solution / suspension, the composition can contain one or more polymers as a suspending agent.Useful polymers include, but are not limited to, water-soluble polymers, such as cellulose polymers, such as hydroxypropylmethylcellulose, and water-insoluble polymers, such as crosslinked carboxy-containing polymers.

[0240] One or more acceptable pH adjusting agents and / or buffers may be included in the composition, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in the amount necessary to maintain the pH of the composition in an acceptable range.

[0241] One or more acceptable salts, solvents or prodrugs can be included in the composition in the amount necessary to make the osmolality of the composition acceptable.Such salts include, but are not limited to, those with sodium, potassium or ammonium cations and chloride, citrate, ascorbic acid, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfate anions.In some embodiments, the salt includes sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.In some embodiments, the salt is sodium chloride.

[0242] Optionally, one or more acceptable surfactants, such as, but not limited to, non-ionic surfactants, or co-solvents, may be included in the composition to enhance the solubility of the components of the composition, or to impart physical stability, or for other purposes. Suitable non-ionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40; polysorbate 20, 60 and 80; polyoxyethylene / polyoxypropylene surfactants (e.g., Pluronic® F-68, F84 and P-103); cyclodextrins; or other agents known to those skilled in the art. Typically, such co-solvents or surfactants are used in the composition at a level of about 0.01% to about 2% by weight.

[0243] In some embodiments, a pharmaceutical pack or kit is provided that includes one or more containers filled with one or more compounds as described herein.Optionally, associated with such containers can be a notice in the form prescribed by the government agency that regulates the manufacture, use or sale of pharmaceuticals or biological products, which reflects the approval by the agency of manufacture, use or sale for human administration to treat conditions, diseases or disorders as described herein.In some embodiments, the kit contains more than one compound as described herein.In some embodiments, the kit includes the compound as described herein in a single injectable dosage form, for example, a single dose in an injection device such as a needle-equipped syringe.

[0244] In some embodiments, the method comprises administering to a subject one or more compounds as described herein, or its pharma-ceutically acceptable salt, solvate or prodrug, or its pharmaceutical composition.In some embodiments, the subject is a subject who needs such treatment.As described herein, in some embodiments, the subject is a mammal, for example, but not limited to, a human.

[0245] In some embodiments, there is also provided one or more of the compounds described above, or pharma- ceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition comprising one or more of the compounds described above, for use in the manufacture of a medicament for the treatment of anemia associated with ribosomal disorders, including but not limited to the conditions described herein, or associated syndromes thereof, such as those described herein, in a subject. In some embodiments, the subject is a subject in need thereof.

[0246] The present embodiments also provide for the use of one or more of the compounds described above, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising one or more of the compounds described above, in inhibiting GlyT1 transporters, e.g., those present on the surface of a cell. In some embodiments, the compound, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof inhibits internalization, transport and / or degradation of the GlyT1 transporter.

[0247] As used herein, "inhibition" can refer to the inhibition of any specific activity. The activity of the GlyT1 transporter can be measured by any method known in the art, including, but not limited to, the methods described herein.

[0248] The compounds described herein are inhibitors of the GlyT1 transporter. The ability of a compound to inhibit GlyT1 transporter activity can be measured using any assay known in the art.

[0249] In general, assays for testing compounds that inhibit GlyT1 transporter activity include the determination of any parameter that is indirectly or directly influenced by the GlyT1 transporter, such as a functional, physical or chemical effect.

[0250] Samples or assays containing the GlyT1 transporter that are treated with a potential inhibitor are compared to a control sample without the inhibitor to determine the degree of inhibition. The control sample (untreated with the inhibitor) is assigned a relative GlyT1 transporter activity value of 100%. Inhibition of the GlyT1 transporter is achieved when the GlyT1 transporter activity value relative to the control is about 80%, 50% or 25%.

[0251] Ligand binding to the GlyT1 transporter can be tested in several formats. Binding can be performed in solution, in a bilayer membrane, bound to a solid phase, in a lipid monolayer, or in a vesicle. For example, in an assay, the binding of a natural ligand to the transporter is measured in the presence of a candidate modulator, such as a compound described herein. Alternatively, the binding of a candidate modulator may be measured in the presence of a natural ligand. Often, a competitive assay is used that measures the ability of a compound to compete with the binding of a natural ligand to the transporter. Binding can be tested, for example, by measuring changes in spectroscopic properties (e.g., fluorescence, absorption, refractive index), hydrodynamic (e.g., shape), or chromatographic or solubility properties.

[0252] After the transporter is expressed in the cells, the cells can be grown in a suitable medium in a suitable cell plate. The cells can be plated, for example, at 5000-10000 cells per well in a 384-well plate. In some embodiments, the cells are plated at about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 cells per well. The plate can have any number of wells and the number of cells can be modified accordingly.

[0253] Any pharmaceutical agent having utility in the applications described herein can be used in combination therapy, co-administration or co-formulation with the above compositions. Thus, the compounds described herein can be administered either before, together with, or after such therapeutic agents are administered to the subject.

[0254] The additional pharmaceutical agents may be administered in combination therapy (including co-formulation) with one or more compounds described herein.

[0255] In some embodiments, the response of the disease or disorder to treatment is monitored, and the treatment regimen is adjusted, if necessary, in light of such monitoring.

[0256] The frequency of administration is typically such that the dosing interval, e.g., the period between one dose and the next during waking hours, is about 1 to about 24 hours, about 2 to about 12 hours, about 3 to about 8 hours, or about 4 to about 6 hours. In some embodiments, doses are administered 1, 2, 3 or 4 times daily. An appropriate dosing interval is determined so that the selected composition is capable of maintaining a concentration of the compound in the subject and / or target tissue (e.g., EC 50 It will be appreciated by those of skill in the art that the duration of time that the EC50 concentration is greater than the lowest concentration of compound that inhibits transporter activity by 90% will depend in part on the length of time that the EC50 concentration is greater than the lowest concentration of compound that inhibits transporter activity by 90%. Ideally, the concentration will be greater than the EC50 concentration for at least 100% of the dosing interval. 50 If this is not achievable, concentrations should remain above the EC 50 or remain above the EC for at least approximately 40% of the dosing interval. 50 It is desirable that the

[0257] How to use The present application provides a method for preventing or treating anemia associated with ribosomal disorder in a subject, comprising administering to the subject one or more glycine transporter inhibitors or their pharma- ceutically acceptable salts, or one or more prodrugs of glycine transporter inhibitors or their pharma- ceutically acceptable salts.In certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as the GlyT1 inhibitor disclosed herein.For example, the present application provides a method for preventing, treating, or reducing the progression rate and / or severity of anemia associated with ribosomal disorder in a subject, comprising administering to the subject one or more glycine transporter inhibitors or their pharma- ceutically acceptable salts. [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of bitopertin or a pharma- ceutically acceptable salt thereof, to a subject.

[0258] In part, the present disclosure relates to a method for treating anemia associated with ribosomal disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the present disclosure relates to a method for preventing, treating, or reducing the progression rate and / or severity of one or more complications of anemia associated with ribosomal disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the ribosomal disorder is Diamond-Blackfan anemia. In some embodiments, the ribosomal disorder is myelodysplastic syndrome (MDS) associated with isolated del(5q). In some embodiments, the ribosomal disorder is Shwachman-Diamond syndrome. In some embodiments, the ribosomal disorder is x-linked dyskeratosis congenita. In some embodiments, the ribosomal disorder is cartilage-hair hypoplasia. The terms "subject", "individual" or "patient" are used interchangeably throughout this specification and refer to either human or non-human animals. These terms include mammals, such as humans, non-human primates, laboratory animals, livestock animals (including cows, pigs, camels, etc.), companion animals (e.g., dogs, cats, other domestic animals, etc.) and rodents (e.g., mice and rats). In certain embodiments, the patient, subject or individual is a human.

[0259] The present application provides a method for preventing, treating, or reducing the progression rate and / or severity of anemia associated with ribosomal disorder in a subject, comprising administering to the subject one or more glycine transporter inhibitors or their pharma- ceutically acceptable salts, or one or more prodrugs of glycine transporter inhibitors or their pharma- ceutically acceptable salts.In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors.In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors disclosed herein.In certain embodiments of the above, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier. For example, the application provides a method of preventing, treating, or reducing the rate of progression and / or severity of anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia) in a subject, comprising administering to the subject bitopertin or a pharma- ceutically acceptable salt thereof, or a prodrug of bitopertin or a pharma- ceutically acceptable salt thereof.

[0260] The present application further provides the use of one or more glycine transporter inhibitors or pharma- ceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharma- ceutically acceptable salts thereof, in the manufacture of a formulation for treating anemia associated with ribosomal disorders (e.g., Diamond-Blackfan anemia) in a subject. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors disclosed herein. In certain such embodiments, the GlyT1 inhibitor is bitopertin or a pharma- ceutically acceptable salt thereof, or a prodrug of bitopertin or a pharma- ceutically acceptable salt thereof. In certain of the above embodiments, the formulation is administered in a therapeutically effective amount.

