Compositions and methods for treating erythrocytosis - Patents.com

Abstract

The present embodiment is directed to a method of using a glycine transporter inhibitor, such as a GlyT1 inhibitor, or a pharma- ceutically acceptable salt, hydrate, or prodrug thereof, or a pharmaceutical composition thereof, to prevent or treat erythrocytosis and its associated syndromes. In some embodiments, the present disclosure provides a method of treating erythrocytosis in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or a pharma- ceutically acceptable salt thereof, or one or more prodrugs of GlyT1 inhibitors or a salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from U.S. Provisional Patent Application No. 63 / 160,412, filed March 12, 2021, and U.S. Provisional Patent Application No. 63 / 185,464, filed May 7, 2021. The foregoing applications are incorporated herein by reference.

[0002] Field Embodiments disclosed herein are directed to methods and uses for preventing or treating erythrocytosis with 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 Polycythemia is a disease characterized by an increase in a patient's red blood cell count, hemoglobin, and total red blood cell volume, typically accompanied by an increase in total blood volume. Polycythemia can be distinguished from relative erythrocytosis, which occurs secondary to fluid loss or decreased intake, because erythrocytosis results in an increase in total blood volume, whereas relative polycythemia does not. Two basic categories of erythrocytosis are typically recognized: primary erythrocytosis, which is due to factors intrinsic to the red cell precursors and includes the diagnoses of primary familial congenital polycythemia (PFCP) and polycythemia vera (PV), and secondary erythrocytosis, which is caused by factors exogenous to the red cell precursors.

[0004] There is a high unmet need for effective therapy for treating erythrocytosis.Therefore, the objective of the present disclosure is to provide a method for treating, preventing, or reducing the progression rate and / or severity of erythrocytosis.The methods and uses 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]

[0005] Overview of the Application In some embodiments, the present disclosure provides a method of treating erythrocytosis 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 of preventing, treating, or reducing the rate of progression and / or severity of erythrocytosis 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 disclosure provides a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of erythrocytosis 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 erythrocytosis are selected from the group consisting of pulmonary embolism, transient ischemic attacks, transient visual defects, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia. In some embodiments, the myelofibrosis is selected from the group consisting of low-risk myelofibrosis, intermediate-risk myelofibrosis, high-risk myelofibrosis, primary myelofibrosis, myelofibrosis after essential thrombocythemia, and myelofibrosis after polycythemia vera. In some embodiments, the erythrocytosis is primary polycythemia. In some embodiments, the primary erythrocytosis is polycythemia vera. In some embodiments, the primary erythrocytosis is pure erythrocytosis. In some embodiments, the primary erythrocytosis is primary familial polycythemia.

[0006] In some embodiments, the erythrocytosis is secondary erythrocytosis. In some embodiments, the secondary erythrocytosis is associated with a disorder selected from the group consisting of hypoxia, central hypoxic process, pulmonary disease, right to left cardiopulmonary shunt (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, smoker's polycythemia, high altitude living environment, renal disease, kidney transplant, hemoglobinopathy with high oxygen affinity, reduced level of erythrocyte 2,3,-DPG, bisphosphoglycerate mutase deficiency, methemoglobinemia, inherited ATP increase, oxygen sensing pathway gene mutation, tumor, drug-induced secondary erythrocytosis, adrenal hypersecretion and idiopathic erythrocytosis. In some embodiments, the pulmonary disease is selected from the group consisting of chronic lung disease, interstitial lung disease, chronic obstructive pulmonary disease (COPD), Pickwickian syndrome, emphysema, pulmonary fibrosis, sleep apnea, hypoventilation syndrome and obesity hypoventilation syndrome. In some embodiments, the heart disease is selected from the group consisting of cyanotic heart disease and congenital heart disease. In some embodiments, the kidney disease is selected from the group consisting of regional renal hypoxia, renal artery stenosis, cysts, polycystic kidney disease, hydronephrosis, nephrotic syndrome, diffuse parenchymal disease, Bartter's syndrome, end-stage renal disease, polycythemia after long-term hemodialysis and kidney transplantation. In some embodiments, the oxygen sensing pathway gene mutation is selected from the group consisting of EpoR, VHL, HIF2A and PHD2. In some embodiments, the tumor is a tumor with excessive production of erythropoietin or erythropoietin-related factors. In some embodiments, the tumor is selected from the group consisting of renal cell carcinoma, renal tumor, hepatocellular carcinoma, pheochromocytoma, cerebellar hemangioblastoma, uterine leiomyoma, ovarian cancer, meningioma, parathyroid carcinoma and parathyroid adenoma. In some embodiments, the drug-related secondary erythrocytosis is selected from the group consisting of erythropoietin administration, androgen administration, anabolic steroid administration, synthetic testosterone administration, protein injections, gentamicin administration, and methyldopa administration. In some embodiments, the erythrocytosis is relative erythrocytosis. In some embodiments, the relative erythrocytosis is selected from the group consisting of Geisbeck syndrome, pseudopolycythemia, or stress polycythemia. In some embodiments, the erythrocytosis is Chuvash polycythemia.

[0007] In some embodiments, the present disclosure provides a method of inhibiting heme synthesis in a subject with erythrocytosis, comprising administering to the subject a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, heme synthesis is inhibited in a dose-dependent manner. In some embodiments, the present disclosure provides a method of inhibiting hemoglobin synthesis in a subject with erythrocytosis, comprising administering to the subject a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, hemoglobin synthesis is inhibited in a dose-dependent manner. In some embodiments, the present disclosure provides a method of inhibiting erythrocyte synthesis in a subject with erythrocytosis, comprising administering to the subject a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, erythrocyte synthesis is inhibited in a dose-dependent manner. In some embodiments, the present disclosure provides a method for reducing red blood cell count in a subject with erythrocytosis, comprising administering a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharma- ceutically acceptable salt thereof to the subject. In some embodiments, the red blood cell count is reduced in a dose-dependent manner. In some embodiments, the subject has a hematocrit level that is at least 10%, 20%, 30%, 40%, or 50% higher than the hematocrit level in a healthy subject before administration of the GlyT1 inhibitor. In some embodiments, the subject has a hematocrit level that is at least 48%. In some embodiments, the subject has a hematocrit level that is at least 49%. In some embodiments, the subject has a red blood cell mass level that is at least 10%, 20%, 30%, 40%, or 50% higher than the red blood cell mass level in a healthy subject before administration of the GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 25% above the mean normal predicted value.In some embodiments, the subject has a red blood cell count that is at least 10%, 20%, 30%, 40% or 50% higher 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 5.1×10. 12 In some embodiments, the subject has a red blood cell count of greater than 5.3×10 12In some embodiments, the subject has a red blood cell count of at least 10%, 20%, 30%, 40%, or 50% higher than the hemoglobin level in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level of at least 16.0 g / dL. In some embodiments, the subject has a hemoglobin level of at least 16.5 g / dL. In some embodiments, the method reduces the subject's hematocrit level 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 hematocrit level to less than 48%. In some embodiments, the method reduces the subject's red blood cell levels 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 red blood cell mass 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 hemoglobin level 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 hemoglobin level to less than 16 g / dL. In some embodiments, the method maintains the subject's iron level. In some embodiments, the subject's stored iron level is increased. In some embodiments, the method reduces the incidence of iron deficiency in the subject.In some embodiments, the method reduces the incidence of iron deficiency 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 improves iron deficiency in the subject. In some embodiments, the method improves iron deficiency 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 subject has an increased spleen size. 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%).

[0008] In some embodiments, the subject has a mutation in Janus kinase 2 (JAK2). In some embodiments, the mutation in JAK2 is a JAK2 V617F exon 14 mutation. In some embodiments, the mutation in JAK2 is a JAK2 exon 12 mutation. In some embodiments, the mutation in JAK2 is a gain-of-function mutation. In some embodiments, the subject's JAK2 enzyme activity is increased. In some embodiments, the subject has a mutation in Tet methylcytosine dioxygenase 2 (TET2) or nuclear factor erythroid 2 (NFE2). In some embodiments, the subject has a mutation in a gene selected from the group consisting of VHL, EPO, EPOR, ELG1, EPAS1, HIF2A, and BPGM. In some embodiments, the subject has a high oxygen affinity variant selected from the group consisting of hemoglobin B (HBB) and hemoglobin A (HBA).

[0009] In some embodiments, the subject has an inadequate response to hydroxyurea. In some embodiments, the subject is intolerant to hydroxyurea. In some embodiments, the method reduces the subject's need for therapeutic phlebotomy. In some embodiments, the method reduces the subject's need for therapeutic phlebotomy 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 eliminates the subject's need for therapeutic phlebotomy. In some embodiments, the method reduces the risk of a thromboembolic event in the subject. In some embodiments, the thromboembolic event is arterial thrombosis. In some embodiments, the thromboembolic event is venous thrombosis. In some embodiments, the method reduces the risk of blurred vision in the subject. In some embodiments, the method reduces the risk of blurred vision 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 the risk of headache in the subject. In some embodiments, the risk of headache in the subject is reduced 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 quality of life of the subject is increased. 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%).

[0010] In some embodiments, the method further comprises administering to the subject an additional active agent and / or supportive care. In some embodiments, the additional active agent and / or supportive care is selected from the group consisting of hydroxyurea (e.g., Droxia®, Hydrea®), interferon alpha, interferon alpha-2b (e.g., Intron® A), ruxolitinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiation treatment, hepcidin mimetics (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors.

[0011] In certain embodiments, the GlyT1 inhibitor is represented by formula I [ka] [wherein 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, NO 2 ,CN,(C 1 ~C 6 )-alkyl, halogen-substituted (C 1 ~C 6 )-alkyl, hydroxy substituted (C 1 ~C 6 )-alkyl, (CH 2 )n-(C 1 ~C 6 )-alkoxy, halogen-substituted (C 1 ~C 6 )-Alkoxy, NR 7 R 8 , C(O)R 9 , SO2R 10 and -C(CH 3 )=NOR 7 or (C 1 ~C 6)-substituted by a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N and O, optionally substituted by alkyl; R 1 is hydrogen or (C 1 ~C 6 )-alkyl; R 2 is hydrogen, (C 1 ~C 6 )-alkyl, (C 2 ~C 6 )-alkenyl, halogen-substituted (C 1 ~C 6 )-alkyl, hydroxy substituted (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkoxy or halogen optionally substituted (CH2)n-(C 3 ~C 7 )-cycloalkyl, CH(CH 3 )-(C 3 ~C 7 )-cycloalkyl, (CH 2 ) n+1 -C(O)-R 9 , (CH 2 ) n+1 -CN, bicyclo[2.2.1]heptyl, (CH 2 ) n+1 -O-(C 1 ~C 6 )-alkyl, (CH 2 ) n -heterocycloalkyl, (CH 2 ) n -aryl or (CH 2 ) n - 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen (CH 2 ) n - 5- or 6-membered heteroaryl, where aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with hydroxy, halogen, (C 1 ~C 6 )-Alkyl and (C 1 ~C6 )-alkoxy; R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkoxy or O-(C 3 ~C 6 )-cycloalkyl; R 5 No 2 , C.N., C(O)R. 9 or SO 2 R 10 ;R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkoxy or NR 7 R 8 ;R 10 is optionally substituted with halogen (C 1 ~C 6 )-alkyl, (CH 2 ) n -(C 3 ~C 6 )-cycloalkyl, (CH 2 ) n -(C 3 ~C 6 )-alkoxy, (CH 2 ) 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.

