Method for treating myeloporphyria, X-linked protoporphyria or congenital erythropoietic porphyria using a glycine transport inhibitor

Abstract

The present embodiments are directed to methods of using a glycine transporter inhibitor, e.g., a GlyT1 inhibitor, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, or a pharmaceutical composition thereof, to prevent or treat erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), and / or congenital erythropoietic porphyria (CEP), and their associated syndromes. The present application provides a method of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or salts thereof.

Description

Technical Field

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 958,892, filed on January 9, 2020, and U.S. Provisional Patent Application No. 63 / 085,942, filed on September 30, 2020, the entire disclosures of which are incorporated herein by reference.

[0002] Field The embodiments disclosed herein relate to methods and uses for preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) using a glycine transporter inhibitor, such as, but not limited to, a GlyT1 inhibitor or a pharmaceutically acceptable salt, hydrate, prodrug, or pharmaceutical composition thereof.

Background Art

[0003] Background Erythropoietic protoporphyria (EPP) is worldwide in spread and affects approximately 5,000 - 10,000 individuals worldwide (Michaels et al. 2010). EPP is considered the most common form of porphyria in children. Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It results from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin IX in erythrocytes, plasma, skin, and liver. Erythropoietic protoporphyria (EPP) is due to a hereditary or acquired deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to a hereditary increase in the activity of delta-aminolevulinic acid synthase-2 (ALAS2). The enzymes that cause both EPP and XLPP are in the heme biosynthetic pathway. EPP and XLPP are clinically almost identical. Congenital erythropoietic porphyria (CEP), also known as Gunther disease, is caused by a mutation in the gene for uroporphyrinogen synthase, resulting in a reduction in the activity of this enzyme and the accumulation of the upstream metabolite coproporphyrin I. Current treatments for erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) are limited. Therefore, there is a need for new methods and compositions for treating and / or preventing erythropoietic protoporphyria, X-linked protoporphyria, and congenital erythropoietic porphyria. The methods and uses of glycine transporter inhibitors, such as, but not limited to, GlyT1 inhibitors, described herein, satisfy these needs as well as others. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0004] SUMMARY OF THE APPLICATION The present application provides a method for treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or salts thereof.

[0005] The present application further provides a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or pharmaceutically acceptable salts thereof. In certain embodiments, one or more complications of EPP, XLPP, or CEP are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, blisters, lesions, scarring, deformity, loss of nails, loss of fingers, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, exacerbation of liver disease, end-stage liver disease, red teeth, hyperplastic bone marrow, myelodysplasia, thrombocytopenia, fetal hydrops, and / or intrauterine death. In certain such embodiments, acute photosensitivity is due to sun exposure.

[0006] The present application further provides a method for use in the prevention or treatment of EPP, XLPP, or CEP in a subject, the use comprising administering to the subject a GlyT1 inhibitor or pharmaceutically acceptable salt thereof, or one or more prodrugs of GlyT1 inhibitors or pharmaceutically acceptable salts thereof.

[0007] The present application further provides a method for use in the manufacture of a medicament for the treatment of EPP, XLPP or CEP in a subject, wherein the use comprises administering to the subject at least one GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more GlyT1 inhibitors or a pharmaceutically acceptable salt thereof.

[0008] The present application further provides a method for use in the manufacture of a medicament for inhibiting protoporphyrin IX (PPIX) synthesis in vivo, wherein the use comprises administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more GlyT1 inhibitors or a pharmaceutically acceptable salt thereof.

[0009] In certain embodiments, the subject has EPP. In other embodiments, the subject has XLPP. In yet other embodiments, the subject has CEP.

[0010] In certain embodiments, the method increases painless light exposure in the subject. In other embodiments, the method decreases photosensitivity in the subject.

[0011] The present application further provides a method for inhibiting PPIX synthesis in vivo, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0012] The present application further provides a method for inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in vivo, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0013] The present application further provides a method for inhibiting uroporphyrin I and / or coproporphyrin I synthesis in vivo, which comprises administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0014] The present application further provides a method for inhibiting 5-aminolevulinic acid (5-ALA) synthesis in vivo, which comprises administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0015] In certain embodiments, the accumulation of one or more heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I and / or 5-ALA. In certain such embodiments, the accumulation of one or more heme intermediates is inhibited in a dose-dependent manner.

[0016] In certain embodiments, the GlyT1 inhibitor demonstrates an EC50 of less than 500 nM. In certain embodiments, the GlyT1 inhibitor demonstrates an EC50 of less than 100 nM.

[0017] In certain embodiments, at least 50% cell viability is maintained. In certain embodiments, at least 90% cell viability is maintained.

[0018] In certain embodiments, the subject has a PPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the PPIX level in a healthy subject prior to administration of the GlyT1 inhibitor.

[0019] In certain embodiments, the subject has a ZPPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the ZPPIX level in a healthy subject prior to administration of the GlyT1 inhibitor.

[0020] In certain embodiments, the subject has an increased ratio of free protoporphyrin IX of ZPPIX (ZPPIX / PPIX ratio) compared to a subject having EPP.

[0021] In certain embodiments, the subject has uroporphyrin I and / or coproporphyrin I levels that are at least 10%, 20%, 30%, 40% or 50% higher than uroporphyrin I and / or coproporphyrin I levels in a healthy subject prior to administration of the GlyT1 inhibitor.

[0022] In certain embodiments, the subject has a 5-ALA level that is at least 10%, 20%, 30%, 40% or 50% higher than the 5-ALA level in a healthy subject prior to administration of the GlyT1 inhibitor.

[0023] In certain embodiments, the PPIX level of the subject decreases while the hemoglobin level of the patient is substantially maintained. In certain embodiments, the PPIX level of the patient decreases by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the hemoglobin level of the patient does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25% and 30%). In certain embodiments, the PPIX level of the patient decreases by at least 85% and the hemoglobin level of the patient does not decrease by more than 15%. In certain embodiments, the hemoglobin level does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25% and 30%). In certain embodiments, dosing of the pharmaceutical composition does not cause a substantial reduction in hemoglobin levels.

[0024] In certain embodiments, the subject has increased levels of free protoporphyrin IX in red blood cells. In certain embodiments, the method reduces the levels of free protoporphyrin IX in the subject. In certain such embodiments, the method reduces the levels of free protoporphyrin IX 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 certain embodiments, the subject has increased levels of protoporphyrin IX in feces. In certain embodiments, the method reduces the levels of protoporphyrin IX in the feces of the subject. In certain such embodiments, the method reduces the levels of protoporphyrin IX in the feces 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%).

[0025] In certain embodiments, the plasma porphyrins of the subject fluoresce at a peak of 634 nm when irradiated with blue light (e.g., light at 400 - 420 nm). In certain embodiments, the plasma porphyrins of the subject fluoresce at peaks of 626 - 634 nm when irradiated with blue light (e.g., light at 400 - 420 nm). In certain embodiments, the skin porphyrins of the subject fluoresce at a peak of 632 nm when irradiated with blue light (e.g., light at 400 - 420 nm). In certain embodiments, the skin porphyrins of the subject fluoresce at peaks of 626 - 634 nm when irradiated with blue light (e.g., light at 400 - 420 nm).

[0026] In certain embodiments, the subject has increased protoporphyrin IX levels in the skin. In certain embodiments, the method decreases the protoporphyrin IX levels in the subject's skin. In certain such embodiments, the method decreases the protoporphyrin IX levels in the subject's skin 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 certain embodiments, the subject has protoporphyrin IX levels in the skin that are higher than 0.2 FluoDerm units (FDU). In certain embodiments, the subject has protoporphyrin IX levels in the skin that are higher than 1.0 FDU. In certain embodiments, the subject has protoporphyrin IX levels in the skin that are between 1.0 FDU and 2.5 FDU. In certain embodiments, the subject has protoporphyrin IX levels in the skin that are higher than 2.5 FDU. In certain embodiments, the method decreases the protoporphyrin IX levels in the subject's skin to less than 0.5 FDU. In certain embodiments, the method decreases the protoporphyrin IX levels in the subject's skin to less than 1.0 FDU. In certain embodiments, the method decreases the protoporphyrin IX levels in the subject's skin to less than 1.5 FDU. In certain embodiments, the method decreases the protoporphyrin IX levels in the subject's skin to less than 2.0 FDU. In certain embodiments, the method decreases the protoporphyrin IX levels in the subject's skin to less than 2.5 FDU.

[0027] In certain embodiments, the subject has increased protoporphyrin IX levels in red blood cells. In certain embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells. In certain such embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells 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 certain embodiments, the subject has protoporphyrin IX levels in red blood cells higher than 31 μmol / L -1 In certain embodiments, the subject has protoporphyrin IX levels in red blood cells higher than 31 μmol / L -1 ~53 μmol / L -1 In certain embodiments, the subject has protoporphyrin IX levels in red blood cells of 53 μmol / L -1 In certain embodiments, the subject has protoporphyrin IX levels in red blood cells higher than 53 μmol / L. In certain embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells to a level less than 53 μmol / L -1 In certain embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells to a level less than 31 μmol / L. In certain embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells to a level less than 15 μmol / L -1 In certain embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells to a level less than 31 μmol / L. In certain embodiments, the method reduces the protoporphyrin IX level in the subject's red blood cells to a level less than 15 μmol / L -1

[0028] In certain embodiments, the subject's ferrochelatase activity level is reduced to 10 - 35% of the ferrochelatase activity level observed in normal subjects. In certain embodiments, the subject's ferrochelatase activity level is reduced to less than 50% of the ferrochelatase activity level observed in normal subjects.

[0029] In certain embodiments, the subject has a gain-of-function mutation in ALAS2. In certain embodiments, the subject's ALAS2 enzyme activity is increased. ​

[0030] In certain embodiments, the subject has increased zinc protoporphyrin IX levels in red blood cells. In certain embodiments, the method decreases the zinc protoporphyrin IX levels in the subject's red blood cells. In certain such embodiments, the method decreases the zinc protoporphyrin IX levels in the subject's red blood cells 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%).

[0031] In certain embodiments, the subject has decreased activity of uroporphyrinogen III synthase. In certain embodiments, the subject has increased levels of uroporphyrin I and / or coproporphyrin I. In certain embodiments, the increased levels of uroporphyrin I and / or coproporphyrin I are measured in the subject's urine or red blood cells. In certain embodiments, the increased levels of coproporphyrin I are measured in the subject's feces. In certain embodiments, the method decreases the levels of uroporphyrin I and / or coproporphyrin I in the subject. In certain embodiments, the method decreases the level of uroporphyrin I in the subject. In certain such embodiments, the method decreases the level of uroporphyrin I 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 certain embodiments, the method decreases the level of coproporphyrin I in the subject. In certain such embodiments, the method decreases the level of coproporphyrin I 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%).

[0032] In certain embodiments, the subject has a mutation in UROS.

[0033] In certain embodiments, the subject has a genetic defect in the GATA-1 erythroid-specific transcription factor.

[0034] In certain embodiments, the subject has red fluorescent urine. In certain embodiments, the subject has a peak at 615 nm - 620 nm using plasma porphyrin fluorescence analysis.

[0035] In certain embodiments, the subject has a liver disease associated with EPP, XLPP, or CEP. In certain embodiments, the liver disease associated with EPP, XLPP, or CEP is cholelithiasis. In certain embodiments, the liver disease associated with EPP, XLPP, or CEP is mild liver disease. In certain embodiments, the liver disease associated with EPP, XLPP, or CEP is deterioration of liver disease. In certain embodiments, the liver disease associated with EPP, XLPP, or CEP is end-stage liver disease.

[0036] In certain embodiments, the method further comprises administering an additional active agent and / or supportive therapy to the subject. In certain such embodiments, the additional active agent and / or supportive therapy is selected from the group consisting of avoidance of sunlight, topical sunscreen, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, proteasome inhibitor, chemical chaperone, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0037] In certain embodiments, the GlyT1 inhibitor is

Chemical formula

[0038] In certain embodiments, the GlyT1 inhibitor is

Chemical Formula

[0039] In certain embodiments, the GlyT1 inhibitor is [Chemical formula] [In the formula, R1 represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrroloimidazolyl, and thiadiazole, where the heteroaryl is optionally substituted by one or more substituents selected from -OH, -NR7R8, halogen, (C1-C8) alkyl, (C3-C 10 ) cycloalkyl, (C1-C8) alkoxy, (C1-C 12 ) alkoxyalkyl, (C1-C8) hydroxyalkyl, (C6-C 14 ) aryl, and benzyl; R2, R3, and A independently represent H or (C1-C8) alkoxy, where the alkyl is optionally substituted by one or more -OH, (C1-C8) alkoxy, -NR7R8, or halogen; Q represents -(CH2) n - (where n = 1, 2, 3, or 4) or -(CH2) m -O- (where m = 2, 3, or 4); Z represents (C6-C 14 ) aryl, (C1-C8) alkyl, or (C3-C8) cycloalkyl; R4 and R5 each independently represent H, halogen, (C1-C8) alkyl, (C6-C 14 ) aryl, (C6-C 14 ) aryloxy, (C1-C8) alkoxy, (3- to 10-membered) heterocycloalkyl, or (C3-C8) cycloalkoxy; where R4 and R5 are optionally substituted by one or more -OH, (C1-C8) alkoxy (aIkoxy), -NR7R8, or halogen; Y represents -R6, -(CH2)o-R6, -C(R6)3, or -CH(R6)2 (where 0 = 1, 2, or 3); R6 represents H, (C6-C 14 ) aryl, (C1- 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C5-C18 ) Bicycloalkyl, (C5-C 18 ) Tricycloalkyl, (3-10 membered) heterocycloalkyl, (5-10 membered) heteroaryl, -C(=O)NR7R8 or -C(=O)OR7 (wherein the R6 group may be optionally substituted by one or more X groups); X = -OH, (C1-C8) alkoxy, -NR 11 R 12 , -SO2R 10 , -C(=O)R 10 , halogen, cyano, (C1-C8) alkyl, (C1-C 10 ) alkoxyalkyl, (5-10 membered) heteroaryl, (C6-C 14 ) aryl, (C6-C 14 ) aryloxy, benzyl or (C1-C8) hydroxyalkyl; R7 and R8 are independently H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl; R7 and R8 may be optionally substituted by one or more X groups; or R7 and R8 together with the nitrogen to which they are attached may form a (3-10 membered) heterocycloalkyl group optionally substituted by one or more X groups; R 10 is (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl; R 11 and R 12 are independently H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl) A compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [Chemical formula] A compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In other such embodiments, the GlyT1 inhibitor is [Chemical formula] PF-3463275, which is a compound having the formula, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0040] In certain embodiments, the GlyT1 inhibitor is [Chemical formula] [In the formula, Z 1 is selected from the group consisting of C 1~4 alkyl, C 3~6 cycloalkyl (CycloaIkVl), C 1~4 alkoxy, C 1~4 alkylthio, halo C 1~4 alkyl, phenyl, halo C 1~4 alkoxy, halophenyl, C 1~4 alkylsulfinyl, C 1~4 alkylsulfonyl, bromo and chloro; Z 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1~4 alkyl, phenyl, halo C 1~4 alkyl, halo C 1~4 alkoxy, halophenyl, C 1~4 alkoxy C 1~4 alkyl and C 3~6 cycloalkyl; Z 3 is selected from the group consisting of hydrogen, halogen, C 1~4 alkyl, C 1~4 alkoxy, C 1~4Alkylthio, halo C 1~4 Alkyl, halo C 1~4 Alkoxy and C 3~6 Selected from the group consisting of cycloalkyl; Z 4 Is hydrogen, halogen, C1-3 alkyl, halo C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, phenyl, halo C 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 Selected from the group consisting of cycloalkyl; Z 5 Is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, phenyl, halo C 1~4 Alkyl, halo C 1~4 Alkoxy, halophenyl, C 1~4 Alkoxy C 1~4 Alkyl and C 3~6 Selected from the group consisting of cycloalkyl; where Z 1 ~Z 5 If more than one of is methoxy, Z 1 And Z 5 Only is methoxy, R 3 And R 4 Are independently hydrogen and C optionally substituted with one or more groups Y 1~4 Selected from 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 group Y'; Y is C 1~4 Alkoxy, hydroxy, halo C 1~4 Alkoxy and C 3~5 Selected from the group consisting of cycloalkyl; Y' is C 1~4 Alkyl, C 1~4 Alkoxy, halogen, hydroxy, halo C 1~4 Alkoxy, C 3~5 Cycloalkyl and C 5~10Selected from the group consisting of aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on a 5-, 6- or 7-membered carbon ring; R 5 and R 6 are, independently, C optionally substituted with one or more groups X 1~4 alkyl; or, R 5 and R 6 together with the carbon atom to which they are attached form a saturated 5- or 6-membered carbon ring optionally substituted with one or more groups X', R 5 and R6, when together with the carbon atom to which they are attached form a 5-membered saturated carbon ring, the ring may further optionally 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 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; provided that, simultaneously, Z 1 is propyloxy, Z 3 is chloro, Z 2 =Z 4 =Z 5 =H, and when R 5 and R 6 are both methyl, R 3 and R 4 do not together with the nitrogen atom to which they are attached form a 2-methylpyrrolidine group; simultaneously, Z 1 is methyl, Z 3 is methoxy, Z 2=Z4=Z5=H and R 5 and R 6 are both methyl, R 3 and R 4 together with the nitrogen atom to which they are attached do not form a pyrrolidine group] A compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [Chemical formula] A compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments, the GlyT1 inhibitor is [Chemical formula] [wherein Z is (CH2) n , O, S, SO, SO2 or N-R5; n is 0, 1 or 2; X is hydrogen, halogen, (C 1~6 ) alkyloxy, (C 3~6 ) cycloalkyloxy, (C 6~12 ) aryloxy, (C 6~12 ) aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6, and halogen, (C 6~12 ) aryl, (C 1~6 ) alkyloxy or (C 6~12 ) aryloxy optionally substituted (C 1~4 ) alkyl represents 1 to 3 substituents independently selected; or two substituents at adjacent positions together form a fused (C 5~6 ) aryl group, a fused (C 5~6 ) cycloalkyl ring or O-(CH2) m -O; m is 1 or 2; Y is hydrogen, halogen, (C 1~4One to three substituents independently selected from alkyloxy, SR6, NR6R6, and halogen, optionally substituted on the (C 1~4 ) alkyl; R1 is COOR7 or CONR8R9; R2 and R6 are (C 1~4 ) alkyl; R3, R4 and R5 are independently hydrogen or (C 1~4 ) alkyl; R7, R8 and R9 are independently hydrogen, (C 1~4 ) alkyl, (C 6~12 ) aryl or arylalkyl] A compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is