[0261] Diamond-Blackfan anemia Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually develops during the neonatal period. DBA is characterized by a low red blood cell count (anemia) with a reduction in erythroid precursors in the bone marrow. In DBA patients, levels of other blood components, such as platelets and white blood cells, are normal. This is in contrast to Shwachman-Diamond syndrome, in which bone marrow deficiency primarily results in a low neutrophil count (neutropenia).

[0262] Ribosomal protein mutations have been implicated in the pathophysiology of DBA. The first gene mutated in approximately 25% of DBA patients was identified as RPS19 (ribosomal protein S19) (Gustavsson et al, Nat Genet. 1997 Aug;l6(4):368-7l;Draptchinskaia et al, Nat Genet. 1999 Feb;2l(2): 169-75). Sequencing of patient samples identified mutations in either the large (60s) or small (40s) subunit ribosomal protein in more than 50% of patients (Vlachos et al, Br J Haematol. 2008 Sep;142(6):859-876). The identified genes include, but are not limited to, RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28 and RPS29, as well as three other non-RP genes TSR2, GATA1 and EPO (Da Costa L, et al. F1000Res. 2018;7). All patients identified to date are heterozygous for these mutations and always maintain a wild-type copy of the affected RP gene. However, approximately 30% of people with DBA do not have detectable RP mutations. For congenital anomalies, several phenotype / genotype correlations are known.

[0263] There are multiple subtypes of DBA, each caused by different mutations in various genes, for example, Diamond-Blackfan anemia-l (DBA1, OMIM number 105650) is caused by heterozygous mutations in the RPS19 gene on chromosome l9ql3. Other forms of DBA include DBA2 (OMIM no. 606129), caused by mutations on chromosome 8p23-p22; DBA3 (OMIM no. 610629), caused by mutations in the RPS24 gene on l0q22; DBA4 (OMIM no. 612527), caused by mutations in the RPS17 gene on 15q; DBA5 (OMIM no. 612528), caused by mutations in the RPL35A gene on 3q29; DBA6 (OMIM no. 612561), caused by mutations in the RPL5 gene on lp22.l; DBA7 (OMIM no. 612562), caused by mutations in the RPL11 gene on lp36; DBA8 (OMIM no. 612563), caused by mutations in the RPS7 gene on 2p25; DBA9 (OMIM no. 613308), caused by mutations in the RPS10 gene on 6p; and DBA10 (OMIM no. 613309), caused by mutations in the RPS11 gene on l2q. DBA10 (OMIM No. 613309), caused by a mutation in the RPL26 gene on chromosome 17r13; DBA11 (OMIM No. 614900), caused by a mutation in the RPL15 gene on 3p24; DBA13 (OMIM No. 615909), caused by a mutation in the RPS29 gene on l4q; DBA14 (OMIM No. 300946), caused by a mutation in the / 'SR2 gene on Xpl1; DBA15 (OMIM No. 606164), caused by a mutation in the RPS28 gene on 19p13; DBA16 (OMIM No. 617408), caused by a mutation in the RPL27 gene on chromosome 17q21; and DBA17 (OMIM No. 617409), caused by a mutation in the RPS27 gene on chromosome lq2l.

[0264] Mutations in ribosomal proteins affect ribosomal protein function, resulting in ribosome failure and increased stress. Impaired ribosome biogenesis is associated with p53 induction and cell cycle arrest. Ribosomal protein knockdown results in an increase in free ribosomal proteins. Some ribosomal proteins, including RPL11, RPL5 and RPL13, bind to MDM2 and block MDM2-mediated p53 ubiquitination and degradation (Lindstrom et al, Cell Cycle 6:4, 434-437, 15 February 2007; Fumagalli et al, Nat Cell Biol. 2009 Apr; ll(4):501-8). Other ribosomal proteins may activate p53 by different mechanisms. For example, RPL26 has been found to increase the translation rate of p53 mRNA by binding to its 5' untranslated region (Tagaki et al., Cell. 2005 Oct 7; l23(l):49-63). The negative impact of DBA on ribosomal protein function results in a decrease in globin synthesis, which is required to produce hemoglobin. Heme synthesis does not appear to be affected. The imbalance between heme synthesis and globin leads to the accumulation of free heme in DBA erythroid cells (Rio S, et al. Blood. 2019;133(12):1358-1370). Heme is toxic to cells by increasing reactive oxygen species production, lipid peroxidation and apoptosis. As a result, excess heme levels resulting from heme / globin imbalance lead to deleterious effects on erythroipoiesis.

[0265] Typically, the diagnosis of DBA is made via blood cell counts and bone marrow biopsy. The diagnosis of DBA is made based on anemia, low reticulocyte (immature red blood cell) counts, and reduced erythroid precursors in the bone marrow. Features supporting the diagnosis of DBA include the presence of congenital anomalies, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells. Most patients are diagnosed in the first two years of life. However, some mildly affected individuals are only noted after more severely affected family members are identified. Genetic testing is frequently used to identify mutations in ribosomal protein genes as well as some other non-ribosomal protein genes. Approximately 20-25% of DBA patients can be identified using genetic testing for mutations in the RPS19 gene. Approximately 10-25% of DBA cases have a family history of the disease, with most pedigrees suggesting an autosomal dominant pattern of inheritance.

[0266] In certain aspects, the present disclosure relates to a method for treating anemia associated with ribosomal disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs or salts thereof of glycine transporter inhibitors (e.g., GlyT1 inhibitors). In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the progression rate and / or severity of anemia associated with ribosomal disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs or salts thereof of glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the anemia associated with ribosomal disorder is Diamond-Blackfan anemia (DBA). In some embodiments, DBA is caused by haploinsufficiency for a ribosomal protein selected from the group consisting of 40S ribosomal protein S14 (RPS14), 40S ribosomal protein S19 (RPS19), 40S ribosomal protein S24 (RPS24), 40S ribosomal protein S17 (RPS17), 60S ribosomal protein L35a (RPL35a), 60S ribosomal protein L5 (RPL5), 60S ribosomal protein L11 (RPL11), and 40S ribosomal protein S7 (RPS7).In some embodiments, DBA is caused by haploinsufficiency for a ribosomal protein selected from the group consisting of 40S ribosomal protein S10 (RPS10), 40S ribosomal protein S26 (RPS26), 60S ribosomal protein L15 (RPL15), 60S ribosomal protein L17 (RPL17), 60S ribosomal protein L19 (RPL19), 60S ribosomal protein L26 (RPL26), 60S ribosomal protein L27 (RPL27), 60S ribosomal protein L31 (RPL31), 40S ribosomal protein S15a (RPS15a), 40S ribosomal protein S20 (RPS20), 40S ribosomal protein S27 (RPS27), 40S ribosomal protein S28 (RPS28) and 40S ribosomal protein S29 (RPS29). In some embodiments, the patient has one or more mutations in a ribosomal protein gene.

[0267] In some embodiments, the GlyT1 inhibitor disclosed herein can be used in a method for treating anemia associated with ribosomal disorders, and the subject has a mutation in ribosomal protein 19 (RPS19). The phenotype of DBA patients shows a hematological stem cell defect that specifically affects erythroid precursor population. RPS19 protein is involved in the production of ribosomes. Disease characteristics can be related to the nature of RPS19 mutation. This disease is characterized by dominant inheritance and thus occurs due to partial loss of RPS19 protein function.

[0268] In an alternative embodiment, the GlyT1 inhibitors disclosed herein may be used in a method of treating anemia associated with a ribosomal disorder, where the subject has a mutation in a ribosomal protein from at least one of, but not limited to, RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28 and RPS29. For example, a mutation or variant in RPS19 causes DBA1, a mutation or variant in RPS24 causes DBA3, a mutation or variant in RPS17 causes DBA4, a mutation or variant in RPS34A causes DBA5, a mutation or variant in RPLS causes DBA6, a mutation or variant in RPL11 causes DBA7, and a mutation or variant in RPS7 causes DBA8. In some embodiments, the subject with a ribosomal disorder has a mutation in a non-ribosomal protein selected from the group consisting of TSR2, GATA1, and EPO.

[0269] In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the progression rate and / or severity of one or more complications of anemia associated with ribosomal disorders in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharma- ceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the one or more complications of anemia associated with ribosomal disorders are selected from the group consisting of thrombocytosis, megakaryotypic hyperplasia, infection, bleeding (e.g., from the nose or gums), purpura, splenomegaly, need for more frequent transfusions, need for increased glucocorticoid use, need for allogeneic hematopoietic stem cell transplantation, need for autologous gene therapy, bone marrow failure, MDS, leukemia, and acute myeloid leukemia.