[0012] 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.

[0013] In certain embodiments, the GlyT1 inhibitor has formula II: [ka] [In the formula, R 1 represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrrolyl, and thiadiazole, wherein said heteroaryl is selected from the group consisting of -OH, -NR 7 R 8 , halogens, (C 1 ~C 8 ) alkyl, (C 3 ~C 10 ) cycloalkyl, (C 1 ~C 8 ) alkoxy, (C 1 ~C 12 ) alkoxyalkyl, (C 1 ~C 8 ) hydroxyalkyl, (C 6 ~C 14 ) optionally substituted with one or more substituents selected from aryl and benzyl; R 2 , R 3 and A are independently H or (C 1 ~C 8 )alkoxy, where the alkyl is selected from one or more -OH, (C 1 ~C 8 ) Alkoxy, -NR 7 R 8 or halogen; Q is -(CH 2 ) n -(wherein n=1, 2, 3 or 4) or -(CH 2 ) m-O- (wherein m=2, 3 or 4); Z represents (C 6 ~C 14 ) aryl, (C 1 ~C 8 ) alkyl or (C 3 ~C 8 ) represents cycloalkyl; R 4 and R 5 are each independently H, halogen, (C 1 ~C 8 ) alkyl, (C 6 ~C 14 ) aryl, (C 6 ~C 14 )aryloxy, (C 1 ~C 8 )alkoxy, (3-10 membered)heterocycloalkyl or (C 3 ~C 8 ) cycloalkoxy; where R 4 and R 5 is one or more -OH, (C 1 ~C 8 )Alkoxy, -NR 7 R 8 or halogen; Y is -R 6 , -(CH 2 )oR 6 , -C(R 6 ) 3 or -CH(R 6 ) 2 (wherein 0=1, 2 or 3); R 6 is H, (C 6 ~C 14 ) aryl, (C 1 ~ 10 ) alkyl, (C 3 ~C 10 ) cycloalkyl, (C 5 ~C 18 ) bicycloalkyl, (C 5 ~C 18 )tricycloalkyl, (3-10 membered)heterocycloalkyl, (5-10 membered)heteroaryl, -C(=O)NR 7 R 8 OR -C(=O)OR 7(Wherein, R 6 The group may be optionally substituted by one or more X groups; X=-OH, (C 1 ~C 8 ) Alkoxy, -NR 11 R 12 , -SO 2 R 10 , -C(=O)R 10 , halogen, cyano, (C 1 ~C 8 ) alkyl, (C 1 ~C 10 )alkoxyalkyl, (5-10 membered)heteroaryl, (C 6 ~C 14 ) aryl, (C 6 ~C 14 )aryloxy, benzyl or (C1-C 8 ) hydroxyalkyl; R 7 and R 8 are independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C 1 ~C 8 ) hydroxyalkyl, (5-10 membered) heteroaryl or (C 1 ~C 10 ) alkoxyalkyl; R 7 and R 8 is optionally substituted with one or more X groups; or R 7 and R 8 may, together with the nitrogen to which they may be attached, form a (3-10 membered) heterocycloalkyl group optionally substituted with one or more X groups; R 10 is (C 1 ~C 8 ) alkyl, (C 3 ~C 8 )cycloalkyl, (3-10 membered)heterocycloalkyl, (C 1 ~C 8 ) hydroxyalkyl, (5-10 membered) heteroaryl or (C 1 ~C10 ) alkoxyalkyl; R 11 and R 12 are independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 8 )cycloalkyl, (5-10 membered)heterocycloalkyl, (C 1 ~C 8 ) hydroxyalkyl, (5-10 membered) heteroaryl or (C 1 ~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.

[0014] 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 1~4selected 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, 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 R3 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 5~10 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 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, Z1 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.

[0015] In certain embodiments, the GlyT1 inhibitor has formula IV: [ka] [Wherein, Z is (CH 2 ) n , O, S, SO, SO 2 or NR 5 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, SR 6 , SOR 6, S.O. 2 R 6 , N.R. 6 R 6 , N.H.R. 6 , N.H. 2 , N.H.C.O.R. 6 , NSO 2 R 6 , CN, COOR 6 , 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-(CH 2 ) m m is 1 or 2; Y is hydrogen, halogen, (C 1~4 ) Alkyloxy, SR 6 , N.R. 6 R 6 , and optionally substituted with halogen (C 1~4 ) 1 to 3 substituents independently selected from alkyl; R 1 COOR 7 or CONR 8 R 9 ;R 2 and R6 is (C 1~4 ) alkyl; R 3 , R 4 and R 5 are independently hydrogen or (C 1~4 ) alkyl; R 7 , R 8 and R 9 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.

[0016] 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 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- or 3- and 6-carbon atoms of a piperazine ring, they combine to form -C 1 ~C 3- an 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 to 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 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 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 iR 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.

[0017] In certain embodiments, the GlyT1 inhibitor has formula VI: [ka]

[0023] In the formula, A is a compound represented by the general formula NR 1 Groups of the general formula N+(O−)R 1 or a group of the general formula N+(R')R 1 (wherein R 1is a straight-chain or branched (C 1 ~C 7 ) alkyl group, or (C 4 ~C 7 ) a cycloalkyl group, or (C 3 ~C 7 )Cycloalkyl(C 1 ~C 3 ) alkyl group, or phenyl optionally substituted with one or two hydroxyl or methoxy groups (C 1 ~C 3 ) alkyl group, or (C 2 ~C 4 ) an alkenyl group, or (C 2 ~C 4 R' represents either a linear or branched (C 1 ~C 7 ) alkyl group; X is a hydrogen atom, or a halogen atom and trifluoromethyl, linear or branched (C1-C4) alkyl and (C 1 ~C 4 ) one or more substituents selected from alkoxy groups; R 2 is a hydrogen atom, or a halogen atom and trifluoromethyl, (C 1 ~C 4 ) alkyl group or (C 1 ~C 4 ) an alkoxy group, or a group of the general formula NR 3 R 4 (wherein R 3 and R 4 are each independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group or, together with the nitrogen atom bearing them, a pyrrolidine ring, a piperidine ring or a 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.

[0018] In certain embodiments, the GlyT1 inhibitor has formula VII: [ka] [In the formula, R 1 is -(CH 2 ) 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 -NR12 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 1~6Alkyl, (5) Hydroxy, (6) -SCF 3 , (7)-SCHF 2 , (8)-S.C.H. 3 , (9)-CO 2 R 9 , (10)-CN, (11)-SO 2 R 9 , (12)-SO 2 -NR 10 R 11 , (13)-NR 10 R 11 , (14)-CONR 10 R 11 , and (15)-NO 2 R 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 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.

[0019] In certain embodiments, the GlyT1 inhibitor has formula VIII: [ka] [In the formula, R 1 is a halogen, C 1 ~C 3 Alkyl, C 3 ~C 6 Cycloalkyl, OR 9 or S.R. 10 phenyl independently substituted 1 to 5 times with, 1 ~C 3 Alkyl and C 3 ~C 6 Cycloalkyl is R 7 is substituted 1 to 10 times as necessary; R 2 is H;R 3 and R4 are each independently H or CH 3 ;R 5 are (1) hydrogen, (2) R 7 C optionally substituted 1 to 11 times with 1 ~C 6 (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 C optionally substituted 1 to 5 times with halogen or deuterium 1 ~C 2 alkyl); 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; R 8 are (1) hydrogen, (2) halogen, and (3) C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 7 Cycloalkyl or C 4 ~C 7 Cycloalkylalkyl (where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each cycloalkylalkyl is independently R 7 substituted 1 to 11 times as needed), or (4)-OR 9 , -NR 11 R 12 , -NR 11 C(O) p R10 , -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, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, C 4 ~C 7 Cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10 wherein C is selected from the group consisting of 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each of the cycloalkylalkyls is R 7 substituted 1 to 11 times as necessary; R 10 is hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, C 4 ~C 7 is selected from the group consisting of cycloalkyl, alkyl, aryl and heteroaryl, 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each cycloalkylalkyl is optionally substituted 1 to 11 times with a substituent defined in R7, and an aryl or heteroaryl is optionally substituted 1 to 11 times with a substituent defined in R 8 is substituted 1 to 10 times as necessary; R 11 and R 12 is hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7Cycloalkyl, C 4 ~C 7 each independently selected from the group consisting of cycloalkyl, alkyl, aryl, and heteroaryl, 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each of the cycloalkylalkyls is 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 the oxide thereof, or an individual enantiomer or diastereomer thereof.

[0020] In certain embodiments, the GlyT1 inhibitor is: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0021] 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.

[0022] 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 3~6 Each of the -cycloalkyl-O- substituents is fluoro, -CF 3 , -CHF 2 , -CH 2may be substituted by one or more substituents independently selected from the group consisting of F 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 is fluoro, -CF 3 , -CHF 2 , -CH 2 optionally substituted with one, two, three or more substituents independently selected from the group consisting of F 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, -CF 3 , -CHF 2 , -CH 2 F, -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 fluoro, -CF 3 , -CHF 2 , -CH 2 F, -CN, C 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-SO 2 -, C 3~6 -Cycloalkyl-SO 2 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 one -SO bonded directly to the ring carbon atom of the phenyl group to which is bonded 2 -member must be present, where the heterocycloalkyl group is fluoro, -CF 3 , -CHF 2 , -CH 2 F, -CN, C 1~4 -Alkyl-, C 1~6 -Alkyl-O- and C3~6 -cycloalkyl-O-, optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of: [ka] or a pharma- ceutically acceptable salt thereof.

[0023] 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, -(CH 2 ) x -cycloalkyl or -(CH 2 ) x -aryl; R 2 is -S(O) 2 -lower alkyl, -S(O) 2 NH-lower alkyl, NO 2 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 3 ~R 10 are each independently hydrogen, hydroxy, halogen, ═O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO 2 , N.H. 2 , 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 with halogen, lower alkoxy substituted with halogen, lower alkyl substituted with hydroxy, -O-(CH 2 ) y -Lower alkoxy, -O(CH 2 ) y C(O)N(lower alkyl) 2 , -C(O)-lower alkyl, -O-(CH 2 ) x -aryl, -O-(CH 2 ) x -cycloalkyl, -O-(CH 2 ) 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) are -(CH 2 ) 4- together form a six-membered ring; R, R', R'' 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 salt thereof.

[0024] In certain embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier.

[0025] In certain embodiments, the subject is a subject in need thereof.

[0026] 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.

