Methods of treating erythropoietic protoporphyria, x-linked protoporphyria, or congenital erythropoietic porphyria with glycine transport inhibitors

Abstract

Embodiments of the present invention relate to methods of preventing or treating erythropoietic protoporphyrinopathy (EPP), X-linked protoporphyrinopathy (XLPP) and / or congenital erythropoietic porphyrinopathy (CEP) and syndromes related thereto using a glycine transporter inhibitor, such as a GlyT1 inhibitor, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition thereof.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511025997.0 (22) Application Date 2021.01.08 (30) Priority Data 62 / 958,892 2020.01.09 US 63 / 085,942 2020.09.30 US (62) Divisional Application Data 202180019091.1 2021.01.08 (71) Applicant Disco Pharmaceuticals Company Address Massachusetts, USA (72) Inventors B.R. McDonald M.G. Becconi V. Hong (74) Patent Agency Beijing Kunrui Law Firm 11494 Patent Attorney Feng Xinqin (51) Int.Cl. A61K 45 / 00 (2006.01) A61K 31 / 496(2006.01) A61P 17 / 18(2006.01) A61P 17 / 00(2006.01) A61P 7 / 06(2006.01) A61P 7 / 00(2006.01) A61P 1 / 14(2006.01) A61P 17 / 02(2006.01) A61P 1 / 16(2006.01) A61P 17 / 16(2006.01) A61P 1 / 02(2006.01) A61P 7 / 10(2006.01) A61P 15 / 00(2006.01) A61P 19 / 08(2006.01) A61P 25 / 00 (2006.01) (54) Invention Title: Method for treating erythropoietic protoporphyria, X-linked protoporphyria or congenital erythropoietic porphyria with glycine transporter inhibitors (57) Abstract: Embodiments of the present invention relate to methods for preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP) and / or congenital erythropoietic porphyria (CEP) and related syndromes using glycine transporter inhibitors such as GlyT1 inhibitors or pharmaceutically acceptable salts, solvates or prodrugs or pharmaceutical compositions thereof. Claims: 1 page Description: 97 pages Drawings: 9 pages CN 121041437 A 2025.12.02 CN 1 21 04 14 37 A 1. A method for inhibiting PPIX synthesis in vivo, the method 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. 2. A method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in vivo, the method comprising administering GlyT1 inhibitor to a subject.3. A method for inhibiting the synthesis of uroporphyrin I and / or coproporphyrin I in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. 4. A method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. 5. The method of any one of claims 1-4, wherein the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. 6. The method of claim 5, wherein the accumulation of the one or more heme intermediates is inhibited in a dose-dependent manner. 7. The method of any one of the preceding claims, wherein the GlyT1 inhibitor exhibits an EC50 of less than 500 nM. 8. The method according to any one of the preceding claims, wherein the GlyT1 inhibitor exhibits an EC50 of less than 100 nM. 9. The method according to any one of the preceding claims, wherein at least 50% cell viability is maintained. 10. The method according to any one of the preceding claims, wherein at least 90% cell viability is maintained. Claims 1 / 1 Page 2 CN 121041437 A Method for treating erythropoietic protoporphyria, X-linked protoporphyria, or congenital erythropoietic porphyria with a glycine transporter inhibitor

[0001] This application is a divisional application of Chinese patent application No. 202180019091.1 (filed on January 8, 2021, entitled: Method for treating erythropoietic protoporphyria, X-linked protoporphyria, or congenital erythropoietic porphyria with a glycine transporter inhibitor).

[0002] Related Applications

[0003] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 958,892, filed January 9, 2020, and U.S. Provisional Patent Application No. 62 / 085,942, filed September 30, 2020, which are incorporated herein by reference in their entirety. Technical Field

[0004] The embodiments disclosed herein relate to methods and uses for the prevention or treatment of erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP) with glycine transporter inhibitors, such as, but not limited to, GlyT1 inhibitors or pharmaceutically acceptable salts, solvates, prodrugs, or pharmaceutical compositions thereof. Background Art

[0005] Erythropoietic protoporphyria (EPP) is prevalent globally, affecting 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 that varies in severity and can be very painful. It arises from a deficiency of ferrochelate synthase, leading to abnormally high levels of protoporphyrin IX in red blood cells, plasma, skin, and liver. Erythropoietic protoporphyria (EPP) is caused by a hereditary or acquired defect in ferrochelate synthase activity. X-linked protoporphyria (XLPP) is caused by a hereditary increase in δ-aminolevulinic acid synthase-2 (ALAS2) activity. The enzymes causing both EPP and XLPP are involved in the heme biosynthesis pathway. EPP and XLPP are clinically very similar. Congenital erythropoietic porphyria (CEP), also known as Gunther's disease, is caused by mutations in the uroporphyrinogen synthase gene, leading to reduced enzyme activity 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 novel methods and compositions for the treatment and / or prevention of 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 meet these and other needs.

[0006] This application provides a method for treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP), the method comprising administering a pharmaceutical composition to the subject, the 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.

[0007] This application also provides a method for preventing, treating, or reducing the rate of progression and / or severity of complications of one or more of EPP, XLPP, or CEP in a subject, the method comprising administering a pharmaceutical composition to the subject, the 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. In some implementations, one or more complications of EPP, XLPP, or CEP are selected from: acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mildSevere hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scars, deformities, nail loss, toe loss, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, end-stage liver disease, red teeth syndrome, high-cytosis bone marrow, spinal dysplasia, thrombocytopenia, fetal hydrops and / or intrauterine death. In some such embodiments, the acute photosensitivity is due to sun exposure.

[0008] This application further provides a method for preventing or treating a subject with EPP, XLPP or CEP, wherein the method 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] This application further provides a method for preparing a pharmaceutical agent for treating a subject with EPP, XLPP, or CEP, the method comprising 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.

[0010] This application further provides a method for preparing a pharmaceutical agent for inhibiting the synthesis of protoporphyrin IX (PPIX) in vivo, the method comprising 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.

[0011] In some embodiments, the subject has EPP. In other embodiments, the subject has XLPP. In still other embodiments, the subject has CEP.

[0012] In some embodiments, the method increases the subject's painless light exposure. In other embodiments, the method reduces the subject's photosensitivity.

[0013] This application further provides a method for inhibiting the synthesis of PPIX in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0014] This application further provides a method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0015] This application further provides a method for inhibiting the synthesis of uroporphyrin I and / or coproporphyrin I in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0016] This application further provides a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in vivo, the method comprising...The method includes administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, to a subject.

[0017] In some embodiments, the accumulation of one or more heme intermediates is inhibited, and said one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some such embodiments, the accumulation of said one or more heme intermediates is inhibited in a dose-dependent manner.

[0018] In some embodiments, the GlyT1 inhibitor exhibits an EC50 of less than 500 nM. In some embodiments, the GlyT1 inhibitor exhibits an EC50 of less than 100 nM.

[0019] In some embodiments, at least 50% cell viability is maintained. In some embodiments, at least 90% cell viability is maintained. Instructions for Use, Page 2 / 97, CN 121041437 A

[0020] In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's PPIX level is at least 10%, 20%, 30%, 40%, or 50% higher than that of a healthy subject.

[0021] In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's ZPPIX level is at least 10%, 20%, 30%, 40%, or 50% higher than that of a healthy subject.

[0022] In some embodiments, compared to a subject with EPP, the subject has an increased ratio of ZPPIX to free protoporphyrin IX (ZPPIX / PPIX ratio).

[0023] In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's uroporphyrin I and / or coprophyrin I levels were at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects.

[0024] In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's 5-ALA levels were at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects.

[0025] In some embodiments, the subject's PPIX levels were reduced, while the patient's heme levels were significantly maintained. In some embodiments, the patient's PPIX level is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the patient's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient's PPIX level is reduced by at least 85% and the patient's heme level is reduced by no more than 15%. In some embodiments, the heme level is reduced by no more than 10% (e.g., 10%).15%, 20%, 25%, and 30%. In some embodiments, the dosage of the pharmaceutical composition does not cause a significant decrease in heme levels.

[0026] In some embodiments, the level of free protoporphyrin IX in the red blood cells of the subject increases. In some embodiments, the method reduces the level of free protoporphyrin IX in the subject. In some such embodiments, the method reduces the level 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 some embodiments, the level of protoporphyrin IX in the feces of the subject increases. In some embodiments, the method reduces the level of protoporphyrin IX in the feces of the subject. In some such embodiments, the method reduces the level of protoporphyrin IX in the subject's feces 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%).

[0027] In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's plasma porphyrins fluoresce at a peak of 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's plasma porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's skin porphyrins fluoresce at a peak of 632 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's skin porphyrins fluoresce at a peak between 626 nm and 634 nm.

[0028] In some embodiments, the level of protoporphyrin IX in the subject's skin increases. In some embodiments, the method reduces the level of protoporphyrin IX in the subject's skin. In some such embodiments, the method reduces the level of protoporphyrin IX 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 some embodiments, the level of protoporphyrin IX in the subject's skin is greater than 0.2 fluorescent units (FDU). In some embodiments, the level of protoporphyrin IX in the subject's skin is greater than 1.0 FDU. In some implementations, the level of protoporphyrin IX in the subject's skinBetween 1.0 FDU and 2.5 FDU. In some embodiments, the protoporphyrin IX level in the subject's skin is greater 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 of the specification (page 3 / 97, CN 121041437 A), 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.

[0029] In some embodiments, the protoporphyrin IX level in the subject's erythrocytes increases. In some embodiments, the method reduces the protoporphyrin IX level in the subject's erythrocytes. In some such embodiments, the method reduces the level of 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%). In some embodiments, the level of protoporphyrin IX in the subject's erythrocytes is greater than 31 μmol L⁻¹. In some embodiments, the level of protoporphyrin IX in the subject's erythrocytes is between 31 μmol L⁻¹ and 53 μmol L⁻¹. In some embodiments, the level of protoporphyrin IX in the subject's erythrocytes is greater than 53 μmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the subject's erythrocytes to below 53 μmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the subject's erythrocytes to below 31 μmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the subject's erythrocytes to below 15 μmol L⁻¹.

[0030] In some embodiments, the subject's ferrochelate activity level is reduced to between 10% and 35% of the ferrochelate activity level observed in normal subjects. In some embodiments, the subject's ferrochelate activity level is reduced to below 50% of the ferrochelate activity level observed in normal subjects.

[0031] In some embodiments, the subject has a gain-of-function mutation in ALAS2. In some embodiments, the subject's ALAS2 enzyme activity is increased.

[0032] In some embodiments, the subject's zinc protoporphyrin IX level in erythrocytes is increased. In some embodiments,The method reduces the level of zinc protoporphyrin IX in the red blood cells of the subject. In some such embodiments, the method reduces the level of zinc protoporphyrin IX 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%).