[0270] In certain aspects, the present disclosure relates to a method for treating splenomegaly associated with anemia associated with ribosomal disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharma- ceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the subject has an increase in spleen size (e.g., splenomegaly). In some embodiments, the GlyT1 inhibitors disclosed herein reduce splenomegaly in subjects with anemia associated with ribosomal disorder (e.g., Diamond-Blackfan anemia). In some embodiments, the method reduces the spleen size of the subject. In some embodiments, the method reduces the subject's spleen size by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's spleen size by at least 15%. In some embodiments, the method reduces the subject's spleen size by at least 20%. In some embodiments, the method reduces the subject's spleen size by at least 25%. In some embodiments, the method reduces the subject's spleen size by at least 30%. In some embodiments, the method reduces the subject's spleen size by at least 35%. In some embodiments, the method reduces the subject's spleen size by at least 40%. In some embodiments, the method reduces the subject's spleen size by at least 45%. In some embodiments, the method reduces the subject's spleen size by at least 50%. In some embodiments, the method reduces the subject's spleen size by at least 55%. In some embodiments, the method reduces the subject's spleen size by at least 60%. In some embodiments, the method reduces the subject's spleen size by at least 65%. In some embodiments, the method reduces the subject's spleen size by at least 70%. In some embodiments, the method reduces the subject's spleen size by at least 75%. In some embodiments, the method reduces the subject's spleen size by at least 80%. In some embodiments, the method reduces the subject's spleen size by at least 85%.In some embodiments, the method reduces the spleen size of the subject by at least 90%. In some embodiments, the method reduces the spleen size of the subject by at least 95%. In some embodiments, the method reduces the spleen size of the subject by at least 100%.

[0271] In some embodiments, the methods and GlyT1 inhibitors disclosed herein may be used to treat a subject having a ribosomal disorder, e.g., DBA, where the subject has symptoms of macrocytic anemia and / or craniofacial abnormalities.

[0272] Myelodysplasia Myelodysplasia or myelodysplastic syndrome (MDS) is a group of hematological disorders associated with the body's inability to produce enough normal blood cells. In MDS patients, immature blood cells in the bone marrow do not mature and instead die in the bone marrow or shortly after entering the bloodstream. MDS can affect the production of any type of blood cell, possibly all types, including red blood cells, platelets and white blood cells (cytopenia). Over time, there become more immature, defective cells than healthy cells. As a result, patients with MDS often have anemia (low red blood cell count or reduced hemoglobin), which can cause fatigue and shortness of breath, neutropenia (low neutrophil count), which can cause increased susceptibility to infection, and / or thrombocytopenia (low platelet count), which can cause bleeding and easy bruising without obvious cause.

[0273] Bone marrow cell derangements in MDS patients range from mild to very severe. In some cases, patients with MDS often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens and patients develop cytopenias caused by progressive bone marrow failure. In approximately 30% of patients with MDS, the disease progresses to acute myeloid leukemia (AML), usually within months to years.

[0274] There are several prognostic scoring systems that use prognostic indicators to predict the course of a patient's disease. These include the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), and the WHO classification-based Prognostic Scoring System (WPSS). The IPSS is the most commonly used prognostic scoring system and uses three prognostic indicators to predict the course of a patient's disease: (1) the percentage of leukemic blast cells in the bone marrow; (2) the type of chromosomal alteration in the bone marrow cells, if present (cytogenetics); and (3) the presence of one or more low blood cell counts (cytopenias). [Table 2]

[0275] Risk groups in the IPSS are based on the total points for each of the above prognostic factors. The overall risk score indicates how fast the disease is likely to progress, and doctors often use this system to assign patients to specific risk groups. Patients with 0 points are considered low risk. Patients with 0.5 to 1 points are considered moderate-1 risk. Patients with 1.5 to 2 points are considered moderate-2 risk. Finally, patients with 2.5 or higher points are considered high risk.

[0276] MDS most often affects adults between the ages of 60 and 75. MDS in children is rare. Men are slightly more commonly affected than women. Previous treatment with chemotherapy or radiation is an important factor in the development of MDS. Exposure to certain chemicals (e.g., tobacco smoke, pesticides, benzene) and heavy metals (e.g., lead, mercury) can increase the risk of myelodysplastic syndrome. Some genetic disorders, including Shwachman-Diamond syndrome and Diamond-Blackfan anemia, can also result in MDS.

[0277] Myelodysplastic syndrome associated with isolated del(5q) Myelodysplastic syndrome (MDS) associated with isolated del(5q), also known as 5q-myelodysplasia, Del 5q, 5q-syndrome, chromosome 5q deletion syndrome or chromosome 5q monosomy, is a rare form of MDS. It is caused by the deletion of a region of DNA in the long arm of human chromosome 5 (q arm, band 5q31.1). Most people with MDS with isolated del(5q) are missing a fragment of about 1.5 million base pairs. MDS with isolated del(5q) is characterized by severe anemia, frequent thrombocytosis, typical dysmegakaryopoiesis and a favorable outcome. Unlike other MDS types, MDS with isolated del(5q) is found primarily in older women.

[0278] The commonly deleted region of DNA in isolated del(5q) MDS contains 40 genes, including the RPS14, MIR145 and MIR146 loci. Loss of the RPS14 gene leads to the problems with red blood cell development characteristic of isolated del(5q) MDS, and loss of the MIR145 and MIR146 loci contributes to the platelet abnormalities and megakaryocytic dysplasia associated with isolated del(5q) MDS.

[0279] Subjects with MDS with isolated del(5q) can be treated with lenalidomide (REVLIMID®) (Bennett et al., N Engl J Med. 2006 Oct 5;355( 14): 1456-65; Raza et al., Blood. 2008 Jan l;lll(l):86-93). One of the side effects of lenalidomide treatment can be low blood cell counts that initially lead individuals to utilize supportive care. Supportive care includes red blood cell transfusions, antibiotics, and iron chelation therapy. For younger individuals, bone marrow transplantation is an option and is the only known cure for MDS.

[0280] In certain aspects, the present disclosure relates to a method for treating MDS with isolated del(5q) in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs or salts thereof of glycine transporter inhibitors (e.g., GlyT1 inhibitors). In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the progression rate and / or severity of MDS with isolated del(5q) in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs or salts thereof of glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the subject has low-risk MDS as classified by IPSS. In some embodiments, the subject has intermediate-1 risk MDS as classified by IPSS. In some embodiments, the subject has intermediate-2 risk MDS as classified by IPSS. In some embodiments, the subject has high risk MDS as classified by IPSS. In some embodiments, the subject is haploinsufficient for a ribosomal protein selected from the group consisting of 40S ribosomal protein S14 (RPS14) and 40S ribosomal protein S19 (RPS19). In some embodiments, the subject has impaired 40S ribosomal subunit maturation. In some embodiments, the subject has impaired 60S ribosomal subunit maturation. In some embodiments, the subject has one or more mutations in a ribosomal protein gene. In some embodiments, the one or more mutations in a ribosomal protein gene are selected from the group consisting of RPS14 or RPS19.

[0281] In certain aspects, the present disclosure contemplates the use of pharmaceutical compositions comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharma- ceutically acceptable salts thereof, or one or more prodrugs or salts thereof of glycine transporter inhibitors (e.g., GlyT1 inhibitors) in combination with one or more additional active agents or other supportive therapies for treating or preventing anemia associated with ribosomal disorders. In some embodiments, the glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharma- ceutically acceptable salts thereof, or one or more prodrugs or salts thereof of glycine transporter inhibitors (e.g., GlyT1 inhibitors) are administered in combination with lenalidomide (REVLIMID®).

[0282] Shwachman-Diamond syndrome Shwachman-Diamond syndrome (SDS) or Shwachman-Bodian-Diamond syndrome is a rare genetic disorder that affects many parts of the body, especially the pancreas, bone marrow, and skeletal system. Shwachman-Diamond syndrome is inherited in an autosomal recessive pattern. Most cases of SDS are caused by mutations in the SBDS gene, which is present on the long arm of chromosome 7 at cytogenetic location 7ql1. The protein encoded by SBDS is thought to play a role in RNA processing and ribosome biogenesis, but the exact mechanism of how SBDS mutations result in the major signs and symptoms of Shwachman-Diamond syndrome remains unclear. Typical symptoms of Shwachman-Diamond syndrome include exocrine pancreatic insufficiency, decreased muscle tone, low blood neutrophil counts (neutropenia), anemia, and abnormal bone development (metaphyseal dysostosis) affecting bones in the rib cage and / or arms and / or legs.

[0283] The diagnosis of Shwachman-Diamond syndrome can be made based on clinical findings, including pancreatic insufficiency and characteristic hematological abnormalities (e.g., neutropenia and thrombocytopenia). Genetic testing can be used to confirm the diagnosis. SBDS gene mutations are known to cause approximately 90% of Shwachman-Diamond syndrome cases. The remaining 10% of cases have unknown genetic causes, and therefore genetic testing is not an option for these cases.

[0284] There is no cure for Shwachman-Diamond syndrome. Treatment usually includes oral pancreatic enzyme supplementation, vitamin supplementation, blood transfusion and / or platelet transfusion, administration of granulocyte colony-stimulating factor (G-CSF), and / or hematopoietic stem cell transplantation. The lack of neutrophils in subjects with Shwachman-Diamond syndrome can lead to neutropenia, which makes subjects more vulnerable to infections such as pneumonia. Patients with Shwachman-Diamond syndrome also have a higher than average probability of developing MDS, aplastic anemia, and leukemia (e.g., acute myeloid leukemia).