[0027] 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]

[0028] [Figure 1A]Figures 1A-G show the effect of bitopertin in an erythropoietin (EPO)-induced polycythemia vera mouse model. Figure 1A shows a schematic image of the experimental strategy used to evaluate the potential effect of the GlyT1 inhibitor bitopertin in a mouse model of polycythemia vera. The different parameters measured using the experimental strategy described in Figure 1A are as follows: body weight change (Figure 1B), drug levels in plasma 6 hours after the last administration of the GlyT1 inhibitor in mice (Figure 1C); spleen index (Figure 1D); change in hematocrit level (Figure 1E); change in red blood cell level (Figure 1F); and change in hemoglobin level (Figure 1G). [Figure 1B] Same as above. [Figure 1C] Same as above. [Figure 1D] Same as above. [Figure 1E] Same as above. [Figure 1F] Same as above. [Figure 1G] Same as above.

[0029] [Figure 2A] Figures 2A-H show the effect of bitopertin in a darbepoietin-alpha (DPO)-induced polycythemia vera mouse model. Figure 2A shows a schematic image of the experimental strategy used to evaluate the potential effect of the GlyT1 inhibitor bitopertin in a mouse model of polycythemia vera. The various parameters measured using the experimental strategy described in Figure 2A are as follows: body weight change (Figure 2B); change in hematocrit level (Figure 2C); change in red blood cell level (Figure 2D); change in hemoglobin level (Figure 2E); reticulocyte-hemoglobin equivalent (RET-He) level (Figure 2F); mean corpuscular hemoglobin (MCH) level (Figure 2G); and mean corpuscular volume (MCV) level (Figure 2H). [Figure 2B] Same as above. [Figure 2C] Same as above. [Figure 2D] Same as above. [Figure 2E] Same as above. [Figure 2F] Same as above. [Figure 2G] Same as above. [Figure 2H] Same as above.

[0030] [Figure 3A] Figure 3A and Figure 3B show schematic images of experimental strategies that can be used to evaluate the potential effects of GlyT1 inhibitors, such as bitopertin, in a mouse model of polycythemia vera. Figure 3A shows a schematic image of an experimental strategy that can be used to prepare a bone marrow transplant mouse model of polycythemia vera that contains the Jak2-V617F mutation. Figure 3B shows a schematic image of an experimental strategy that can be used to evaluate the effects of GlyT1 inhibitors, such as bitopertin, in a mouse model of polycythemia vera that contains the Jak2-V617F mutation described in Figure 3A. [Figure 3B] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] 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.

[0032] As used herein, the terms "a" or "an" mean "at least one" or "one or more than one," unless the context clearly dictates otherwise.

[0033] 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.

[0034] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0035] 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)CH. 3 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)CH 3 It is.

[0036] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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 -NHCH 2 CH 3 It is.

[0041] 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 2 -).

[0042] 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 -SCH 2 CH 3 It is.

[0043] 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.

[0044] 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.

[0045] As used herein, the term "amidino" refers to -C(=NH)NH 2 means...

[0046] 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).

[0047] As used herein, the term "aminoalkoxy" refers to an alkoxy group substituted with an amino group. An example of an aminoalkoxy is -OCH 2 CH 2 NH 2 It is.

[0048] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group. An example of an aminoalkyl is -CH 2 CH 2 NH 2 It is.

[0049] As used herein, the term "aminosulfonyl" refers to -S(=O) 2 NH 2 means.

[0050] As used herein, the term "aminoalkylthio" refers to an alkylthio group substituted with an amino group. An example of an aminoalkylthio is -SCH 2 CH 2 NH 2 It is.

[0051] 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.

[0052] 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.

[0053] 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:

[0054] As used herein, the term "arylalkyl" refers to a C substituted with aryl. 1~6 It means alkyl.

[0055] As used herein, the term "arylamino" refers to an amino group substituted with an aryl group. An example of an arylamino is -NH (phenyl).

[0056] 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.

[0057] 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.

[0058] As used herein, the term "carbamoyl" refers to -C(=O)NH 2 means...

[0059] 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.

[0060] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0061] The term "carbonate" is art-recognized and refers to the group -OCO 2 -R 30 (In the formula, R 30 represents a hydrocarbyl group).

[0062] The term "carboxy" as used herein refers to a group of the formula -CO 2 H.

[0063] 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.

[0064] As used herein, the term "compound" refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0065] 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.

[0066] 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.

[0067] As used herein, the term "cyano" means --CN.

[0068] 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).

[0069] As used herein, the term "cycloalkylalkyl" refers to a C substituted with cycloalkyl. 1~6 It means alkyl.

[0070] As used herein, the term "dialkylamino" means an amino group substituted with two alkyl groups each having 1 to 6 carbon atoms.

[0071] As used herein, the term "diazamino" refers to -N(NH 2 ) 2 means.

[0072] The term "ester" as used herein refers to the group -C(O)OR 30 (In the formula, R 30 represents a hydrocarbyl group).

[0073] 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.

[0074] 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.

[0075] 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).

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] As used herein, the term "guanidino" refers to -NH(=NH)NH 2means.

[0081] As used herein, the term "halo" means a halogen radical, including, but not limited to, fluoro, chloro, bromo and iodo.

[0082] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group. An example of a haloalkoxy group is OCF 3 It is.

[0083] As used herein, the term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1~6 An example of a haloalkyl group is, but is not limited to, CF 3 , C 2 F 5 , C.H. 2 F, CHF 2 , CCl 3 , CHCl 2 , C.H. 2 CF 3 etc.

[0084] 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.

[0085] As used herein, the term "heteroarylalkyl" refers to a C substituted with a heteroaryl group. 1~6 It means an alkyl group.

[0086] 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).

[0087] As used herein, the term "heteroarylene" means a heteroaryl linking group, ie, a heteroaryl group that links one group to another group in a molecule.

[0088] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0089] 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.

[0090] 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, and the like. In addition, ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted with oxo or sulfide. For example, ring-forming S atoms can be substituted with one or two oxos (S(O) or S(O)). 2For another example, ring-forming C atoms can be substituted by oxo (forming carbonyl). Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to a non-aromatic heterocyclic ring (having a common bond with the 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.

[0091] As used herein, the term "heterocycloalkylalkyl" refers to a C substituted with heterocycloalkyl. 1~6 Refers to alkyl.

[0092] 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, -CH 2 OH and -CH 2 CH 2 OH is an example.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] As used herein, the term "nitro" refers to -NO 2 means...

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] "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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] As used herein, the term "phenyl" refers to a -C 6 H 5 A phenyl group can be unsubstituted or substituted with one, two or three suitable substituents.

[0112] 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.

[0113] 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 enzyme 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.

[0114] 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.

[0115] 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). - , C.H. 3 COO - and CF 3 COO -such as methylation or ethylation), for example by converting the tertiary amine moiety to a quaternary ammonium cation via methylation or ethylation.

[0116] As used herein, the term "semicarbazone" refers to =NNHC(=O)NH 2 means...

[0117] As used herein, the phrase "solubilizing agent" means an agent that results in the formation of a micellar or true solution of a drug.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] The term "sulfate" is art-recognized and refers to the group -OSO 3 H or a pharma- ceutically acceptable salt thereof.

[0122] 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).

[0123] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 30 (In the formula, R 30 represents hydrocarbyl).

[0124] The term "sulfonate" is art-recognized and refers to the group SO 3 H or a pharma- ceutically acceptable salt thereof.

[0125] The term "sulfone" is art-recognized and refers to the group -S(O) 2 -R 30 (In the formula, R 30 represents hydrocarbyl).

[0126] 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.

[0127] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0128] 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).

[0129] The term "thioether," as used herein, is an equivalent to an ether where the oxygen is replaced with a sulfur.

[0130] 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 erythrocytosis" or "treating erythrocytosis" refers to activities that reduce or ameliorate either the primary phenomena or secondary symptoms associated with erythrocytosis or other conditions described herein.

[0131] 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.

[0132] 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" includes methyl, ethyl, propyl, C 4 Alkyl, C 5 Alkyl and C 6 It is specifically intended to disclose alkyl individually.

[0133] 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 CH 2 , NH, etc., any H can be replaced with a substituent.

[0134] 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.

[0135] 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).

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] The compounds also include derivatives called prodrugs.

[0147] 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).

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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, NO 2 ,CN,(C 1 ~C 6 )-alkyl, halogen-substituted (C 1 ~C 6 )-alkyl, hydroxy substituted (C 1 ~C 6 )-alkyl, (CH 2 )n-(C 1 ~C 6 )-alkoxy, halogen-substituted (C 1 ~C 6 )-Alkoxy, NR 7 R 8 , C(O)R 9 , SO2R 10 and -C(CH 3 )=NOR 7or (C 1 ~C 6 )-substituted by a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N and O, optionally substituted by alkyl; R 1 is hydrogen or (C 1 ~C 6 )-alkyl; R 2 is hydrogen, (C 1 ~C 6 )-alkyl, (C 2 ~C 6 )-alkenyl, halogen-substituted (C 1 ~C 6 )-alkyl, hydroxy substituted (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkoxy or halogen optionally substituted (CH2)n-(C 3 ~C 7 )-cycloalkyl, CH(CH 3 )-(C 3 ~C 7 )-cycloalkyl, (CH 2 ) n+1 -C(O)-R 9 , (CH 2 ) n+1 -CN, bicyclo[2.2.1]heptyl, (CH 2 ) n+1 -O-(C 1 ~C 6 )-alkyl, (CH 2 ) n -heterocycloalkyl, (CH 2 ) n -aryl or (CH 2 ) n - 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen (CH 2 ) n- 5- or 6-membered heteroaryl, where aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with hydroxy, halogen, (C 1 ~C 6 )-Alkyl and (C 1 ~C 6 )-alkoxy; R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkoxy or O-(C 3 ~C 6 )-cycloalkyl; R 5 No 2 , C.N., C(O)R. 9 or SO 2 R 10 and; R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkoxy or NR 7 R 8 and; R 10 is optionally substituted with halogen (C 1 ~C 6 )-alkyl, (CH 2 ) n -(C 3 ~C 6 )-cycloalkyl, (CH 2 ) n -(C 3 ~C 6 )-alkoxy, (CH 2 ) n -heterocycloalkyl or NR 7 R8 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.

[0153] 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.