Chemical formula

[0042] In certain embodiments, the GlyT1 inhibitor is

Chemical formula

Chemical formula

[0043] In certain embodiments, the GlyT1 inhibitor is [Chemical Formula] [wherein, A represents a group of the general formula N-R1, a group of the general formula N+(O-)R1 or a group of the general formula N+(R’)R1 (wherein, R1 represents a hydrogen atom, or a linear or branched (C1-C7) alkyl group optionally substituted with one or more fluorine atoms, or a (C4-C7) cycloalkyl group, or a (C3-C7) cycloalkyl(C1-C3)alkyl group, or a phenyl(C1-C3)alkyl group optionally substituted with one or two hydroxyl groups or methoxy groups, or a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group; R’ represents a linear or branched (C1-C7) alkyl group); X represents a hydrogen atom, or one or more substituents selected from a halogen atom and trifluoromethyl, linear or branched (C1-C4) alkyl and (C1-C4) alkoxy groups; R2 represents a hydrogen atom, or one or more substituents selected from a halogen atom and trifluoromethyl, a (C1-C4) alkyl group or a (C1-C4) alkoxy group, or an amino group of the general formula NR3R4 (wherein, R3 and R4 each independently represent a hydrogen atom or a (C1-C4) alkyl group, or together with the nitrogen atom bearing them, form a pyrrolidine ring, a piperidine ring or a morpholine ring, or a phenyl group optionally substituted with the atoms or groups defined for the above symbol X)] a compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [Chemical Formula] a compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0044] In certain embodiments, the GlyT1 inhibitor is

Chemical formula

Chemical formula

[0045] In certain embodiments, the GlyT1 inhibitor is

Chemical formula

Chemical formula

Chemical formula

[0046] In certain embodiments, the GlyT1 inhibitor is

Chemical formula

Chemical formula

Chemical formula

[0047] In certain embodiments, the GlyT1 inhibitor is of formula IX [Chemical formula] [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, wherein phenyl or heteroaryl is optionally substituted with one or more R 3 ; R 2 represents aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl, and the monocyclic or bicyclic heteroaryl has 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein aryl or heteroaryl is optionally substituted with one or more R 4 ; R 3 is halogen, C 1~4 -alkyl or C 3~6 -cycloalkyl, wherein 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 -O-C 1~6 alkyl, wherein C 1~4 -alkyl, C 3~6 -cycloalkyl, -C 1~3 -alkyl-C 3~6 -cycloalkyl or -O-C 1~6 -alkyl is optionally substituted with one or more halogens] The compound of, or a pharmaceutically acceptable salt thereof, or a tautomer or stereoisomer of the compound or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0048] In certain embodiments, the GlyT1 inhibitor is of formula X [Chemical formula] [wherein, R 1 is selected from the group consisting of: 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 9- or 10-membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) r (wherein r is 0, 1 or 2); wherein each of said groups a), b) and c) is optionally substituted with one or more substituents independently 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-; and when substituted, the substituent is attached to a nitrogen ring atom, and said substituent is selected from the group consisting of C 1~4 -alkyl-, C 1~4 -alkyl-CO-, C 3~6 -cycloalkyl- and C 3~6 -cycloalkyl-CO-; wherein each of said 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 -cycloalkyl-O- substituents may be substituted with one or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 2 is hydrogen, C 1~4 -alkyl-, C 1~4 -alkyl-O-, -CN and C3~6 -cycloalkyl-, where the C 1~4 -alkyl-, C 1~4 -alkyl-O- and C 3~6 -cycloalkyl- groups may each be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 3 is C 1~6 -alkyl-O-, C 3~6 -cycloalkyl-O-, morpholino, pyrazolyl, and 4- to 7-membered monocyclic heterocycloalkyl-O- having 1 or 2 heteroatoms independently selected from the group consisting of 1 oxygen atom and optionally O, N and S(O) s (where s = 0, 1 or 2), where the C 1~6 -alkyl-O- and the C 3~6 -cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 3~6 -cycloalkyl-, C 1~6 -alkyl-O- and C 3~6 -cycloalkyl-O-; R 4 is hydrogen; or R 3 and R 4 together with the ring atoms of the phenyl group to which they are attached form a 4-, 5- or 6-membered monocyclic partially saturated heterocycloalkyl, or a heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) s (where s = 0, 1 or 2), where in general formula (I) there must be 1 ring oxygen atom directly bonded to the ring carbon atom of the phenyl group to which R 3 is attached; where the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C3~6 -Cycloalkyl-, C 1~6 -Alkyl-O-, C 3~6 -Cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-, independently selected from the group consisting of 1, 2, 3 or more substituents, may be optionally substituted; R 5 is hydrogen; R 6 is hydrogen, C 1~4 -Alkyl-SO2-, C 3~6 -Cycloalkyl-SO2 and -CN, selected from the group consisting of; R 7 is hydrogen; or a) R 6 and R 7 or b) R 6 and R 5 One of the pair forms a 5- or 6-membered partially saturated monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) u (where u = 0, 1 or 2), where one -SO2- atom directly bonded to the ring carbon atom of the phenyl group to which R 6 is bonded in general formula (I) must be present, where the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -Alkyl-, C 1~6 -Alkyl-O- and C 3~6 -Cycloalkyl-O-, independently selected from the group consisting of 1, 2, 3 or more substituents, may be optionally substituted] or a pharmaceutically acceptable salt thereof.

[0049] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0050] In certain embodiments, the subject is a subject in need thereof.

[0051] In certain embodiments, a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.

Brief Description of the Drawings

[0052]

Figure 1

[0053]

Figure 2

[0054]

Figure 3

[0055]

Figure 4

[0056]

Figure 5

[0057]

Figure 6

[0058]

Figure 7

[0059]

Figure 8

[0060]

Figure 9

[0061]

Figure 10

[0062]

Figure 11

BEST MODE FOR CARRYING OUT THE INVENTION

[0063] Detailed Description of the Application Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0064] As used herein, the term "a" or "an" means "at least one" or "one or more than one" unless the context clearly dictates otherwise.

[0065] As used herein, the term "about" means approximations and minor variations that would not significantly affect the implementation of the disclosed embodiments. When numerical limitations are used, unless otherwise indicated by the context, "about" means that the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0066] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0067] As used herein, the term "acylamino" means an amino group substituted by an acyl group (e.g., -O-C(=O)-H or -O-C(=O)-alkyl). Examples of acylamino are -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" refers to an amino group substituted by a lower acyl group (e.g., -O-C(=O)-H or -O-C(=O)-C 1~6 alkyl). Examples of lower acylamino are -NHC(=O)H or -NHC(=O)CH3.

[0068] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0069] As used herein, the term "alkenyl" means a straight-chain 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, and the like. 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.

[0070] The terms "alkoxy", "phenyloxy", "benzyloxy" and "pyrimidinyl-oxy" refer to an alkyl group, a phenyl group, a benzyl group or a pyrimidinyl group, respectively, which are each optionally substituted and bonded through an oxygen atom. For example, the term "alkoxy" means a linear or branched -O-alkyl group having 1 to 20 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy and the like. In some embodiments, the alkoxy chain has a length of 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0071] As used herein, the term "alkyl" means a linear or branched saturated hydrocarbon group. The alkyl group can contain 1 to 20, 2 to 20, 1 to 10, 2 to 10, 1 to 8, 2 to 8, 1 to 6, 2 to 6, 1 to 4, 2 to 4, 1 to 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-methyl-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.

[0072] As used herein, the term "alkylamino" means an amino group substituted by an alkyl group having 1 to 6 carbon atoms. An example of alkylamino is -NHCH2CH3.

[0073] As used herein, the term "alkylene" or "alkylenyl" means a divalent alkyl linking group. Examples of alkylene (or alkylenyl) are methylene or methylenyl (-CH2-).

[0074] As used herein, the term "alkylthio" means an -S-alkyl group having 1 to 6 carbon atoms. An example of an alkylthio group is -SCH2CH3.

[0075] As used herein, the term "alkynyl" means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2 to 20 carbon atoms, including but not limited to, acetylene, 1-propylene, 2-propylene, etc. In some embodiments, the alkynyl 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.

[0076] The term "amide", as used herein, refers to the group [Chemical formula] (wherein each R 30 independently represents hydrogen or a hydrocarbyl group, or two Rs 30 together with the N atom to which they are attached complete a heterocyclic ring having 4 to 8 atoms in the ring structure).

[0077] As used herein, the term "amidinio" means -C(=NH)NH2. The terms "amine" and "amino" are recognized in the art and include both unsubstituted and substituted amines, as well as their salts, e.g., [Chemical formula] (In the formula, each R 30 independently represents hydrogen or a hydrocarbyl group, or two Rs 30 together with the N atom to which they are attached complete a heterocyclic ring having 4 to 8 atoms in the ring structure).) refers to a moiety that can be represented by

[0078] As used herein, the term "aminoalkoxy" means an alkoxy group substituted by an amino group. An example of aminoalkoxy is -OCH2CH2NH2.

[0079] As used herein, the term "aminoalkyl" means an alkyl group substituted by an amino group. An example of aminoalkyl is -CH2CH2NH2.

[0080] As used herein, the term "aminosulfonyl" means -S(=O)2NH2.

[0081] As used herein, the term "aminoalkylthio" means an alkylthio group substituted by an amino group. An example of aminoalkylthio is -SCH2CH2NH2.

[0082] As used herein, the term "amphiphilic" means a three-dimensional structure having distinct hydrophobic and hydrophilic regions. Amphiphilic compounds preferably have the presence of both hydrophobic and hydrophilic elements.

[0083] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates, such as wild animals, domesticated animals, and livestock.

[0084] As used herein, the term "aryl" means a monocyclic, bicyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon. In some embodiments, the 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, [Chemical formula] [Chemical formula] include.

[0085] As used herein, the term "arylalkyl" means a C 1~6 alkyl substituted by aryl.

[0086] As used herein, the term "arylamino" means an amino group substituted by an aryl group. An example of arylamino is -NH(phenyl).

[0087] As used herein, the term "arylene" means an aryl linking group, i.e., an aryl group that links one group to another group in a molecule.

[0088] The term "carbamate" is recognized in the art and the group [Chemical formula] (wherein R 29 and R 30 each independently represents hydrogen or a hydrocarbyl group, e.g., an alkyl group, or R 29 and R 30 together with the intervening atoms complete a heterocyclic ring having 4 to 8 atoms in the ring structure).

[0089] As used herein, the term "carbamoyl" means -C(=O)NH2.

[0090] As used herein, the term "carbocycle" means a 5- or 6-membered saturated or unsaturated cyclic ring optionally containing O, S or N atoms 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.

[0091] The term "carbocyclic alkyl" as used herein refers to an alkyl group substituted with a carbocyclic group.

[0092] The term "carbonate" is recognized in the art and refers to the group -OCO2-R 30 (wherein R 30 represents a hydrocarbyl group).

[0093] The term "carboxy" as used herein refers to the group represented by the formula -CO2H.

[0094] As used herein, the term "carrier" means a diluent, adjuvant or excipient administered with a compound. A pharmaceutical carrier can be a liquid, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. A pharmaceutical carrier can also be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants can be used.

[0095] As used herein, the term "compound" means all stereoisomers, tautomers and isotopes of the compounds described herein.

[0096] As used herein, the term "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") is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0097] As used herein, the term "contacting" means bringing two elements together in an in vitro or in vivo system. For example, "contacting" a GlyT1 transporter inhibitor with the GlyT1 transporter of an individual or patient or cell includes not only administering the compound to the individual or patient, e.g., a human, but also introducing the compound into a sample containing, e.g., a cell preparation containing the GlyT1 transporter or a purified preparation.

[0098] As used herein, the term "cyano" means -CN.

[0099] As used herein, the term "cycloalkyl" means a non-aromatic cyclic hydrocarbon and includes cyclic alkyl, alkenyl, and alkynyl groups containing up to 20 ring-forming carbon atoms. The cycloalkyl group may include monocyclic or polycyclic ring systems, such as fused ring systems, bridged ring systems, and spiro ring systems. In some embodiments, the polycyclic ring system includes 2, 3, or 4 fused rings. The cycloalkyl group 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. The ring-forming carbon atoms of the cycloalkyl group can be optionally substituted by oxo or sulfide. 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, etc. Also included in the definition of cycloalkyl is a moiety having one or more aromatic rings fused to the cycloalkyl ring (having a bond common to the cycloalkyl ring), such as benzo or thienyl derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-one-1-yl).

[0100] As used herein, the term "cycloalkylalkyl" means a C 1~6 alkyl substituted by cycloalkyl.

[0101] As used herein, the term "dialkylamino" means an amino group substituted by two alkyl groups each having 1 to 6 carbon atoms.

[0102] As used herein, the term "diazamino" means -N(NH2)2.

[0103] The term "ester", as used herein, means the group -C(O)OR 30(wherein, R 30 represents a hydrocarbyl group).

[0104] The term "ether", as used herein, refers to a hydrocarbyl group linked through oxygen to another hydrocarbyl group. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether can be either symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. An ether includes an "alkoxyalkyl" group, which can be represented by the general formula alkyl-O-alkyl.

[0105] As used herein, the terms "apparently amphiphilic" or "surface amphiphilic" mean a compound having polar and nonpolar side chains that adopt a conformation that results in the separation of polar (hydrophilic) and nonpolar (hydrophobic) side chains on opposite faces or separate regions of the structure or molecule.