[0285] In certain aspects, the present disclosure relates to a method of treating Shwakman-Diamond syndrome in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In certain aspects, the present disclosure relates to a method of preventing, treating, or reducing the rate of progression and / or severity of Shwakman-Diamond syndrome in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the subject has one or more mutations in the SBDS gene. In some embodiments, the subject has a reduced need for hematopoietic stem cell transplantation. In some embodiments, the subject has reduced neutropenia. In some embodiments, the subject has reduced thrombocytopenia. In some embodiments, the subject's risk of developing myelodysplastic syndrome is reduced. In some embodiments, the subject's risk of developing leukemia is reduced. In some embodiments, the subject's risk of developing an infection is reduced. In some embodiments, the subject's risk of developing pneumonia is reduced. In some embodiments, the subject has low neutrophil levels.

[0286] Congenital dyskeratosis Dyskeratosis congenita, also known as Zinsser-Engman-Cole syndrome, is a rare inherited form of bone marrow failure classically associated with oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Inheritance is most commonly x-linked recessive. Thus, men are three times more likely to be affected than women. Symptoms vary widely and can include atrophic wrinkled skin, eye disease, and bone marrow failure. Patients with dyskeratosis congenita are at increased risk of developing leukemia and other cancers (e.g., cancer of the head, neck, anus, or genitals) and fibrosis (e.g., pulmonary fibrosis and liver fibrosis).

[0287] The majority of patients have mutations in the dyskerin gene (DKC1), a protein directly involved in stabilizing an enzyme called telomerase, responsible for catalyzing the reaction that maintains telomere length. In the absence of proteins such as dyskerin, telomeres gradually shorten, leading to apoptosis or senescence of cells. Other genes have been shown to be mutated in dyskeratosis congenita, including TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, and RTEL1.

[0288] Treatment options for patients with dyskeratosis congenita are limited. The only long-term treatment option for bone failure in patients with dyskeratosis congenita is hematopoietic stem cell transplantation. However, long-term outcomes remain poor, with an estimated 10-year survival rate of 23%. Short-term treatment options include anabolic steroids (e.g., oxymetholone), granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin.

[0289] In certain aspects, the present disclosure relates to a method for treating dyskeratosis congenita in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the progression rate and / or severity of dyskeratosis congenita in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the subject has dyskeratosis congenita. In some embodiments, the dyskeratosis congenita is x-linked dyskeratosis congenita. In some embodiments, the subject has one or more mutations in the DKC1 gene. In some embodiments, the subject has one or more mutations in genes selected from the group consisting of TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, PARN, CTC1 and RTEL1. In some embodiments, the method reduces the risk of bone marrow failure in the subject. In some embodiments, the method reduces the risk of pulmonary fibrosis in the subject. In some embodiments, the method reduces the risk of liver fibrosis in the subject.

[0290] cartilage hypoplasia Cartilaginous hair hypoplasia, also known as metaphyseal chondrodysplasia of the McKusick type, is a disorder of bone growth characterized by short stature (dwarfism) with other skeletal abnormalities; thin, sparse hair; joint hypermobility; anemia; increased risk of malignant disease; gastrointestinal dysfunction; impaired spermatogenesis; and abnormal immune system function that often results in recurrent infections. Patients with Cartilaginous Hair Hypoplasia. Most patients with Cartilaginous Hair Hypoplasia have mutations in the RMRP gene (OMIM number 157660), with a 70A→G transition mutation commonly present. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA processing ribonuclease RNase MRP.

[0291] The diagnosis of cartilage-hair hypoplasia is based primarily on clinical findings, characteristic radiographic findings, and, in some cases, evidence of immune dysfunction, macrocytic anemia, and / or gastrointestinal problems. Molecular genetic testing can be used in patients to identify pathogenic variants due to RMRP.

[0292] Patient treatment often includes repeated blood transfusions, as well as surgery to fuse unstable vertebrae or to treat progressive kyphoscoliosis that impairs pulmonary function. Corrective osteotomy may also be required to treat progressive varus deformity associated with ligamentous laxity in the knee. For patients with immunodeficiency, frequent treatment of underlying infections is required. Prophylactic antibiotic therapy and / or immunoglobulin replacement therapy is often required. Recurrent severe infections and / or the presence of severe combined immunodeficiency (SCID) and / or severely suppressed erythropoiesis may justify bone marrow transplantation.

[0293] In certain aspects, the present disclosure relates to a method for treating cartilage hair hypoplasia in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of cartilage hair hypoplasia in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug or salt of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the subject has one or more mutations in the RMRP gene. In some embodiments, the method reduces the need for bone marrow transplantation in the subject.

[0294] Defects in erythropoiesis Erythropoiesis generally refers to the process by which red blood cells (erythrocytes) are produced from HSCs and includes the formation of erythroid progenitor cells. Erythropoiesis is a carefully ordered series of events. Occurring first in fetal liver cells, the process is taken over by the bone marrow in children and adults. Although multiple cytokines and growth factors are responsible for the proliferation of red blood cells, the primary regulator is erythropoietin (EPO). Erythropoiesis is initially regulated by stem cell factor (SCF), which commits hematopoietic stem cells to develop into erythroid precursors. Subsequently, EPO continues to stimulate the development and terminal differentiation of these precursors. In the fetus, EPO is produced by monocytes and macrophages found in the liver. After birth, EPO is produced in the kidney; however, Epo messenger RNA (mRNA) and EPO protein are also found in the brain and red blood cells (RBCs), suggesting the existence of paracrine and autocrine functions.

[0295] Erythropoiesis is increased stepwise when increased expression of the EPO gene produces higher levels of circulating EPO. EPO gene expression is increased by hypoxemia, transition metals (Co 2+ , Ni 2+ , Mn 2+ It is known that EPO production is affected by several factors, including iron chelators and iron chelators. However, the primary effect is hypoxia, which includes factors such as reduced oxygen tension, red blood cell loss, and increased oxygen affinity of hemoglobin. For example, EPO production can increase by as much as 1000-fold in severe hypoxia.

[0296] Erythropoiesis requires proper biosynthesis of heme, and as erythroblasts mature, their demand for heme and iron increases dramatically. Erythroid cells synthesize large amounts of heme and hemoglobin while simultaneously absorbing a lot of iron into the cell. An imbalance between globin chains and heme synthesis is known to occur in erythroid cells of Diamond-Blackfan anemia patients. This imbalance leads to the accumulation of excess free heme and increased production of reactive oxygen species.

[0297] The blockade of erythroid differentiation and proliferation in Diamond-Blackfan anemia has been shown to affect immature progenitor cells or erythroid burst-forming units (BFU-e), resulting in impaired hematopoiesis. Circulating EPO levels are increased in Diamond-Blackfan anemia patients, indicating anemia-associated bone marrow unresponsiveness to EPO stimulation. An increased tendency of erythroid precursors to apoptosis during in vitro EPO deficiency and in RPS19 deficiency has also been reported.

[0298] Glycine is one of the important initial substrates for heme synthesis.Therefore, the reduction of glycine level caused by GlyT1 inhibition can lead to a decrease in heme synthesis.In certain aspects, the present disclosure relates to a method for inhibiting heme synthesis in a subject with anemia associated with ribosomal disorders, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or their pharma-ceutically acceptable salts, or one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) prodrugs or their salts.In some embodiments, heme synthesis is inhibited in a dose-dependent manner.

[0299] In some embodiments, a subject with anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia) has elevated heme levels. In some embodiments, the subject has a heme level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% higher than the heme level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level that is at least 10% higher than the heme level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level that is at least 20% higher than the heme level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level that is at least 30% higher than the heme level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level that is at least 40% higher than the heme level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level at least 50% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level at least 60% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level at least 70% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level at least 80% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level at least 90% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a heme level at least 100% higher than the heme level in a healthy subject prior to administration of a GlyT1 inhibitor.

[0300] In some embodiments, the method reduces heme levels in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces heme levels in a subject by at least 15%. In some embodiments, the method reduces heme levels in a subject by at least 20%. In some embodiments, the method reduces heme levels in a subject by at least 25%. In some embodiments, the method reduces heme levels in a subject by at least 30%. In some embodiments, the method reduces heme levels in a subject by at least 35%. In some embodiments, the method reduces heme levels in a subject by at least 40%. In some embodiments, the method reduces heme levels in a subject by at least 45%. In some embodiments, the method reduces heme levels in a subject by at least 50%. In some embodiments, the method reduces heme levels in the subject by at least 55%. In some embodiments, the method reduces heme levels in the subject by at least 60%. In some embodiments, the method reduces heme levels in the subject by at least 65%. In some embodiments, the method reduces heme levels in the subject by at least 70%. In some embodiments, the method reduces heme levels in the subject by at least 75%. In some embodiments, the method reduces heme levels in the subject by at least 80%. In some embodiments, the method reduces heme levels in the subject by at least 85%. In some embodiments, the method reduces heme levels in the subject by at least 90%. In some embodiments, the method reduces heme levels in the subject by at least 95%. In some embodiments, the method reduces heme levels in the subject by at least 100%.