[0154] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor has formula II: [ka] [In the formula, R 1 represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrrolyl, and thiadiazole, wherein said heteroaryl is selected from the group consisting of -OH, -NR 7 R 8 , halogens, (C 1 ~C 8 ) alkyl, (C 3 ~C 10 ) cycloalkyl, (C 1 ~C 8 ) alkoxy, (C 1 ~C 12 ) alkoxyalkyl, (C 1 ~C 8 ) hydroxyalkyl, (C 6 ~C 14 ) optionally substituted with one or more substituents selected from aryl and benzyl; R 2 , R 3 and A are independently H or (C1 ~C 8 )alkoxy, where the alkyl is selected from one or more -OH, (C 1 ~C 8 ) Alkoxy, -NR 7 R 8 or optionally substituted by halogen; Q is -(CH 2 ) n -(wherein n=1, 2, 3 or 4) or -(CH 2 ) m -O- (wherein m=2, 3 or 4); Z is (C 6 ~C 14 ) aryl, (C 1 ~C 8 ) alkyl or (C 3 ~C 8 ) represents cycloalkyl; R 4 and R 5 are each independently H, halogen, (C 1 ~C 8 ) alkyl, (C 6 ~C 14 ) aryl, (C 6 ~C 14 )aryloxy, (C 1 ~C 8 )alkoxy, (3-10 membered)heterocycloalkyl or (C 3 ~C 8 ) cycloalkoxy; where R 4 and R 5 is one or more -OH, (C 1 ~C 8 ) Alkoxy, -NR 7 R 8 or optionally substituted by halogen; Y is -R 6 , -(CH 2 )oR 6 , -C(R 6 ) 3 or -CH(R 6 ) 2 where 0=1, 2 or 3; R6 is H, (C 6 ~C 14 ) aryl, (C 1~10 ) alkyl, (C 3 ~C 10 ) cycloalkyl, (C 5 ~C 18 ) bicycloalkyl, (C 5 ~C 18 )tricycloalkyl, (3-10 membered)heterocycloalkyl, (5-10 membered)heteroaryl, -C(=O)NR 7 R 8 OR -C(=O)OR 7 (Wherein, R 6 The group may be optionally substituted with one or more X groups; X=-OH, (C 1 ~C 8 ) Alkoxy, -NR 11 R 12 , -SO 2 R 10 , -C(=O)R 10 , halogen, cyano, (C 1 ~C 8 ) alkyl, (C 1 ~C 10 )alkoxyalkyl, (5-10 membered)heteroaryl, (C 6 ~C 14 ) aryl, (C 6 ~C 14 )aryloxy, benzyl or (C1-C 8 ) hydroxyalkyl; R 7 and R 8 are independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C 1 ~C 8 ) hydroxyalkyl, (5-10 membered) heteroaryl or (C 1 ~C 10 ) alkoxyalkyl; R 7 and R 8is optionally substituted with one or more X groups; Or R 7 and R 8 may, together with the nitrogen to which they may be attached, form a (3-10 membered) heterocycloalkyl group optionally substituted with one or more X groups; R 10 is (C 1 ~C 8 ) alkyl, (C 3 ~C 8 )cycloalkyl, (3-10 membered)heterocycloalkyl, (C 1 ~C 8 ) hydroxyalkyl, (5-10 membered) heteroaryl or (C 1 ~C 10 ) alkoxyalkyl; R 11 and R 12 are independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 8 )cycloalkyl, (5-10 membered)heterocycloalkyl, (C 1 ~C 8 ) hydroxyalkyl, (5-10 membered) heteroaryl or (C 1 ~C 10 ) represents alkoxyalkyl] or a pharma- ceutically acceptable salt thereof, or a prodrug of the compound or a pharma- ceutically acceptable salt thereof.

[0155] 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.

[0156] 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.

[0157] 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, C 1~4 Alkoxy, C 1~4 Alkylthio, Phenyl, HaloC1~4 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 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 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 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.

[0158] 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.

[0159] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula IV: [ka] [In the formula, Z is (CH 2 ) n , O, S, SO, SO 2 or NR 5 and; 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, SO 2 R 6 , N.R. 6 R 6 , N.H.R. 6 , N.H. 2 , N.H.C.O.R. 6 , NSO 2 R 6 , CN, COOR 6 , 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 (C5~6 ) aryl group, fused (C 5~6 ) cycloalkyl ring or O-(CH 2 ) m represents -O; m is 1 or 2; Y is hydrogen, halogen, (C 1~4 ) Alkyloxy, SR 6 , N.R. 6 R 6 , and optionally substituted with halogen (C 1~4 ) represents 1 to 3 substituents independently selected from alkyl; R 1 COOR 7 or CONR 8 R 9 and; R 2 and R6 is (C 1~4 ) alkyl; R 3 , R 4 and R 5 are independently hydrogen or (C 1~4 ) alkyl; R 7 , R 8 and R 9 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.

[0160] 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.

[0161] 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 , R b 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- or 3- and 6-carbon atoms of a piperazine ring, they combine to form -C 1 ~C 3 - an alkylene chain can be formed, 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 2is 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 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 lwith 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.

[0162] 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.

[0163] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is represented by formula VI: [ka] [In the formula, A is a group of the general formula NR 1 Groups of the general formula N+(O−)R 1 or a group of the general formula N+(R')R 1 (wherein R 1 is a straight-chain or branched (C 1 ~C 7 ) alkyl group, or (C 4 ~C 7 ) a cycloalkyl group, or (C 3 ~C 7 )Cycloalkyl(C 1 ~C 3) alkyl group, or phenyl optionally substituted with one or two hydroxyl or methoxy groups (C 1 ~C 3 ) alkyl group, or (C 2 ~C 4 ) an alkenyl group, or (C 2 ~C 4 ) an alkynyl group; R' is a linear or branched (C 1 ~C 7 ) representing an alkyl group; X is a hydrogen atom, or a halogen atom and trifluoromethyl, linear or branched (C1-C4) alkyl and (C 1 ~C 4 ) alkoxy groups; R 2 is a hydrogen atom, or a halogen atom and trifluoromethyl, (C 1 ~C 4 ) alkyl group or (C 1 ~C 4 ) an alkoxy group, or a group of the general formula NR 3 R 4 (wherein R 3 and R 4 are each independently a hydrogen atom or (C 1 ~C 4 ) an alkyl group or, together with the nitrogen atom which they bear, 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.

[0164] 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.

[0165] 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 -(CH 2 ) 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 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)-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 2c phenyl 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)-SCF 3 , (7)-SCHF 2 , (8)-SCH 3 , (9)-CO 2 R 9 , (10)-CN, (11)-SO 2 R 9 , (12)-SO 2 -NR 10 R 11 , (13)-NR 10 R 11 , (14)-CONR 10 R 11 , and (15)-NO 2 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.

[0166] 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.

[0167] 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 a halogen, C 1 ~C 3 Alkyl, C 3 ~C 6 Cycloalkyl, OR 9 or S.R. 10 phenyl independently substituted 1 to 5 times with, 1 ~C 3 Alkyl and C 3 ~C 6 Cycloalkyl is R 7 is substituted 1 to 10 times as necessary; R 2 is H; R 3 and R4 are each independently H or CH 3 and; R 5 teeth, (1) Hydrogen, (2)R 7 C optionally substituted 1 to 11 times with 1 ~C 6 Alkyl, (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 7 may 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 C optionally substituted 1 to 5 times with halogen or deuterium 1 ~C2 alkyl); R 7 teeth, (1) Hydrogen, (2) halogens, (3) Deuterium, (4) gem-dialkyl, (5) gem-dihalogeno (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) C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 7 Cycloalkyl or C 4 ~C 7 Cycloalkylalkyl (Here, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each cycloalkylalkyl is independently R 7 substituted 1 to 11 times as necessary), or (4)-OR9 , -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 selected from the group consisting of; R 9 is hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, C 4 ~C 7 Cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10 wherein C is selected from the group consisting of 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each of the cycloalkylalkyls is R 7 with 1 to 11 optional substitutions; R 10 is hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, C 4 ~C 7 is selected from the group consisting of cycloalkyl, alkyl, aryl and heteroaryl, 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each cycloalkylalkyl is optionally substituted 1 to 11 times with a substituent defined in R7, and an aryl or heteroaryl is optionally substituted 1 to 11 times with a substituent defined in R 8is substituted 1 to 10 times as necessary; R 11 and R 12 is hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, C 4 ~C 7 each independently selected from the group consisting of cycloalkyl, alkyl, aryl, and heteroaryl, 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl and C 4 ~C 7 Each of the cycloalkylalkyls is 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 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 the oxide thereof, or an individual enantiomer or diastereomer thereof.

[0168] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is one of the following: [ka] [ka] [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 is [ka] 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 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 C3~6 -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.

[0171] 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.

[0172] 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.

[0173] 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]

[0174] 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-, C3~6 -Cycloalkyl-CO- or C 3~6 Each of the -cycloalkyl-O- substituents is fluoro, -CF 3 , -CHF 2 , -CH 2 optionally substituted with one or more substituents independently selected from the group consisting of F 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 of the -cycloalkyl groups is fluoro, -CF 3 , -CHF 2 , -CH 2 optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of F 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, -CF 3 , -CHF 2 , -CH 2 F, -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 a 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, -CF 3 , -CHF 2 , -CH 2 F, -CN, C 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-SO 2 -, C 3~6 -Cycloalkyl-SO 2 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 one -SO bonded directly to the ring carbon atom of the phenyl group to which is bonded 2 -member must be present, wherein the heterocycloalkyl group is fluoro, -CF 3 , -CHF 2 , -CH 2 F, -CN, C 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.

[0175] 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]

[0176] 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]

[0177] In certain embodiments, the compound of formula X has the formula [ka] 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 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, -(CH 2 ) x -cycloalkyl or -(CH 2 )x -aryl; R 2 -S(O) 2 -Lower alkyl, -S(O) 2 NH-lower alkyl, NO 2 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, NO 2 , N.H. 2 , 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 with halogen, lower alkoxy substituted with halogen, lower alkyl substituted with hydroxy, -O-(CH 2 ) y -Lower alkoxy, -O(CH 2 ) y C(O)N(lower alkyl) 2 , -C(O)-lower alkyl, -O-(CH 2 ) x-aryl, -O-(CH 2 ) x -cycloalkyl, -O-(CH 2 ) 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''' are each independently -(CH 2 ) 4 - together to form a six-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 salt thereof.

[0179] 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.

[0180] 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]

[0181] In certain methods and uses disclosed herein, the subject is a subject in need thereof.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] The compounds described herein can be made according to the methods described in the patents or published patent applications cited herein.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] The compounds described herein can be administered alone or in combination with other pharmaceutical agents (either together or sequentially).For example, the compounds can be administered in combination with other drugs, such as for the treatment of erythrocytosis.Examples of other pharmaceutical agents or drugs are known to those skilled in the art and include, but are not limited to, those described herein.

[0190] 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)).

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] For buccal administration, the compositions may take the form of, for example, tablets or lozenges formulated in conventional manner.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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).

[0208] 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.).

[0209] 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.

[0210] 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.

[0211] In some embodiments, the formulation can be lyophilized to a solid and reconstituted, for example, with water prior to use.

[0212] When administered to mammals (eg, animals for veterinary use or humans for clinical use), the compounds can be administered in isolated form.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] In some embodiments, there is also provided one or more compounds as described above, or pharma- ceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition comprising one or more compounds as described above, for use in the manufacture of a medicament for the treatment of erythrocytosis, including but not limited to the conditions described herein, in a subject, or a method of treating and / or preventing those described herein. In some embodiments, the subject is a subject in need thereof.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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%.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] The additional pharmaceutical agents may be administered in combination therapy (including co-formulation) with one or more compounds described herein.