[0106] As used herein, the term "glycine transporter" or "GlyT" refers to a membrane protein that facilitates the transport of glycine across the cell membrane of a cell. Non-limiting examples of glycine transporters include glycine transporter 1 (GlyT1) and glycine transporter 2 (GlyT2).

[0107] As used herein, the term "GlyT1" or "GlyT1 transporter" means the sodium and chloride-dependent glycine transporter 1, also known as glycine transporter 1, which in humans is the 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 hereby incorporated by reference in their entirety.

[0108] As used herein, the terms "GlyT2" or "GlyT2 transporter" mean the sodium- and chloride-dependent glycine transporter 2, also known as glycine transporter 2, which in humans is the 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 hereby incorporated by reference in its entirety.

[0109] As used herein, the term "GlyT1 inhibitor" means a compound that inhibits or blocks the activity of the GlyT1 transporter and includes 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, which means that the inhibitor has a higher inhibitor activity against GlyT1 compared to GlyT2. In some embodiments, the inhibitor has a selectivity of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% for inhibiting GlyT1 compared to GlyT2. In some embodiments, the GlyT1 inhibitor inhibits GlyT1 but does not inhibit or significantly inhibit the activity of GlyT2. A GlyT1 inhibitor that does not significantly inhibit the activity of GlyT2 inhibits the activity of GlyT2 by less than 5%, 4%, 3%, 2% or 1% in that case. The selectivity of the GlyT1 inhibitor is determined based on assays known in the art, for example, the assays described in published academic papers (B. N. Atkinson, S. C. Bell, M. De Vivo, L. R. Kowalski, S. M. Lechner, V. I. Ognyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and M. A. Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is hereby incorporated by reference in its entirety.

[0110] As used herein, the term "GlyT2 inhibitor" means a compound that inhibits or blocks the activity of the GlyT2 transporter and includes compounds that inhibit the activity of any isoform of GlyT2. In some embodiments, the GlyT2 inhibitor is a non-specific inhibitor, which means that it can also inhibit or block the activity of GlyT1. In some embodiments, the GlyT2 inhibitor is a specific GlyT2 inhibitor, which means that the inhibitor has a higher inhibitor activity against GlyT2 compared to GlyT1. In some embodiments, the inhibitor has a selectivity of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% compared to GlyT1, or inhibits GlyT2 with a selectivity of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%. In some embodiments, the GlyT2 inhibitor inhibits GlyT2 activity but does not inhibit or significantly inhibit the activity of GlyT1. A GlyT2 inhibitor that does not significantly inhibit the activity of GlyT1 inhibits the activity of GlyT1 by less than 5%, 4%, 3%, 2% or 1% in that case. The selectivity of the GlyT2 inhibitor is determined based on assays known in the art, for example, assays based on those described in published academic papers (B. N. Atkinson, S. C. Bell, M. De Vivo, L. R. Kowalski, S. M. Lechner, V. I. Ognyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and M. A. Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is hereby incorporated by reference in its entirety.

[0111] As used herein, the term "guanidino" means -NH(=NH)NH2.

[0112] As used herein, the term "halo" means a halogen group and includes, without limitation, fluoro, chloro, bromo and iodo.

[0113] As used herein, the term "haloalkoxy" means an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0114] As used herein, the term "haloalkyl" means a C alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, without limitation, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like. 1~6 alkyl group. Examples of haloalkyl groups include, without limitation, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.

[0115] As used herein, the term "heteroaryl" means an aromatic heterocyclic ring having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which is independently sulfur, oxygen or nitrogen. In some embodiments, the 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, the heteroaryl group contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the 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), pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, 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, phenoxazinyl groups and the like.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.

[0116] As used herein, the term "heteroarylalkyl" means a C 1~6 alkyl group substituted by a heteroaryl group.

[0117] As used herein, the term "heteroarylamino" means an amino group substituted by a heteroaryl group. An example of heteroarylamino is -NH-(2-pyridyl).

[0118] As used herein, the term "heteroarylene" means a heteroaryl linking group, i.e., a heteroaryl group that links one group to another group in a molecule.

[0119] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0120] As used herein, the term "heterocyclic ring" or "heterocyclic ring system" means a monocyclic or bicyclic 5- to 7-membered, or a bicyclic 7- to 10-membered heterocyclic ring system, where any ring thereof may be saturated or unsaturated, which is composed of carbon atoms and 1 to 3 heteroatoms selected from N, O and S, wherein the N and S heteroatoms may optionally be oxidized, the N heteroatoms may optionally be quaternized, and includes any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. Rings containing one oxygen or sulfur, 1 to 3 nitrogen atoms, or one oxygen or sulfur in combination with 1 or 2 nitrogen atoms are particularly useful. The heterocyclic ring may be bonded by any heteroatom or carbon atom, which 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-oxazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and oxadiazolyl. Morpholino is the same as morpholinyl.

[0121] As used herein, the term "heterocycloalkyl" means a non-aromatic heterocyclic ring having up to 20 ring-forming atoms, including a cyclized alkyl group, alkenyl group, and alkynyl group, where one or more ring-forming carbon atoms are replaced by heteroatoms such as O, N, or S atoms. A heterocycloalkyl group can be monocyclic or polycyclic (e.g., fused, bridged, or spiro). In some embodiments, the heterocycloalkyl group has 1 to 20 carbon atoms, or 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, etc. In addition, the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfide. For example, a ring-forming S atom can be substituted by 1 or 2 oxo (forming S(O) or S(O)2). For another example, a ring-forming C atom can be substituted by oxo (forming a carbonyl).Also, a moiety having one or more aromatic rings fused to a non-aromatic heterocyclic ring (having a bond common to the non-aromatic heterocyclic ring) is included in the definition of heterocycloalkyl, and includes, but is not limited to, heterocyclic pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives such as indene, isoindene, 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-3-yl groups. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted by oxo or sulfide as needed.

[0122] As used herein, the term "heterocycloalkylalkyl" refers to a C 1~6 alkyl substituted by heterocycloalkyl.

[0123] As used herein, the term "hydroxy" or "hydroxyl" means an -OH group.

[0124] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" means an alkyl group substituted by a hydroxyl group. Examples of hydroxyalkyl include, but are not limited to, -CH2OH and -CH2CH2OH.

[0125] As used herein, the terms "individual" or "patient," used interchangeably, mean any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates such as humans.

[0126] As used herein, the phrase "inhibitory activity," e.g., enzyme or transporter activity, means reducing the activity of an enzyme or transporter, e.g., the GlyT1 transporter, by any measurable amount.

[0127] As used herein, the phrase "in need thereof" means that an animal or mammal is identified as having a need for a particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. For any of the methods and treatments described herein, an animal or mammal may be in need thereof. In some embodiments, the animal or mammal is in, or is progressing into, an environment where a particular disease, disorder or condition is prevalent.

[0128] As used herein, the phrase "gelatable in situ" means not only a low-viscosity liquid that forms a gel upon contact with the eye or tear fluid outside the eye, but also more viscous liquids such as semi-fluid and thixotropic gels that exhibit a substantial increase in viscosity or gel firmness upon administration to the eye.

[0129] As used herein, the phrase "an integer from X to Y" means any integer including the endpoints. For example, the phrase "an integer from X to Y" means 1, 2, 3, 4 or 5.

[0130] The term "lower", when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, means a group having 10 or fewer non-hydrogen atoms, preferably 6 or fewer non-hydrogen atoms, in the substituent. "Lower alkyl" refers to an alkyl group containing, for example, 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, whether they appear alone or in combination with other substituents, for example, in the description, where hydroxyalkyl and aralkyl (in this case, for example, when counting carbon atoms in the alkyl substituent, atoms within the aryl group are not counted), the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents as defined herein are each a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively.

[0131] As used herein, the term "mammal" means a rodent (i.e., mouse, rat or guinea pig), monkey, cat, dog, cow, horse, pig or human. In some embodiments, the mammal is a human.

[0132] 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,

Chemical formula

[0133] As used herein, the term "nitro" means -NO2.

[0134] As used herein, the term "n-membered" (where n is an integer) typically refers to 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.

[0135] As used herein, the phrase "ophthalmically acceptable" means having no persistent adverse effects on the treated eye or its function, or on the overall health of the subject being treated. However, transient effects such as mild irritation or a "stinging" sensation are common with topical instillation of drugs, and the presence of such transient effects will be recognized as not inconsistent with a composition, formulation or ingredient (e.g., excipient) being "ophthalmically acceptable" as defined herein.

[0136] As used herein, the phrase "optionally substituted" means that a 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 substitution results in a stable compound. For example, if a methyl group is optionally substituted, the three hydrogen atoms on the carbon atom can be replaced with substituents.

[0137] As used herein, the phrase "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, more specifically humans.

[0138] "Pharmaceutically acceptable salts" are intended to mean salts of the free acids or free bases of the compounds represented herein that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. Generally, see S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are free of excessive toxicity, irritation, or allergic response, are pharmacologically effective, and are suitable for contact with the tissues of a subject. The compounds described herein can have sufficient acidic groups, sufficient basic groups, both types of functional groups, or more than one of each type, and can thus react with several inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0139] For compounds described herein that contain basic groups such as amines, pharmaceutically acceptable salts can be prepared by treatment of the free base with any suitable method available in the art, such as inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphorous acid, etc., or 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, pyranosidic acids, such as glucuronic acid or galacturonic acid, alpha-hydroxy acids, such as mandelic acid, citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acids, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any suitable mixture of acids shown as examples herein, and any other acids and mixtures thereof considered to be equivalents or acceptable substitutions in view of the ordinary level of skill in the art.

[0140] For the compounds described herein containing acidic groups such as carboxylic acid groups, base addition salts can be prepared by treating such compounds with a sufficient amount of a desired base in any suitable method available in the art, for example, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts of lithium, sodium, potassium, calcium, ammonium, zinc or magnesium, or other metal salts; organic amino salts such as alkyl, dialkyl, trialkyl or tetraalkylammonium salts.

[0141] Other examples of pharmaceutically acceptable salts include, but are not limited to, camphorsulfonate, 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-dioate, 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. An enumeration of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0142] The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound in a 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 the purposes of this application.

[0143] As used herein, the term "phenyl" means -C6H5. The phenyl group may be unsubstituted or substituted with one, two or three suitable substituents.

[0144] The terms "polycyclic", "polycycle" and "polycyclic ring system" 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 polycyclic rings may be substituted or unsubstituted. In certain embodiments, each of the polycyclic rings contains from 3 to 10 atoms, preferably from 5 to 7 atoms in the ring.

[0145] As used herein, the term "prodrug" means a derivative of a known direct-acting drug, which derivative has enhanced delivery characteristics and therapeutic value compared to the drug and is converted to the active drug by an enzymatic or chemical process. A common method for making prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to yield the desired molecule. In certain embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, a prodrug having a nitro group on an aromatic ring can be reduced by reductase in vivo to yield the desired amino group of the corresponding active compound. In another example, a functional group such as a hydroxyl, carbonate, or carboxylic acid in the parent compound is present as an ester, which can be cleaved by an esterase. In addition, an amine group in the parent compound is present in carbamate, N-alkylated, or N-acylated forms, among others (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 represented above can be replaced with the corresponding suitable prodrugs.

[0146] As used herein, the term "purified," when isolated, means that the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of the compound described herein, by weight of the isolate.

[0147] As used herein, the phrase "quaternary ammonium salt" is a derivative of a disclosed compound having one or more tertiary amine moieties, where at least one tertiary amine moiety in the parent compound is alkylated (and the cation is Cl - , CH3COO - and CF3COO -(counterbalanced by anions such as), for example, modified by converting a tertiary amine moiety to a quaternary ammonium cation via methylation or ethylatation.

[0148] As used herein, the term "semicarbazone" means =NNHC(=O)NH2.

[0149] As used herein, the phrase "solubilizing agent" means an agent that results in the formation of a micellar solution or true solution of a drug.

[0150] As used herein, the term "solution / suspension" means a liquid composition in which a first portion of the active agent is present in solution and a second portion of the active agent is present in a suspension in a liquid matrix in a particular form.

[0151] 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.

[0152] The term "substituted" refers to a moiety having a substituent that replaces one or more hydrogens on one or more carbons of the backbone. It is understood that the terms "substituted" or "substituted with" are implied, provided that such substitution follows the accepted valences of the atoms and substituents being substituted and that the substitution results in a stable compound that does not undergo spontaneous conversion, such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all acceptable substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Acceptable substituents can be one or more and can be the same or different for a suitable organic compound. For the purposes of this application, a heteroatom such as nitrogen can have a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of the heteroatom.

[0153] Examples of substituents 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, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. One of ordinary skill in the art will understand that a substituent can itself be substituted where appropriate. Unless specifically stated as "unsubstituted", references herein to chemical moieties are understood to include substituted variants. For example, a reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0154] The term "sulfate" is recognized in the art and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0155] The term "sulfonamide" is recognized in the art and has the general formula [Chemical Formula] (wherein R 29 and R 30 each independently represents hydrogen or hydrocarbyl, such as alkyl, or R 29 and R 30 together with the intervening atoms complete a heterocyclic ring having 4 to 8 atoms in the ring structure) refers to a group represented by.

[0156] The term "sulfoxide" is recognized in the art and refers to the group -S(O)-R 30 (wherein R 30 represents hydrocarbyl).

[0157] The term "sulfonate" is recognized in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0158] The term "sulfone" is recognized in the art and refers to the group -S(O)2-R 30 (wherein R 30 represents hydrocarbyl).

[0159] As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response required by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or human. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, the therapeutic effect can be a reduction in the severity of the symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or can improve the treatment, cure, prevention or elimination of the disorder or side effects. The amount required to elicit a therapeutic response can be determined based on the age, health, size and gender of the subject. The optimal amount can also be determined based on monitoring the response of the subject to the treatment.

[0160] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0161] As used herein, the term "thioester" refers to the group -C(O)SR 30 or -SC(O)R 30 (wherein R 30 represents a hydrocarbyl).

[0162] As used herein, the term "thioether" is the equivalent of an ether in which oxygen is replaced by sulfur.

[0163] As used herein, the terms "treat", "treated" or "treating" mean both therapeutic treatment and prophylactic measures, where the goal is to delay (reduce) an undesired physiological condition, disorder or disease, or to obtain a beneficial clinical outcome or a desired clinical outcome. Beneficial clinical outcomes or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder or disease; stabilization of the condition, disorder or disease (i.e., does not worsen); delay or deceleration in the onset of progression of a condition, disorder or disease; recovery or remission (whether partial or total) of a condition, disorder or disease, whether detectable or not; recovery of at least one measurable physical parameter not necessarily recognized by the patient; or enhancement or improvement of a condition, disorder or disease. Treatment includes inducing a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to survival expected in the absence of treatment. Thus, "treatment of erythropoietic protoporphyria" or "treating erythropoietic protoporphyria" means an activity that reduces or restores either the primary phenomenon or secondary symptoms associated with erythropoietic protoporphyria or other conditions described herein.

[0164] The term "urea" is recognized in the art and has the general formula [Chemical formula] (wherein R 29 and R 30 each independently represents hydrogen or hydrocarbyl, such as alkyl, or the occurrence of R 29 together with R 30 and intervening atoms completes a heterocyclic ring having 4 to 8 atoms in the ring structure) can be represented by.

[0165] At various places in this specification, substituents of compounds may be disclosed in groups or ranges. It is specifically intended that embodiments include each and all individual subcombinations of the members of such groups and ranges. For example, the term "C 1~6 alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0166] For compounds in which a variable appears more than once, each variable can be a different moiety selected from the Markush groups that define the variable. For example, if a structure is described as having two R groups present simultaneously in the same compound, the two R groups can represent different moieties selected from the Markush group defined for R. In another example, where multiple substituents are specified, for example, [Chemical formula] in the form of, it is understood that the substituent R can appear s times on the ring and that R can be a different moiety in each occurrence. In the above example, if the variable T 1 is defined to include hydrogen, for example, when T 1 is CH2, NH, etc., any H can be replaced by a substituent.