[0301] In some embodiments, the method reduces heme synthesis in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces heme synthesis in the subject by at least 15%. In some embodiments, the method reduces heme synthesis in the subject by at least 20%. In some embodiments, the method reduces heme synthesis in the subject by at least 25%. In some embodiments, the method reduces heme synthesis in the subject by at least 30%. In some embodiments, the method reduces heme synthesis in the subject by at least 35%. In some embodiments, the method reduces heme synthesis in the subject by at least 40%. In some embodiments, the method reduces heme synthesis in the subject by at least 45%. In some embodiments, the method reduces heme synthesis in the subject by at least 50%. In some embodiments, the method reduces heme synthesis in the subject by at least 55%. In some embodiments, the method reduces heme synthesis in the subject by at least 60%. In some embodiments, the method reduces heme synthesis in the subject by at least 65%. In some embodiments, the method reduces heme synthesis in the subject by at least 70%. In some embodiments, the method reduces heme synthesis in the subject by at least 75%. In some embodiments, the method reduces heme synthesis in the subject by at least 80%. In some embodiments, the method reduces heme synthesis in the subject by at least 85%. In some embodiments, the method reduces heme synthesis in the subject by at least 90%. In some embodiments, the method reduces heme synthesis in the subject by at least 95%. In some embodiments, the method reduces heme synthesis in the subject by at least 100%. In some embodiments, the method reduces intracellular heme levels. In some embodiments, the method reduces intracellular heme levels in erythroid progenitors.

[0302] In some embodiments, the method reduces the risk of heme toxicity in a subject. In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 15%. In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 20%. In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 25%. In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 30%. In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 35%. In some embodiments, the method reduces the risk of heme toxicity in a subject by at least 40%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 45%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 50%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 55%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 60%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 65%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 70%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 75%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 80%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 85%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 90%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 95%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 100%.

[0303] In some embodiments, the subject has hepatic iron overload. In some embodiments, the method reduces the risk of hepatic iron overload. In some embodiments, the method reduces the level of iron in the liver. In some embodiments, the method reduces the level of iron in the liver by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of iron in the liver by at least 15%. In some embodiments, the method reduces the level of iron in the liver by at least 20%. In some embodiments, the method reduces the level of iron in the liver by at least 25%. In some embodiments, the method reduces the level of iron in the liver by at least 30%. In some embodiments, the method reduces the level of iron in the liver by at least 35%. In some embodiments, the method reduces the level of iron in the liver by at least 40%. In some embodiments, the method reduces the level of iron in the liver by at least 45%. In some embodiments, the method reduces the level of iron in the liver by at least 50%. In some embodiments, the method reduces the level of iron in the liver by at least 55%. In some embodiments, the method reduces the level of iron in the liver by at least 60%. In some embodiments, the method reduces the level of iron in the liver by at least 65%. In some embodiments, the method reduces the level of iron in the liver by at least 70%. In some embodiments, the method reduces the level of iron in the liver by at least 75%. In some embodiments, the method reduces the level of iron in the liver by at least 80%. In some embodiments, the method reduces the level of iron in the liver by at least 85%. In some embodiments, the method reduces the level of iron in the liver by at least 90%. In some embodiments, the method reduces the level of iron in the liver by at least 95%. In some embodiments, the method reduces the level of iron in the liver by at least 100%.

[0304] In some embodiments, the subject has cardiac iron overload. In some embodiments, the method reduces the risk of cardiac iron overload. In some embodiments, the method reduces the level of iron in the heart. In some embodiments, the method reduces the level of iron in the heart by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of iron in the heart by at least 15%. In some embodiments, the method reduces the level of iron in the heart by at least 20%. In some embodiments, the method reduces the level of iron in the heart by at least 25%. In some embodiments, the method reduces the level of iron in the heart by at least 30%. In some embodiments, the method reduces the level of iron in the heart by at least 35%. In some embodiments, the method reduces the level of iron in the heart by at least 40%. In some embodiments, the method reduces the level of iron in the heart by at least 45%. In some embodiments, the method reduces the level of iron in the heart by at least 50%. In some embodiments, the method reduces the level of iron in the heart by at least 55%. In some embodiments, the method reduces the level of iron in the heart by at least 60%. In some embodiments, the method reduces the level of iron in the heart by at least 65%. In some embodiments, the method reduces the level of iron in the heart by at least 70%. In some embodiments, the method reduces the level of iron in the heart by at least 75%. In some embodiments, the method reduces the level of iron in the heart by at least 80%. In some embodiments, the method reduces the level of iron in the heart by at least 85%. In some embodiments, the method reduces the level of iron in the heart by at least 90%. In some embodiments, the method reduces the level of iron in the heart by at least 95%. In some embodiments, the method reduces the level of iron in the heart by at least 100%.

[0305] In some embodiments, the subject has a decrease in erythroid precursor survival compared to a healthy subject. In some embodiments, the subject has a decrease in erythroid precursor differentiation into mature erythrocytes compared to a healthy subject. In some embodiments, the subject has impaired hematopoiesis. In some embodiments, the method increases erythroid precursor survival in the subject. In some embodiments, the method increases erythroid precursor survival in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases erythroid precursor survival in the subject by at least 15%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 20%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 25%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 30%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 35%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 40%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 45%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 50%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 55%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 60%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 65%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 70%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 75%. In some embodiments, the method increases erythroid precursor survival in the subject by at least 80%. In some embodiments, the method increases erythroid progenitor survival in the subject by at least 85%. In some embodiments, the method increases erythroid progenitor survival in the subject by at least 90%. In some embodiments, the method increases erythroid progenitor survival in the subject by at least 95%.In some embodiments, the method increases erythroid progenitor survival in a subject by at least 100%.

[0306] In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells in the subject. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 15%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 20%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 25%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 30%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 35%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 40%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 45%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 50%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 55%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation into mature red blood cells by at least 60%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation to mature red blood cells by at least 65%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation to mature red blood cells by at least 70%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation to mature red blood cells by at least 75%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation to mature red blood cells by at least 80%. In some embodiments, the method increases erythroid precursor erythroid precursor differentiation to mature red blood cells by at least 85%.In some embodiments, the method increases red blood cell precursor erythroid progenitor differentiation into mature red blood cells by at least 90%. In some embodiments, the method increases red blood cell precursor erythroid progenitor differentiation into mature red blood cells by at least 95%. In some embodiments, the method increases red blood cell precursor erythroid progenitor differentiation into mature red blood cells by at least 100%. In some embodiments, the subject has elevated red blood cell adenosine deaminase activity. In some embodiments, the subject has normal bone marrow cell density with a deficiency of red cell precursors. In some embodiments, the subject has normal neutrophil and / or platelet counts.

[0307] In some embodiments, the anemia results from a failure in red blood cell production. In some embodiments, the method reduces anemia in the subject. In some embodiments, the method reduces anemia in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces anemia in the subject by at least 15%. In some embodiments, the method reduces anemia in the subject by at least 20%. In some embodiments, the method reduces anemia in the subject by at least 25%. In some embodiments, the method reduces anemia in the subject by at least 30%. In some embodiments, the method reduces anemia in the subject by at least 35%. In some embodiments, the method reduces anemia in the subject by at least 40%. In some embodiments, the method reduces anemia in the subject by at least 45%. In some embodiments, the method reduces anemia in the subject by at least 50%. In some embodiments, the method reduces anemia in the subject by at least 55%. In some embodiments, the method reduces anemia in the subject by at least 60%. In some embodiments, the method reduces anemia in the subject by at least 65%. In some embodiments, the method reduces anemia in the subject by at least 70%. In some embodiments, the method reduces anemia in the subject by at least 75%. In some embodiments, the method reduces anemia in the subject by at least 80%. In some embodiments, the method reduces anemia in the subject by at least 85%. In some embodiments, the method reduces anemia in the subject by at least 90%. In some embodiments, the method reduces anemia in the subject by at least 95%. In some embodiments, the method reduces anemia in the subject by at least 100%. In some embodiments, the subject has macrocytic anemia. In some embodiments, the method reduces anemia in the subject by reducing free heme toxicity.

[0308] In some embodiments, the method increases red cell mass. In some embodiments, the method decreases red cell mean corpuscular volume. In some embodiments, the method decreases red cell adenosine deaminase. In some embodiments, the method decreases red cell adenosine deaminase in subjects with DBA. In some embodiments, the method decreases fetal hemoglobin content in red cells.

[0309] Red blood cell count and hematocrit Certain embodiments of the present disclosure relate to methods of administering a GlyT1 inhibitor disclosed herein to a subject in need thereof, the subject having a low red blood cell count (e.g., less than about 4.5 million red blood cells per μL of blood for men, and less than about 4.1 million red blood cells per μL of blood for women, often in a clinically or statistically significant amount) or a low hematocrit (e.g., greater than about 38% for men, or greater than about 35% for women, often in a clinically or statistically significant amount). In some embodiments, the subject has a hematocrit level that is less than 38%. In some embodiments, the subject has a hematocrit level that is less than 35%.