[0240] 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.

[0241] 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

[0242] How to use The present application provides a method for preventing or treating erythrocytosis in a subject, comprising administering to the subject 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 certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as the GlyT1 inhibitors disclosed herein.For example, the present application provides a method for preventing, treating, or reducing the progression rate and / or severity of erythrocytosis in a subject, comprising administering to the subject one or more glycine transporter inhibitors or pharma- ceutically acceptable salts thereof. [ka] or a pharma- ceutically acceptable salt thereof, or a prodrug of bitopertin or a pharma- ceutically acceptable salt thereof, to a subject.

[0243] In part, the disclosure relates to a method of treating erythrocytosis 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 disclosure relates to a method of preventing, treating, or reducing the rate of progression and / or severity of one or more complications of erythrocytosis 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 erythrocytosis is primary erythrocytosis (e.g., polycythemia vera). In some embodiments, the erythrocytosis is secondary erythrocytosis. In some embodiments, the erythrocytosis is relative erythrocytosis. In some embodiments, the erythrocytosis is Chuvash polycythemia. 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.

[0244] The present application provides a method for preventing, treating, or reducing the progression rate and / or severity of erythrocytosis (e.g., polycythemia vera) in a subject, comprising administering to the subject 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 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 foregoing, 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 erythrocytosis (e.g., polycythemia vera) in a subject, comprising administering to the subject bitopeltin or a pharma- ceutically acceptable salt thereof, or a prodrug of bitopeltin or a pharma- ceutically acceptable salt thereof.

[0245] The present application further provides the use of one or more glycine transporter inhibitors or their pharmaceutically acceptable salts, or one or more prodrugs of glycine transporter inhibitors or their pharmaceutically acceptable salts, in the manufacture of a formulation for treating erythrocytosis 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 its pharmaceutically acceptable salts, or a prodrug of bitopertin or its pharmaceutically acceptable salts.In certain of the above embodiments, the formulation is administered in a therapeutically effective amount.

[0246] Polycythemia Polycythemia or polycythemia is a disease characterized by abnormally high levels of red blood cells, often resulting in hyperviscosity and increased risk of thrombosis. The increase in red blood cells can be due to an increase in red blood cell mass ("absolute polycythemia") or a decrease in plasma volume ("relative polycythemia"). Absolute polycythemia can be distinguished from relative polycythemia, which is secondary to fluid loss or decreased intake, because absolute polycythemia results in an increase in total blood volume, whereas relative polycythemia does not. Two basic categories of erythrocytosis are typically recognized: primary polycythemia, which is due to factors intrinsic to red cell precursors and includes the diagnoses of polycythemia vera and pure polycythemia, and secondary polycythemia, which is caused by factors external to the red cell precursors.

[0247] Primary polycythemia Primary polycythemia refers to various myeloproliferative syndromes, including, for example, polycythemia vera and pure polycythemia. Polycythemia vera has a significant genetic component. For example, an activating mutation in the tyrosine kinase JAK2 (JAK2V617F) is responsible for most primary cases in adults. Several other mutations in JAK2 have also been described (e.g., exon 12, JAK2H538-K539delinsI). These and possibly other JAK2 mutations are thought to cause hypersensitivity to EPO via the EPO receptor. Familial clustering suggests a genetic predisposition. Also, the clonality of polycythemia vera is well established. Studies have also suggested hypersensitivity of myeloid progenitor cells to growth factors, including EPO, IL-3, SCF, GM-CSF, and insulin-like growth factor (IGF)-1, while other studies have shown defects in programmed cell death. Pure polycythemia includes patients with isolated elevated RBC mass in the absence of any other precipitating factors.

[0248] Primary familial erythrocytosis is caused by hypersensitivity of erythroid precursors to EPO. Several mutations (approximately 14) have been identified in the EPO receptor gene (EPOR). Most of the identified EPOR mutations cause truncations of the c-terminal cytoplasmic receptor domain of the receptor. These truncated receptors have increased sensitivity to circulating EPO due to the lack of negative feedback regulation.

[0249] In certain aspects, the present disclosure relates to a method for treating erythrocytosis 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 erythrocytosis is primary polycythemia. In some embodiments, the primary polycythemia is polycythemia vera. In some embodiments, the primary polycythemia is pure polycythemia. In some embodiments, the primary polycythemia is primary familial polycythemia. Thus, the GlyT1 inhibitors disclosed herein can be used in treating or reducing the risk of primary erythrocytosis, such as polycythemia vera, pure polycythemia, or primary familial polycythemia.

[0250] In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of erythrocytosis 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 erythrocytosis are selected from the group consisting of pulmonary embolism, transient ischemic attacks, transient visual defects, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia. In some embodiments, the myelofibrosis is selected from the group consisting of low-risk myelofibrosis, intermediate-risk myelofibrosis, high-risk myelofibrosis, primary myelofibrosis, myelofibrosis after essential thrombocythemia, and myelofibrosis after polycythemia vera.

[0251] In certain aspects, the present disclosure relates to a method for treating splenomegaly associated with erythrocytosis 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 erythrocytosis. 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 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 spleen size of the subject 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%.

[0252] In certain aspects, the present disclosure relates to a method for treating erythrocytosis associated with Janus kinase 2 (JAK2) mutation 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 mutation in JAK2 is a JAK2 V617F exon 14 mutation. In some embodiments, the mutation in JAK2 is a JAK2 exon 12 mutation. In some embodiments, the mutation in JAK2 is a gain-of-function mutation. In some embodiments, the subject's JAK2 enzyme activity is increased.

[0253] In certain aspects, the present disclosure relates to a method for treating erythrocytosis associated with a genetic mutation 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 a mutation in Tet methylcytosine dioxygenase 2 (TET2) or Nuclear Factor Erythroid 2 (NFE2). In some embodiments, the subject has a mutation in a gene selected from the group consisting of VHL, EPO, EPOR, ELG1, EPAS1, HIF2A, and BPGM. In some embodiments, the subject has a high oxygen affinity variant selected from the group consisting of hemoglobin B (HBB) and hemoglobin A (HBA).

[0254] Secondary erythrocytosis Secondary erythrocytosis can result from functional hypoxia induced by lung disease, cardiac disease, increased altitude (4% hemoglobin increase for each 1000m increase in altitude), congenital methemoglobinemia, and other high oxygen affinity hemoglobinopathies that stimulate increased EPO production. Secondary erythrocytosis can also result from increased EPO production secondary to benign and malignant EPO-secreting lesions. Secondary erythrocytosis can also be benign familial erythrocytosis. In some embodiments, secondary erythrocytosis results from genetic abnormalities. For example, Chuvash polycythemia, the first congenital erythrocytosis recognized in endemic Russian populations, has a mutation in the von Hippel-Lindau (VHL) gene, which is associated with disrupted oxygen-dependent regulation of EPO synthesis. Neonatal secondary polycythemia is fairly common and can result from either chronic or acute fetal hypoxia or delayed umbilical cord clamping and removal.Similar to primary polycythemia, secondary polycythemia is associated with many complications, including ischemic events in particular.Therefore, GlyT1 inhibitors can be used to treat or reduce the risk of primary polycythemia, such as polycythemia vera, or secondary polycythemia.

[0255] In certain aspects, the present disclosure relates to a method for treating secondary erythrocytosis 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 secondary erythrocytosis is associated with a disorder selected from the group consisting of hypoxia, central hypoxic process, pulmonary disease, right-to-left cardiopulmonary shunt (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, smoker's polycythemia, high altitude habitat, renal disease, kidney transplant, hemoglobinopathies with high oxygen affinity, reduced levels of erythrocyte 2,3,-DPG, bisphosphoglycerate mutase deficiency, methemoglobinemia, inherited ATP increase, oxygen sensing pathway gene mutation, tumor, drug-induced secondary erythrocytosis, adrenal cortical hypersecretion, and idiopathic erythrocytosis. In some embodiments, the patient has elevated erythropoietin (EPO) levels. Elevated EPO levels, usually as a secondary response to chronic hypoxemia, often result in secondary polycythemia. In some embodiments, the elevated EPO levels in the patient are in response to chronic hypoxemia. In some embodiments, the secondary polycythemia is associated with chronic hypoxemia.

[0256] In some embodiments, the secondary erythrocytosis is associated with a pulmonary disease. In some embodiments, the pulmonary disease is selected from the group consisting of chronic pulmonary disease, interstitial lung disease, chronic obstructive pulmonary disease (COPD), Pickwickian syndrome, emphysema, pulmonary fibrosis, sleep apnea, hypoventilation syndrome, and obesity hypoventilation syndrome. In some embodiments, the secondary erythrocytosis associated with a pulmonary disease occurs as a result of functional hypoxia. In some embodiments, the secondary erythrocytosis associated with a pulmonary disease occurs as a result of chronic hypoxemia. In some embodiments, the secondary erythrocytosis is associated with a cardiac disease. In some embodiments, the cardiac disease is selected from the group consisting of cyanotic heart disease and congenital heart disease. In some embodiments, the secondary erythrocytosis is associated with a renal disease. In some embodiments, the renal disease is selected from the group consisting of regional renal hypoxia, renal artery stenosis, cysts, polycystic kidney disease, hydronephrosis, nephrotic syndrome, diffuse parenchymal disease, Bartter's syndrome, end stage renal disease, long-term hemodialysis, and polycythemia after renal transplantation.

[0257] In some embodiments, the secondary erythrocytosis is associated with an oxygen sensing pathway gene mutation. In some embodiments, the oxygen sensing pathway gene mutation is selected from the group consisting of EpoR, VHL, HIF2A, and PHD2. In some embodiments, the secondary erythrocytosis is associated with a tumor. In some embodiments, the tumor is a tumor with excessive production of erythropoietin or erythropoietin-related factors. In some embodiments, the tumor is selected from the group consisting of renal cell carcinoma, renal tumor, hepatocellular carcinoma, pheochromocytoma, cerebellar hemangioblastoma, uterine leiomyoma, ovarian cancer, meningioma, parathyroid carcinoma, and parathyroid adenoma. In some embodiments, the secondary erythrocytosis is drug-associated secondary erythrocytosis. In some embodiments, the drug-associated secondary erythrocytosis is selected from the group consisting of erythropoietin administration, androgen administration, anabolic steroid administration, synthetic testosterone administration, protein injections, gentamicin administration, and methyldopa administration.

[0258] In some embodiments, the erythrocytosis is relative erythrocytosis. In some embodiments, the relative erythrocytosis is selected from the group consisting of Geisbeck syndrome, pseudopolycythemia, or stress polycythemia. In some embodiments, the erythrocytosis is Chuvash polycythemia.

[0259] Certain primary treatment regimes may result in undesirable increases in red blood cells.For example, drugs gentamicin and methyldopa have been associated with increasing the number of red blood cells in subjects.Therefore, GlyT1 inhibitors may be used in conjunction with or in combination with one or more of gentamicin, methyldopa, or other drugs that increase the production of red blood cells, primarily to offset the undesirable effect of producing too many red blood cells.In certain embodiments, by reducing their undesirable side effects, combination therapy with GlyT1 inhibitors may allow the use of higher concentrations of gentamicin, methyldopa, or related drugs.