[0167] It is further recognized that certain features described herein in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features described in the context of a single embodiment for brevity can also be provided separately or in any suitable sub-combination.

[0168] It is understood that this embodiment includes, where applicable, the use of stereoisomers, diastereomers, and optical stereoisomers of the compound, and mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compound, and mixtures thereof, are within the scope of the embodiment. By way of non-limiting example, the mixture may be a racemate or the mixture may contain one particular stereoisomer in a proportion that is not equivalent to the others. Additionally, the compound can be provided as a substantially pure stereoisomer, diastereomer, and optical stereoisomer (such as an epimer).

[0169] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiment unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active form or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers, such as olefins, C=N double bonds, etc., can also be present in the compounds described herein, and all such stable isomers are provided herein. The cis and trans geometric isomers of the compound are also included within this embodiment 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 specific reference to an R / S or cis / trans configuration, it is intended that all such isomers are contemplated.

[0170] In some embodiments, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure, which means 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 completely in the form of one enantiomer over 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% compared to the amount of the other enantiomer in, for example, the 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.

[0171] 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% compared to the amount of the other enantiomer in, for example, the 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.

[0172] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolution acid, which is an optically active organic acid that forms an optically active salt. Suitable resolving agents for the fractional recrystallization method include, but are not limited to, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable resolving agents for the fractional crystallization method include, but are not limited to, α-methylbenzylamine in a stereoisomerically pure form (e.g., S and R forms, or diastereomerically pure form), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. The resolution of the racemic mixture can also be carried out by elution in a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of the suitable elution solvent can be determined by those skilled in the art.

[0173] The compound may also contain tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond, along with the movement of a proton. Tautomeric forms include prototropic tautomers, which are protonation states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms where two or more positions in 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, can be occupied by a proton. Tautomeric forms can be in equilibrium or can be stereochemically fixed in one form by appropriate substitution.

[0174] Glycine transporter inhibitors, e.g., GlyT1 inhibitors, including their pharmaceutically acceptable salts (e.g., GlyT1 inhibitors disclosed herein), can also exist as hydrates and solvates, as well as in anhydrous and unsolvated forms. A "hydrate" is a compound that exists as a composition with water molecules. The composition can include a stoichiometric amount of water, e.g., a monohydrate or dihydrate, or can include a non-stoichiometric amount of water. A "solvate" is a similar composition except that a solvent other than water, e.g., methanol, ethanol, dimethylformamide, diethyl ether, etc., replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. Mixtures of such solvates or hydrates can also be prepared. The origin of such solvates or hydrates can be from the crystallization solvent, inherent in the preparation or crystallization solvent, or an adjunct of such a solvent.

[0175] The compounds of the present application can exist in various polymorphic, pseudopolymorphic, or amorphous states, including their pharmaceutically acceptable salts and prodrugs. As used herein, the term "polymorph" refers to different crystalline forms of the same compound, as well as other solid-state molecular forms such as hydrates, solvates, or salts of the same compound, i.e., pseudopolymorphs. Different crystalline polymorphs have different crystal structures due to different packings of the 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, e.g., X-ray diffraction characteristics, stability, melting point, solubility, or rate of dissociation in a particular solvent. Therefore, the form of crystalline polymorphs is an important aspect in the development of suitable dosage forms in the pharmaceutical industry.

[0176] Compounds can also include atoms of all isotopes that occur in the intermediate or final compound. Isotopes include atoms that have the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0177] In some embodiments, the compound or a salt thereof is substantially isolated. Partial separation may include, for example, a composition enriched in 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 a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0178] While 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 aromatic rings can affect the geometric pattern of the compound and can be substituted as needed or this distance can be altered by introducing aliphatic chains of different lengths that may contain amino acids, dicarboxylic acids or diamines. The distance between monomers within the compound and their relative orientation can also be altered by replacing the amide bond with a surrogate having additional atoms. Thus, replacement of the carbonyl group by a dicarbonyl changes the distance between monomers and the tendency of the dicarbonyl unit to select an anti-configuration for the two carbonyl moieties, changing the periodicity of the compound. Pyromellitic dianhydride represents yet another alternative to the simple amide linkage, which can alter the conformation and physical properties of the compound. Recent methods of solid-phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) enable here the synthesis of homodisperse compounds having a molecular weight approaching 5,000 daltons. Other substitution patterns are equally effective.

[0179] The compounds also include derivatives referred to as prodrugs.

[0180] Compounds containing an amine functional group can also form N-oxides. References herein to compounds containing an amine functional group include N-oxides as well. 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 N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).

[0181] Thus, by reserving the right to append a proviso to, or exclude from, any individual member of any such group that includes any subrange or combination of subranges within the group, this can be claimed in accordance with the range, or in any similar manner, and less than the full measure of the present disclosure can be claimed for any reason. Further, thus, by reserving the right to append a proviso to, or exclude from, any individual substituent, analog, compound, ligand, structure or group thereof, or any member of the group recited in the claims, less than the full measure of the present disclosure can be claimed for any reason. Throughout the present disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art known to those of ordinary skill in the art as of the date of the present disclosure. In the event of any inconsistencies between the cited patents, patent applications and publications and the present disclosure, the present disclosure shall control.

[0182] For the sake of brevity, certain terms used in this specification, the examples and the claims are collected herein. 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 pertains.

[0183] Embodiments of various compounds and their salts are provided. Where a variable is not specifically recited, the variable can be any of the options described herein, except as otherwise recited or indicated by context.

[0184] In some embodiments, the compound is as described in the appended exemplary and non-limiting claims, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0185] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0186] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0187] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0188] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical Formula

[0189] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0190] or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

Chemical formula

[0191] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0192] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0193] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0194] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0195] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] is a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] [wherein, A represents a group of general formula N-R1, a group of general formula N+(O-)R1 or a group of general formula N+(R’)R1 (wherein, R1 represents a hydrogen atom, or a linear or branched (C1-C7) alkyl group optionally substituted with one or more fluorine atoms, or a (C4-C7) cycloalkyl group, or a (C3-C7) cycloalkyl(C1-C3)alkyl group, or a phenyl(C1-C3)alkyl group optionally substituted with one or two hydroxyl groups or methoxy groups, or a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group); R’ represents a linear or branched (C1-C7) alkyl group); X represents a hydrogen atom, or one or more substituents selected from a halogen atom and a trifluoromethyl, linear or branched (C1-C4) alkyl, and (C1-C4) alkoxy group; R2 represents a hydrogen atom, or one or more substituents selected from a halogen atom and a trifluoromethyl, (C1-C4) alkyl group or (C1-C4) alkoxy group, or an amino group of the general formula NR3R4 (wherein R3 and R4 each independently represent a hydrogen atom or a (C1-C4) alkyl group, or together with the nitrogen atom they carry, form a pyrrolidine ring, a piperidine ring or a morpholine ring, or a phenyl group optionally substituted with an atom or group defined for the above symbol X); is a compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0198] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor has the formula

Chemical formula

[0199] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] A compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] [In the formula, R 1 is phenyl independently substituted 1 to 5 times with halogen, C1-C3 alkyl, C3-C6 cycloalkyl, OR 9 or SR 10 wherein C1-C3 alkyl and C3-C6 cycloalkyl are optionally substituted 1 to 10 times with R 7 ; R 2 is H; R 3 and R4 are each independently H or CH3; R 5 is (1) hydrogen, (2) C1-C6 alkyl optionally substituted 1 to 11 times with R 7 , (3) gem-dialkyl, and (4) gem-dihalo selected from the group consisting of; or Two R 5 substituents on the same carbon, together with the carbon atom to which they are attached, form R 7may form a 3-, 4- or 5-membered cycloalkyl optionally substituted 1 to 10 times; or two Rs on adjacent carbons of the ring to which they are attached 5 the substituents may, together, form a 3-, 4-, 5- or 6-membered cycloalkyl optionally substituted 1 to 10 times with R 7 ; R 6 is [Chemical formula] (wherein E, F, and G are each independently nitrogen or carbon, and R 6a is C1-C2 alkyl optionally substituted 1 to 5 times with halogen or deuterium); R 7 is (1) hydrogen, (2) halogen, (3) deuterium, (4) gem-dialkyl, (5) gem-dihalo, (6) -OR 9 , -NR 11 R 12 , -NR 11 C(O) p R 10 , -S(O) p R 10 , -CN, -NO2, -C(O) p R 10 , -C(O)NR 11 R 12 or NR 11 C(S)R 10 , and (7) oxo or thio selected from the group consisting of; R 8 is (1) hydrogen, (2) halogen, (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C4-C7 cycloalkylalkyl (Here, each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl is independently substituted 7 1 to 11 times as needed with R (4)-OR 9 , -NR 11 R 12 , -NR 11 C(O) p R 10 , -S(O) p R 10 , -CN, -NO2, -C(O) p R 10 , -C(O)NR 11 R 12 or -NR 11 C(S)R 10 selected from the group consisting of; R 9 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10 , where each of C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl is substituted 1 to 11 times as needed with R 7 ; R 10 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, where each of C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl is substituted 1 to 11 times as needed with the substituents defined in R7, and aryl or heteroaryl is substituted 1 to 10 times as needed with R 8 ; R 11 and R 12is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein each of C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl is optionally substituted 1 to 11 times with a substituent defined in R 7 and aryl or heteroaryl is optionally substituted 1 to 10 times with R 8 or R 11 and R 12 together with the nitrogen to which they are attached form a saturated or partially saturated monocyclic or fused bicyclic heterocyclic ring optionally substituted 1 to 11 times with R 7 ; A is

Chemical formula

[0201] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0202] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0203] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0204] In certain embodiments, the compound of formula IX is of formula IX(a):

Chemical formula

[0205] In certain embodiments, the compound of formula IX is of formula IX(b):

Chemical formula

[0206] In certain embodiments, the compound of formula IX is a compound selected from any of the following, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0207] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical] [wherein, 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 9- or 10-membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) r (wherein r is 0, 1 or 2) (In the formula, r is 0, 1 or 2) selected from the group consisting of; wherein each of said groups a), b) and c) is optionally substituted with one or more substituents independently 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-, and when there are substituents, they are attached to a nitrogen ring atom, and said substituents are C 1~4 -alkyl-, C 1~4 -alkyl-CO-, C 3~6 -cycloalkyl- and C 3~6 -cycloalkyl-CO-, selected from the group consisting of, wherein each of said 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 -cycloalkyl-O- substituents may each be substituted with one or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 2 is hydrogen, C 1~4 -alkyl-, C1~4 -Alkyl-O-, -CN and C 3~6 -Cycloalkyl- selected from the group consisting of; wherein said C 1~4 -Alkyl-, C 1~4 -Alkyl-O- and C 3~6 -Each of the cycloalkyl groups may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 3 is C 1~6 -Alkyl-O-, C 3~6 -Cycloalkyl-O-, morpholino, pyrazolyl, and a 4- to 7-membered monocyclic heterocycloalkyl-O- having 1 or 2 heteroatoms independently selected from the group consisting of 1 oxygen atom and optionally O, N and S(O) s (where s = 0, 1 or 2), selected from the group consisting of; wherein said C 1~6 -Alkyl-O- and said C 3~6 -Cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -Alkyl-, C 3~6 -Cycloalkyl-, C 1~6 -Alkyl-O- and C 3~6 -Cycloalkyl-O-; R 4 is hydrogen; or R 3 and R 4 together with the ring atoms of the phenyl group to which they are attached, may form a 4-, 5- or 6-membered monocyclic partially saturated heterocycloalkyl, or a heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) s (where s = 0, 1 or 2), and in general formula (I), R 3There must be one ring oxygen atom directly bonded to the ring carbon atom of the phenyl group to which it is attached; Here, the heterocycloalkyl group may optionally be substituted with one, two, three or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 3~6 -cycloalkyl-, C 1~6 -alkyl-O-, C 3~6 -cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-; R 5 is hydrogen; R 6 is hydrogen, C 1~4 -alkyl-SO2-, C 3~6 -cycloalkyl-SO2 and -CN; R 7 is hydrogen or a) R 6 and R 7 or b) R 6 and R 5 together with the ring atoms of the phenyl group to which they are attached form a 5- or 6-membered partially saturated monocyclic heterocycloalkyl group having one, two or three heteroatoms independently selected from the group consisting of O, N and S(O) u (where u = 0, 1 or 2), provided that in general formula (I) there must be one -SO2- atom directly bonded to the ring carbon atom of the phenyl group to which R 6 is attached, Here, the heterocycloalkyl group may optionally be substituted with one, two, three or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 1~6 -alkyl-O- and C 3~6 -cycloalkyl-O-] A compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0208] 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 pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0209] For example, the compound of formula X can be a mixture of diastereomers or a single diastereomer of any of the following, or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0210] In certain methods and uses disclosed herein, the subject is the subject in need thereof.

[0211] In some embodiments of the uses and methods disclosed herein, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.

[0212] In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is selected from the compounds described herein. Any of the compounds provided herein can be prepared as a pharmaceutically acceptable salt, solvate or prodrug and / or as part of a pharmaceutical composition described in the patents or patent application publications cited herein.

[0213] The compounds described herein may exhibit a particular stereochemistry, e.g., cis or trans, around certain atoms, but the compounds can also be made in the reverse orientation or as a racemic mixture. Such isomers or racemic mixtures are encompassed by the present disclosure. In addition, the compounds are presented in a table, but any compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be selected from the table and used in the embodiments provided herein.

[0214] The compounds described herein can be made according to the methods described in the patents or patent application publications cited herein.

[0215] The compounds can be used to inhibit the GlyT1 transporter. Thus, in some embodiments, the compounds can be referred to as compounds that inhibit the GlyT1 transporter or GlyT1 inhibitors.

[0216] The compounds described herein can be administered in any conventional manner by any route by which they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual or ophthalmic routes, or intravaginal, by inhalation, by depot injection, or by implant. The method of administration can depend on the target or the condition or disease being treated. The specific choice of route of administration can be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.

[0217] In some embodiments, it may be desirable to administer one or more compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof, locally to the area in need of treatment. This can be achieved, for example, but not limited to, by local injection during surgery, by topical application, for example, in combination with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, where the implant is of a porous, non-porous or jelly-like material containing a membrane such as a silicone membrane, or fibers.

[0218] The compounds described herein can be administered either alone or in combination with other pharmaceuticals (either together or sequentially). For example, the compounds can be administered in combination with other drugs for the treatment of, for example, EPP, XLPP or CEP. Examples of other pharmaceuticals or medicaments are known to those of skill in the art and include, but are not limited to, those described herein.

[0219] Means and methods for administration are known in the art, and the skilled person can refer to various pharmacological references for guidance (see, for example, 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)).

[0220] The amount of the compound administered is a therapeutically effective amount. The dosage administered depends on the characteristics of the subject being treated, such as the particular animal being treated, age, weight, health, if any, the type of co-treatment, and the frequency of treatment, and can be readily determined by one of ordinary skill in the art (e.g., by a clinician). Standard dosages for protamine can be used and adjusted (i.e., increased or decreased) according to the above factors. The selection of a specific dosing regimen can be selected, adjusted, or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response.

[0221] The amount of the compounds described herein that are effective in the treatment and / or prevention of a particular disease, condition or disorder depends on the nature and extent of the disease, condition or disorder and can be determined by standard clinical techniques. Additionally, in vitro or in vivo assays may be used as needed to assist in identifying the optimal dosage range. The exact dosage to be used in the composition also depends on the route of administration and the severity of the disorder and should be determined according to the judgment of the practicing physician and the circumstances of each patient. 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 dosage is about 5 milligrams per kilogram of body weight.

[0222] In some embodiments, suitable dosage ranges for intravenous (i.v.) 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 ordinary skill in the art. For example, recommended dosages for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration, or administration by inhalation are in 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. The effective dosage may be extrapolated from a dose-response curve derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.