[0310] In some embodiments, the hematocrit level of the subject is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the hematocrit level of the subject is at least 10% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the hematocrit level of the subject is at least 20% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the hematocrit level of the subject is at least 30% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the hematocrit level of the subject is at least 40% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject's hematocrit level is at least 50% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject's hematocrit level is at least 60% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject's hematocrit level is at least 70% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject's hematocrit level is at least 80% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject's hematocrit level is at least 90% lower than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor.

[0311] In some embodiments, the subject has a red blood cell count that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the red blood cell count in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 10% lower than the red blood cell count in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 20% lower than the red blood cell count in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 30% lower than the red blood cell count in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 40% lower than the red blood cell count in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 50% lower than the red blood cell count in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 60% lower than the red blood cell count in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 70% lower than the red blood cell count in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 80% lower than the red blood cell count in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 90% lower than the red blood cell count in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count that is at least 4.5×10 12 In some embodiments, the subject has a red blood cell count of less than 4.1×10 12 Have a red blood cell count of less than / L.

[0312] In some embodiments, the GlyT1 inhibitors disclosed herein can be used to increase red blood cell synthesis (also known as erythropoiesis) and treat conditions associated with a reduction in red blood cells. In some embodiments, the GlyT1 inhibitors disclosed herein can modulate red blood cell synthesis by reducing the formation of heme. In some embodiments, the present disclosure relates to a method of increasing red blood cell synthesis in a subject with anemia associated with a ribosomal disorder, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharma- ceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, red blood cell synthesis is increased in a dose-dependent manner. In some embodiments, red blood cell count is increased in a dose-dependent manner. In some embodiments, merely by way of non-limiting example, a GlyT1 inhibitor can be administered directly to a subject to increase red blood cell count, if desired. Red blood cell count may also be reflected by an individual's hematocrit (i.e., packed cell volume (PCV) or erythrocyte volume fraction (EVF)), which is the proportion or percentage of blood volume occupied by red blood cells. Normal hematocrit is usually about 49% for men and about 48% for women. A lower hematocrit value indicates a lower number of red blood cells.

[0313] In certain embodiments, administering a GlyT1 inhibitor (e.g., bitopertin) to such a subject increases the red blood cell count or hematocrit of the subject. Also included are methods for increasing red blood cells in a subject, including a subject with a red blood cell count or hematocrit lower than normal red blood cell count or hematocrit, or a subject at risk of developing such a condition, and methods for increasing hematocrit in a subject, comprising administering a GlyT1 inhibitor (e.g., bitopertin) of the present disclosure to the subject, thereby increasing the red blood cell count or hematocrit in the subject.

[0314] In some embodiments, the method increases the subject's red blood cell count. In some embodiments, the method increases the subject's red blood cell count by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the subject's red blood cell count by at least 15%. In some embodiments, the method increases the subject's red blood cell count by at least 20%. In some embodiments, the method increases the subject's red blood cell count by at least 25%. In some embodiments, the method increases the subject's red blood cell count by at least 30%. In some embodiments, the method increases the subject's red blood cell count by at least 35%. In some embodiments, the method increases the subject's red blood cell count by at least 40%. In some embodiments, the method increases the subject's red blood cell count by at least 45%. In some embodiments, the method increases the subject's red blood cell count by at least 50%. In some embodiments, the method increases the subject's red blood cell count by at least 55%. In some embodiments, the method increases the subject's red blood cell count by at least 60%. In some embodiments, the method increases the subject's red blood cell count by at least 65%. In some embodiments, the method increases the subject's red blood cell count by at least 70%. In some embodiments, the method increases the subject's red blood cell count by at least 75%. In some embodiments, the method increases the subject's red blood cell count by at least 80%. In some embodiments, the method increases the subject's red blood cell count by at least 85%. In some embodiments, the method increases the subject's red blood cell count by at least 90%. In some embodiments, the method increases the subject's red blood cell count by at least 95%. In some embodiments, the method increases the subject's red blood cell count by at least 100%. In some embodiments, the method increases the subject's red blood cell count to normal levels. In some embodiments, the method increases the subject's red blood cell count by 4.5-5.9 x 10 12 In some embodiments, the method increases the subject's red blood cell count to between 4.1 and 5.1 x 10 / L.12 / L.

[0315] In some embodiments, the method increases the hematocrit level of the subject. In some embodiments, the method increases the red blood cell level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the red blood cell level of the subject by at least 15%. In some embodiments, the method increases the red blood cell level of the subject by at least 20%. In some embodiments, the method increases the red blood cell level of the subject by at least 25%. In some embodiments, the method increases the red blood cell level of the subject by at least 30%. In some embodiments, the method increases the red blood cell level of the subject by at least 35%. In some embodiments, the method increases the red blood cell level of the subject by at least 40%. In some embodiments, the method increases the red blood cell level of the subject by at least 45%. In some embodiments, the method increases the subject's red blood cell levels by at least 50%. In some embodiments, the method increases the subject's red blood cell levels by at least 55%. In some embodiments, the method increases the subject's red blood cell levels by at least 60%. In some embodiments, the method increases the subject's red blood cell levels by at least 65%. In some embodiments, the method increases the subject's red blood cell levels by at least 70%. In some embodiments, the method increases the subject's red blood cell levels by at least 75%. In some embodiments, the method increases the subject's red blood cell levels by at least 80%. In some embodiments, the method increases the subject's red blood cell levels by at least 85%. In some embodiments, the method increases the subject's red blood cell levels by at least 90%. In some embodiments, the method increases the subject's red blood cell levels by at least 95%. In some embodiments, the method increases the subject's red blood cell levels by at least 100%.

[0316] Reticulocyte count and hemoglobin In certain embodiments, the present disclosure relates to a method of administering a GlyT1 inhibitor disclosed herein to a subject in need thereof, wherein the subject has a decrease in reticulocytes (e.g., often in a clinically or statistically significant amount, less than 1%) or a decrease in hemoglobin levels (e.g., often in a clinically or statistically significant amount, less than about 13.2 g / dL for men, or less than about 11.6 g / dL for women).

[0317] In some embodiments, the subject has a hemoglobin level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 10% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 20% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 30% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 40% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 50% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 60% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 70% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 80% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is at least 90% lower than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level that is less than 13 g / dL. In some embodiments, the subject has a hemoglobin level that is less than 11 g / dL. In some embodiments, the subject has an elevated fetal hemoglobin level.

[0318] In some embodiments, the subject has a low reticulocyte count, also known as reticulocytopenia. In some embodiments, the subject has a reticulocyte count of less than 1%. In some embodiments, the subject has a reticulocyte count of less than 0.9%. In some embodiments, the subject has a reticulocyte count of less than 0.8%. In some embodiments, the subject has a reticulocyte count of less than 0.7%. In some embodiments, the subject has a reticulocyte count of less than 0.6%. In some embodiments, the subject has a reticulocyte count of less than 0.5%. In some embodiments, the subject has a reticulocyte count of less than 0.4%. In some embodiments, the subject has a reticulocyte count of less than 0.3%. In some embodiments, the subject has a reticulocyte count of less than 0.2%. In some embodiments, the subject has a reticulocyte count of less than 0.1%.

[0319] In certain embodiments, administering a GlyT1 inhibitor (e.g., bitopertin) to such a subject increases the reticulocyte or hemoglobin level of the subject.Also included are the method of increasing reticulocytes in a subject, including the subject with reticulocyte or hemoglobin level lower than normal reticulocyte or hemoglobin level, or the subject at risk of developing such a condition, and the method of increasing hemoglobin level in a subject, comprising administering the GlyT1 inhibitor (e.g., bitopertin) of the present disclosure to the subject, thereby reducing the reticulocyte or hemoglobin level in the subject.

[0320] In some embodiments, the GlyT1 inhibitor disclosed herein can be used to increase hemoglobin synthesis in subjects with anemia associated with ribosomal disorders and treat conditions associated with a decrease in red blood cells.In some embodiments, the GlyT1 inhibitor disclosed herein can modulate hemoglobin synthesis by reducing the formation of heme.In some embodiments, the present disclosure relates to a method for increasing hemoglobin synthesis in subjects with anemia associated with ribosomal disorders, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharma- ceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.In some embodiments, hemoglobin synthesis is increased in a dose-dependent manner.