[0260] Thus, in certain embodiments, the GlyT1 inhibitors disclosed herein can be used to reduce erythropoiesis, and also to reduce the formation of erythroid precursors, erythrocytes, or both.In certain embodiments, the methods of reducing erythropoiesis or erythropoiesis can be used to treat subjects with or at risk of having increased red blood cell counts, increased hemoglobin levels, or increased total red blood cell volume, as described herein.

[0261] Treatment for polycythemia Existing, well-established methods for treating erythrocytosis include treatment using regularly scheduled phlebotomy (phlebotomy). When first diagnosed, phlebotomy is usually scheduled fairly frequently, e.g., multiple times a week, until RBC levels are within the normal range (e.g., hematocrit less than 45%), after which phlebotomy is scheduled monthly or bimonthly, depending on the patient's RBC formation rate. Because phlebotomy does not suppress the production of RBCs in the bone marrow, the effect of each phlebotomy is transient until the patient becomes iron deficient.

[0262] Another approach to treat erythrocytosis attempts to reduce RBC formation by reducing the amount of available iron in serum by increasing iron removal from the body. Iron is an important trace element for almost all living organisms, and is particularly associated with the growth and synthesis of blood. The balance of iron metabolism is regulated primarily in this case at the level of iron salvage from the hemoglobin of senescent red blood cells and duodenal absorption of dietary iron. Free iron is taken up via the intestine, particularly via specific transport systems (DMT-1, ferroportin), and transferred into the blood circulation, where it is transported to the appropriate tissues and organs (transferrin, transferrin receptor).

[0263] In the human body, elemental iron is crucial for, inter alia, oxygen transport, oxygen uptake, cellular functions such as mitochondrial electron transport, cognitive function, etc., and ultimately for the entire energy metabolism.

[0264] Iron uptake and storage are regulated by hepcidin. Hepcidin is produced in the liver and acts as a master iron regulatory hormone that controls intestinal iron uptake and also regulates iron storage in other organs. Hepcidin restricts iron uptake by binding to the iron transport molecule ferroportin and causing its degradation. Hepcidin deficiency is a frequent pathogenic feature found in patients with iron overload.

[0265] One method for reducing iron level in patients is to use hepcidin agonist, such as hepcidin mimic.In animal models, it has been shown that high doses of hepcidin mimic can reverse certain erythrocytosis, such as polycythemia vera, by reducing erythropoiesis.However, overdosing of hepcidin agonist can cause the inhibition of intestinal iron uptake and macrophage iron recycling, as well as the potential deterioration of suboptimal production of RBC, similar to polycythemia vera.In addition, hepcidin is limited in its use as a drug due to its complex structure, which requires complicated production, and also due to its limited in vivo duration of action.

[0266] Another method of reducing iron levels in patients involves the use of chelating agents. For example, deferoxamine (also known as Desferal®), a bacterial siderophore, is an established drug used in chelation therapy. As a chelator, deferoxamine binds to iron in the bloodstream and enhances its elimination via urine and feces. Two additional drugs licensed for use in patients receiving regular blood transfusions, which results in the development of iron overload, are deferasirox and deferiprone. A disadvantage of using chelation therapy to reduce iron levels is that iron chelation therapy is known to exhibit toxicity potential.

[0267] Certain embodiments of the present disclosure relate to a method of administering a GlyT1 inhibitor disclosed herein to a subject in need thereof, the subject having erythrocytosis. In some embodiments, the GlyT1 inhibitor disclosed herein treats erythrocytosis while maintaining the iron level of the subject. In some embodiments, the GlyT1 inhibitor disclosed herein treats erythrocytosis while increasing the stored iron level of the subject. In some embodiments, the GlyT1 inhibitor disclosed herein treats erythrocytosis while reducing the incidence of iron deficiency. In some embodiments, the GlyT1 inhibitor disclosed herein reduces erythrocytosis while maintaining the iron level of the subject. In some embodiments, the GlyT1 inhibitor disclosed herein reduces erythrocytosis while increasing the stored iron level of the subject. In some embodiments, the GlyT1 inhibitor disclosed herein reduces erythrocytosis while reducing the incidence of iron deficiency.

[0268] Certain embodiments of the present disclosure relate to a method of administering a GlyT1 inhibitor disclosed herein to a subject in need thereof, wherein the subject has iron deficiency associated with erythrocytosis. In some embodiments, the method reduces the incidence of iron deficiency 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 incidence of iron deficiency by at least 15%. In some embodiments, the method reduces the incidence of iron deficiency by at least 20%. In some embodiments, the method reduces the incidence of iron deficiency by at least 25%. In some embodiments, the method reduces the incidence of iron deficiency by at least 30%. In some embodiments, the method reduces the incidence of iron deficiency by at least 35%. In some embodiments, the method reduces the incidence of iron deficiency by at least 40%. In some embodiments, the method reduces the incidence of iron deficiency by at least 45%. In some embodiments, the method reduces the incidence of iron deficiency by at least 50%. In some embodiments, the method reduces the incidence of iron deficiency by at least 55%. In some embodiments, the method reduces the incidence of iron deficiency by at least 60%. In some embodiments, the method reduces the incidence of iron deficiency by at least 65%. In some embodiments, the method reduces the incidence of iron deficiency by at least 70%. In some embodiments, the method reduces the incidence of iron deficiency by at least 75%. In some embodiments, the method reduces the incidence of iron deficiency by at least 80%. In some embodiments, the method reduces the incidence of iron deficiency by at least 85%. In some embodiments, the method reduces the incidence of iron deficiency by at least 90%. In some embodiments, the method reduces the incidence of iron deficiency by at least 95%. In some embodiments, the method reduces the incidence of iron deficiency by at least 100%.

[0269] In some embodiments, the method further improves iron deficiency in the subject. In some embodiments, the method improves iron deficiency 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 improves iron deficiency in the subject by at least 15%. In some embodiments, the method improves iron deficiency in the subject by at least 20%. In some embodiments, the method improves iron deficiency in the subject by at least 25%. In some embodiments, the method improves iron deficiency in the subject by at least 30%. In some embodiments, the method improves iron deficiency in the subject by at least 35%. In some embodiments, the method improves iron deficiency in the subject by at least 40%. In some embodiments, the method improves iron deficiency in the subject by at least 45%. In some embodiments, the method improves iron deficiency in the subject by at least 50%. In some embodiments, the method improves iron deficiency in the subject by at least 55%. In some embodiments, the method improves iron deficiency in the subject by at least 60%. In some embodiments, the method improves iron deficiency in the subject by at least 65%. In some embodiments, the method improves iron deficiency in the subject by at least 70%. In some embodiments, the method improves iron deficiency in the subject by at least 75%. In some embodiments, the method improves iron deficiency in the subject by at least 80%. In some embodiments, the method improves iron deficiency in the subject by at least 85%. In some embodiments, the method improves iron deficiency in the subject by at least 90%. In some embodiments, the method improves iron deficiency in the subject by at least 95%. In some embodiments, the method improves iron deficiency in the subject by at least 100%. erythropoiesis

[0270] 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.

[0271] 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.

[0272] 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. Glycine is one of the important initial substrates for heme and globin synthesis. Therefore, the reduction in the level of glycine due to GlyT1 inhibition can result in a decrease in heme synthesis. In certain aspects, the present disclosure relates to a method of inhibiting heme synthesis in a subject with erythrocytosis, 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, heme synthesis is inhibited in a dose-dependent manner.

[0273] In some embodiments, the GlyT1 inhibitors disclosed herein can be used to reduce red blood cell synthesis (also known as erythropoiesis) and treat conditions related to an increase 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 inhibiting red blood cell synthesis in a subject with erythrocytosis, 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 inhibited in a dose-dependent manner. In some embodiments, the present disclosure relates to a method of reducing red blood cell count in a subject having erythrocytosis, 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 a prodrug or salts of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors). In some embodiments, the red blood cell count is reduced in a dose-dependent manner. In some embodiments, merely by way of non-limiting example, a GlyT1 inhibitor may be administered directly to a subject to reduce the red blood count, if desired. In this regard, normal red blood cell counts typically range from about 4.7 million to about 6.1 million red blood cells per μl for men and about 4.2 million to about 5.4 million red blood cells per μl for women. A high red blood cell count is generally defined as more than about 5.3 million red blood cells per μl for men and more than about 5.1 million red blood cells per μl for women. In children, the threshold for a high red blood cell count varies with age and sex. Red blood cell count can also be reflected by an individual's hematocrit (i.e., packed cell volume (PCV) or red blood cell 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 higher hematocrit indicates a greater number of red blood cells. In severe cases, a high red blood cell count can impair circulation and lead to abnormal clotting, among other problems.

[0274] In some embodiments, the GlyT1 inhibitors disclosed herein can be used to reduce hemoglobin synthesis in subjects with erythrocytosis and treat conditions related to increased red blood cells. In some embodiments, the GlyT1 inhibitors disclosed herein can modulate hemoglobin synthesis by reducing the formation of heme. In some embodiments, the present disclosure relates to a method of inhibiting hemoglobin synthesis in a subject with erythrocytosis, 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 inhibited in a dose-dependent manner.

[0275] Red blood cell count and hematocrit Certain embodiments of the present disclosure relate to a method of administering a GlyT1 inhibitor disclosed herein to a subject in need thereof, wherein the subject has an increased red blood cell count (e.g., more than about 5.3 million red blood cells per μL of blood for men, more than about 5.1 million red blood cells per μL of blood for women, often in a clinically or statistically significant amount) or an increased hematocrit (e.g., more than about 49% for men, more than about 48% for women, often in a clinically or statistically significant amount). In some embodiments, the subject has a hematocrit level that is at least 48%. In some embodiments, the subject has a hematocrit level that is at least 49%.

[0276] In some embodiments, the hematocrit level of the subject is at least 10%, 20%, 30%, 40% or 50% higher 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% higher 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% higher 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% higher 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% higher 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 50% higher than the hematocrit level in a healthy subject before administration of a GlyT1 inhibitor.

[0277] In some embodiments, the subject has a red blood cell count at least 10%, 20%, 30%, 40% or 50% higher than the red blood cell count in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count at least 10% higher than the red blood cell count in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count at least 20% higher than the red blood cell count in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count at least 30% higher than the red blood cell count in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count at least 40% higher than the red blood cell count in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count at least 50% higher than the red blood cell count in a healthy subject prior to administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell count of 5.1×10 12 In some embodiments, the subject has a red blood cell count of greater than 5.3×1012 Have a red blood cell count higher than / L.

[0278] In certain embodiments, administering a GlyT1 inhibitor (e.g., bitopertin) to such a subject reduces the red blood cell count or hematocrit of the subject. Also included are methods for reducing red blood cells in subjects, including subjects with red blood cell counts or hematocrits higher than normal red blood cell counts or hematocrits, or subjects at risk of developing such conditions, and methods for reducing hematocrit in subjects, comprising administering a GlyT1 inhibitor (e.g., bitopertin) of the present disclosure to the subject, thereby reducing the red blood cell count or hematocrit in the subject.