[0033] In some embodiments, the urinary porphyrinogen III synthase activity of the subject is reduced. In some embodiments, the urinary porphyrin I and / or coprophyrin I levels of the subject are increased. In some embodiments, the increased urinary porphyrin I and / or coprophyrin I levels are measured in the urine or red blood cells of the subject. In some embodiments, the increased coprophyrin I levels are measured in the feces of the subject. In some embodiments, the method reduces the subject's urinary porphyrin I and / or coprophyrin I levels. In some embodiments, the method reduces the subject's urinary porphyrin I levels. In some embodiments, the method reduces the subject's urinary porphyrin I levels by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's coprophyrin I levels. In some embodiments, the method reduces the subject's coprophyte I level by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0034] In some embodiments, the subject has a mutation in UROS.

[0035] In some embodiments, the subject has a gene defect in the GATA-1 erythroid-specific transcription factor.

[0036] In some embodiments, the subject has red fluorescent urine. In some embodiments, using plasma porphyrin fluorescence analysis, the subject has a peak between 615 nm and 620 nm.

[0037] In some embodiments, the subject has liver disease associated with EPP, XLPP, or CEP. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is cholelithiasis. In some embodiments, liver disease associated with EPP, XLPP, or CEP (see page 4 / 97, CN 121041437 A) is mild liver disease. In some embodiments, liver disease associated with EPP, XLPP, or CEP is severe liver disease. In some embodiments, liver disease associated with EPP, XLPP, or CEP is end-stage liver disease.

[0038] In some embodiments, the method further includes administering additional active agents and / or supportive therapies to the subject. In some such embodiments, the additional active agents and / or supportive therapies are selected from: sun avoidance, local sun protection, skin protection, UVB phototherapy, afanotide bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0039] In some embodiments, the GlyT1 inhibitor is a compound having the formula I, wherein Ar is an unsubstituted or substituted aryl group or a 6-membered heteroaryl group containing 1, 2 or 3 nitrogen atoms, wherein the substituted aryl group and the substituted heteroaryl group are substituted by one or more substituents selected from: hydroxyl, halogen, NO2, CN, (C1-C6)-alkyl, halogen-substituted (C1-C6)-alkyl, hydroxyl-substituted (C1-C6)-alkyl, (CH2)n-(C1-C6)-alkoxy, halogen-substituted (C1-C6)-alkoxy, NR7R8, C(O)R9, SO2R10 and -C(CH3)=NOR7, or substituted by a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N and O, wherein the aromatic heterocycle is optionally substituted by (C1-C6)-alkyl. R1 is hydrogen or (C1-C6)-alkyl; R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen-substituted (C1-C6)-alkyl, hydroxyl-substituted (C1-C6)-alkyl, optionally (C1-C6)-alkoxy or halogen-substituted (CH2)n-(C3-C7)-cycloalkyl, CH(CH3)-(C3-C7)-cycloalkyl, (CH2)n+1-C(O)-R9, (CH2)n+1-CN, bicyclo[2.2.1]heptyl, (CH2)n+1- O-(C1-C6)-alkyl, (CH2)n-heterocyclic alkyl, (CH2)n-aryl, or (CH2)n-5 or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein the aryl, heterocyclic alkyl, and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from hydroxyl, halogen, (C1-C6)-alkyl, and (C1-C6)-alkoxy; R3, R4, and R6 are each independently hydrogen, hydroxyl, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, or O-(C3-C6)-cycloalkyl; R5 is NO2, CN, C(O)R9, or SO2R10. R7 and R8 are each independently hydrogen or (C1-C6)-alkyl; R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, or NR7R8; R10 is optionally halogen-substituted (C1-C6)-alkyl, (CH2)n-(C3-C6)-cycloalkyl, (CH2)n-(C3-C6)-alkoxy, or (CH2)n-heterocyclic alkyl.The compound is a compound having the formula NR7R8; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the GlyT1 inhibitor is a compound having the formula bitopertin or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof. Specification 5 / 97 pages 7 CN 121041437 A

[0041] In some embodiments, the GlyT1 inhibitor is a compound having the formula II, wherein R1 represents a heteroaryl group selected from: imidazolyl, thiazolyl, pyridinyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrroloimidazolyl, and thiadiazole, wherein the heteroaryl group is optionally substituted by one or more substituents selected from: -OH, -NR7R8, halogen, (C1-C8)alkyl, (C3-C10)cycloalkyl, (C1-C8)alkoxy, (C1- (C12)alkoxyalkyl, (C1-C8)hydroxyalkyl, (C6-C14)aryl, and benzyl; R2, R3, and A independently represent H or (C1-C8)alkoxy, wherein the alkyl group is optionally substituted with 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-C14)aryl, (C1-C8)alkyl or (C3-C8)cycloalkyl; R4 and R5 each independently represent H, halogen, (C1-C8)alkyl, (C6-C14)aryl, (C6-C14)aryloxy, (C1-C8)alkoxy, (3-10)heterocyclic alkyl or (C3-C8)cycloalkoxy; wherein R4 and R5 are optionally substituted by one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen; Y represents -R6, -(CH2)o-R6, -C(R6)3 or -CH(R6)2, where 0 =1, 2, or 3; R6 represents H, (C6-C14)aryl, (C1-10)alkyl, (C3-C10)cycloalkyl, (C5-C18)bicycloalkyl, (C5-C18)tricycloalkyl, (3-10-membered)heterocyclic alkyl, (5-10-membered)heteroaryl, -C(=O)NR7R8, or -C(=O)OR7, wherein the R6 group may optionally be substituted by one or more X groups; wherein X = -OH, (C1-C8)alkoxy, -NR11R12, -SO2R10, -C(=O)R10, halogen, cyano, (C1-C8)alkyl, (C1-C10)alkoxyalkyl, (5-10-membered)heteroaryl, (C6-C14)aryl, (C6-C14) aryloxy, benzyl, or (C1-C8) hydroxyalkyl; wherein R7 and R8 independently represent H, (C1-C8) alkyl, or (C3-C8) cycloalkyl.Alkyl, (5-10-membered) heterocyclic alkyl, (C1-C8) hydroxyalkyl, (5-10-membered) heteroaryl, or (C1-C10) alkoxyalkyl; wherein R7 and R8 may optionally be substituted with one or more X groups; or R7 and R8 together with nitrogen to which they may be attached can form (3-10-membered) heterocyclic alkyl, optionally substituted with one or more X groups; wherein R10 represents (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10-membered) heterocyclic alkyl, (C1-C8) hydroxyalkyl, (5-10-membered) heteroaryl, or (C1-C10) alkoxyalkyl; wherein R11 and R12 independently represent H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10-membered) heterocyclic alkyl, (C1-C8) hydroxyalkyl, or (5-10-membered) alkyl. Heteroaryl or (C1-C10)alkoxyalkyl; or a pharmaceutically acceptable salt thereof or a prodrug of said compound or a pharmaceutically acceptable salt thereof. In some such embodiments, the GlyT1 inhibitor is a compound having the formula PF-3463275 or a pharmaceutically acceptable salt thereof or a prodrug of said compound or a pharmaceutically acceptable salt thereof. In other such embodiments, the GlyT1 inhibitor is a compound having the formula PF-3463275 or a pharmaceutically acceptable salt thereof or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the GlyT1 inhibitor is a compound having the formula III Compounds of the formula Z1 are selected from C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, halo-C1-4 alkyl, phenyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkylthionyloxy, C1-4 alkylsulfonyl, bromine, and chlorine; Z2 is selected from hydrogen, halogen, cyano, C1-4 alkyl, phenyl, halo-C1-4 alkyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkoxy-C1-4 alkyl, and C3-6 cycloalkyl; Z3 is selected from... R1 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-C1-4 alkyl, halo-C1-4 alkoxy, and C3-6 cycloalkyl; Z4 is selected from hydrogen, halogen, C1-3 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkoxy-C1-4 alkyl, and C3-6 cycloalkyl; Z5 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, halo-C1-4 alkyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkoxy-C1-4 alkyl, and C3-6 cycloalkyl; wherein if more than one of Z1 to Z5 is methoxy, then only Z1 and Z5 are methoxy, and R3 and R4 are independently selected from hydrogen and anyC1-4 alkyl groups optionally substituted with one or more groups Y; or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated A, 5, 6, or 7-membered carbon ring optionally substituted with group Y'; Y is selected from C1-4 alkoxy, hydroxyl, halo-C1-4 alkoxy, and C3-5 cycloalkyl; Y' is selected from C1-4 alkyl, C1-4 alkoxy, halogen, hydroxyl, halo-C1-4 alkoxy, C3-5 cycloalkyl, and C5-10 aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on the A, 5, 6, or 7-membered carbon ring; R5 and R6 are independently optionally substituted with one or more groups X. C1-4 alkyl; or R5 and R6 together with the carbon atoms to which they are attached form a saturated 5- or 6-membered carbon ring optionally substituted with one or more groups X'. In the case where R5 and R6 together with the carbon atoms to which they are attached form a 5-membered saturated carbon ring, the ring may optionally further comprise additional heteroatomic groups selected from O, N, and S(O)m, where m = 0, 1, or 2; X is selected from halogen, hydroxyl, C1-4 alkoxy, halo-C1-4 alkyl, halo-C1-4 alkoxy, and C5-10 aryl; and X' is selected from halogen, hydroxyl, C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkyl, halo-C1-4 alkoxy, and C5-10 aryl. Aryl; wherein R3, R4, R5, and R6 are not all simultaneously unsubstituted methyl groups; provided that when Z1 is propoxy, Z3 is chlorine, Z2 = Z4 = Z5 = H, and R5 and R6 are both methyl, then R3 and R4 together with their attached nitrogen atoms do not form a 2-methylpyrrolyl group; when Z1 is methyl, Z3 is methoxy, Z2 = Z4 = Z5 = H, and R5 and R6 are both methyl, then R3 and R4 together with their attached nitrogen atoms do not form a pyrrolyl group, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In some such embodiments, the Gly T1 inhibitor is a compound having formula (page 7 / 97, ​​CN 121041437 A) or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the GlyT1 inhibitor is a compound having the formula IV, wherein Z is (CH2)n, O, S, SO, SO2, or N-R5; n is 0, 1, or 2; X represents 1-3 substituents independently selected from hydrogen, halogen, (C1-6)alkoxy, (C3-6)cycloalkoxy, (C6-12)aryloxy, (C6-12)aryl, thiophene, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6, and (C1-4)alkyl, optionally substituents of halogen, (C6-12)aryl,(C1-6)alkoxy or (C6-12)aryloxy substitution; or two substituents in adjacent positions together represent fused (C5-6)aryl, fused (C5-6)cycloalkyl, or O-(CH2)m-O; m is 1 or 2; Y represents 1-3 substituents independently selected from hydrogen, halogen, (C1-4)alkoxy, SR6, NR6R6, and (C1-4)alkyl, optionally substituted with halogen; R1 is COOR7 or CONR8R9; R2 and R6 are (C1-4)alkyl; R3, R4, and R5 are independently hydrogen or (C1-4)alkyl; R7, R8, and R9 are independently hydrogen, (C1-4)alkyl, (C6-12)aryl, or aralkyl, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In some such embodiments, the GlyT1 inhibitor is a compound having formula

[0044] or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the GlyT1 inhibitor is