[0223] The compounds described herein can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. In some embodiments, the compounds can be administered by subcutaneous continuous infusion over a period of about 15 minutes to about 24 hours. Formulations for injection can be present in unit dosage forms, for example, in ampoules or multiple-dose containers, with preservatives added as required. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. In some embodiments, the injectable substance is in the form of an immediate-release, depot, or implant form, and in the form of pellets to be injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is in the form of a solution, suspension, emulsion, or dry powder.

[0224] For oral administration, the compounds described herein can be formulated by combining the compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compound to be formulated as tablets, pills, dragees, capsules, emulsions, solutions, gels, syrups, cachets, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, etc. for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained, for example, by adding solid excipients, optionally grinding the resulting mixture, and then treating the mixture of granules, optionally adding suitable auxiliaries, to obtain the core of tablets or dragees. Suitable excipients include, but are not limited to, bulking agents such as sugars including, but not limited to, lactose, sucrose, mannitol and sorbitol; cellulose preparations such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP). Optionally, disintegrants such as, but not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added.

[0225] Oral compositions can contain one or more optional agents, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide pharmaceutically palatable preparations. Also, in the form of tablets or pills, the composition may be coated to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a long period. A selective permeable membrane surrounding an osmotically active driving compound is also suitable for compounds administered orally. Oral compositions can include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.

[0226] The core of the dragee can be provided with a suitable coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, as well as suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the coating of the tablets or dragees to identify or characterize different combinations of the doses of the active compound.

[0227] Pharmaceutical preparations that can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and plasticizers, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with bulking agents, such as lactose, binders, such as starch, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added.

[0228] For buccal administration, the composition can take the form of, for example, tablets or lozenges formulated in a conventional manner.

[0229] For administration by inhalation, the compounds described herein can be delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a mixture of the compound and a suitable powder base, such as lactose or starch.

[0230] The compounds described herein can also be formulated into rectal compositions, such as suppositories or retention enemas, containing, for example, conventional suppository bases, such as cocoa butter or other glycerides. The compounds described herein can also be formulated into vaginal compositions, such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine contraceptive devices.

[0231] For transdermal administration, the compound can be applied to a patch or can be applied by a transdermal therapeutic system that results in delivery to the organism. In some embodiments, the compound is present in or contains creams, solutions, powders, liquid emulsions, liquid suspensions, semi-solids, ointments, pastes, gels, jellies, and foamy substances, or in patches containing any of the foregoing.

[0232] 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 using a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil), or an ion exchange resin, or as a poorly soluble derivative, e.g., as a poorly soluble salt.

[0233] In some embodiments, the compounds can be delivered in a controlled release system. In one embodiment, a pump may 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, a polymeric material 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; also see 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 proximity to the target of the compounds described herein, such as the liver, so that only very small amounts of a systemic dose are required (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 be used.

[0234] It is also known in the art that the compound can be contained in such formulations together with pharmaceutically acceptable diluents, extenders, disintegrants, binders, lubricants, surfactants, hydrophobic media, water-soluble media, emulsifiers, buffers, water-retaining agents, humectants, solubilizers, preservatives, etc. The pharmaceutical composition can also include a suitable solid or gel phase carrier or excipient. 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 can be used in combination with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair) or rinsing agents (e.g., Caphosol).

[0235] In some embodiments, the compounds described herein can be delivered in a medium, particularly in liposomes (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).

[0236] Suitable compositions include, but are not limited to, oral non-absorbable compositions. Suitable compositions also include, but are not limited to, physiological saline, water, cyclodextrin solutions, and buffers at pH 3-9.

[0237] The compounds described in this specification, or pharmaceutically acceptable salts, solvates or prodrugs thereof, can be formulated using a number of excipients including, but not limited to, purified water, propylene glycol, PEG400, glycerin, DMA, ethanol, benzyl alcohol, citric acid / sodium citrate (pH3), citric acid / sodium citrate (pH5), tris(hydroxymethyl)aminomethane HCl (pH7.0), 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.

[0238] In some embodiments, the formulation can be lyophilized to a solid, for example, and reconstituted with water prior to use.

[0239] When administered to a mammal (e.g., to an animal for veterinary use or to a human for clinical use), the compound can be administered in isolated form.

[0240] When administered to a human, the compound can be sterile. When the compounds of Formulas I - VIII are administered intravenously, water is a suitable carrier. Aqueous saline solutions, as well as aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers 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, etc. The composition can also contain, if desired, minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0241] The compositions described herein can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing a liquid, powders, sustained release formulations, suppositories, aerosols, sprays, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A.R. Gennaro (Editor) Mack Publishing Co.

[0242] In some embodiments, the compound is formulated as a pharmaceutical composition adapted for administration to humans according to routine procedures. Typically, the compound is a solution in a sterile, isotonic, aqueous buffer. If necessary, the composition can also contain solubilizing agents. Compositions for intravenous administration may optionally contain a local anesthetic, such as lidocaine, to relieve the pain at the site of injection. Generally, the components are supplied either separately or mixed together, in unit dosage form, for example, as a dry lyophilized powder or an anhydrous concentrate in a sealed container, such as an ampoule or sachet indicating the amount of the active agent. When the compound is administered by infusion, this can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed prior to administration.

[0243] The pharmaceutical composition can be in unit dosage form. In such form, the composition can be divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, a package containing discrete amounts of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be any of the appropriate number of any of these packaged forms.

[0244] In some embodiments, the composition is in liquid form, where the active agent (i.e., one of the surface amphiphilic polymers or oligomers disclosed herein) is present in solution, in 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.

[0245] In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, an ophthalmic composition is a solid article that can be inserted into a suitable location in the eye, such as between the eye and the eyelid or conjunctival sac, where, for example, it releases the active agent as described in U.S. Patent No. 3,863,633; U.S. Patent No. 3,867,519; U.S. Patent No. 3,868,445; U.S. Patent No. 3,960,150; U.S. Patent No. 3,963,025; U.S. Patent No. 4,186,184; U.S. Patent No. 4,303,637; U.S. Patent No. 5,443,505; and U.S. Patent No. 5,869,079. Release from such articles is typically to the cornea, either via the tears that bathe the surface of the cornea or directly to the cornea itself, and the solid article is generally in intimate contact. Suitable solid articles for implantation into the eye in such methods are generally composed primarily of polymers and can be biodegradable or non-biodegradable. Biodegradable polymers that can be used in the preparation of eye implants that carry one or more compounds include, but are not limited to, aliphatic polyesters such as polymers and copolymers of poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate), and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates, and polyether lactones. Suitable non-biodegradable polymers include silicone elastomers.

[0246] The compositions described herein can contain preservatives. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercury salts (e.g., phenylmercury acetate, phenylmercury borate, and phenylmercury 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.

[0247] Optionally, one or more stabilizers can be included in the composition, if necessary, to enhance chemical stability. Suitable stabilizers include, but are not limited to, chelating or complexing agents such as ethylenediaminetetraacetic acid (EDTA), a calcium complexing agent. For example, an appropriate amount of EDTA, or its salt, such as the disodium salt, can be included in the composition to complex excess calcium ions and prevent gel formation during storage. EDTA or its salt can preferably be included in an amount of about 0.01% to about 0.5%. In these embodiments containing preservatives other than EDTA, EDTA or its salt, more specifically disodium EDTA, can be present in an amount of about 0.025% to about 0.1% by weight.

[0248] 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, disodium edetate, sorbic acid, or other agents known to those skilled in the art. Such preservatives are typically used at levels of about 0.001% to about 1.0% by weight.

[0249] In some embodiments, the compound is solubilized, at least in part, by an acceptable solubilizing agent. Certain acceptable nonionic surfactants, such as polysorbate 80, may be useful as solubilizing agents, as well as ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400 (PEG-400), and glycol ethers.

[0250] A preferred solubilizing agent for solutions and solution / suspension compositions is cyclodextrin. 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), and the like. The ophthalmic applications of cyclodextrins are reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.

[0251] In some embodiments, the composition optionally contains a suspending agent. For example, in these embodiments where the composition is an aqueous suspension or solution / suspension, the composition can contain one or more polymers as suspending agents. Useful polymers include, but are not limited to, water-soluble polymers such as cellulose polymers such as hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxy-containing polymers.

[0252] One or more acceptable pH adjusters and / or buffers can be included in the composition, which include 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 amounts necessary to maintain the pH of the composition within an acceptable range.

[0253] One or more acceptable salts, solvents or prodrugs can be included in the composition in the amounts necessary to bring the osmotic pressure of the composition within an acceptable range. Such salts include, but are not limited to, those having sodium, potassium or ammonium cations, and chloride, citrate, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfate, thiosulfate or bisulfate anions. In some embodiments, salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In some embodiments, the salt is sodium chloride.

[0254] Optionally, one or more acceptable surfactants, such as, but not limited to, nonionic 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 nonionic 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); cyclodextrin; or other agents known to those skilled in the art. Typically, such co-solvents or surfactants are used in the composition at levels of about 0.01 wt% to about 2 wt%.

[0255] In some embodiments, there is provided a pharmaceutical pack or kit comprising one or more containers filled with one or more of the compounds described herein. Optionally, associated with such containers may be a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency for manufacture, use or sale for human administration to treat the conditions, diseases or disorders described herein. In some embodiments, the kit contains more than one of the compounds described herein. In some embodiments, the kit comprises a single injectable dosage form, e.g., a single dose of the compounds described herein within an injection device such as a syringe with a needle.

[0256] In some embodiments, the method comprises administering to a subject one or more of the compounds described herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is a subject in need of such treatment. As described herein, in some embodiments, the subject is a mammal, such as, but not limited to, a human.

[0257] In some embodiments, but not limited to, use in the manufacture of a medicament for the treatment of EPP, XLPP or CEP, or related syndromes including the conditions described herein in a subject, such as those described herein, and / or for the prevention of a method of treatment for one or more of the above compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising one or more of the above compounds is also provided. In some embodiments, the subject is a subject in need thereof.

[0258] This embodiment also provides the use of one or more of the above compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising one or more of the above compounds, in the inhibition of a GlyT1 transporter, such as one present on the surface of a cell. In some embodiments, the compound, its pharmaceutically acceptable salt, or its pharmaceutical composition inhibits the internalization, transport and / or degradation of the GlyT1 transporter.

[0259] 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.

[0260] 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.

[0261] Generally, assays for testing compounds that inhibit GlyT1 transporter activity involve determining any parameter, either indirect or direct, under the influence of the GlyT1 transporter, such as a functional, physical, or chemical effect.

[0262] A sample or assay containing the GlyT1 transporter treated with a potential inhibitor is compared to a control sample without the inhibitor to examine the degree of inhibition. The control sample (untreated with 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 approximately 80%, 50%, or 25%.

[0263] Ligand binding to the GlyT1 transporter can be tested in several formats. Binding can be carried out 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 its transporter is measured in the presence of a candidate modulator, such as a compound described herein. Alternatively, the binding of a candidate modulator can be measured in the presence of a natural ligand. Often, a competition assay is used to measure 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) changes, or changes in chromatographic or solubility properties.

[0264] After the transporter is expressed in the cells, the cells can grow in an appropriate medium in an appropriate cell plate. The cells can be seeded, for example, at 5000 - 10000 cells per well in a 384-well plate. In some embodiments, the cells are seeded 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.

[0265] Any pharmaceutical having utility in the applications described herein can be used in combination therapy, co - administration or co - formulation with the above - described compositions. Thus, the compounds described herein can be administered either before, together with, or after such therapeutic agents are administered to a subject.

[0266] Additional pharmaceuticals can be administered in combination therapy (including co - formulations) with one or more compounds described herein.

[0267] In some embodiments, the response of a disease or disorder to treatment is monitored and the treatment regimen is adjusted as needed taking such monitoring into account.

[0268] The frequency of administration typically is such that the period between doses, e.g., 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, the dose is administered 1, 2, 3, or 4 times per day. Appropriate dosing intervals will depend in part on the length of time the selected composition can maintain the concentration of the compound in the subject and / or target tissue (e.g., exceed the EC 50 (minimum concentration of the compound that inhibits the activity of the transporter by 90%)), as will be understood by those skilled in the art. Ideally, the concentration remains above the EC 50 for at least 100% of the dosing interval. If this is not achievable, the concentration should remain above the EC 50 for at least about 60% of the dosing interval, or desirably, remain above the EC 50 for at least about 40% of the dosing interval. Methods of Use

[0269] The present application provides a method for preventing or treating a disorder associated with the accumulation of PPIX in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as a GlyT1 inhibitor disclosed herein. For example, the present application provides a method for preventing or treating a disorder associated with the accumulation of PPIX in a subject, comprising

Chemical formula

[0270] In part, the present disclosure relates to a method of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In certain embodiments, the present disclosure provides a method of preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof. These methods are particularly directed to therapeutic and prophylactic treatment of animals, more specifically, humans. The terms "subject," "individual," or "patient" are interchangeable throughout this specification and refer to either a human or a non-human animal. These terms include mammals such as humans, non-human primates, laboratory animals, domestic animals (including cows, pigs, camels, etc.), companion animals (e.g., dogs, cats, other pet animals, etc.), and rodents (e.g., mice and rats). In certain embodiments, the patient, subject, or individual is a human.

[0271] The present application provides a method for preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, or a related syndrome thereof (e.g., an EPP-related syndrome, an XLPP-related syndrome, or a CEP-related syndrome), the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. The present application further provides a method for preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. For example, the present application provides a method for treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically 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, e.g., one or more GlyT1 inhibitors disclosed herein. For example, the present application provides a method for preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject vitropeltine or a pharmaceutically acceptable salt thereof, or a prodrug of vitropeltine or a pharmaceutically acceptable salt thereof.

[0272] The present application further provides a method for preventing or treating EPP, XLPP or CEP in a subject, or a related syndrome thereof (e.g., an EPP-related syndrome, an XLPP-related syndrome or a CEP-related syndrome), which comprises administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. The present application further provides a method for preventing or treating EPP, XLPP or CEP in a subject, which comprises administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. For example, the present application provides a method for treating EPP, XLPP or CEP in a subject, which comprises administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically 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, e.g., one or more GlyT1 inhibitors disclosed herein. In certain specific embodiments described above, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. For example, the present application provides a method for preventing or treating EPP, XLPP or CEP in a subject, which comprises administering to the subject a pharmaceutical composition comprising vitropeltine or a pharmaceutically acceptable salt thereof, or a prodrug of vitropeltine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0273] Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLPP) are erythropoietic cutaneous porphyrias characterized by acute non-blistering photosensitivity, intolerance to sunlight and a marked reduction in quality of life. EPP is caused by a partial deficiency in ferrochelatase (FECH), which catalyzes the final step in the heme biosynthetic pathway. The deficiency in FECH increases the levels of metal-free erythrocyte PPIX (also referred to herein as "free protoporphyrin IX" and "PPIX"). XLPP is typically caused by a C-terminal deletion in the ALAS2 gene that results in a gain-of-function mutation. These gain-of-function mutations increase the enzymatic activity of ALAS2 and cause the accumulation of both metal-free and zinc-bound PPIX. Both EPP and XLPP result in the accumulation of PPIX in erythrocytes and other tissues or biological fluids (e.g., skin, liver, bile or feces). PPIX, which is lipophilic and excreted via bile, is hepatotoxic at high concentrations.

[0274] Patients with EPP or XLPP typically develop photosensitivity during early childhood. Patients frequently exhibit symptoms of burns, pruritus, pain, erythema and edema in areas exposed to sunlight. Skin symptoms may be associated with abnormal liver enzyme activity, hepatobiliary damage, e.g., jaundice and cirrhosis, iron deficiency, and corresponding microcytic anemia.

[0275] The diagnosis of EPP and XLPP can be determined by measuring the levels of total erythrocytes, free protoporphyrin IX and zinc protoporphyrin IX in lysed anticoagulated whole blood. The diagnosis of EPP and / or XLPP can be made based on increased levels of free protoporphyrin IX in the blood. Patients with XLPP have a significantly higher ratio of zinc protoporphyrin IX to free protoporphyrin IX (e.g., >25%) compared to patients with EPP (e.g., ≤15%).