[0279] In some embodiments, the method reduces the subject's red blood cell levels 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 red blood cell levels by at least 15%. In some embodiments, the method reduces the subject's red blood cell levels by at least 20%. In some embodiments, the method reduces the subject's red blood cell levels by at least 25%. In some embodiments, the method reduces the subject's red blood cell levels by at least 30%. In some embodiments, the method reduces the subject's red blood cell levels by at least 35%. In some embodiments, the method reduces the subject's red blood cell levels by at least 40%. In some embodiments, the method reduces the subject's red blood cell levels by at least 45%. In some embodiments, the method reduces the subject's red blood cell levels by at least 50%. In some embodiments, the method reduces the subject's red blood cell levels by at least 55%. In some embodiments, the method reduces the subject's red blood cell levels by at least 60%. In some embodiments, the method reduces the subject's red blood cell levels by at least 65%. In some embodiments, the method reduces the subject's red blood cell levels by at least 70%. In some embodiments, the method reduces the subject's red blood cell levels by at least 75%. In some embodiments, the method reduces the subject's red blood cell levels by at least 80%. In some embodiments, the method reduces the subject's red blood cell levels by at least 85%. In some embodiments, the method reduces the subject's red blood cell levels by at least 90%. In some embodiments, the method reduces the subject's red blood cell levels by at least 95%. In some embodiments, the method reduces the subject's red blood cell levels by at least 100%.

[0280] In some embodiments, the method reduces the subject's hematocrit level 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 hematocrit level by at least 15%. In some embodiments, the method reduces the subject's hematocrit level by at least 20%. In some embodiments, the method reduces the subject's hematocrit level by at least 25%. In some embodiments, the method reduces the subject's hematocrit level by at least 30%. In some embodiments, the method reduces the subject's hematocrit level by at least 35%. In some embodiments, the method reduces the subject's hematocrit level by at least 40%. In some embodiments, the method reduces the subject's hematocrit level by at least 45%. In some embodiments, the method reduces the subject's hematocrit level by at least 50%. In some embodiments, the method reduces the subject's hematocrit level by at least 55%. In some embodiments, the method reduces the subject's hematocrit level by at least 60%. In some embodiments, the method reduces the subject's hematocrit level by at least 65%. In some embodiments, the method reduces the subject's hematocrit level by at least 70%. In some embodiments, the method reduces the subject's hematocrit level by at least 75%. In some embodiments, the method reduces the subject's hematocrit level by at least 80%. In some embodiments, the method reduces the subject's hematocrit level by at least 85%. In some embodiments, the method reduces the subject's hematocrit level by at least 90%. In some embodiments, the method reduces the subject's hematocrit level by at least 95%. In some embodiments, the method reduces the subject's hematocrit level by at least 100%. In some embodiments, the method reduces the subject's hematocrit level to less than 48%.

[0281] There are many common diseases or conditions that can be improved or treated by the GlyT1 inhibitors disclosed herein that increase the red blood cell count or hematocrit of a subject.As one common illustrative example, high red blood cell counts can result from an increase in red blood cell production, mainly to compensate for low oxygen levels that can be caused by insufficient heart or lung function.Also, high red blood cell counts can result from increased release of erythropoietin (EPO) from the kidney (EPO enhances red blood cell production), which can create a relatively high level of red blood cells in terms of volume, production of too many red blood cells by bone marrow, impaired oxygen-carrying capacity of red blood cells (leading to overproduction), compensation for limited oxygen supply at higher altitudes, and loss of plasma (i.e., the liquid component of blood).

[0282] Further examples of conditions associated with high red blood cell count include, without limitation, living at high altitude, smoking, congenital heart disease, right-sided heart failure (i.e., cor pulmonale), scarring and thickening of lung tissue (i.e., pulmonary fibrosis), bone marrow disorders (e.g., polycythemia vera), dehydration, e.g., from severe diarrhea or excessive sweating, kidney disease / cancer, exposure to carbon monoxide, anabolic steroid use, COPD or other lung disease, e.g., pulmonary fibrosis, and EPO doping, primarily for enhancing athletic performance.Therefore, the GlyT1 inhibitors disclosed herein can be used to treat or reduce the risk of developing high red blood cell count or volume, as it is associated with these or any other conditions known in the art.

[0283] Thus, in certain embodiments, GlyT1 inhibitors can be used to reduce erythropoiesis and also to reduce the formation of erythrocytes.In certain embodiments, the method of reducing erythropoiesis or erythropoiesis can be used to treat subjects with or at risk of having increased erythrocyte count, increased hemoglobin level or increased total erythrocyte volume, as described herein and known in the art. Red blood cell mass and hemoglobin

[0284] 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 an increased red blood cell mass (e.g., often in a clinically or statistically significant amount, greater than 25% above the mean normal predicted value) or an increased hemoglobin level (e.g., often in a clinically or statistically significant amount, greater than about 16.5 g / dL for men, or greater than about 16.0 g / dL for women).

[0285] In some embodiments, the subject has a red blood cell mass level that is at least 10%, 20%, 30%, 40% or 50% higher than the red blood cell mass level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 10% higher than the red blood cell mass level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 20% higher than the red blood cell mass level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 30% higher than the red blood cell mass level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 40% higher than the red blood cell mass level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 50% higher than the red blood cell mass level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a red blood cell mass level that is at least 25% above the mean normal predicted value.

[0286] In some embodiments, the subject has a hemoglobin level at least 10%, 20%, 30%, 40%, 50% or 60% higher than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level at least 10% higher than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level at least 20% higher than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level at least 30% higher than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level at least 40% higher than the hemoglobin level in a healthy subject before administration of a GlyT1 inhibitor. In some embodiments, the subject has a hemoglobin level at least 50% higher 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% higher than the hemoglobin level in healthy subjects before administration of GlyT1 inhibitor.In some embodiments, the subject has a hemoglobin level that is higher than 16.0 g / dL.In some embodiments, the subject has a hemoglobin level that is higher than 16.5 g / dL.

[0287] In certain embodiments, administering a GlyT1 inhibitor (e.g., bitopertin) to such a subject reduces the red blood cell mass or hemoglobin level of the subject.Also included are methods for reducing red blood cell mass in a subject, including a subject with red blood cell mass or hemoglobin level higher than normal red blood cell mass or hemoglobin level, or a subject at risk of developing such a condition, and methods for reducing hemoglobin level in a subject, comprising administering a GlyT1 inhibitor (e.g., bitopertin) of the present disclosure to the subject, thereby reducing red blood cell mass or hemoglobin level in the subject.

[0288] In some embodiments, the method reduces the red blood cell mass 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 red blood cell mass of the subject by at least 15%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 20%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 25%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 30%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 35%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 40%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 45%. In some embodiments, the method reduces the red blood cell mass of the subject by at least 50%. In some embodiments, the method reduces the subject's red blood cell mass by at least 55%. In some embodiments, the method reduces the subject's red blood cell mass by at least 60%. In some embodiments, the method reduces the subject's red blood cell mass by at least 65%. In some embodiments, the method reduces the subject's red blood cell mass by at least 70%. In some embodiments, the method reduces the subject's red blood cell mass by at least 75%. In some embodiments, the method reduces the subject's red blood cell mass by at least 80%. In some embodiments, the method reduces the subject's red blood cell mass by at least 85%. In some embodiments, the method reduces the subject's red blood cell mass by at least 90%. In some embodiments, the method reduces the subject's red blood cell mass by at least 95%. In some embodiments, the method reduces the subject's red blood cell mass by at least 100%.

[0289] In some embodiments, the method reduces the subject's hemoglobin level 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 hemoglobin level by at least 15%. In some embodiments, the method reduces the subject's hemoglobin level by at least 20%. In some embodiments, the method reduces the subject's hemoglobin level by at least 25%. In some embodiments, the method reduces the subject's hemoglobin level by at least 30%. In some embodiments, the method reduces the subject's hemoglobin level by at least 35%. In some embodiments, the method reduces the subject's hemoglobin level by at least 40%. In some embodiments, the method reduces the subject's hemoglobin level by at least 45%. In some embodiments, the method reduces the subject's hemoglobin level by at least 50%. In some embodiments, the method reduces the subject's hemoglobin level by at least 55%. In some embodiments, the method reduces the subject's hemoglobin level by at least 60%. In some embodiments, the method reduces the subject's hemoglobin level by at least 65%. In some embodiments, the method reduces the subject's hemoglobin level by at least 70%. In some embodiments, the method reduces the subject's hemoglobin level by at least 75%. In some embodiments, the method reduces the subject's hemoglobin level by at least 80%. In some embodiments, the method reduces the subject's hemoglobin level by at least 85%. In some embodiments, the method reduces the subject's hemoglobin level by at least 90%. In some embodiments, the method reduces the subject's hemoglobin level by at least 95%. In some embodiments, the method reduces the subject's hemoglobin level by at least 100%. In some embodiments, the method reduces the subject's hemoglobin level to less than 16 g / dL. In some embodiments, the methods reduce the subject's hemoglobin level to less than 16.5 g / dL.

[0290] Complications of polycythemia In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of erythrocytosis 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 erythrocytosis are thromboembolic events. In some embodiments, the method reduces the risk of thromboembolic events. In some embodiments, the thromboembolic events are arterial thrombosis. In some embodiments, the thromboembolic events are venous thrombosis. In some embodiments, the one or more complications of erythrocytosis are blurred vision. In some embodiments, the method reduces the risk of blurred vision 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 one or more complications of polycythemia are headaches. In some embodiments, the method reduces the risk of headaches 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%).

[0291] In some embodiments, the one or more complications of polycythemia are selected from the group consisting of pulmonary embolism, transient ischemic attacks, transient visual defects, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia. In some embodiments, the myelofibrosis is selected from the group consisting of low-risk myelofibrosis, intermediate-risk myelofibrosis, high-risk myelofibrosis, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis.

[0292] Combination therapy Certain embodiments may include combination therapy for treating erythrocytosis, including administration of one or more GlyT1 inhibitors disclosed herein in combination with other erythrocytosis-based therapeutic agents or treatment modalities. Examples of combination therapy include, without limitation, any one or more additional active agents and / or supportive therapies selected from the group consisting of hydroxyurea (e.g., Droxia®, Hydrea®), interferon alpha, interferon alpha-2b (e.g., Intron®A), ruxolitinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiation treatment, hepcidin mimetics (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors and HDAC inhibitors.

[0293] Common treatments for high-risk polycythemia vera patients include hydroxyurea or interferon. Hydroxyurea is a chemotherapy agent that can be used for decades, but some studies suggest that it can increase the risk of PV transforming into acute myeloid leukemia. In addition, many patients do not respond well to hydroxyurea or are intolerant to hydroxyurea (mucocutaneous ulcers are the main toxicity) and require different treatment. In some embodiments, the GlyT1 inhibitors disclosed herein are useful in treating subjects who have an inadequate response to hydroxyurea or who are intolerant to hydroxyurea. In some embodiments, the subject has an inadequate response to hydroxyurea. In some embodiments, the subject is intolerant to hydroxyurea.