[0046] a compound having formula V, wherein n is an integer from 1 to 3; R1 and R2 are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic groups, wherein the aforementioned ring is optionally substituted by Ra, Rb, or Rc, wherein Ra, Rb, or Rc is independently selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, monosubstituted amino, or disubstituted amino; or R1 and R2, when attached to the same carbon atom, can combine to form a cycloalkyl or monocyclic saturated heterocyclic group to obtain a spirocyclic group, wherein the cycloalkyl or monocyclic saturated heterocyclic group may optionally be substituted by Rd, Rc, or Rf. The substitutions, wherein Rd, Rc, or Rf are independently selected from alkyl, alkoxy, fluorine, fluoroalkyl, fluoroalkoxy, hydroxyl, monosubstituted amino, or disubstituted amino; or R1 and R2, when attached to carbon atoms at positions 2 and 5 or 3 and 6 of the piperazine ring, can combine to form a -C1-C3-alkyl chain, wherein one carbon atom of the alkyl chain is optionally replaced by -NR-, -O-, -S(O)n- (where R is hydrogen or alkyl and n is 0-2), and further wherein one or two hydrogen atoms of the alkyl chain may optionally be replaced by one or two alkyl groups; R3, R4, and R5 are independently hydrogen, alkyl, fluorine, or fluoroalkyl; and Ar1 and Ar2 are independently aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein each of the above rings is optionally replaced by Rg, Rh, or Ri, wherein Rg is an alkyl, -C=C- R6 (where R6 is aryl or heteroaryl), halogen, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkylThe group Rh and Ri are independently selected from alkyl, halogen, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acyl, aryl, heteroaryl, cycloalkyl, or heterocyclic. The aromatic or alicyclic rings in Rg, Rh, and Ri are optionally substituted by Rj, Rk, or Rl, wherein Rj, Rk, or Rl is independently selected from alkyl, halogen, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or amide; or pharmaceutically acceptable salts thereof, provided that: the compound of formula V is not 2-(4-diphenylmethylpiperazin-1-yl)acetic acid, 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid, 2-((2R,5S)-4-((R)-(4-(1H-tetrazol-5-yl)phenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin- 1-yl)acetic acid, or 2-((2R,5S)-4-((R)-(4-cyanophenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)acetic acid, or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof. In some such embodiments, the GlyT1 inhibitor is a compound having the formula, or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the GlyT1 inhibitor is a compound having the formula VI, wherein A represents a group of the general formula N-R1, the general formula N+(O-)R1, or the general formula N+(R')R1, and wherein R1 represents a hydrogen atom, or a straight-chain or branched (C1-C7) alkyl, or (C4-C7) cycloalkyl, or (C3-C7) cycloalkyl (C1-C3) alkyl, or a phenyl (C1-C3) alkyl, optionally substituted with one or two hydroxyl or methoxy groups, . R' represents a (C2-C4)alkenyl or (C2-C4)ynyl; R' represents a straight-chain or branched (C1-C7) alkyl group; X represents a hydrogen atom or one or more substituents selected from halogen atoms and trifluoromethyl, straight-chain or branched (C1-C4) alkyl and (C1-C4) alkoxy groups; R2 represents a hydrogen atom or one or more substituents selected from halogen atoms and trifluoromethyl, (C1-C4) alkyl or (C1-C4) alkoxy groups, or...The amino group of formula NR3R4, wherein R3 and R4 each independently represent a hydrogen atom or a (C1-C4) alkyl group, or together with the nitrogen atom carrying them to form a pyrrolidine, piperidine, or morpholine ring, or optionally substituted with an atom or group as defined above for the symbol X, or a phenyl group, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In some such embodiments, the GlyT1 inhibitor is a compound having formula

[0048] or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the GlyT1 inhibitor is a compound having the formula VII, wherein R1 is -(CH2)n-R1a, wherein n is independently 0-6, and R1a is selected from: (1) C1-6 alkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups, (2) phenyl substituted with R2a, R2b and R2c, (3) C3-6 cycloallyl, which is unsubstituted or substituted with C1-6 alkyl, 1-6 halogens, hydroxyl groups or -NR10R11, (4) -O-C1-6 alkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11, (5) -CO2R9, wherein R9 is independently selected from: (a) hydrogen, (b) -C1-6 alkyl, which is unsubstituted or substituted with 1-6 fluorine groups, (c) benzyl, and (d) phenyl,

[0050] (6) -NR10R11, wherein R10 and R11 are independently selected from: (a) hydrogen, (b) -C1-6 alkyl, which is unsubstituted or substituted with hydroxyl, 1-6 fluorine or -NR12R13, wherein R12 and R13 are independently selected from hydrogen and -C1-6 alkyl, (c) -C3-6 cycloalkyl, which is unsubstituted or substituted with hydroxyl, 1-6 fluorine or -NR12R13, (d) benzyl, (e) phenyl, and (7) -CONR10R11; R2 is selected from: (1) phenyl, which is substituted with R2a, R2b and R2c, (2) C1-8 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl, -NR10R11, phenyl or heterocyclic, wherein the phenyl or heterocyclic is substituted with R2a, R2b and R2c, (3) C3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, (3) hydroxyl or -NR10R11 substituted, and (4) -C1-6 alkyl-(C3-6 cycloalkyl), which is unsubstituted or substituted with 1-6 halogens, hydroxyl or -NR10R11; R2a, R2b and R2c are independently selected from: (1) hydrogen, (2) halogen, (3) -C1-6 alkyl, which is unsubstituted or substituted with: (a) 1-6 halogens, (b) phenyl, (c) C3-6 cycloalkyl or (d) -NR10R11, (4) -O-C1-6 alkyl, which is unsubstituted orReplaced by 1-6 halogens: (5) hydroxyl, (6)-SCF3, (7)-SCHF2, (8)-SCH3, (9)-CO2R9, (10)-CN, (11)-SO2R9, (12)-SO2-NR10R11, (13)-NR10R11, (14)-CONR10R11 and (15)-NO2; R3 The compound is selected from: (1) C1-6 alkyl groups that are unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11; (2) C3-6 cycloalkyl groups that are unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11; R4 and R5 are independently selected from: (1) hydrogen and (2) C1-6 alkyl groups that are unsubstituted or substituted with halogens or hydroxyl groups, or R4 and R5 together form a C3-6 cycloalkyl ring; A is selected from: (1) -O- and (2) -NR10-; m is 0 or 1, wherein when m is 0, R2 is directly attached to the carbonyl group; and pharmaceutically acceptable salts thereof and their individual enantiomers and diastereomers, or pharmaceutically acceptable salts thereof or prodrugs of the compound or pharmaceutically acceptable salts thereof. In some such embodiments, as described on pages 10 / 97 of CN 121041437 A, a GlyT1 inhibitor is a compound having the formula VIII or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, a GlyT1 inhibitor is a compound having the formula VIII, wherein R1 is a phenyl group independently substituted 1 to 5 times with a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, OR9, or SR10, wherein the C1-C3 alkyl group and the C3-C6 cycloalkyl group are optionally substituted 1 to 10 times with R7; R2 is H; R3 and R4 are each independently H or CH3; R5 The following are selected from: (1) hydrogen, (2) a C1-C6 alkyl group optionally substituted 1 to 11 times with R7, (3) a geminal dialkyl group, and (4) a geminal dihalogenated group; or two R5 substituents on the same carbon atom together with the carbon atom to which they are attached can form a 3, 4 or 5-membered cycloalkyl group optionally substituted 1 to 10 times with R7; or two R5 substituents on adjacent carbons of the ring to which they are attached can together form a 3, 4, 5 or 6-membered cycloalkyl group optionally substituted 1 to 10 times with R7; R6 is wherein E, F and G are each independently nitrogen or carbon, and R6a is a C1-C2 alkyl group optionally substituted 1 to 5 times with halogen or deuterium; R7 is selected from: (1) hydrogen, (2) halogen, (3) deuterium, (4) geminal dialkyl group, (5) geminal dihalogenated group, (6) -OR9, -NR11R12, -NR11C(O)pR 10,‑S(O)pR 10,‑CN,‑NO2,‑C(O)pR 10,‑C(O)NR11R12 or -NR11C(S)R10, and (7) oxo or thio; R8 is selected from: (1) hydrogen, (2) halogen, (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl or C4-C7 cycloalkylalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each independently and optionally substituted by R7 1 to 11 times, or (4) -OR9, -NR11R12, -NR11C(O)pR10, -S(O)pR10, -CN, -NO2, -C(O)pR10, -C(O)NR11R12 or -NR11C(S)R10; R9 is selected from hydrogen, C1-C4 Alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR11R12 and -C(O)pR10, wherein the C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally substituted by R7 1 to 11 times; R10 is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein the C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally substituted by substituents as defined in R7 1 to 11 times, and the aryl or heteroaryl is optionally substituted by R8 1 to 10 times; R11 and R12 Each is independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, wherein the C1-C4 alkyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl are each optionally substituted 1 to 11 times by substituents as defined in R7, and the aryl or heteroaryl is optionally substituted 1 to 10 times by R8, or R11 and R12 together with the nitrogen to which they are attached form a group optionally substituted by R7. (Specification 11 / 97 pages 13 CN 121041437 A) The substituted monocyclic or fused bicyclic heterocycle is 1 to 11 times saturated or partially saturated; A is N; X is N; Y is N; p is 1 or 2; and m is 0; provided that R6 is not (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl; or an oxide thereof, a pharmaceutically acceptable salt of said compound or its oxide, or either an enantiomer or diastereomer thereof.