[0276] The diagnosis of EPP can also be determined by measuring the level of ferrochelatase activity in a subject. Ferrochelatase is a mitochondrial enzyme that catalyzes the insertion of ferrous iron into protoporphyrin IX (PPIX) to form heme. Ferrochelatase also catalyzes the insertion of zinc to form zinc protoporphyrin IX (ZPPIX) from any PPIX, which remains as such after the completion of heme synthesis. In EPP, the formation of both heme and ZPPIX is impaired, so free PPIX accumulates in bone marrow reticulocytes. In some embodiments, the present disclosure relates to a method of treating a subject in which the ferrochelatase activity level is reduced to 10-35% of the ferrochelatase activity level observed in a normal subject. In some embodiments, the present disclosure relates to a method of treating a subject in which the ferrochelatase activity level is reduced to less than 50% of the ferrochelatase activity level observed in a normal subject.

[0277] XLPP has a phenotype similar to EPP and can be identified based on genetic analysis of ALAS2 or by determining the enzyme activity level of ALAS2. In some embodiments, the present disclosure relates to a method of treating a subject having a gain-of-function mutation in ALAS2. In some embodiments, the ALAS2 enzyme activity of the subject is increased. Since ferrochelatase is not deficient in XLPP, a portion of the excess PPIX measured in erythrocytes is ZPPIX and a lower percentage (e.g., 50-85%) is metal-free. In some embodiments, the subject has an increased level of zinc protoporphyrin IX in erythrocytes. In some embodiments, the method reduces the level of zinc protoporphyrin IX in the subject's erythrocytes. In some embodiments, the method reduces the level of zinc protoporphyrin IX in the subject's erythrocytes 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%).

[0278] In certain embodiments, the present disclosure is a method of treating erythropoietic protoporphyria (EPP) and / or X-linked protoporphyria (XLPP) 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has elevated PPIX levels. In some embodiments, the method relates to a subject having a PPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the PPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a PPIX level that is at least 10% higher than the PPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a PPIX level that is at least 20% higher than the PPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a PPIX level that is at least 30% higher than the PPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a PPIX level that is at least 40% higher than the PPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a PPIX level that is at least 50% higher than the PPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the subject has elevated protoporphyrin IX levels in feces. In some embodiments, the subject has elevated protoporphyrin IX levels in the skin. In some embodiments, the subject has elevated free protoporphyrin IX levels in erythrocytes. In some embodiments, the subject has a protoporphyrin IX level in erythrocytes higher than 31 μmolL-1.In some embodiments, the subject has protoporphyrin IX levels in erythrocytes of 31 μmol / L to 53 μmol / L. In some embodiments, the subject has protoporphyrin IX levels in erythrocytes that are higher than 53 μmol / L.

[0279] The present application further provides a method for inhibiting PPIX synthesis in vivo, which comprises administering a glycine transporter inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more glycine transporter inhibitors or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo, which comprises administering a glycine transporter inhibitor (e.g., a GlyT1 inhibitor) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor) or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 20%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 30%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 40%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 50%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 60%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 70%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 80%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 90%. In some embodiments, the present disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 100%. The present application further provides a method for decreasing the rate of PPIX synthesis in vivo, which comprises administering a glycine transporter inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more glycine transporter inhibitors or a pharmaceutically acceptable salt thereof.In certain embodiments of the methods and uses disclosed herein, PPIX accumulation is inhibited, either directly or indirectly. In certain such embodiments, PPIX accumulation is inhibited in a dose-dependent manner. In certain embodiments of the methods described above, the glycine transporter inhibitor is a GlyT1 inhibitor, such as a GlyT1 inhibitor disclosed herein. For example, the present application provides a method of inhibiting PPIX synthesis in vivo, a method of reducing the rate of PPIX synthesis in vitro, and / or a method of inhibiting PPIX accumulation in vivo, comprising administering to a subject vigabatrin or a pharmaceutically acceptable salt thereof, or a prodrug of vigabatrin or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in the red blood cells of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the red blood cells of a subject to a level less than 53 μmol / L. In some embodiments, the method reduces the level of protoporphyrin IX in the red blood cells of a subject to a level less than 31 μmol / L. In some embodiments, the method reduces the level of protoporphyrin IX in the red blood cells of a subject to a level less than 15 μmol / L. In some embodiments, the method relates to reducing the level of protoporphyrin IX in the feces of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the skin of a subject. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 15%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 20%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 25%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 30%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 35%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 40%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 45%. In some embodiments, the method relates to a method of reducing the level of free protoporphyrin IX in a subject by at least 50%.In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 55%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 60%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 65%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 70%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 75%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 80%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 85%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 90%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 95%. In some embodiments, the method relates to a method of reducing the free protoporphyrin IX level in a subject by at least 100%.

[0281] In certain embodiments, the present disclosure provides a method of treating X-linked protoporphyria (XLPP) in a subject, the method 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has elevated zinc protoporphyrin IX (ZPPIX) levels. In some embodiments, the method relates to a subject having a ZPPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the ZPPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a ZPPIX level that is at least 10% higher than the ZPPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a ZPPIX level that is at least 20% higher than the ZPPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a ZPPIX level that is at least 30% higher than the ZPPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a ZPPIX level that is at least 40% higher than the ZPPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a ZPPIX level that is at least 50% higher than the ZPPIX level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the subject has elevated ZPPIX levels in erythrocytes.

[0282] In certain embodiments, the present disclosure relates to a method of treating X-linked protoporphyria (XLPP) in a subject, the method 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has an increased ratio of zinc protoporphyrin IX to free protoporphyrin IX (ZPPIX / PPIX ratio) compared to a subject having EPP. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 15% (e.g., 15%, 20%, 25%, 30%, 35%, 40% or 45%). In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 20%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 25%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 30%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 35%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 40%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 45%.

[0283] In certain embodiments, the present disclosure relates to a method of inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 20%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 30%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 40%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 50%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 60%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 70%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 80%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 90%. In some embodiments, the present disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 100%.

[0284] In certain embodiments, the present disclosure provides a method of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, the method 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has elevated 5-aminolevulinic acid (5-ALA) levels. In some embodiments, the method relates to a subject having a 5-ALA level that is at least 10%, 20%, 30%, 40%, or 50% higher than the 5-ALA level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a 5-ALA level that is at least 10% higher than the 5-ALA level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a 5-ALA level that is at least 20% higher than the 5-ALA level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a 5-ALA level that is at least 30% higher than the 5-ALA level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a 5-ALA level that is at least 40% higher than the 5-ALA level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a 5-ALA level that is at least 50% higher than the 5-ALA level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor).

[0285] In certain embodiments, the present disclosure relates to a method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 20%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 30%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 40%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 50%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 60%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 70%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 80%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 90%. In some embodiments, the present disclosure relates to a method of inhibiting 5-ALA synthesis in vivo by at least 100%.

[0286] This application further provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, in the manufacture of a formulation for the treatment of EPP, XLPP, CEP, or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome or CEP-related syndrome) in a subject. In some embodiments, this application provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, in the manufacture of a formulation for the treatment of EPP, XLPP or CEP 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, e.g., one or more GlyT1 inhibitors disclosed herein. In certain such embodiments, the GlyT1 inhibitor is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof. In certain of the foregoing embodiments, the formulation is administered in a therapeutically effective amount.

[0287] This application provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for the treatment of EPP, XLPP or CEP, or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome or CEP-related syndrome) in a subject. In some embodiments, this application provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for the treatment of EPP, XLPP or CEP 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, e.g., one or more GlyT1 inhibitors disclosed herein. In certain such embodiments, the GlyT1 inhibitor is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof. In certain of the foregoing embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0288] Congenital erythropoietic porphyria (CEP) is an erythropoietic cutaneous porphyria characterized by blistering photosensitivity. Severe cases of CEP can present with fetal hydrops in utero or, immediately after birth, with severe blistering photosensitivity, red urine, splenomegaly, hemolysis and transfusion dependence. Mild cases and later onset typically present with red urine, severe blistering and hemolytic anemia.

[0289] Individuals with CEP are often homozygous or compound heterozygous for UROS mutations. Some cases of CEP are due to mutations in the gene encoding the transcription factor GATA1. These mutations result in reduced enzymatic activity of uroporphyrinogen III synthase (UROIII-S), the fourth enzyme in the heme biosynthetic pathway. The decreased activity of UROIII-S further leads to the accumulation of hydroxymethylbilane, which spontaneously forms uroporphyrinogen I that is further metabolized to coproporphyrinogen I. Uroporphyrinogen I and coproporphyrinogen I accumulate in tissues.

[0290] The diagnosis of CEP can be determined by analyzing the enzymatic activity of uroporphyrinogen III synthase (UROIII-S), evaluating mutations in the UROS gene, evaluating the function of the GATA-1 erythroid-specific transcription factor, evaluating mutations in GATA1, and determining the levels of uroporphyrin I and coproporphyrin I in the subject. In some embodiments, the subject has a mutation in UROS. In some embodiments, the subject has a genetic deficiency in the GATA-1 erythroid-specific transcription factor. In some embodiments, the method is a method of treating a subject, wherein the subject has reduced activity of uroporphyrinogen III synthase. In some embodiments, the increased levels of uroporphyrin I and / or coproporphyrin I are measured in the urine or erythrocytes of the subject. In some embodiments, the increased level of coproporphyrin I is measured in the feces of the subject.

[0291] In certain embodiments, the disclosure is a method of treating congenital erythropoietic porphyria (CEP) 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has increased levels of uroporphyrin I and / or coproporphyrin I. In some embodiments, the subject has increased levels of uroporphyrin I and / or coproporphyrin I. In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 10%, 20%, 30%, 40% or 50% higher than the uroporphyrin I level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 10% higher than the uroporphyrin I level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 20% higher than the uroporphyrin I level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 30% higher than the uroporphyrin I level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 40% higher than the uroporphyrin I level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor). In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 50% higher than the uroporphyrin I level in a healthy subject prior to administration of the glycine transporter inhibitor (e.g., GlyT1 inhibitor).

[0292] In some embodiments, the present disclosure relates to a method of treating a subject having a coproporphyrin I level that is at least 10%, 20%, 30%, 40% or 50% higher than the coproporphyrin I level in a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method relates to a subject having a coproporphyrin I level that is at least 10% higher than the coproporphyrin I level in a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method relates to a subject having a coproporphyrin I level that is at least 20% higher than the coproporphyrin I level in a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method relates to a subject having a coproporphyrin I level that is at least 30% higher than the coproporphyrin I level in a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method relates to a subject having a coproporphyrin I level that is at least 40% higher than the coproporphyrin I level in a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method relates to a subject having a coproporphyrin I level that is at least 50% higher than the coproporphyrin I level in a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor).

[0293] In certain embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I and / or coproporphyrin I synthesis in vivo, comprising administering a glycine transporter inhibitor (e.g., a GlyT1 inhibitor) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor) or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 20%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 30%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 40%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 50%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 60%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 70%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 80%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 90%. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin I synthesis in vivo by at least 100%.

[0294] In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 20%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 30%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 40%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 50%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 60%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 70%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 80%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 90%. In some embodiments, the present disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 100%.

[0295] Porphyrins (e.g., PPIX, ZPPIX, uroporphyrin I, and coproporphyrin I) can be found in various biological samples including skin, urine, feces, plasma, and red blood cells. In some embodiments, the porphyrins may be extracted from the biological sample into a solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., light at 400 - 420 nm). Porphyrins have a maximum absorption wavelength near 400 - 420 nm, and their highest absorption peaks occur at 415 nm. The maximum emission of porphyrins is typically around 600 nm and varies slightly based on the type of porphyrin and the solvent used for analysis. In some embodiments, the diagnosis of EPP, XLPP, and CEP may be performed using fluorescence analysis. In some embodiments, skin porphyrin levels (e.g., PPIX levels) can be measured by calculating the difference before and after complete photobleaching of PPIX using controlled illumination. See, for example, Heerfordt IM. Br J Dermatol. 2016;175(6):1284 - 1289.

[0296] In some embodiments, the plasma porphyrin of interest fluoresces with a peak at 634 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the plasma porphyrin of interest fluoresces with peaks in the range of 626 nm - 634 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the skin porphyrin of interest fluoresces with a peak at 632 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the skin porphyrin of interest fluoresces with peaks in the range of 626 nm - 634 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the subject has a protoporphyrin IX level in the skin that is higher than 0.2 Fluoderma units (FDU). In some embodiments, the subject has a protoporphyrin IX level in the skin that is higher than 1.0 FDU. In some embodiments, the subject has a protoporphyrin IX level in the skin in the range of 1.0 FDU - 2.5 FDU. In some embodiments, the subject has a protoporphyrin IX level in the skin that is higher than 2.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 0.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 1.0 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 1.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 2.0 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 2.5 FDU. In some embodiments, the subject has red fluorescent urine. In some embodiments, the subject has a peak at 615 nm - 620 nm using plasma porphyrin fluorescence analysis.

[0297] In certain embodiments, the present disclosure relates to a method of preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, one or more complications of EPP, XLPP, or CEP are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, loss of nails, loss of fingers, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic liver failure, red teeth, hyperplastic bone marrow, myelodysplasia, thrombocytopenia, fetal hydrops, and / or intrauterine death. In some embodiments, the present disclosure contemplates a method of treating one or more complications of EPP, XLPP, or CEP (e.g., acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, loss of nails, loss of fingers, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic liver failure, red teeth, hyperplastic bone marrow, myelodysplasia, thrombocytopenia, fetal hydrops, and / or intrauterine death), the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, one or more complications are improved indirectly.In some embodiments, the present disclosure contemplates a method of preventing one or more complications of EPP, XLPP, or CEP, the method comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure contemplates a method of reducing the rate of progression of one or more complications of EPP, XLPP, or CEP, the method comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure contemplates a method of reducing the severity of one or more complications of EPP, XLPP, or CEP, the method comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.

[0298] Optionally, the methods disclosed herein for preventing or treating one or more complications of EPP, XLPP or CEP, or reducing the rate of progression and / or severity thereof, in a subject may further comprise administering to the patient one or more supportive therapies or additional active agents for treating EPP, XLPP or CEP. For example, the patient may also be administered one or more supportive therapies or active agents selected from the group consisting of sun avoidance, topical sunscreen, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy and blood transfusion. In some embodiments, the methods described herein may further comprise administering afamelanotide (Scenesse®) to the patient.

[0299] Porphyrin photosensitivity in EPP, XLPP, and CEP gives rise to two distinct clinical syndromes: (1) an acute photosensitivity to sunlight with erythema and edema, and (2) a syndrome in which subepidermal blisters occur in areas of the skin exposed to sunlight. In certain embodiments, the present disclosure is a method of preventing, treating, or reducing the rate of progression and / or severity of EPP, XLPP, or CEP in a subject, the method 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, the method increasing painless light exposure in the subject. In some embodiments, the method increases painless light exposure in the subject by at least 10%, 20%, 30%, 40%, or 50% compared to painless light exposure prior to administration of the GlyT1 inhibitor. In some embodiments, the method reduces photosensitivity in the subject. In some embodiments, the method reduces photosensitivity in the subject by at least 10%, 20%, 30%, 40%, or 50% compared to photosensitivity prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a history of phototoxic reactions from EPP. In some embodiments, the subject is an adult, pediatric, infant, or pregnant female.

[0300] Glycine is one of the important first substances for heme and globin synthesis. Therefore, a decrease in glycine levels due to GlyT1 inhibition can lead to a decrease in heme synthesis. In certain embodiments, the present disclosure is a method of treating EPP, XLPP, or CEP 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the heme level of the subject does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the present disclosure relates to a method of treating EPP, XLPP, or CEP in a subject, wherein the heme level of the subject does not decrease by more than 15%. In some embodiments, the present disclosure relates to a method of treating EPP, XLPP, or CEP in a subject, wherein the heme level of the subject does not decrease by more than 20%. In some embodiments, the present disclosure relates to a method of treating EPP, XLPP, or CEP in a subject, wherein the heme level of the subject does not decrease by more than 25%. In some embodiments, the present disclosure relates to a method of treating EPP, XLPP, or CEP in a subject, wherein the heme level of the subject does not decrease by more than 30%.