[0321] In some embodiments, the method increases the hemoglobin level of the subject. In some embodiments, the method increases the hemoglobin level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the hemoglobin level of the subject by at least 15%. In some embodiments, the method increases the hemoglobin level of the subject by at least 20%. In some embodiments, the method increases the hemoglobin level of the subject by at least 25%. In some embodiments, the method increases the hemoglobin level of the subject by at least 30%. In some embodiments, the method increases the hemoglobin level of the subject by at least 35%. In some embodiments, the method increases the hemoglobin level of the subject by at least 40%. In some embodiments, the method increases the hemoglobin level of the subject by at least 45%. In some embodiments, the method increases the subject's hemoglobin level by at least 50%. In some embodiments, the method increases the subject's hemoglobin level by at least 55%. In some embodiments, the method increases the subject's hemoglobin level by at least 60%. In some embodiments, the method increases the subject's hemoglobin level by at least 65%. In some embodiments, the method increases the subject's hemoglobin level by at least 70%. In some embodiments, the method increases the subject's hemoglobin level by at least 75%. In some embodiments, the method increases the subject's hemoglobin level by at least 80%. In some embodiments, the method increases the subject's hemoglobin level by at least 85%. In some embodiments, the method increases the subject's hemoglobin level by at least 90%. In some embodiments, the method increases the subject's hemoglobin level by at least 95%. In some embodiments, the method increases the subject's hemoglobin level by at least 100%. In some embodiments, the method increases the subject's hemoglobin level to at least 13 g / dL. In some embodiments, the methods increase the subject's hemoglobin level to at least 11 g / dL.

[0322] In some embodiments, the method increases the reticulocyte count of the subject. In some embodiments, the method increases the reticulocyte count of the subject by 1% to 2%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.5%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.6%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.7%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.8%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.9%. In some embodiments, the method increases the reticulocyte count of the subject by at least 1%. In some embodiments, the method increases the reticulocyte count of the subject by at least 1.5%. In some embodiments, the method increases the reticulocyte count of the subject by at least 2%. In some embodiments, the method increases the reticulocyte count of the subject by 0.5%. In some embodiments, the method increases the subject's reticulocyte count by 1%.

[0323] Combination therapy Certain embodiments may include combination therapy for treating anemia associated with ribosomal disorders, including administration of one or more GlyT1 inhibitors disclosed herein in combination with other therapeutic agents or treatment modalities. Examples of combination therapy include, without limitation, any one or more additional active agents and / or supportive care selected from the group consisting of trifluoperazine, HDAC inhibitors, glucocorticoids, sotatercept, luspatercept, iron chelators, blood transfusions, platelet transfusions, allogeneic hematopoietic stem cell transplants, autologous gene therapy, lenalidomide (REVLIMID®) and antibiotics. In some embodiments, the method further includes administering another therapeutic agent for treating ribosomal protein deficiency, selected from the group consisting of corticosteroids and bone marrow transplants, and other treatments known to those skilled in the art. For example, corticosteroids can be used to treat anemia associated with ribosomal disorders, such as DBA. Blood transfusions can also be used to treat anemia associated with ribosomal disorders, such as DBA. There may be a period of palliative care during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can treat the hematological aspects of DBA. However, adverse events may occur in transfused patients. In some embodiments, the method reduces the need for corticosteroid treatment in the subject. In some embodiments, the method reduces the dose of corticosteroid treatment required in the subject. In some embodiments, the corticosteroid is a glucocorticoid steroid.

[0324] As mentioned above, the common treatment for treating anemia associated with ribosomal disorders includes the use of regularly scheduled blood transfusions. In some embodiments, the GlyT1 inhibitors disclosed herein are useful in treating subjects with anemia associated with ribosomal disorders that require blood transfusions (e.g., Diamond-Blackfan anemia). In some embodiments, the method reduces the subject's need for blood transfusions. In some embodiments, the method reduces the subject's need for blood transfusions by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's need for blood transfusions by at least 15%. In some embodiments, the method reduces the subject's need for blood transfusions by at least 20%. In some embodiments, the method reduces the subject's need for blood transfusions by at least 25%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 30%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 35%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 40%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 45%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 50%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 55%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 60%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 65%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 70%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 75%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 80%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 85%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 90%.In some embodiments, the method reduces the subject's need for a blood transfusion by at least 95%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 100%. In some embodiments, the method eliminates the subject's need for a blood transfusion.

[0325] Quality of Life and Survival In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of anemia associated with a ribosomal disorder (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of anemia associated with a ribosomal disorder), comprising administering an effective amount of a GlyT1 inhibitor (e.g., bitopertin) to a patient in need thereof, and increasing the quality of life of the patient by at least 1% (e.g., 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%). In some embodiments, the method relates to increasing the quality of life of the patient. In some embodiments, the method relates to increasing the quality of life of the patient by at least 1%. In some embodiments, the method relates to increasing the quality of life of the patient by at least 2%. In some embodiments, the method relates to increasing the patient's quality of life by at least 3%. In some embodiments, the method relates to increasing the patient's quality of life by at least 4%. In some embodiments, the method relates to increasing the patient's quality of life by at least 5%. In some embodiments, the method relates to increasing the patient's quality of life by at least 10%. In some embodiments, the method relates to increasing the patient's quality of life by at least 15%. In some embodiments, the method relates to increasing the patient's quality of life by at least 20%. In some embodiments, the method relates to increasing the patient's quality of life by at least 25%. In some embodiments, the method relates to increasing the patient's quality of life by at least 30%. In some embodiments, the method relates to increasing the patient's quality of life by at least 35%. In some embodiments, the method relates to increasing the patient's quality of life by at least 40%. In some embodiments, the method relates to increasing the patient's quality of life by at least 45%.In some embodiments, the method relates to increasing the patient's quality of life by at least 50%. In some embodiments, the method relates to increasing the patient's quality of life by at least 55%. In some embodiments, the method relates to increasing the patient's quality of life by at least 60%. In some embodiments, the method relates to increasing the patient's quality of life by at least 65%. In some embodiments, the method relates to increasing the patient's quality of life by at least 70%. In some embodiments, the method relates to increasing the patient's quality of life by at least 75%. In some embodiments, the method relates to increasing the patient's quality of life by at least 80%. In some embodiments, the method relates to increasing the patient's quality of life by at least 85%. In some embodiments, the method relates to increasing the patient's quality of life by at least 90%. In some embodiments, the method relates to increasing the patient's quality of life by at least 95%. In some embodiments, the method relates to increasing the patient's quality of life by at least 100%. In some embodiments, the patient has a low quality of life.

[0326] In some embodiments, the patient's quality of life is measured using the Functional Assessment of Cancer Therapy - Anemia (FACT-An). In some embodiments, the patient's quality of life is measured using the Functional Assessment of Cancer Therapy - Fatigue (FACT-Fatigue). In some embodiments, the patient's quality of life is measured using the Functional Assessment of Chronic Illness Therapy (FACIT). In some embodiments, the patient's quality of life is measured using the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue). In some embodiments, the patient's quality of life is measured using the Functional Assessment of Chronic Illness Therapy - Anemia (FACIT-Anemia). In some embodiments, the patient's quality of life is measured using the SF-36 Generic PRO Tool. In some embodiments, the patient's quality of life is measured using the SF-6D Generic PRO Tool. In some embodiments, the patient's quality of life is measured using the Linear Analog Scale Assessment (LASA).

[0327] In certain aspects, the disclosure relates to a method of preventing, treating, or reducing the rate of progression and / or severity of anemia associated with a ribosomal disorder (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of anemia associated with a ribosomal disorder), comprising administering an effective amount of a GlyT1 inhibitor (e.g., bitopertin) to a patient in need thereof, and increasing patient survival by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases patient survival. In some embodiments, the method increases patient survival by at least 15%. In some embodiments, the method increases patient survival by at least 20%. In some embodiments, the method increases patient survival by at least 25%. In some embodiments, the method increases patient survival by at least 30%. In some embodiments, the method increases patient survival by at least 35%. In some embodiments, the method increases patient survival by at least 40%. In some embodiments, the method increases patient survival by at least 45%. In some embodiments, the method increases patient survival by at least 50%. In some embodiments, the method increases patient survival by at least 55%. In some embodiments, the method increases patient survival by at least 60%. In some embodiments, the method increases patient survival by at least 65%. In some embodiments, the method increases patient survival by at least 70%. In some embodiments, the method increases patient survival by at least 75%. In some embodiments, the method increases patient survival by at least 80%. In some embodiments, the method increases patient survival by at least 85%. In some embodiments, the method increases patient survival by at least 90%. In some embodiments, the method increases patient survival by at least 95%. In some embodiments, the method increases patient survival by at least 100%.

[0328] In some embodiments, the method increases patient survival by at least 1 month. In some embodiments, the method increases patient survival by at least 2 months. In some embodiments, the method increases patient survival by at least 3 months. In some embodiments, the method increases patient survival by at least 4 months. In some embodiments, the method increases patient survival by at least 5 months. In some embodiments, the method increases patient survival by at least 6 months. In some embodiments, the method increases patient survival by at least 7 months. In some embodiments, the method increases patient survival by at least 8 months. In some embodiments, the method increases patient survival by at least 9 months. In some embodiments, the method increases patient survival by at least 10 months. In some embodiments, the method increases patient survival by at least 11 months.