[0052] In some embodiments, the GlyT1 inhibitor is a compound having the formula

[0053] Specification 12 / 97 pages 14 CN 121041437 A

[0054] Specification 13 / 97 pages 15 CN 121041437 A

[0055] or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or its pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the GlyT1 inhibitorIt is a compound of formula IX, wherein R1 represents a phenyl or a 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N, or S, wherein the phenyl or heteroaryl is optionally substituted by one or more R3; R2 represents an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl, wherein the monocyclic or bicyclic heteroaryl has 1, 2, or 3 heteroatoms independently selected from O, N, or S, wherein the aryl or heteroaryl is optionally substituted by one or more R4; R3 is a halogen, a C1-4 alkyl, or a C3-6 cycloalkyl, wherein the C1-4 alkyl or C3-6 cycloalkyl is optionally substituted by one or more halogens; and R4 is a halogen, -CN, C1-4 alkyl, C3-6 cycloalkyl, -C1-3 alkyl-C3-6 cycloalkyl, or -O-C1-6 alkyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, - C1-3 alkyl, C3-6 cycloalkyl, or O-C1-6 alkyl may optionally be substituted with one or more halogens; or a pharmaceutically acceptable salt thereof, or a tautomer or stereoisomer of the compound or a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0057] In some embodiments, the GlyT1 inhibitor is a compound of formula X, wherein R1 is selected from a) a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S(O)r; b) a 5- or 6-membered monocyclic partially saturated heterocyclic alkyl group having 1, 2, or 3 heteroatoms independently selected from O, N, and S(O)r; and c) a 9- or 10-membered bicyclic heteroaryl group having 1, 2, or 3 heteroatoms independently selected from O, N, and S(O)r, wherein r is 0, 1, or 2; wherein each of the groups a), b), and c) is optionally substituted by one or more substituents independently selected from: C1-4-alkyl-, C1-4- Alkyl-O-, oxetane-butyl, tetrahydrofuranyl, tetrahydropyranyl, C3-6-cycloalkyl-, and C3-6-cycloalkyl-O-, and when the substituent is attached to a nitrogen ring atom, the substituent is selected from C1-4-alkyl-, C1-4-alkyl-CO-, C3-6-cycloalkyl-, and C3-6-cycloalkyl-CO-, and wherein the C1-4-alkyl-, C1-4-alkyl-O-, C1-4-alkyl-CO-, oxetane-butyl, The tetrahydrofuranyl, tetrahydropyranyl, C3-6-cycloalkyl-, C3-6-cycloalkyl-CO-, or C3-6-cycloalkyl-O- substituents may be substituted by one or more substituents independently selected from fluorine, -CF3, -CHF2, -CH2F, and -CN; R2 is selected from hydrogen, C1-4-alkyl-, C1-4-alkyl-O-, -CN, and C3-6-cycloalkyl-, wherein each of the C1-4-alkyl-, C1-4-alkyl-O-, and C3-6-cycloalkyl groups may be optionally substituted. (See page 14 / 97 of the specification, 16 CN 121041437 A)The base is substituted with 1, 2, 3 or more substituents independently selected from fluorine, -CF3, -CHF2, -CH2F and -CN; R3 is selected from C1-6-alkyl-O-, C3-6-cycloalkyl-O-, morpholino, pyrazolyl and 4 to 7-membered monocyclic heterocyclic alkyl-O-, having one oxygen atom as a ring member and optionally one or two heteroatoms independently selected from O, N and S(O)s, wherein s = 0, 1 or 2, wherein the C1-6-alkyl-O- The C3-6 cycloalkyl-O- may optionally be substituted with 1, 2, 3 or more substituents independently selected from fluorine, -CF3, -CHF2, -CH2F, -CN, C1-4-alkyl-, C3-6-cycloalkyl-, C1-6-alkyl-O- and C3-6-cycloalkyl-O-; R4 is hydrogen; or R3 and R4 together with the ring atom of the phenyl to which they are attached may form a 4, 5 or 6-membered monocyclic partially saturated heterocyclic alkyl or heteroaryl group, each having 1, 2 or 3 heteroatoms independently selected from O, N and S(O)s, where s = 0, 1 or 2, wherein in general formula (I) there must be one epoxy atom directly attached to the ring carbon atom of the phenyl to which R3 is attached; wherein the heterocyclic alkyl may optionally be substituted with 1, 2, 3 or more substituents independently selected from: fluorine, -CF3, - CHF2, -CH2F, -CN, C1-4-alkyl-, C3-6-cycloalkyl-, C1-6-alkyl-O-, C3-6-cycloalkyl-O-, oxacyclobutyl-O-, tetrahydrofuranyl-O-, and tetrahydropyranyl-O-; R5 is hydrogen; R6 is selected from hydrogen, C1-4-alkyl-SO2-, C3-6-cycloalkyl-SO2-, and -CN; R7 is hydrogen; or a) one of the pairs of R6 and R7 or b) one of the pairs of R6 and R5 together with the ring atom of the phenyl to which they are bonded forms a 5- or 6-membered partially saturated monocyclic heterocyclic alkyl group having 1, 2, or 3 heteroatoms independently selected from O, N, and S(O)u, where u = 0, 1, or 2, wherein in general formula (I) there must be one -SO2- directly bonded to the ring carbon atom of the phenyl to which R6 is bonded. Member; wherein the heterocyclic alkyl group may optionally be substituted by 1, 2, 3 or more substituents independently selected from: fluorine, -CF3, -CHF2, -CH2F, -CN, C1-4-alkyl-, C1-6-alkyl-O- and C3-6-cycloalkyl-O- or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0059] In some embodiments, the subject is a subject in need.

[0060] In some embodiments, a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of said GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount. Brief Description of the Drawings

[0061] Figure 1 shows the Western blot determination of ferrochelate (FECH) protein expression levels in various K562 clones.

[0062] Figure 2 shows the flow cytometry determination of protoporphyrin IX (PPIX) levels in K562 clones.

[0063] Figure 3 shows the heme and PPIX levels in WT K562 and clone 1-9 cells as determined by LC / MS / MS.

[0064] Figure 4 shows the effects of bitopertin and PF-03463275 on PPIX levels as determined by flow cytometry.

[0065] Figure 5 shows the effects of bitopertin and PF-03463275 on cell viability as measured by the Vi-CELL XR complete system.

[0066] Figure 6 shows the effect of bitopertin treatment on 5-aminolevulinic acid (5-ALA) levels in clone 1-9 cells.

[0067] Figure 7 shows the effect of bitopertin treatment on PPIX levels in clone 1-9 cells.

[0068] Figure 8 shows the effect of bitopertin treatment on heme levels in clones 1-9.

[0069] Figure 9 shows the relative FECH mRNA levels in human hematopoietic stem cells after transduction with a lentiviral vector expressing FECH shRNA.

[0070] Figure 10 shows the flow cytometry determination of the effect of bitopertin treatment on erythroid cell antigen profiles and protoporphyrin IX (PPIX) levels in human hematopoietic stem cells.

[0071] Figure 11 shows that treatment with biotopertin (100 nM) reduced PPIX accumulation by 60%. Specification 15 / 97 pages 17 CN 121041437 A Detailed Description

[0072] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments pertain.

[0073] As used herein, unless the context clearly indicates otherwise, “a” means “at least one” or “one or more”.

[0074] As used herein, the term “about” means an index value that is approximate and small variations will not significantly affect the practice of the disclosed embodiments. Where numerical limits are used, the “about” index value may vary by ±10% and remain within the range of the disclosed embodiments unless the context otherwise indicates.

[0075] The term “acyl” is recognized in the art and refers to a group represented by the general formula hydrocarbon C(O)-, preferably alkyl C(O)-.

[0076] As used herein, the term “amide” means a group replaced by an acyl group (e.g., -O-C(=O)-H or -O-C(=O)-alkyl).The amino group is substituted. Examples of acylamino groups are -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" refers to an amino group substituted with a lower acyl group (e.g., -O-C(=O)-H or -O-C(=O)-C1-6 alkyl). Examples of lower acylamino groups are -NHC(=O)H or -NHC(=O)CH3.

[0077] The term "acyloxy group" is recognized in the art and refers to a group represented by the general formula alkyl group C(O)O-, preferably alkyl group C(O)O-.

[0078] As used herein, the term "alkenyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds and 2-20 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In some embodiments, the alkenyl chain has a length of 2 to 10 carbon atoms, a length of 2 to 8 carbon atoms, a length of 2 to 6 carbon atoms, or a length of 2 to 4 carbon atoms.

[0079] The terms “alkoxy,” “phenoxy,” “benzyloxy,” and “pyrimidinoxy” refer to each optionally substituted alkyl, phenyl, benzyl, or pyrimidinyl group bonded by an oxygen atom. For example, the term “alkoxy” refers to a straight-chain or branched -O-alkyl group of 1 to 20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, etc. In some embodiments, the alkoxy chain has a length of 1 to 10 carbon atoms, a length of 1 to 8 carbon atoms, a length of 1 to 6 carbon atoms, a length of 1 to 4 carbon atoms, a length of 2 to 10 carbon atoms, a length of 2 to 8 carbon atoms, a length of 2 to 6 carbon atoms, or a length of 2 to 4 carbon atoms.

[0080] As used herein, the term “alkyl” refers to a straight-chain or branched saturated hydrocarbon group. Alkyl groups may 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, tert-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, etc.

[0081] As used herein, the term "alkylamino" refers to an amino group substituted with an alkyl group having 1 to 6 carbon atoms. An example of an alkylamino group is -NHCH2CH3.

[0082] As used herein, the term "alkylene" refers to a divalent alkyl linking group. An example of an alkylene group is methylene (or methylenyl) (-CH2-).

[0083] As used herein, the term "alkylthio" refers to a -S-alkyl group having 1 to 6 carbon atoms. An example of an alkylthio group is -SCH2CH3.

[0084] As used herein, the term "alkynyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds and 2 to 20 carbon atoms, including but not limited to acetylene, 1-propene, 2-propene, etc. In some embodiments, the length of the alkynyl chain is 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0085] As used herein, the term "amide" refers to a group

[0086]

[0087] wherein each R30 independently represents a hydrogen or hydrocarbon group, or two R30s together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in a ring structure.

[0088] As used herein, the term "amidinyl" refers to -C(=NH)NH2.

[0089] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, for example, portions that may be represented by:

[0090]

[0091] wherein each R30 independently represents a hydrogen or hydrocarbon group, or two R30s together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in a ring structure.

[0092] As used herein, the term “aminoalkoxy” refers to an alkoxy group substituted with an amino group. An example of an aminoalkoxy group is -OCH2CH2NH2.

[0093] As used herein, the term “aminoalkyl” refers to an alkyl group substituted with an amino group. An example of an aminoalkyl group is -CH2CH2NH2.

[0094] As used herein, the term “aminosulfonyl” refers to -S(=O)2NH2.

[0095] As used herein, the term “aminoalkylthio” refers to an alkylthio group substituted with an amino group. An example of an aminoalkylthio is -SCH2CH2NH2.

[0096] As used herein, the term “amphiphilic” refers to a three-dimensional structure having discrete hydrophobic and hydrophilic regions. Amphiphilic compounds suitably possess both hydrophobic and hydrophilic elements.

[0097] As used herein, the term “animal” includes, but is not limited to, human and non-human vertebrates, such as wild animals, domesticated animals, and farm animals.

[0098] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings).Hydrocarbons. 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, anthracene, phenanthryl, indanyl, indenyl, tetrahydronaphthyl, etc. Examples of aryl groups include, but are not limited to: Specification 17 / 97 pages 19 CN 121041437 A

[0099] Specification 18 / 97 pages 20 CN 121041437 A

[0100]

[0101] As used herein, the term “arylalkyl” refers to a C1-6 alkyl group substituted with an aryl group.

[0102] As used herein, the term “arylamino” refers to an amino group substituted with an aryl group. An example of an arylamino is -NH(phenyl).

[0103] As used herein, the term “arylene” refers to an aryl linking group, that is, an aryl group that links one group in a molecule to another group.

[0104] The term “carbamate” is recognized in the art and refers to a group

[0105]

[0106] wherein R29 and R30 independently represent hydrogen or hydrocarbon groups, such as alkyl, or R29 and R30 together with one or more inserted atoms form a heterocycle having 4 to 8 atoms in a ring structure.

[0107] As used herein, the term “carbamoyl” refers to -C(=O)-NH2.

[0108] As used herein, the term “carbocyclic” refers to a 5- or 6-membered saturated or unsaturated ring, optionally containing O, S, or N atoms as part of the ring. Examples of carbocyclic rings include, but are not limited to, cyclopentyl, cyclohexyl, cyclopent-1,3-diene, phenyl, and any of the above-described heterocycles.