[0301] In certain embodiments, the disclosure provides a method of treating EPP, XLPP, or CEP 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the PPIX level in the subject is decreased while the hemoglobin level in the patient is substantially maintained. In some embodiments, the PPIX level in the patient is decreased by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%), and the hemoglobin level in the patient is not decreased by more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the PPIX level in the patient is decreased by at least 85%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 80%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 75%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 70%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 65%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 60%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 55%, and the hemoglobin level in the patient is not decreased by more than 15%. In some embodiments, the PPIX level in the patient is decreased by at least 50%, and the hemoglobin level in the patient is not decreased by more than 15%.

[0302] In certain embodiments, the present disclosure provides a method of treating EPP, XLPP, or CEP in a subject, the method 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 prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein administration of the pharmaceutical composition does not cause a substantial reduction in hemoglobin levels. In some embodiments, the PPIX level in the patient is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the PPIX level in the patient is reduced by at least 55%. In some embodiments, the PPIX level in the patient is reduced by at least 60%. In some embodiments, the PPIX level in the patient is reduced by at least 65%. In some embodiments, the PPIX level in the patient is reduced by at least 70%. In some embodiments, the PPIX level in the patient is reduced by at least 75%. In some embodiments, the PPIX level in the patient is reduced by at least 80%. In some embodiments, the PPIX level in the patient is reduced by at least 85%. In some embodiments, the PPIX level in the patient is reduced by at least 90%. In some embodiments, the PPIX level in the patient is reduced by at least 95%. In some embodiments, the PPIX level in the patient is reduced by at least 100%. In some embodiments, the hemoglobin level in the patient is not reduced by more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the hemoglobin level in the patient is not reduced by more than 15%. In some embodiments, the hemoglobin level in the patient is not reduced by more than 20%. In some embodiments, the hemoglobin level in the patient is not reduced by more than 25%. In some embodiments, the hemoglobin level in the patient is not reduced by more than 30%.

[0303] In some embodiments, the accumulation of one or more successive heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some embodiments, the present disclosure relates to a method of inhibiting the accumulation of PPIX, comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure relates to a method of inhibiting the accumulation of ZPPIX, comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure relates to a method of inhibiting the accumulation of uroporphyrin I, comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure relates to a method of inhibiting the accumulation of coproporphyrin I, comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure relates to a method of inhibiting the accumulation of 5-ALA, comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.In some embodiments, the accumulation of one or more heme intermediates (e.g., PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA) is inhibited in a dose-dependent manner. See, for example, FIG. 7.

[0304] Protoheme accumulation in EPP, XLPP, and CEP can cause liver damage when the liver load exceeds the canalicular excretion capacity. Accumulation of PPIX in hepatocytes and canaliculi can lead to cell damage, cholestasis, cell lysis, and further retention of protoporphyrin. Excess protoporphyrin can exhibit a cholestatic effect that results in changes in the hepatobiliary system that can range from mild inflammation to fibrosis and cirrhosis (e.g., cholelithiasis, mild liver disease, worsening of liver disease, and end-stage liver disease). 3-5% of patients with EPP or XLPP develop protoporphyric liver injury, a severe liver disease that progresses rapidly and may require liver transplantation. Approximately 2% of patients develop severe liver disease.

[0305] In certain aspects, the disclosure provides a method for preventing, treating, or reducing the rate of progression and / or severity of a liver disease associated with EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is cholelithiasis. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is mild liver disease. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is worsening of liver disease. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is end-stage liver disease.

[0306] Liver function in patients with EPP, XLPP, and CEP can be evaluated using a variety of known clinical assays. In some embodiments, liver function tests can be used to determine the levels of various biochemical parameters (e.g., elevated levels of aspartate transaminase, alkaline phosphatase, or γ-glutamyltransferase). In some embodiments, histopathology of a liver biopsy can be used to evaluate one or more parameters in a subject (e.g., protoporphyrin deposition, fibrosis, infiltration, portal fibrosis, and periportal fibrosis). In some embodiments, ultrastructural studies of biopsy specimens can be used to determine whether crystals containing vacuoles are present in the subject. Deterioration of liver function results in increased coproporphyrin excretion in the urine. In some embodiments, coproporphyrin excretion in the urine can be analyzed to evaluate liver function in a subject. In some embodiments, ultrasound or magnetic resonance elastometry can be used to measure liver stiffness in a subject.

[0307] In certain embodiments of the methods and uses disclosed herein, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the present application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 100 nM. In certain embodiments of the present application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 50 nM. In certain such embodiments, the EC50 is measured in a flow cytometry assay. In certain of the foregoing embodiments, the GlyT1 inhibitor is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof.

[0308] In certain embodiments of the methods and uses disclosed herein, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95% cell viability is maintained. In certain such embodiments, at least 90% cell viability is maintained. The present disclosure also provides the following non-limiting embodiments.

[0309] To better understand the embodiments disclosed herein, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the embodiments in any way. Throughout these examples, molecular cloning reactions and other standard recombinant DNA techniques may exist, which, unless otherwise stated, were performed using commercially available reagents according to the methods described in Maniatis et al., Molecular Cloning - A Laboratory Manual, 2nd ed., Cold Spring Harbor Press (1989).

[0310] The following examples are illustrative, not limiting, of the methods and compositions described herein. Other suitable modifications and adaptations of the various conditions and parameters commonly encountered in the therapies, syntheses, and other embodiments disclosed herein are within the spirit and scope of the embodiments.

Examples

[0311] (Example 1) Synthesis of Compounds The compounds disclosed herein can be made by processes known and disclosed in the art according to well-known procedures. For example, compounds of Formula I, such as vitupercetin, can be prepared according to the synthetic protocols provided in U.S. Patent Nos. 7,319,099, 9,877,963, and 7,812,161, the contents of which are incorporated herein by reference in their entirety. Additionally, compounds of Formula II, such as PF-3463275, can be prepared according to the synthetic protocol provided in U.S. Patent No. 8,124,639, the content of which is incorporated herein by reference in its entirety. (Example 2) GlyT1 Inhibitors for Treating Subjects with Erythropoietic Protoporphyria (EPP), X-Linked Protoporphyria (XLPP), and Congenital Erythropoietic Porphyria (CEP) (Predictive Example)

[0312] The synthesis of large amounts of heme is a fundamental requirement in erythroid cell development to support the production of large amounts of hemoglobin. In this cell lineage, the amount of heme required to meet this demand is excessive compared to any other cell type. Heme synthesis begins with the condensation of glycine and succinyl-CoA by the enzyme ALAS. This is the rate-limiting step in heme biosynthesis, ensuring that no toxic heme intermediates accumulate. Erythroid cells acquire the erythroid-specific form of ALAS (ALAS2) and the glycine transporter GlyT1 to increase the availability of glycine to meet this high demand for heme.

[0313] Animal and human studies on the elimination of GlyT1 activity by gene deletion (Garcia-Santos et al, 2017) or the reduction of GlyT1 activity by the administration of specific GlyT1 inhibitors (Pinard et al, 2018) have shown that heme synthesis in erythroid cells is reduced, resulting in moderate microcytic hypochromic anemia as a consequence of impaired hemoglobin production. These findings indicate that modulation of glycine uptake in red blood cells can regulate the heme biosynthetic pathway.

[0314] In patients with either X-linked protoporphyria or congenital erythropoietic porphyria, specific mutations in individual genes encoding enzymes of the heme biosynthetic pathway result in changes in enzyme activity and the accumulation of heme intermediates upstream of the affected enzyme. These metabolic products accumulate because the mutated enzyme becomes the rate-limiting step in the pathway due to its inability to fully convert upstream metabolites to the next step in the pathway. Three diseases are of specific interest. 1. EPP caused by mutations in the ferrochetalase gene that result in reduced activity of this enzyme and the accumulation of the upstream metabolite protoporphyrin IX (PPIX). Rarely, an acquired form of EPP is observed in elderly humans who develop new clones containing ferrochetalase mutations as a feature of myelodysplasia. 2. XLPP, which is caused by activating mutations in the ALAS2 gene and results in high levels of PPIX. In this case, due to overproduction that cannot be completely converted to heme even by normal levels of ferrochelatase, the accumulation of metabolites is downstream of the affected enzyme. 3. CEP, which is caused by mutations in the gene for uroporphyrinogen synthase, resulting in reduced activity of this enzyme and the accumulation of the upstream metabolite coproporphyrin I.

[0315] These heme intermediates can be released from red blood cells either by cell lysis (in CEP) or by active transport outside the cell (in EPP and XLPP), causing toxicity. A consistent feature of all three diseases is a skin reaction with severe pain accompanied by blister formation following sun exposure that causes persistent scarring and deformation. This is caused by the local production of reactive intermediates by the action of sunlight on PPIX or coproporphyrin I, which induces a severe inflammatory response. PPIX is hydrophobic and is therefore excreted through the bile ducts. High bile concentrations can lead to cholelithiasis, cholestasis, and potentially severe liver damage, resulting in liver failure. In the case of CEP, the accumulation of coproporphyrin in mature red blood cells can lead to severe hemolytic anemia.

[0316] These disease manifestations of EPP, XLPP, and CEP are caused by the overproduction of intermediate heme metabolites due to genetic abnormalities in the heme biosynthesis pathway. The accumulated metabolites are toxic to red blood cells, either upon accumulation in the skin and exposure to sunlight or for bile excretion by the liver. GlyT1 has been shown to control the availability of one of the first substances in the heme biosynthesis pathway and downregulate heme production in humans or animals having the normal heme pathway described above. Without being bound by any particular theory, GlyT1 is capable of reducing the production of heme intermediate metabolites in the same manner, particularly when its intermediate products accumulate as a result of abnormal enzyme activity. Accordingly, a subject having EPP, XLPP, or CEP is treated with GlyT1, which reduces the production of toxic metabolites in red blood cells in such a subject, resulting in a reduction in the skin accumulation of these metabolites, a reduction in hepatic bile excretion, or in the case of CEP, a reduction in hemolysis, and in all cases, a reduction in the severity of the disease. In this way, the disease is treated.

[0317] (Example 3) A Met GlyT1 inhibitor is effective in reducing the levels of heme metabolites in an erythroleukemia cell line containing a mutation that causes disease for EPP, XLPP, or CEP

[0318] Erythroleukemia cells are genetically modified to obtain a cell line containing a mutation that causes disease for EPP, XLPP, or CEP. These genetically modified cell lines are treated with a GlyT1 inhibitor, and the production of heme metabolites is evaluated photometrically, biochemically, or in radiolabeling studies. The level of photohemolysis induced by PPIX is evaluated in these cell lines and is found to be reduced in the presence of the GlyT1 inhibitor. (Example 4) A GlyT1 inhibitor is effective in reducing the levels of heme metabolites in red blood cells containing a mutation that causes disease for EPP, XLPP, or CEP (predictive example)

[0319] Erythrocytes are collected from the bone marrow or peripheral blood of animals having a disease that causes mutations in specific genes that cause EPP, XLPP or CEP. These cell lines are treated with a GlyT1 inhibitor and the production of heme metabolites is evaluated photometrically, biochemically, or in radiolabeling studies. The level of photolysis induced by PPIX is evaluated in these cell lines and is found to be reduced in the presence of the GlyT1 inhibitor. (Example 5) GlyT1 inhibitors are effective in reducing the levels of heme metabolites in erythrocytes of patients containing mutations that cause disease for EPP, XLPP or CEP (Predictive Example)

[0320] Erythrocytes (reticulocytes and erythrocytes) are obtained from patients with EPP, XLPP and CEP (if available). These patient-derived cells are treated with a GlyT1 inhibitor and the production of heme metabolites is evaluated photometrically, biochemically, or in radiolabeling studies. The level of photolysis induced by PPIX is evaluated in these cell lines and is found to be reduced in the presence of the GlyT1 inhibitor. (Example 6) GlyT1 inhibitors are effective in reducing the severity of EPP or XLPP in animals (Predictive Example)

[0321] Animals with EPP and XLPP are treated with one or more GlyT1 inhibitors at various doses over a period of time. It is found that the levels of toxic heme intermediates in such animals are reduced and that the symptoms of such diseases, such as the severity of skin reactions, hepatobiliary disease and / or hemolysis, are found to recover.

[0322] The embodiments and examples provided herein demonstrate that GlyT1 inhibitors can be used to treat EPP, XLPP or CEP. This is a surprising and unexpected result. (Example 7) EPP cell model

[0323] The knockout guide sequences were designed to target exon 3 of the ferrochelatase gene. The tested guide sequences are shown in Table 1. [Table 1]

[0324] K562 cells were cultured in Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (PS). The CRISPR Cas9 RNP complex with guide RNA was electroporated into K562 cells. Genomic DNA from pooled cells was isolated, amplified by PCR, and sequenced by Sanger sequencing to determine the knockout efficiency. Single cell clones were isolated by fluorescence-activated cell sorting (FACS). TA cloning and Sanger sequencing were used to confirm single cell clones and genotypes. Five clones were selected for further characterization by Western blot (clone IDs are clone 1-7; clone 1-9; clone 1-10, clone 1-32; clone 1-51; and K562 WT) (Figure 1), the FECH protein expression level (antibody: FECH antibody rabbit polyclonal, Proteintech, 14466-1-AP) was determined, and the PPIX level was determined by flow cytometry (Figure 2). LC / MS / MS confirmed the accumulation of PPIX in clone 1-9 compared to WT K562 cells (Figure 3). The genotype characteristics of the five clones are as presented in Table 2. [Table 2]

[0325] 2×10 in IMDM medium with 10% FBS and 1% PS 5900 μL of K562 clone 9 cells at [[number of cells]] cells / mL were seeded in 24-well plates. After 24 hours of incubation, 100 μL of compounds in DMSO / media were added at different concentrations. The final concentration of DMSO was 0.1%. The compounds were incubated at 37 °C for 96 hours. Cell viability and cell count were measured by the Vi-CELL XR complete system. Finally, the effect of the compounds on PPIX levels was determined by flow cytometry. Figure 4 shows that both vitropeltin and PF-03463275 demonstrated dose-dependent inhibition of PPIX accumulation by up to 50% by flow cytometry. Vitropeltin showed an EC50 of 7 nM and PF-03463275 showed an EC50 of 46 nM. Figure 5 shows that both vitropeltin and PF-03463275 had no negative effect on cell viability. Importantly, the LC / MS / MS method demonstrated that vitropeltin decreased 5-aminolevulinic acid (5-ALA) and PPIX levels in the EPP K562 cell model with minimal effect on heme formation (Figures 6, 7, and 8).

[0326] Additional GlyT1 inhibitors also showed dose-dependent inhibition of PPIX accumulation, but the GlyT2 inhibitor, ORG-25543,

Chemical formula

Table 3

[0327] (Example 8) GlyT1 inhibitors are effective in reducing PPIX levels in human hematopoietic stem cells transduced with lentivirus expressing small hairpin RNA (shRNA) of FECH

[0328] To investigate the effect of GlyT1 inhibitors in human hematopoietic stem cells with the EPP phenotype, a lentiviral vector expressing shRNA for FECH was constructed (Table 4) and transduced into human cord blood CD34+ cells purchased from Stemexpress at 25 MOI.

Table 4

[0329] RT-qPCR of the obtained CD34+ cells showed a 60% reduction in FECH mRNA levels compared to cells treated with the control lentiviral vector (Figure 9). The transduced CD34+ cells were differentiated into erythroid cells for 9 days in StemSpan SFEM II medium supplemented with StemSpan Erythroid Expansion Supplement in the presence of vitropetin (100 nM) or DMSO control. The erythroid cell antigen profile was analyzed using a cell fluorescence measurement strategy with the following surface markers: CD71 (PE mouse anti-human CD71, BD Biosciences), glycophorin A (APC mouse anti-human CD235a, BD Biosciences). After 9 days in the differentiation culture, the cell viability was higher than 60% in all samples, and more than 80% of the cells transduced with the lentivirus expressing shRNA for FECH showed an increase in PPIX determined by flow cytometry (Figure 10). Treatment with vitropetin (100 nM) had no negative effect on the erythroid cell surface markers and reduced the accumulation of PPIX by 60% (Figure 11).