[0329] In some embodiments, the method increases patient survival by at least 1 year. In some embodiments, the method increases patient survival by at least 2 years. In some embodiments, the method increases patient survival by at least 3 years. In some embodiments, the method increases patient survival by at least 4 years. In some embodiments, the method increases patient survival by at least 5 years. In some embodiments, the method increases patient survival by at least 6 years. In some embodiments, the method increases patient survival by at least 7 years. In some embodiments, the method increases patient survival by at least 8 years. In some embodiments, the method increases patient survival by at least 9 years. In some embodiments, the method increases patient survival by at least 10 years. EXAMPLES

[0330] Example Having now generally described the invention, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain specific embodiments of the invention and are not intended to be limiting of the invention.

[0331] Example 1 Compound synthesis The compounds disclosed herein can be prepared by the process known and disclosed in the art according to well-known procedures.For example, the compound of formula I, such as Bitopertin, can be prepared according to the synthesis protocol provided in U.S. Patent No. 7,319,099, U.S. Patent No. 9,877,963 and U.S. Patent No. 7,812,161, the contents of which are incorporated herein by reference in their entirety.In addition, the compound of formula II, such as PF-3463275, can be prepared according to the synthesis protocol provided in U.S. Patent No. 8,124,639, the contents of which are incorporated herein by reference in their entirety.

[0332] Example 2 Establishment of stable TF-1 / RPS19 knockdown cell lines To generate an RPS19-deficient Diamond-Blackfan anemia (DBA) model, TF-1 erythroid cell lines were transduced with lentiviruses encoding shRNAs targeting RPS19 (referred to as "shRNA#a" and "shRNA#b") and a scrambled shRNA control (referred to as "scrambled shRNA" or "scrambled") (see Table 1). Stable cell lines were generated by selecting infected cells with puromycin (1ug / ml) for 3 weeks. shRNA expression is doxycycline inducible. In stable cell lines, RPS19 mRNA expression was measured using qRT-PCR after 2 days (Figure 1A) and 4 days (Figure 1B) of doxycycline treatment. The qPCR primers used are listed in Table 1. shRNA#a and shRNA#b gradually induced knockdown of RPS19, reducing RPS19 mRNA expression by more than 85% by day 4 (Figure 1A and Figure 1B). Furthermore, RPS19 protein levels were reduced by more than 70% by day 5 by shRNA#b (Figure 2A and Figure 2B). The antibodies used in determining RPS19 protein levels are listed in Table 1. [Table 1]

[0333] Example 3 Knocking down RPS19 in TF-1 erythroid cells reduces cell growth It has been previously reported that RPS19 knockdown in TF-1 cells adversely affects erythroid cell growth due to an imbalance in heme and globin synthesis. See, for example, Yang, Z. et al. Sci Transl Med 8, 338ra67 (2016). TF-1 cell line is an immature erythroid origin cell line that requires cytokines, such as granulocyte macrophage colony stimulating factor (GMCSF) or erythropoietin (EPO), for its growth. The cell growth potential of stable TF-1 line shRNA#a, shRNA#b and scrambled shRNA was evaluated in vitro by cell counting after 6 days of cell culture in the presence of doxycycline induction. The cells were washed from normal growth medium and seeded in equal numbers in medium containing either GMCSF (2 ng / ml), a growth factor that induces the proliferation of TF-1 cells, or EPO (1 ng / ml), a hormone that induces the proliferation of TF-1 cells and induces their differentiation along the erythroid lineage. Cell growth was monitored by counting cells using trypan blue staining (Figure 3A and Figure 3B). The data in Figure 3A and Figure 3B demonstrate a RPS19-dependent moderate effect on cell proliferation in shRNA#a (lower knockdown efficiency) and a more substantial effect in shRNA#b (higher knockdown efficiency) compared to scrambled shRNA in GMCSF conditions (Figure 3B). EPO is a weak inducer of cell proliferation in TF-1 cells, and in this condition we also observed a dose-dependent growth inhibition of shRNA#a and shRNA#b (Figure 3A).

[0334] Similarly, the cell growth potential of stable TF-1-based shRNA#a, shRNA#b and scrambled shRNA was evaluated in vitro by cell viability assay. As described above, washed cells were seeded in 96-well plates in equal numbers in medium containing either GMCSF or EPO in separate plates for each day of reading (Figure 4A and Figure 4B). Cell viability was measured using CellTiter-Glo® (CTG), which determines the number of viable cells in culture by quantifying ATP, which indicates the presence of metabolically active cells. As with the cell counting method, a moderate cell growth inhibitory effect was observed in shRNA#a, and a high degree of inhibition in cell growth was observed in shRNA#b, compared to similarly doxycycline-treated scrambled shRNA-expressing TF-1 cells, which responded to strong proliferative GMCSF and weaker EPO stimulation (Figure 4A and Figure 4B).

[0335] Thus, knocking down RPS19 in TF-1 erythroid cells resulted in reduced cell growth as determined by cell counting and cell viability assays.

[0336] Example 4 Treatment with bitopertin increases cell growth in RPS19 knockdown of TF-1 cells We investigated whether blocking the uptake of the heme biosynthetic pathway precursor glycine into cells with bitopertin could restore the balance between heme and globin and reverse the anti-proliferative effect caused by RPS19 knockdown. To test this hypothesis, washed cells were seeded in 6-well plates containing doxycycline and GMSCSF as described above to induce shRNA expression and cell proliferation for 4 days. On the fourth day, 1 × 10 5Cells were seeded in 12-well plates containing 4nM or 37nM bitopertin. After 2 days of treatment with bitopertin, we counted the number of cells. Bitopertin had no effect on TF-1 cells expressing scrambled shRNA; however, the protective effect on TF-1shRNA#a cells (low knockdown) was achieved even with 4nM bitopertin (Figure 5).

[0337] Example 5 Treatment with bitopertin increased cell viability in RPS19 knockdown TF-1 cells Furthermore, in a similar setting, equal numbers of cells were seeded in 96-well plates after 4 days of doxycycline treatment and incubated with various doses of bitopertin (maximum concentration of 1 μM, 9 points with 3-fold dilution) for 2 days, and on the 6th day, we performed a CTG assay to measure cell viability. Cells were cultured in the presence of GMCSF during the entire cell culture period. A dose-dependent bitopertin protective effect was observed in TF-1 / shRNA#b cells compared to TF-1 / scrambled shRNA cells (Figure 6).

[0338] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference herein.

[0339] While specific embodiments of the subject matter have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined with reference to the claims, along with their full scope of equivalents, and with reference to the specification, along with such variations.

Claims

1. 1. A pharmaceutical composition for use in a method of treating Diamond-Blackfan anemia in a subject, said pharmaceutical composition comprising a compound of the formula: 【Chemical 78】 (bitopertin) or a pharma- ceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the subject has impaired hematopoiesis.

3. The pharmaceutical composition of claim 1 or 2, wherein the subject has elevated erythrocyte adenosine deaminase activity.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject has macrocytic anemia.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the subject has reticulocytopenia.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject has normal bone marrow cellularity with a deficiency of red cell precursors.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the subject has a normal neutrophil and / or platelet count.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the subject has elevated fetal hemoglobin levels.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the method reduces heme levels in the subject by at least 30%.

10. A pharmaceutical composition described in any one of claims 1 to 9, wherein the method reduces heme synthesis in the subject by at least 30%.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the method reduces intracellular heme levels.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the method reduces intracellular heme levels in erythroid precursors.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the method increases the subject's red blood cell count.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the method increases the hemoglobin level of the subject.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the method increases the hematocrit level of the subject.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the method reduces anemia in the subject.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the method increases the subject's reticulocyte count.

18. A pharmaceutical composition described in any one of claims 1 to 17, wherein the method increases the subject's reticulocyte count by between 1% and 2%.

19. A pharmaceutical composition described in any one of claims 1 to 18, wherein the method increases erythroid progenitor survival in the subject by at least 30%.

20. A pharmaceutical composition described in any one of claims 1 to 19, wherein the method increases erythroid precursor differentiation into mature red blood cells in the subject.

21. A pharmaceutical composition described in any one of claims 1 to 20, wherein the method reduces the risk of heme toxicity in the subject.

22. A pharmaceutical composition described in any one of claims 1 to 21, wherein the method reduces the risk of hepatic iron overload.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the method reduces iron levels in the liver.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein the method reduces the risk of cardiac iron overload.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the method reduces iron levels in the heart.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the method reduces spleen size in the subject.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the method reduces the subject's need for blood transfusions.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the method reduces the need for corticosteroid treatment in the subject.

29. The pharmaceutical composition of any one of claims 1 to 28, wherein the method increases survival by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

30. A pharmaceutical composition described in any one of claims 1 to 29, characterized in that the pharmaceutical composition is administered to the subject in combination with an additional active agent and / or supportive therapy.

31. 31. The pharmaceutical composition of claim 30, wherein the additional active agent and / or supportive care is selected from the group consisting of trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotatercept, luspatercept, iron chelators, blood transfusions, platelet transfusions, allogeneic hematopoietic stem cell transplantation, autologous gene therapy and antibiotics.

32. The pharmaceutical composition according to any one of claims 1 to 31, further comprising a pharma- ceutically acceptable carrier.

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