[0109] As used herein, the term “carbocyclic alkyl” refers to an alkyl group substituted with a carbocyclic group.

[0110] The term “carbonate” is recognized in the art and refers to the group -OCO2-R30, where R30 represents a hydrocarbon group.

[0111] As used herein, the term “carboxyl group” refers to a group represented by the formula CO2H.

[0112] As used herein, the term “carrier” refers to a diluent, adjuvant, or excipient applied with the compound. Drug carriers can be liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Drug carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, and colorants may be used.

[0113] As used herein, the term “compound” refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0114] 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") are inclusive or open-ended and do not exclude additional unlisted elements or method steps.

[0115] As used herein, the term "contact" means bringing two elements together in an in vitro or in vivo system. For example, "contacting" a GlyT1 transporter inhibitor with GlyT1 transporter and an individual or patient or cell includes administering the compound to an individual or patient, such as a human, and, for example, introducing the compound into a sample containing cells or a purified formulation (containing GlyT1 transporter).

[0116] As used herein, the term "cyano" means -CN.

[0117] As used herein, the term "cycloalkyl" means a non-aromatic cyclic hydrocarbon, including cycloalkyl, alkenyl, and ynyl groups containing up to 20 cyclic carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic systems, such as fused ring systems, bridged ring systems, and spirocyclic systems. In some embodiments, a polycyclic system contains 2, 3, or 4 fused rings. Cycloalkyl groups can contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 cyclic carbon atoms. The cyclic carbon atoms of a cycloalkyl group can optionally be substituted with an oxo group or a sulfido group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, norbornyl, norpinel, norcarelyl, adamantyl, etc. The definition of cycloalkyl also includes portions having one or more aromatic rings fused to (with a common bond) with a cycloalkyl ring, such as benzo or thiophene derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-one-1-yl).

[0118] As used herein, the term "cycloalkylalkyl" means a C1-6 alkyl group substituted with a cycloalkyl group.

[0119] As used herein, the term "dialkylamino" means an amino group substituted with two alkyl groups each having 1 to 6 carbon atoms.

[0120] As used herein, the term "diazoamino" refers to -N(NH2)2.

[0121] As used herein, the term "ester" refers to the group -C(O)OR30, where R30 represents a hydrocarbon group.

[0122] As used herein, the term "ether" refers to a hydrocarbon group connected to another hydrocarbon group via oxygen. Therefore, the ether substituent of a hydrocarbon group can be hydrocarbon-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocyclic-O-heterocycles and aryl-O-heterocycles. Ethers include "alkoxyalkyl," which can be represented by the general formula alkyl-O-alkyl.

[0123] As used herein, the term "faciallyamphiphilic" (or "facially amphiphilicity") means a compound having polar (hydrophilic) and nonpolar (hydrophobic) side chains, said side chains taking one or more conformations that cause the polar and nonpolar side chains to separate into opposite faces or individual regions of the structure or molecule.

[0124] As used herein, the term "glycine transporter" or "GlyT" refers to a membrane protein that facilitates the transport of glycine across the cell membrane. Non-limiting examples of glycine transporters include glycine transporter 1 (GlyT1) and glycine transporter 2 (GlyT2).

[0125] As used herein, the term “GlyT1” or “GlyT1 transporter” refers to sodium and chloride-dependent glycine transporter 1, also known as glycine transporter 1, a protein encoded by the SLC6A9 gene in humans (Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B (June 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 (November 1995). "Assignment of SLC6A9 to human chromosome band 1p33 by in

[0126] (2012) situ hybridization.Cytogenet Cell Genet.71(3): 211), which is hereby incorporated by reference in its entirety.As used herein, the term “GlyT2” or “GlyT2 transporter” means sodium and chloride-dependent glycine transporter 2, also known as glycine transporter 2, a protein encoded by the SLC6A5 gene in humans (Morrow JA, Collie IT, Dunbar DR, Walker GB, Shahid M, Hill DR (November 1998). “Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome.” FEBS Lett. 439(3):334-40), which is incorporated herein by reference in its entirety.

[0127] As used herein, the term “GlyT1 inhibitor” means a compound that inhibits or blocks the activity of the GlyT1 transporter, including compounds that inhibit the activity of any GlyT1 isotype. Non-limiting examples of GlyT1 inhibitors are provided herein. In some embodiments, the GlyT1 inhibitor is a specific GlyT1 inhibitor, meaning that the inhibitor has greater inhibitory activity against GlyT1 compared to GlyT2. In some embodiments, the inhibitor selectively inhibits GlyT1 by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to GlyT2. In some embodiments, the GlyT1 inhibitor inhibits GlyT1 but does not inhibit or significantly inhibits the activity of GlyT2. If the GlyT1 inhibitor inhibits the activity of GlyT2 by less than 5%, 4%, 3%, 2%, or 1%, then the GlyT1 inhibitor does not significantly inhibit the activity of GlyT2. The selectivity of GlyT1 inhibitors is determined based on assays known in the art, such as those described in published journal articles (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).November 2001, 60(6)1414-1420), which is incorporated herein by reference in its entirety.

[0128] As used herein, the term “GlyT2 inhibitor” means a compound that inhibits or blocks the activity of the GlyT2 transporter, including compounds that inhibit the activity of any GlyT2 isotype. In some embodiments, the GlyT2 inhibitor is a nonspecific inhibitor, meaning that it also inhibits or blocks the activity of GlyT1. In some embodiments, the GlyT2 inhibitor is a specific GlyT2 inhibitor, meaning that the inhibitor has greater inhibitory activity against GlyT2 than GlyT1. In some embodiments, the inhibitor selectively inhibits GlyT2 by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to GlyT1. In some implementations, the GlyT2 inhibitor inhibits GlyT2 activity but does not inhibit or significantly inhibits GlyT1 activity. If the GlyT2 inhibitor inhibits GlyT1 activity by less than 5%, 4%, 3%, 2%, or 1%, then the GlyT1 inhibitor does not significantly inhibit GlyT1 activity. The selectivity of GlyT2 inhibitors is determined based on assays known in the art, such as those described in published journal articles (B.N. Atkinson, SCBell, M.De Vivo, LR. Kowalski, SM. Lechner, VIOgnyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and MAKlitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology, Nov 2001, 60(6) 1414-1420), which are incorporated herein by reference in their entirety.

[0129] As used herein, the term “guanidino” means -NH (=NH)NH2.

[0130] As used herein, the term “halogenated” means a halogen group, including but not limited to fluorine, chlorine, bromine and iodine.

[0131] As used herein, the term "haloalkoxy" means -O-haloalkyl. An example of a haloalkoxy is OCF3.

[0132] As used herein, the term "haloalkyl" means a C1-6 alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, etc.

[0133] As used herein, the term "heteroaryl" refers to an aromatic heterocycle having up to 20 cyclic atoms (e.g., C) and at least one heteroatom ring member (cyclic atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl has at least one or more heteroatom ring atoms, each independently being sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl has 3 to 20 cyclic atoms, 3 to 10 cyclic atoms, 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms. In some embodiments, the heteroaryl contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryls include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indoleyl (such as indole-3-yl), pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl. 1,2,4-Thiadiazolyl, isothiazolyl, benzothiophene, purine, carbazole, benzimidazolyl, dihydroindolyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thiaanthryl, pyrazolyl, indoleazinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthonyl, 2H-pyrroleyl, pyrroleyl, 3H-indolyl, 4H-quinazinyl, phthalazinyl, naphthidyl, quinazolinyl, phenanthridineyl, acridineyl, piperidinyl, phenanthridineyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenothiazinyl, etc. Suitable heteroaryl groups include 1,2,3-triazoles, 1,2,4-triazoles, 5-amino-1,2,4-triazoles, imidazoles, oxazoles, isoxazoles, 1,2,3-oxadiazoles, 1,2,4-oxadiazoles, 3-amino-1,2,4-oxadiazoles, 1,2,5-oxadiazoles, 1,3,4-oxadiazoles, pyridines, and 2-aminopyridines.

[0134] As used herein, the term "heteroarylalkyl" means a C1-6 alkyl group substituted with a heteroaryl group.

[0135] As used herein, the term "heteroarylamino" means an amino group substituted with a heteroaryl group. An example of a heteroarylamino is -NH-(2-pyridyl).

[0136] As used herein, the term "hybridaryl" means a heteroaryl linking group, i.e., a heteroaryl group that links one group in a molecule to another group.

[0137] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0138] As used herein, the term "heterocycle" means a 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic system, wherein any ring may be saturated or unsaturated, and it consists of carbon atoms and 1It consists of up to three heteroatoms selected from N, O, and S, wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatoms may optionally be quaternized, and includes any bicyclic group in which any of the heterocycles defined above are fused to a benzene ring. Particularly useful are those containing an oxygen or sulfur ring combined with one or two nitrogen atoms, one to three nitrogen atoms, or an oxygen or sulfur ring as described on page 22 / 97 of the specification, CN 121041437 A. The heterocycle can be attached to any heteroatom or carbon atom, resulting in a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiratinyl, 2-oxopiratinyl, 2-oxopirarylyl, 2-oxoazadiyl, azaheptenyl, pyrroleyl, 4-piperidinoneyl, pyrroleylyl, pyrazolyl, pyrazolylylyl, imidazolyl, imidazolinyl, imidazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolylyl, isoxazolyl, isoxazolylyl, morpholinyl, thiazolyl, thiazolinylyl, isothiazolyl, quininyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl, benzothiaphenyl, thiomorpholinyl, thioamine linyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl. Morpholinyl is the same as morpholino.

[0139] As used herein, the term "heterocyclic alkyl" means a non-aromatic heterocycle having up to 20 cyclic atoms, including cyclic alkyl, alkenyl, and alkynyl groups, wherein one or more cyclic carbon atoms are replaced by heteroatoms such as O, N, or S atoms. Heterocyclic alkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic systems). In some embodiments, the heterocyclic alkyl group has 1 to 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, the heterocyclic alkyl group contains 3 to 14 cyclic atoms, 3 to 7 cyclic atoms, or 5 or 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 triple bonds. Examples of heterocyclic alkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, 2,3-dihydrobenzofuranyl, 1,3-benzo-dioxacyclopentene, benzo-1,4-dioxane, piperidinyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, pyrazolyl, thiazolyl, imidazolyl, pyrrolidine-2-one-3-yl, etc. Furthermore, the cyclic carbon atom and heteroatom of a heterocyclic alkyl group may optionally be substituted with an oxo or thioanion. For example, the cyclic S atom may be substituted with one or two oxo groups (forming S(O) or S(O)2). In another example, the cyclic C atom may be substituted with an oxo group (forming a carbonyl group). The definition of heterocyclic alkyl also includes groups having one or more non-...The aromatic ring portion of a fused (commonly bonded) heterocyclic ring includes, but is not limited to, pyridinyl, thiopheneyl, phthalimide, naphthalimide, and heterocyclic benzo[a] derivatives such as indoleene, isoindoleene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindoline-1-one-3-yl, and 3,4-dihydroisoquinoline-1(2H)-one-3-yl. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be substituted with an oxo or thioanion.