[0330] Preferred embodiments of the present application are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present application. It should be understood that various changes to the embodiments of the application described herein may be used in the practice of the present application. The following claims define the scope of the present application, and it is intended that methods and structures within the scope of these claims and their equivalents be included therein. Incorporation by reference

[0331] All references cited in the present application and those references cited therein are hereby incorporated by reference in their entirety herein, where appropriate, for additional or alternative details, features, and / or teachings of the technical background. The present invention provides, for example, the following items. (Item 1) A method for treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP) or congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of the one or more GlyT1 inhibitors or salts thereof. (Item 2) A method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of the one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof. (Item 3) The method according to item 2, wherein one or more of the complications of EPP, XLPP or CEP are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformation, loss of nails, loss of fingers, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening of liver disease, end-stage liver disease, red teeth, hyperplastic bone marrow, myelodysplasia, thrombocytopenia, fetal hydrops and / or intrauterine death. (Item 4) A method for use in the prevention or treatment of EPP, XLPP or CEP in a subject, the use comprising administering to the subject a GlyT1 inhibitor or pharmaceutically acceptable salt thereof, or a prodrug of the one or more GlyT1 inhibitors or pharmaceutically acceptable salt thereof. (Item 5) A method for use in the manufacture of a medicament for the treatment of EPP, XLPP or CEP in a subject, wherein said use comprises administering to said subject at least one GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more GlyT1 inhibitors or a pharmaceutically acceptable salt thereof. (Item 6) A method for use in the manufacture of a medicament for inhibiting protoporphyrin IX (PPIX) synthesis in vivo, wherein said use comprises administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more GlyT1 inhibitors or a pharmaceutically acceptable salt thereof. (Item 7) The method according to any one of items 1 to 6, wherein the subject has EPP. (Item 8) The method according to any one of items 1 to 6, wherein the subject has XLPP. (Item 9) The method according to any one of items 1 to 6, wherein the subject has CEP. (Item 10) The method according to item 3, wherein the acute photosensitivity is caused by sun exposure. (Item 11) The method according to any one of items 1 to 10, wherein the method increases painless light exposure in the subject. (Item 12) The method according to any one of items 1 to 10, wherein the method reduces photosensitivity in the subject. (Item 13) A method for inhibiting PPIX synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of said GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. (Item 14) A method for inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of said GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. (Item 15) A method for inhibiting uroporphyrin I and / or coproporphyrin I synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of said GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. (Item 16) A method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. (Item 17) (Item 18) The method according to any one of Items 1 to 16, wherein the accumulation of one or more heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I and / or 5-ALA. (Item 18) (Item 19) The method according to Item 17, wherein the accumulation of the one or more heme intermediates is inhibited in a dose-dependent manner. (Item 19) (Item 20) The method according to any one of the preceding items, wherein the GlyT1 inhibitor demonstrates an EC50 of less than 500 nM. (Item 20) (Item 21) The method according to any one of the preceding items, wherein the GlyT1 inhibitor demonstrates an EC50 of less than 100 nM. (Item 21) (Item 22) The method according to any one of the preceding items, wherein at least 50% of cell viability is maintained. (Item 22) (Item 23) The method according to any one of the preceding items, wherein at least 90% of cell viability is maintained. (Item 23) (Item 24) The method according to any one of Items 1 to 22, wherein the subject has a PPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the PPIX level in a healthy subject before administration of the GlyT1 inhibitor. (Item 24) (Item 25) The method according to any one of Items 1 to 22, wherein the subject has a ZPPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the ZPPIX level in a healthy subject before administration of the GlyT1 inhibitor. (Item 25) (Item 26) The method according to any one of Items 1 to 22, wherein the subject has an increased ratio of ZPPIX to free protoporphyrin IX (ZPPIX / PPIX ratio) compared to a subject having EPP. (Item 26) (Item 27) The method according to any one of Items 1 to 22, wherein the subject has a uroporphyrin I and / or coproporphyrin I level that is at least 10%, 20%, 30%, 40% or 50% higher than the uroporphyrin I and / or coproporphyrin I level in a healthy subject before administration of the GlyT1 inhibitor. (Item 27) The method according to any one of items 1 to 22, wherein the subject has a 5-ALA level that is at least 10%, 20%, 30%, 40% or 50% higher than the 5-ALA level in a healthy subject before administration of the GlyT1 inhibitor. (Item 28) The method according to any one of items 1 to 27, wherein the PPIX level of the subject decreases while the heme level of the patient is substantially maintained. (Item 29) The method according to any one of items 1 to 28, wherein the PPIX level of the patient decreases by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%), and the heme level of the patient does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25% and 30%). (Item 30) The method according to item 28 or 29, wherein the PPIX level of the patient decreases by at least 85%, and the heme level of the patient does not decrease by more than 15%. (Item 31) The method according to any one of items 1 to 29, wherein the heme level does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25% and 30%). (Item 32) The method according to any one of items 1 to 31, wherein administration of the pharmaceutical composition does not cause a substantial reduction in the heme level. (Item 33) The method according to any one of items 1 to 8, 10 to 15, 17 to 25 and 27 to 32, wherein the subject has an increased free protoporphyrin IX level in red blood cells. (Item 34) The method according to any one of items 1 to 8, 10 to 15, 17 to 25 and 27 to 33, wherein the method reduces the free protoporphyrin IX level in the subject. (Item 35) The method according to any one of items 1 to 8, 10 to 15, 17 to 25 and 27 to 34, wherein the method reduces the free protoporphyrin IX level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). (Item 36) The method according to any one of items 1 to 8, 10 to 15, 17 to 25 and 27 to 35, wherein the subject has an increased protoporphyrin IX level in feces. (Item 37) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 36, wherein the method reduces the protoporphyrin IX level in the feces of the subject. (Item 38) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 37, wherein the method reduces the protoporphyrin IX level in the feces 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%). (Item 39) The method according to any one of items 1 to 38, wherein the plasma porphyrin of the subject fluoresces at a peak of 634 nm when irradiated with blue light (e.g., light of 400 to 420 nm). (Item 40) The method according to any one of items 1 to 39, wherein the plasma porphyrin of the subject fluoresces at a peak of 626 nm to 634 nm when irradiated with blue light (e.g., light of 400 to 420 nm). (Item 41) The method according to any one of items 1 to 38, wherein the skin porphyrin of the subject fluoresces at a peak of 632 nm when irradiated with blue light (e.g., light of 400 to 420 nm). (Item 42) The method according to any one of items 1 to 38, wherein the skin porphyrin of the subject fluoresces at a peak of 626 nm to 634 nm when irradiated with blue light (e.g., light of 400 to 420 nm). (Item 43) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 42, wherein the subject has an increased protoporphyrin IX level in the skin. (Item 44) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 43, wherein the method reduces the protoporphyrin IX level in the skin of the subject. (Item 45) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 44, wherein the method reduces the protoporphyrin IX level in the skin 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%). (Item 46) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 45, wherein the subject has a protoporphyrin IX level in the skin higher than 0.2 FluoDerm units (FDU). (Item 47) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 45, wherein the subject has a protoporphyrin IX level in the skin higher than 1.0 FDU. (Item 48) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 45, wherein the subject has a protoporphyrin IX level in the skin of 1.0 FDU to 2.5 FDU. (Item 49) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 45, wherein the subject has a protoporphyrin IX level in the skin higher than 2.5 FDU. (Item 50) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 49, wherein the method reduces the protoporphyrin IX level in the subject's skin to less than 0.5 FDU. (Item 51) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 49, wherein the method reduces the protoporphyrin IX level in the subject's skin to less than 1.0 FDU. (Item 52) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 49, wherein the method reduces the protoporphyrin IX level in the subject's skin to less than 1.5 FDU. (Item 53) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 49, wherein the method reduces the protoporphyrin IX level in the subject's skin to less than 2.0 FDU. (Item 54) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 49, wherein the method reduces the protoporphyrin IX level in the subject's skin to less than 2.5 FDU. (Item 55) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 54, wherein the subject has an increased protoporphyrin IX level in red blood cells. (Item 56) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 55, wherein the method reduces the protoporphyrin IX level in the subject's red blood cells. (Item 57) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 56, wherein the method reduces the protoporphyrin IX level in the red blood cells 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%). (Item 58) The subject has a protoporphyrin IX level in red blood cells higher than 31 μmol / L -1 The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 57, wherein the subject has a protoporphyrin IX level in red blood cells higher than 31 μmol / L (Item 59) The subject has a protoporphyrin IX level in red blood cells of -1 ~53 μmol / L -1 The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the subject has a protoporphyrin IX level in red blood cells of 31 μmol / L to 53 μmol / L (Item 60) The subject has a protoporphyrin IX level in red blood cells higher than 53 μmol / L -1 The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the subject has a protoporphyrin IX level in red blood cells higher than 53 μmol / L (Item 61) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level less than 53 μmol / L -1 The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level less than 53 μmol / L (Item 62) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level less than 31 μmol / L -1 The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level less than 31 μmol / L (Item 63) The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level less than 15 μmol / L -1 The method according to any one of items 1 to 8, 10 to 15, 17 to 25, and 27 to 58, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level less than 15 μmol / L (Item 64) The method according to any one of items 1 to 7, 10 to 14, 17 to 25, and 27 to 63, wherein the ferrochelatase activity level of the subject is reduced to 10% to 35% of the ferrochelatase activity level observed in a normal subject (Item 65) The method according to any one of items 1 to 7, 10 to 14, 17 to 25, and 27 to 64, wherein the ferrochelatase activity level of the subject is reduced to less than 50% of the ferrochelatase activity level observed in a normal subject (Item 66) The method according to any one of items 1 to 6, 8, 10 to 15, 17 to 25, and 27 to 63, wherein the subject has a gain-of-function mutation in ALAS2. (Item 67) The method according to any one of items 1 to 6, 8, 10 to 15, 17 to 25, 27 to 63, and 66, wherein the ALAS2 enzyme activity of the subject is increased. (Item 68) The method according to any one of items 1 to 6, 8, 10 to 15, 17 to 25, 27 to 63, 66, and 67, wherein the subject has an increased zinc protoporphyrin IX level in erythrocytes. (Item 69) The method according to any one of items 1 to 6, 8, 10 to 15, 17 to 25, 27 to 63, and 66 to 68, wherein the method reduces the zinc protoporphyrin IX level in the erythrocytes of the subject. (Item 70) The method according to any one of items 1 to 6, 8, 10 to 15, 17 to 25, 27 to 63, and 66 to 69, wherein the method reduces the zinc protoporphyrin IX level in the erythrocytes 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%). (Item 71) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, and 39 to 42, wherein the subject has a decreased activity of uroporphyrinogen III synthase. (Item 72) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71, wherein the subject has an increased level of uroporphyrin I and / or coproporphyrin I. (Item 73) The method according to item 72, wherein the increased level of uroporphyrin I and / or coproporphyrin I is measured in the urine or erythrocytes of the subject. (Item 74) The method according to item 72, wherein the increased level of coproporphyrin I is measured in the feces of the subject. (Item 75) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 74, wherein the method reduces the level of uroporphyrin I and / or coproporphyrin I in the subject. (Item 76) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 74, wherein the method reduces the level of uroporphyrin I in the subject. (Item 77) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 76, wherein the method reduces the level of uroporphyrin I 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%). (Item 78) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 77, wherein the method reduces the level of coproporphyrin I in the subject. (Item 79) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 78, wherein the method reduces the level of coproporphyrin I 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%). (Item 80) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 79, wherein the subject has a mutation in UROS. (Item 81) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 80, wherein the subject has a gene deletion in the GATA-1 erythroid-specific transcription factor. (Item 82) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 81, wherein the subject has red fluorescent urine. (Item 83) The method according to any one of items 1 to 5, 9 to 13, 16 to 23, 26, 27, 31, 32, 39 to 42, and 71 to 82, wherein the subject has a peak at 615 nm to 620 nm using plasma porphyrin fluorescence analysis. (Item 84) The method according to any one of items 1 to 83, wherein the subject has a liver disease associated with EPP, XLPP, or CEP. (Item 85) The method according to any one of items 1 to 75, wherein the liver disease associated with the EPP, XLPP or CEP is cholelithiasis. (Item 86) The method according to any one of items 1 to 75, wherein the liver disease associated with the EPP, XLPP or CEP is a mild liver disease. (Item 87) The method according to any one of items 1 to 75, wherein the liver disease associated with the EPP, XLPP or CEP is a deterioration of liver disease. (Item 88) The method according to any one of items 1 to 75, wherein the liver disease associated with the EPP, XLPP or CEP is end-stage liver disease. (Item 89) The method according to any one of items 1 to 88, further comprising administering an additional active agent and / or supportive therapy to the subject. (Item 90) The method according to item 89, wherein the additional active agent and / or supportive therapy is selected from the group consisting of avoidance of sunlight, topical sunscreen, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, proteasome inhibitor, chemical chaperone, cholestyramine, activated carbon, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy and blood transfusion. (Item 91) The GlyT1 inhibitor is

Chem.

Chem.

Claims

1. A pharmaceutical composition for use in a method of treating erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLPP) in a subject, the composition comprising a compound of the formula 【Chemical Formula 93】 (vitopeltin) or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, wherein the subject has acute photosensitivity and / or cutaneous photosensitivity.

3. The composition according to claim 1, wherein the subject has EPP.

4. The composition according to claim 1, wherein the subject has XLPP.

5. The composition according to claim 2, wherein the acute photosensitivity is caused by sunlight exposure.

6. The composition according to claim 1, wherein the method increases painless light exposure in the subject.

7. The composition according to claim 1, wherein the method decreases photosensitivity in the subject.

8. The composition according to claim 1, wherein the accumulation of protoporphyrin IX (PPIX) is inhibited.

9. The composition according to claim 8, wherein the accumulation of PPIX is inhibited in a dose-dependent manner.

10. The composition according to claim 1, wherein vitopeltin demonstrates an EC50 of less than 100 nM.

11. The composition according to claim 8, wherein the subject has a PPIX level that is at least 10%, 20%, 30%, 40% or 50% higher than the PPIX level in a healthy subject prior to administration of vitopeltin.

12. The composition according to claim 8, wherein the PPIX level of the subject decreases while the hemoglobin level of the patient is substantially maintained.

13. The composition according to claim 1, wherein the hemoglobin level of the subject does not decrease by more than 10%.

14. The composition according to claim 1, wherein the free protoporphyrin IX level of the subject decreases by at least 50%.

15. The composition according to claim 1, wherein the method decreases the level of protoporphyrin IX in the feces of the subject.

16. The composition according to claim 1, wherein the method decreases the level of protoporphyrin IX in the skin of the subject.

17. The composition according to claim 1, wherein the method decreases the level of protoporphyrin IX in the skin of the subject to less than 0.5 FDU.

18. The composition according to claim 1, wherein the method decreases the level of protoporphyrin IX in the erythrocytes of the subject.

19. The composition according to claim 1, wherein the method reduces the protoporphyrin IX level in the red blood cells of the subject to a level of less than 53 μmol / L. －１ The composition according to claim 1, which reduces the protoporphyrin IX level in the red blood cells of the subject to a level of less than 53 μmol / L. Claim 20 The composition according to claim 1, wherein the method reduces the zinc protoporphyrin IX level in the red blood cells of the subject. Claim 21 The composition according to claim 1, wherein the method further comprises administering an additional active agent and / or supportive therapy to the subject. Claim 22 The composition according to claim 21, wherein the additional active agent and / or supportive therapy is selected from the group consisting of avoidance of sunlight, topical sunscreen, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, proteasome inhibitor, chemical chaperone, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. Claim 23 The composition according to claim 1, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

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