[0294] Another well-established method for treating erythrocytosis includes treatment using regularly scheduled phlebotomy (phlebotomy). In some embodiments, the GlyT1 inhibitors disclosed herein are useful in treating subjects with erythrocytosis who require therapeutic phlebotomy. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy 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 patient's need for therapeutic phlebotomy by at least 15%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 20%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 25%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 30%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 35%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 40%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 45%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 50%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 55%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 60%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 65%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 70%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 75%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 80%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 85%.In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 90%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 95%. In some embodiments, the method reduces the patient's need for therapeutic phlebotomy by at least 100%. In some embodiments, the method eliminates the patient's need for therapeutic phlebotomy.

[0295] Quality of Life In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of erythrocytosis (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of erythrocytosis), 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 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 quality of life of the patient 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%.

[0296] In some embodiments, the patient's quality of life is measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). In some embodiments, the patient's quality of life is measured using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). In some embodiments, the patient's quality of life is measured using the Pruritus Symptom Impact Scale (PSIS). In some embodiments, the patient's quality of life is measured using the Patient Global Impression of Change (PGIC). EXAMPLES

[0297] 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.

[0298] 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.

[0299] Example 2 Effect of GlyT1 inhibitors in a mouse model of erythropoietin (EPO)-induced secondary polycythemia The EPO-induced secondary polycythemia model was used to evaluate the in vivo pharmacodynamic effects of GlyT1 inhibitors in preventing, treating, or reducing the rate of progression and / or severity of polycythemia vera. Erythropoietin (EPO) stimulates the production of red blood cells, resulting in an increase in hematocrit in mice after daily administration at 50 IU for 7 days. Thus, the EPO model mimics the hematological parameters of polycythemia vera, in which JAK2 mutations drive polycythemia. Briefly, 30 mg / kg of the GlyT1 inhibitor bitopertin or vehicle control was administered orally once daily from days 1 to 15 to wild-type C57BL / 6J mice (10 mice per group). 50 IU of EPO was administered daily by intraperitoneal route from days 8 to 14 to induce polycythemia resembling the pathological process of polycythemia vera (Figure 1A). Blood samples were collected submandibularly before the first EPO dose on day 8 and 6 hours after the last dose of GlyT1 inhibitor on day 15 for CBC panel analysis using a Sysmex XN-1000TM hematology analyzer. Bioanalysis of drug concentration was performed on plasma collected 6 hours after the last dose. All mice were weighed and humanely euthanized. Spleens were weighed and spleen index was calculated via dividing spleen weight by total body weight.

[0300] No significant changes in body weight were observed with GlyT1 inhibitor treatment over the 14-day treatment period (Figure 1B).The mean plasma drug concentration 6 hours after the last dose was 639±38 ng / mL in mice treated with 30 mg / kg of GlyT1 inhibitor (Figure 1C).

[0301] The spleen index increased from 0.39% in normal mice to 1.56% in mice administered EPO and vehicle. Treatment with 30 mg / kg of GlyT1 inhibitor reduced the spleen index to 1.26% (Figure 1D). Consistently, treatment with GlyT1 inhibitor reduced hematocrit (HCT%), RBC count and hemoglobin levels (Figure 1E; Figure 1F; and Figure 1G), suggesting that inhibiting GlyT1 is a potential therapeutic approach for treating polycythemia vera.

[0302] Example 3 Effect of GlyT1 inhibitors in a mouse model of darbepoetin-alpha (DPO)-induced secondary polycythemia Darbepoetin-alpha (DPO) is a long-lasting analog of EPO. To investigate the in vivo pharmacodynamic effects of GlyT1 inhibitors in preventing, treating, or reducing the rate and / or severity of polycythemia vera over a longer period of time, DPO was used to stimulate red blood cell production and mimic the hematological features of polycythemia vera, where JAK2 mutations drive the polycythemia.

[0303] Briefly, C57BL / 6J mice were administered DPO subcutaneously at 10 μg / kg / week for 2 weeks to induce polycythemia resembling the pathological process of polycythemia vera (Figure 2A). Wild-type C57BL / 6J mice (10 mice per group for vehicle and 30 mg / kg groups; 15 mice for the 60 mg / kg group) were orally administered 30 mg / kg or 60 mg / kg of the GlyT1 inhibitor bitopertin or vehicle control once daily from days 7 to 15. The 60 mg / kg group was administered 20 mg / kg on day 7, 40 mg / kg on days 8-9, 50 mg / kg on days 10-11, and 60 mg / kg on days 12-15. Blood samples were collected submandibular prior to the first DPO dose on day 0, prior to the first dose of GlyT1 inhibitor on day 7, and 6 hours after administration of GlyT1 inhibitor on day 15 for CBC panel analysis using a Sysmex XN-1000TM hematology analyzer.

[0304] No significant body weight change was observed with bitopeltin over the 8-day treatment duration (Figure 2B). Bitopeltin reduced hematocrit (HCT%), RBC count and hemoglobin levels (HGB) in a dose-dependent manner (Figure 2C, D, E). A significant reduction in reticulocyte hemoglobin (RET-He) and mean corpuscular hemoglobin (MCH) was observed with GlyT1 inhibitor treatment (Figure 2F, G), suggesting that bitopeltin treatment reduced hemoglobin levels in erythrocyte precursors. Treatment slightly reduced mean corpuscular volume (MCV) (Figure 2H). This study confirmed the effect of bitopertin in reducing hemoglobin in erythrocyte precursors and hematocrit in a DPO-induced secondary polycythemia model, suggesting that inhibition of GlyT1 may be a potential therapeutic approach for treating polycythemia vera.

[0305] Example 4 Effect of GlyT1 inhibitor on Jak2V617F bone marrow transplantation in mice The effect of GlyT1 inhibitors is tested in a polycythemia vera mouse model containing the Jak2-V617F mutation in bone marrow cells to evaluate the efficacy of GlyT1 inhibitors compared to placebo for the treatment of polycythemia vera.

[0306] Activating mutations in Janus kinase 2 (e.g., Jak2-V617F) are present in approximately 95% of all polycythemia vera patients. Increased hematocrit, hemoglobin concentration, red cell count and splenomegaly are the prominent clinical features of the disease.

[0307] Inhibition of glycine uptake using the GlyT1 inhibitor bitopertin may alleviate disease symptoms in PV patients by limiting heme synthesis in erythroid cells and inhibiting erythroid cell expansion and splenomegaly. This study evaluates the effect of bitopertin on reducing disease symptoms in a bone marrow transplant mouse model of PV. Experimental design

[0308] Male BALB / c mice between 4 and 8 weeks of age can be used for the experiments. Myeloid stem progenitor lineage negative, c-Kit positive (hereafter referred to as LK cells) cells are isolated from the BALB / c mice. The isolated LK cells are then transduced with lentiviral vectors encoding the Jak2 gene carrying the V617F mutation (Jak2V617F) or wild type Jak2 (Jak2WT), or an empty vector control, along with GFP expression from the same lentiviral construct. Approximately 5×10 5 or 1×10 6 The transduced LK cells are transplanted into irradiated (two doses of 450 rads) BALB / c recipient mice (Figure 3A). Transplantation of Jak2V617F-overexpressing bone marrow cells into acclimatized syngeneic recipient mice faithfully recapitulates PV-like disease accompanied by peripheral hematocrit increase by 15-18 days after transplantation.

[0309] Three weeks after the bone marrow transplant procedure, blood is collected from the recipient mice and used to determine the level of bone marrow engraftment as determined by the percentage of GFP positive cells in the peripheral blood. Mice are assigned to a total of 10 treatment groups as outlined below. [Table 1]

[0310] During the next 4 weeks, mice in the treatment groups receive daily oral administration of vehicle or 30 mg / kg or 60 mg / kg of Bitopertin. Blood is collected on day -1, at the end of week 2, and at the end of week 4. All groups are monitored for PV symptoms and levels of engraftment via peripheral blood by performing CBC analysis (hematocrit, hemoglobin, serum iron, red cell and platelet counts) and GFP expression. GFP expression can be measured using flow cytometry. At the end of the study, mice are humanely euthanized and spleen and bone marrow pathology are analyzed. Erythroid colony output of bone marrow cells in colony assays from all treatment groups is measured (Figure 3B). Bitopertin is predicted to reduce hematocrit as well as other PV symptoms, such as splenomegaly, RBC counts, MCV and hemoglobin, after 4 weeks of administration in the bone marrow transplanted PV mouse model.

[0311] 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.

[0312] 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 preventing, treating, or reducing the rate of progression and / or severity of one or more complications of erythrocytosis in a subject, said pharmaceutical composition comprising a compound of the formula: 【Chemistry 1】 (bitopertin) or a pharma- ceutically acceptable salt thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the one or more complications of erythrocytosis are selected from the group consisting of pulmonary embolism, transient ischemic attacks, transient visual defects, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis and acute myeloid leukemia.

3. 3. The pharmaceutical composition of claim 2, wherein the myelofibrosis is selected from the group consisting of low-risk myelofibrosis, intermediate-risk myelofibrosis, high-risk myelofibrosis, primary myelofibrosis, post-essential thrombocythemia myelofibrosis and post-polycythemia vera myelofibrosis.

4. The target is 5.1×10 １２ 4. The pharmaceutical composition of claim 1, having a red blood cell count of greater than 100 / L.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the subject has a hemoglobin level greater than 16.0 g / dL.

6. A pharmaceutical composition described in any one of claims 1 to 5, wherein the method reduces the hematocrit level of the subject by at least 30%.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the method reduces red blood cell levels in the subject by at least 10%.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the method reduces the subject's hemoglobin level to less than 16 g / dL.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the iron level of the subject is maintained.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the stored iron level of the subject is increased.

11. A pharmaceutical composition described in any one of claims 1 to 10, wherein the method reduces the incidence of iron deficiency in the subject.

12. A pharmaceutical composition described in any one of claims 1 to 11, wherein the method improves iron deficiency in the subject.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the method reduces spleen size in the subject.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the subject has an inadequate response to hydroxyurea.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the subject is intolerant to hydroxyurea.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the method reduces the subject's need for therapeutic phlebotomy.

17. A pharmaceutical composition described in any one of claims 1 to 16, characterized in that the pharmaceutical composition is administered to the subject in combination with an additional active agent and / or supportive therapy.

18. 18. The pharmaceutical composition of claim 17, wherein the additional active agent and / or supportive care is selected from the group consisting of hydroxyurea (e.g., Droxia®, Hydrea®), interferon alpha, interferon alpha-2b (e.g., Intron® A), ruxolitinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiation treatment, hepcidin mimetics (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors.

19. The pharmaceutical composition according to any one of claims 1 to 18, further comprising a pharma- ceutically acceptable carrier.

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