[0140] As used herein, the term "heterocyclic alkyl alkyl" refers to a C1-6 alkyl group substituted with a heterocyclic alkyl group.

[0141] As used herein, the term "hydroxyl (hydroxy or hydroxyl)" means a -OH group.

[0142] As used herein, the term “hydroxyalkyl” means an alkyl group substituted with a hydroxyl group. Examples of hydroxyalkyl include, but are not limited to, -CH2OH and -CH2CH2OH.

[0143] As used herein, the interchangeable terms “individual” or “patient” mean any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates such as humans.

[0144] As used herein, the phrase “inhibitory activity” such as enzyme activity or transporter activity means reducing the activity of an enzyme or transporter (such as the GlyT1 transporter) by any measurable amount.

[0145] As used herein, the phrase “in need” means that an animal or mammal has been identified as needing a particular method or treatment. In some embodiments, the identification may be performed by any diagnostic means. In any of the methods and treatments described herein, the animal or mammal may be in need. In some embodiments, the animal or mammal is in or will be traveling to an environment where a particular disease, obstacle, or condition is prevalent.

[0146] As used herein, the phrase “in situ gelatable” means not only low-viscosity liquids that form a gel upon contact with tears on or outside the eye, but also more viscous liquids, such as semi-fluids and thixotropic gels, that exhibit a significant increase in viscosity or gel stiffness when applied to the eye.

[0147] As used herein, the phrase “integer of X to Y” means any integer including the endpoints. For example, the phrase “integer of X to Y” means 1, 2, 3, 4, or 5.

[0148] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term “lower” is intended to include groups in which ten or fewer, preferably six or fewer, non-hydrogen atoms are present among the substituents. For example,"Lower alkyl" means an alkyl group containing 10 or fewer, preferably 6 or fewer carbon atoms. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as hydroxyalkyl and aralkyl as listed (in which case, for example, when counting carbon atoms in alkyl substituents, atoms in aryl are not counted).

[0149] As used herein, the term "mammal" means rodent (i.e., mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is human.

[0150] As used herein, the term "N-alkyl" means an alkyl chain substituted with an amine group. Non-limiting examples include, but are not limited to, etc. The alkyl chain can be straight, branched, cyclic, or any combination thereof. In some embodiments, the alkyl group comprises 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 carbons.

[0151] As used herein, the term "nitro" means -NO2.

[0152] As used herein, the term "n-membered" (where n is an integer) typically describes the number of cyclic atoms in a portion, where the number of cyclic 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.

[0153] As used herein, the phrase "ophthalmologically acceptable" means that it has no lasting harmful effects on the treated eye or its function or on the general health of the treated subject. However, it should be recognized that transient effects such as mild irritation or "tingling" sensations are common with topical ophthalmic application of drugs, and the presence of such transient effects does not contradict the fact that the composition, formulation, or ingredient (e.g., excipient) discussed is "ophthalmologically acceptable" as defined herein.

[0154] As used herein, the phrase “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and portions. A “substituted” atom or portion means that any hydrogen atom or portion may be selectively substituted from a specified substituent, provided that the substitution does not exceed the normal valence of the specified atom or portion and that the substitution produces a stable compound. For example, if a methyl group is optionally substituted, then the three hydrogen atoms on the carbon atom may be substituted.

[0155] As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms suitable for contact with tissues in humans and animals to the extent reasonably medically permissible. In some embodiments, the term “pharmaceutically acceptable” means those approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans.

[0156] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of the compound described herein, which is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally SMBerge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without excessive toxicity, irritation, or anaphylactic reactions. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or more than one of each type, and thus react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. Instructions 24 / 97 pages 26 CN 121041437 A

[0157] For compounds described herein containing basic groups (such as amines), pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example by treating the free base with: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxyethylsulfonic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, Salicylic acid, oleic acid, palmitic acid, lauric acid, pyranoside (such as glucuronic acid or galacturonic acid), α-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, naphtholic acid or cinnamic acid), sulfonic acids (such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid); or any compatible mixture of acids, such as those given by way of example herein; and any other acids and mixtures thereof considered equivalents or acceptable substitutes according to the ordinary level of skill in the art.

[0158] For compounds containing acidic groups (such as carboxylic acid groups) as described herein, base addition salts can be prepared by any suitable method available in the art, for example, by treating such compounds with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, ammonium, zinc, or magnesium salts, or other metal salts; organic amino salts, such as alkyl, dialkyl, trialkyl, or tetraalkylammonium salts.

[0159] Other examples of pharmaceutically acceptable salts include, but are not limited to, camphor sulfonates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates,Heptanoates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methanesulfonates, propylsulfonates, benzenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985.

[0160] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (such as solubility in polar solvents), but in other respects, for the purposes of this application, the salts are equivalent to the parent form of the compound.

[0161] As used herein, the term "phenyl" means -C6H5. The phenyl group may be unsubstituted or substituted with one, two, or three suitable substituents.

[0162] The terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) wherein two or more atoms are common to two adjacent rings, for example, the ring is a "fused ring." Each ring of a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring of a polycyclic compound contains 3 to 10 atoms, preferably 5 to 7.

[0163] As used herein, the term "prodrug" means a derivative of a known direct-acting drug that, compared to the drug, has enhanced delivery characteristics and therapeutic value and is converted into an active drug by enzymatic or chemical methods. A common method for preparing prodrugs involves hydrolyzing one or more selected portions under physiological conditions to produce the desired molecule. In some 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 a reductase to produce the desired amino group of the corresponding active compound in vivo. In another example, functional groups in the parent compound, such as hydroxyl, carbonate, or carboxylic acid, are presented as esters, which can be cleaved by esterases. Additionally, the amine group in the parent compound is presented as, but not limited to, a carbamate, N-alkylated, or N-acylated form (Simplício et al., "Prodrugs for Amines," specification 25 / 97 pages 27 CN 121041437 A Molecules, (2008)).,13:519-547). In some embodiments, some or all of the compounds described herein in the formulations indicated above may be replaced by a suitable prodrug.

[0164] As used herein, the term “purified” means that, when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% by weight of the isolate of the compound described herein.

[0165] As used herein, the phrase “quaternary ammonium salt” means a derivative of the disclosed compound having one or more tertiary amine moieties, wherein at least one tertiary amine moiety in the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation (and the cation is balanced by anions such as Cl-, CH3COO-, and CF3COO-) (e.g., methylation or ethylation).

[0166] As used herein, the term “aminourea” means =NNHC(=O)NH2.

[0167] As used herein, the phrase “solvent” means an agent that results in the formation of a micelle solution or true solution of the drug.

[0168] As used herein, the term “solution / suspension” means a liquid composition wherein the first portion of the active agent is present in a solution and the second portion of the active agent is present in a suspension in particulate form within a liquid matrix.

[0169] As used herein, the phrase “substantially isolated” means a compound that is at least partially or substantially isolated from the environment in which it is formed or detected.

[0170] The term “substituted” refers to a portion having a substituent having replaced hydrogen on one or more carbons of the main chain. It should be understood that “substituted” or “replaced” includes the implicit condition that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that said substitution produces a stable compound, for example, a stable compound that does not spontaneously transform, such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds that satisfy heteroatom valences as described herein.

[0171] Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfinylamino groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties.Those skilled in the art should understand that, where appropriate, the substituted element itself can be replaced. Unless specifically stated as “unsubstituted,” references to the chemical elements herein should be understood to include substituted variants. For example, references to an “aryl” group or partly implicitly include both substituted and unsubstituted variants.

[0172] The term “sulfate” is recognized in the art and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0173] The term “sulfonamide” is recognized in the art and refers to a group represented by the following general formula:

[0174]

[0175] wherein R29 and R30 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R29 and R30 together with one or more inserted atoms form a heterocycle having 4 to 8 atoms in a ring structure.

[0176] The term “sulfoxide” is recognized in the art and refers to the group -S(O)-R30, wherein R30 represents a hydrocarbon group.

[0177] The term “sulfonate” is recognized in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0178] The term “sulfone” is recognized in the art and refers to the group -S(O)2-R30, where R30 represents a hydrocarbon group.

[0179] As used herein, the phrase “therapeutic effective amount” means the amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, a therapeutic effect can be a reduction in the severity of symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or a 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 subject’s age, health status, body size, and sex. The optimal amount can also be determined based on monitoring the subject’s response to treatment.

[0180] As used herein, the term “alkylthio” refers to an alkyl group substituted with a thiol group.

[0181] As used herein, the term “thioester” refers to the group -C(O)SR30 or -SC(O)R30, wherein R30 represents a hydrocarbon group.

[0182] As used herein, the term “thioether” is equivalent to an ether in which oxygen is replaced by sulfur.

[0183] As used herein, the term “treat, treated, or treating” means therapeutic treatment and preventive measures in which the aim is to alleviate (reduce) an undesirable physical symptom, disorder, or disease, or to achieve a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the severity of the symptom, disorder, or disease; a stable (i.e., non-worsening) state of the symptom, disorder, or disease; delay or slowing of the onset of the symptom, disorder, or disease; and detectableImprovement or relief (whether partial or complete) of a symptom, disorder, or disease state that is detectable or undetectable; improvement of at least one measurable physical parameter, which is not necessarily identifiable to the patient; or enhancement or improvement of the symptom, disorder, or disease. Treatment includes causing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival without treatment. Thus, “treatment of erythropoietic protoporphyria” means any activity that alleviates or improves any primary or secondary phenomenon or symptom associated with erythropoietic protoporphyria or other conditions described herein.

[0184] The term “urea” is recognized in the art and can be represented by the following general formula

[0185]

[0186] wherein R29 and R30 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R29 together with R30 and one or more inserted atoms constitutes a heterocycle having 4 to 8 atoms in a ring structure.

[0187] In various places throughout this specification, substituents of compounds may be disclosed as groups or ranges. In particular, it is intended that embodiments include each individual subcombination of members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0188] For compounds in which a variable appears more than once, each variable may be a different part of the Markush group for which the variable is optionally defined. For example, in the case where the structure is described as having two R groups present simultaneously on the same compound, the two R groups may represent different parts selected from the Markush group defined for R. In another example, when optional multiple substituents are specified, for example, it should be understood that the substituent R may appear s times on the ring, and R may be a different part each time it appears. In the above example, when the variable T1 is defined to include hydrogen, such as when T1 is CH2, NH, etc., any H may be substituted by a substituent.

[0189] It should also be understood that certain features described herein in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, the various features described in the context of a single embodiment may also be provided individually or in any suitable sub-combination. Specification 27 / 97 pages 29 CN 121041437 A

[0190] It should be understood that embodiments of the invention include the use, where applicable, of stereoisomers, diastereomers, and optical stereoisomers of the compound, and mixtures thereof. Furthermore, it should be understood that stereoisomers, diastereomers, and optical stereoisomers of the compound...Optical stereoisomers and mixtures thereof are within the scope of the embodiments. As a non-limiting example, a mixture may be a racemic mixture or a mixture may contain one particular stereoisomer in unequal proportions relative to another. Additionally, the compound may be provided as substantially pure stereoisomers, diastereomers, and optical stereoisomers (such as epimers).

[0191] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereomers) are intended to be included within the scope of the embodiments. Compounds containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometrical isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometrical isomers of the compound are also included in this embodiment, and they may be isolated as mixtures of isomers or as separate isomeric forms. When a compound capable of stereoisomerization or geometric isomerization is specified in its structure or name without mentioning a specific R / S or cis / trans configuration, it is intended to cover all such isomers.

[0192] In some embodiments, the composition comprises at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure of the compound or its pharmaceutically acceptable salt, solvate, or prodrug, meaning that the ratio of one enantiomer to another in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or entirely in the form of one enantiomer in greater quantity than the other. In some embodiments, the compound rich in one enantiomer is substantially free of the other enantiomer, wherein substantially free means, for example, that the substance in question accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% of the amount of the other enantiomer in the composition or mixture of compounds. For example, if a composition or compound mixture contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it would be said to contain 98 mol% of the first enantiomer and only 2% of the second enantiomer.

[0193] In some embodiments, a compound rich in one enantiomer is substantially free of the other enantiomer, where substantially free means, for example, that the substance in question accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% of the amount of the other enantiomer in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, thenIt would be stated that it contains 98 mol% of the first enantiomer and only 2% of the second enantiomer.

[0194] Resolution of racemic mixtures of compounds can be carried out by any of a variety of methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods include, but are not limited to, optically active acids such as tartaric acid in D and L forms, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional recrystallization methods include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by column elution packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0195] The compound may also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying migration of protons. Tautomeric forms include proton-transfer tautomeric forms, which are isoprotonated states having the same empirical formula and total charge. Examples of proton-transfer tautomers include, but are not limited to, keto-enol pairs, amide-imine acid pairs, lactam-lactamimide pairs, amide-imine acid pairs, enamine-imine pairs, and cyclic forms in which a proton may occupy two or more positions in a heterocyclic system, including, but not limited to, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomer forms may be in equilibrium by appropriate substitution or spatially locked into one form.

[0196] Glycine transporter inhibitors, such as GlyT1 inhibitors, including their pharmaceutically acceptable salts (e.g., GlyT1 inhibitors as disclosed herein), may also exist as hydrates and solvates, as well as anhydrous and non-solventized forms. A “hydrate” is a compound present in the composition along with water molecules. The composition may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or may contain a random amount of water. A “solvent” is a similar composition in which a solvent other than water is used, such as methanol, ethanol, dimethylformamide, diethyl ether, etc., instead of water. For example, methanol or ethanol can form an “alcoholic compound,” which can be stoichiometric or non-stoichiometric. Mixtures of such solvates or hydrates can also be prepared. Such solvates or hydrates may originate from a crystallization solvent, be prepared from or be inherent in the crystallization solvent, or be derived from or related to this solvent.The solvent is foreign.

[0197] The compounds of this application, including their pharmaceutically acceptable salts and prodrugs, may exist in various polymorphs, pseudopolymorphs, or in an amorphous state. As used herein, the term "polymorph" refers to different crystalline forms and other solid molecular forms of the same compound, including pseudopolymorphs such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to variations in temperature, pressure, or the different packing of molecules in the crystal lattice caused by variations in the crystallization process. Polymorphs have different physical properties from one another, such as X-ray diffraction characteristics, stability, melting point, solubility, or dissolution rate in certain solvents. Therefore, crystalline polymorphism is an important aspect of developing suitable dosage forms in the pharmaceutical industry.

[0198] The compound may also include all isotopes of the atoms present in the intermediate or final compound. Isotopes include those atoms that have the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0199] In some embodiments, the compound or its salts are substantially isolated. Partial separation may include, for example, compositions rich in compounds. Substantial separation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound or its salts. Methods for separating compounds and their salts are conventional in the art.

[0200] While the disclosed compounds are suitable, other functional groups may 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 may affect the geometric pattern of the compound, and this distance can be altered by incorporating aliphatic chains of different lengths, which may optionally be substituted or may contain amino acids, dicarboxylic acids, or diamines. The distance and relative orientation between monomers within the compound can also be altered by replacing amide bonds with substitutes having additional atoms. Thus, replacing carbonyl groups with dicarbonyl groups changes the distance between monomers and the tendency of dicarbonyl units to adopt an anti-arrangement of two carbonyl moieties and alters the periodicity of the compound. Pyromellitic anhydride represents another alternative to the simple amide bond, which can alter the conformation and physical properties of compounds. Modern methods of solid-phase organic chemistry (E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, Oxford 1989) now allow the synthesis of uniformly dispersed compounds with molecular weights approaching 5,000 Daltons. Other substitution modes are equally effective.

[0201] The compounds also include derivatives called prodrugs.

[0202] Compounds containing amine functional groups can also form N-oxides. The amine functional group compounds mentioned herein...Also included are N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Examples of N-oxides include N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see Advanced Specification 29 / 97, page 31, CN 121041437 A Organic Chemistry, Jerry March, 4th edition, Wiley Interscience).

[0203] By limiting or excluding the rights of any individual member of any such group (including any sub-scopes or combinations of sub-scopes within the group) that may be claimed according to the scope or in any similar manner, protection may be claimed for any reason less than the entire scope of this disclosure. Furthermore, by limiting or excluding the rights of any individual substituent, analogue, compound, ligand, structure or group thereof or any member of the claimed group, protection may be claimed for any reason less than the entire scope of this disclosure. Throughout this disclosure, references are made to numerous patents, patent applications and publications. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety to provide a more comprehensive description of the prior art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0204] For convenience, certain terms used in the specification, embodiments, and 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.

[0205] Embodiments of various compounds and their salts are provided. Unless specifically enumerated, a variable may be any option described herein, unless otherwise stated or indicated by context.

[0206] In some embodiments, the compound is as described in the appended exemplary non-limiting claims, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0207] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula:

[0208]

[0209] wherein:

[0210] Ar is an unsubstituted or substituted aryl group or a 6-membered heteroaryl group containing 1, 2 or 3 nitrogen atoms, wherein the substituted aryl group and the substituted heteroaryl group are substituted by one or more substituents selected from: hydroxyl, halogen, NO2, CN, (C1-C6)-alkyl, halogen-substituted (C1-C6)-alkyl, hydroxyl-substituted (C1-C6)-alkyl, (CH2)n-(C1-C6)-alkoxy, halogen-substituted (C1-C6)-alkoxy, NR7R8, C(O)R9, SO2R10 and -C(CH3)=NOR7, or substituted with a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, wherein the aromatic heterocycle is optionally substituted with (C1-C6)-alkyl;

[0211] R1 is hydrogen or (C1-C6)-alkyl;

[0212] R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen-substituted (C1-C6)-alkyl, hydroxyl-substituted (C1-C6)-alkyl, optionally (C1-C6)-alkoxy or halogen-substituted (CH2)n-(C3-C7)-cycloalkyl, CH(CH3)-(C3-C7)-cycloalkyl, (CH2)n+1-C(O)-R 9. (CH2)n+1-CN, bicyclo[2.2.1]heptyl, (CH2)n+1-O-(C1-C6)-alkyl, (CH2)n-heterocyclic alkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur or nitrogen, wherein the aryl, heterocyclic alkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from hydroxyl, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;

[0213] R3, R4 and R6 are each independently hydrogen, hydroxyl, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl;

[0214] R5 is NO2, CN, C(O)R9 or SO2R10; Specification 30 / 97 pages 32 CN 121041437 A

[0215] R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;

[0216] R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, or NR7R8;

[0217] R10 is optionally halogen-substituted (C1-C6)-alkyl, (CH2)n-(C3-C6)-cycloalkyl, (CH2)n-(C3-C6)-alkoxy, (CH2)n-heterocyclic alkyl, or NR7R8;

[0218] n is 0, 1, or 2;

[0219] or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the formula bitopertin or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula:

[0222]

[0223] wherein:

[0224] R1 represents a heteroaryl group selected from: imidazolyl, thiazolyl, pyridinyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolinyl, isoxazolyl, pyrroloimidazolyl, and thiadiazole, wherein the heteroaryl group is optionally substituted by one or more substituents selected from: -OH, -NR7R8, halogen, (C1-C8)alkyl, (C3-C10)cycloalkyl, (C1-C8)alkoxy, (C1-C12)alkoxyalkyl, (C1-C8)hydroxyalkyl, (C6-C14)aryl, and benzyl;

[0225] R2, R3, and A independently represent H or (C1-C8)alkoxy, wherein the alkyl group is optionally substituted by one or more -OH, (C1-C8)alkoxy, -NR7R8, or halogen;

[0226] Q represents -(CH2)n-, where n = 1, 2, 3 or 4, or -(CH2)m-O-, where m = 2, 3 or 4;

[0227] Z represents (C6-C14)aryl, (C1-C8)alkyl or (C3-C8)cycloalkyl;

[0228] R4 and R5 each independently represent H, halogen, (C1-C8)alkyl, (C6-C14)aryl, (C6-C14)aryloxy, (C1-C8)alkoxy, (3-10)heterocyclic alkyl or (C3-C8)cycloalkoxy; wherein R4 and R5 are optionally substituted by one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen;

[0229] Y represents -R6, -(CH2)o-R6, -C(R6)3 or -CH(R6)2, where O = 1, 2 or 3;

[0230] R6 represents H, (C6-C14)aryl, (C1-10)alkyl, (C3-C10)cycloalkyl, (C5-C18)bicycloalkyl, (C5-C18)tricycloalkyl, (3-10-membered)heterocycloalkyl, (5-10-membered)heteroaryl, -C(=O)NR7R8 or -C(=O)OR7, wherein the R6 group may optionally be substituted by one or more X groups;

[0231] Wherein X = -OH, (C1-C8)alkoxy, -NR11R12, -SO2R10, -C(=O)R10, halogen, cyano, (C1-C8)alkyl, (C1-C10)alkoxyalkyl, (5-10-membered)heteroaryl, (C6-C14)aryl, (C6-C14)aryloxy, benzyl, or (C1-C8)hydroxyalkyl;

[0232] Wherein R7 and R8 independently represent H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10-membered)heterocyclic alkyl, (C1-C8)hydroxyalkyl, (5-10-membered)heteroaryl, or (C1-C10)alkoxyalkyl; wherein R7 and R8 may optionally be substituted by one or more X groups;

[0233] Alternatively, R7 and R8, together with the nitrogen to which they may be attached, may form a (3-10) heterocyclic alkyl group optionally substituted with one or more X groups;

[0234] wherein R10 represents (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10) heterocyclic alkyl, (C1-C8) hydroxyalkyl, (5-10) heteroaryl, or (C1-C10) alkoxyalkyl;

[0235] wherein R11 and R12 independently represent H, (C1-C8) alkyl, (C3-C8) cycloalkyl, (5-10) heterocyclic alkyl, (C1-C8) hydroxyalkyl, (5-10) heteroaryl, or (C1-C10) alkoxyalkyl; or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula

[0237] or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula

[0239] PF-3463275, or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula:

[0241]

[0242] Wherein:

[0243] Z1 is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, halo-C1-4 alkyl, phenyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkylsulfonyloxy, C1-4 alkylsulfonyl, bromine, and chlorine;

[0244] Z2 is selected from hydrogen, halogen, cyano, C1-4 alkyl, phenyl, halo-C1-4 alkyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkoxy-C1-4 alkyl, and C3-6 cycloalkyl;

[0245] Z3 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-C1-4 alkyl, halo-C1-4 alkoxy, and C3-6 cycloalkyl;

[0246] Z4 is selected from hydrogen, halogen, C1-3 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkoxy-C1-4 alkyl, and C3-6 cycloalkyl;

[0247] Z5 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, halo-C1-4 alkyl, halo-C1-4 alkoxy, halophenyl, C1-4 alkoxy-C1-4 alkyl, and C3-6 cycloalkyl;

[0248] Wherein, if more than one of Z1 to Z5 is methoxy, then only Z1 and Z5 are methoxy, R3 and R4 are independently selected from hydrogen and C1-4 alkyl groups optionally substituted with one or more groups Y; or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated A, 5, 6, or 7-membered carbon ring optionally substituted with group Y';

[0249] Y is selected from C1-4 alkoxy, hydroxy, halo-C1-4 alkoxy, and C3-5 cycloalkyl;

[0250] Y' is selected from C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, halo-C1-4 alkoxy, C3-5 cycloalkyl, and C5-10 aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on the A, 5, 6, or 7-membered carbon ring;

[0251] R5 and R6 are independently C1-4 alkyl groups optionally substituted with one or more groups X; or R5 and R6 together with the carbon atoms to which they are attached form a saturated 5- or 6-membered carbon ring optionally substituted with one or more groups X'. In the case where R5 and R6 together with the carbon atoms to which they are attached form a 5-membered saturated carbon ring, the ring may optionally further comprise additional heteroatomic groups selected from O, N, and S(O)m; where m = 0, 1, or 2.

[0252] X is selected from halogen, hydroxyl, C1-4 alkoxy, halo-C1-4 alkyl, halo-C1-4 alkoxy, and C5-10 aryl; and X' is selected from halogen, hydroxyl, C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkyl, halo-C1-4 alkoxy, and C5-10 aryl;

[0253] wherein R3, R4, R5, and R6 are not simultaneously unsubstituted methyl groups;

[0254] the condition is that when Z1 is propoxy, Z3 is chlorine, Z2 = Z4 = Z5 = H, and R5 and R6 are both methyl, then R3 and R4 together with the nitrogen atom to which they are attached do not form a 2-methylpyrrolidinyl group; when Z1 is methyl, Z3 is methoxy, Z2 =Z4=Z5=H, and R5 and R6 are both methyl, then R3 and R4 together with the nitrogen atom to which they are attached do not form a pyrrolidinyl group, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula (page 33 / 97, CN 121041437 A

[0256] ) or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula

[0258]

[0259] wherein:

[0260] Z is (CH2)n, O, S, SO, SO2 or N-R5;

[0261] n is 0, 1 or 2;

[0262] X represents 1-3 substituents independently selected from the following: hydrogen, halogen,

[0263] (C1-6)alkoxy, (C3-6)cycloalkoxy, (C6-12)aryloxy, (C6-12)aryl, thiophene, SR6, SOR6,

[0264] SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6 and (C1-4)alkyl, optionally substituted by halogen, (C6-12)aryl, (C1-6)alkoxy or (C6-12)aryloxy; or two substituents in adjacent positions together represent fused (C5-6)aryl, fused (C5-6)cycloalkyl ring or O-(CH2)m-O; m is 1 or 2;

[0265] Y represents 1-3 substituents independently selected from hydrogen, halogen, (C1-4)alkoxy, SR6, NR6R6, and (C1-4)alkyl, optionally substituted with halogen;

[0266] R1 is COOR7 or CONR8R9;

[0267] R2 and R6 are (C1-4)alkyl;

[0268] R3, R4, and R5 are independently hydrogen or (C1-4)alkyl;

[0269] R7, R8, and R9 are independently hydrogen, (C1-4)alkyl, (C6-12)aryl, or aralkyl, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the formula

[0271] ORG-25935, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula:

[0273]

[0274] where:

[0275] n is an integer from 1 to 3;

[0276] R1 and R2 are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic groups, wherein the aforementioned ring is optionally substituted independently by Ra, Rb, or Rc selected from: alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, monosubstituted amino, or disubstituted amino; or R1 and R2, when attached to the same carbon atom, can combine to form a cycloalkyl or monocyclic saturated heterocyclic group to obtain a spirocyclic group, wherein the cycloalkyl or monocyclic saturated heterocyclic group can optionally be substituted independently by Rd, Rc, or Rf selected from: alkyl, alkoxy, fluorine, fluoroalkyl, fluoroalkoxy, hydroxyl, monosubstituted amino, or disubstituted amino; or R1 and R2, when attached to carbon atoms at positions 2 and 5 or 3 and 6 of a piperazine ring, can combine to form a -C1-C3-alkylene chain, wherein one carbon atom of the alkylene chain is optionally substituted by -NR-, -O-, or -S(O)n-.(where R is hydrogen or alkyl and n is 0-2) substitution, and further wherein one or two hydrogen atoms in the alkylene chain may optionally be substituted with one or two alkyl groups;

[0277] R3, R4 and R5 are independently hydrogen, alkyl, fluorine or fluoroalkyl; and Ar1 and Ar2 are independently aryl, heteroaryl, cycloalkyl or heterocyclic, wherein each of the above rings is optionally substituted with Rg, Rh or Ri, wherein Rg is alkyl, -C=C-R6 (wherein R6 is aryl or heteroaryl), halogen, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, The amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or amide group is disubstituted, and Rh and Ri are independently selected from alkyl, halogen, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, amide, aryl, heteroaryl, cycloalkyl, or heterocyclic groups, wherein the aromatic or alicyclic ring in Rg, Rh, and Ri is optionally substituted by Rj, Rk, or Rl, wherein Rj, Rk, or Rl is independently selected from alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, or alkyl groups. Acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or amide; or a pharmaceutically acceptable salt thereof, provided that: the compound of formula V is not 2-(4-diphenylmethylpiperazin-1-yl)acetic acid, 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid, 2-((2R,5S)-4-((R)-(4-(1H-tetrazol-5-yl)phenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)acetic acid, or 2-((2R,5S)-4-((R)-(4-cyanophenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)acetic acid, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula (page 35 / 97, CN 121041437 A

[0279] ) or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula

[0281]

[0282] wherein:

[0283] 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, and wherein R1 represents a hydrogen atom, or a straight-chain or branched (C1-C7) alkyl, or (C4-C7) cycloalkyl, or (C3-C7) cycloalkyl (C1-C3) alkyl, or a phenyl (C1-C3) alkyl, or (C2-C4) alkenyl, or (C2-C4) alkynyl, optionally substituted with one or two hydroxyl or methoxy groups,

[0284] R' represents a straight-chain or branched (C1-C7) alkyl,

[0285] X represents a hydrogen atom or one or more substituents selected from halogen atoms and trifluoromethyl, straight-chain or branched (C1-C4) alkyl, and (C1-C4) alkoxy groups;

[0286] R2 represents a hydrogen atom, or one or more substituents selected from halogen atoms and trifluoromethyl, (C1-C4)alkyl or (C1-C4)alkoxy, or an amino group of the general formula NR3R4, wherein R3 and R4 each independently represent a hydrogen atom or (C1-C4)alkyl, or a phenyl group that, together with the nitrogen atom carrying them, forms a pyrrolidine, piperidine or morpholine ring, or is optionally substituted with an atom or group as defined above for the symbol X, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the formula

[0288] SSR-504734, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula: Specification 36 / 97 Page 38 CN 121041437 A

[0290]

[0291] wherein:

[0292] R1 is -(CH2)n-R1a, wherein n is independently 0-6, and R1a is selected from:

[0293] (1) C1-6 alkyl, which is unsubstituted or substituted with 1-6 halogens or hydroxyl groups,

[0294] (2) phenyl substituted with R2a, R2b and R2c,

[0295] (3) C3-6 cycloallyl, which is unsubstituted or substituted with C1-6 alkyl, 1-6 halogens, hydroxyl groups or -NR10R11,

[0296] (4) -O-C1-6 alkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11,

[0297] (5)-CO2R9,

[0298] wherein R9 is independently selected from:

[0299] (a) hydrogen,

[0300] (b)-C1-6 alkyl, which is unsubstituted or substituted with 1-6 fluorine,

[0301] (c) benzyl, and

[0302] (d) phenyl,

[0303] (6)-NR10R11,

[0304] Wherein R10 and R11 are independently selected from:

[0305] (a) hydrogen,

[0306] (b) -C1-6 alkyl, which is unsubstituted or substituted with hydroxyl, 1-6 fluorine or -NR12R13, wherein R12 and R13 are independently selected from hydrogen and -C1-6 alkyl,

[0307] (c) -C3-6 cycloalkyl, which is unsubstituted or substituted with hydroxyl, 1-6 fluorine or -NR12R13,

[0308] (d) benzyl,

[0309] (e) phenyl, and

[0310] (7) -CONR10R11;

[0311] R2 is selected from:

[0312] (1) phenyl, which is substituted with R2a, R2b and R2c,

[0313] (2) C1-8 alkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups, -NR10R11, phenyl or heterocyclic rings, wherein the phenyl or heterocyclic rings are substituted with R2a, R2b and R2c,

[0314] (3) C3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11, and

[0315] (4) -C1-6 alkyl-(C3-6 cycloalkyl), which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11;

[0316] R2a, R2b and R2c are independently selected from:

[0317] (1) hydrogen,

[0318] (2) halogen,

[0319] (3) -C1-6 alkyl, which is unsubstituted or substituted with:

[0320] (a) 1-6 halogens, Specification 37 / 97 pages 39 CN 121041437 A

[0321] (b) phenyl,

[0322] (c) C3-6 cycloalkyl, or

[0323] (d) -NR10R11,

[0324] (4) -O-C1-6 alkyl, which is unsubstituted or substituted with 1-6 halogens,

[0325] (5) hydroxyl,

[0326] (6) -SCF3,

[0327] (7) -SCHF2,

[0328] (8) -SCH3,

[0329] (9) -CO2R9,

[0330] (10) -CN,

[0331] (11) -SO2R9,

[0332] (12) -SO2-NR10R11,

[0333] (13) -NR10R11,

[0334] (14) -CONR10R11, and

[0335] (15) -NO2;

[0336] R3 is selected from:

[0337] (1) C1-6 alkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11,

[0338] (2) C3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogens, hydroxyl groups or -NR10R11,

[0339] R4 and R5 are independently selected from:

[0340] (1) Hydrogen, and

[0341] (2) C1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl, or R4 and R5 together form a C3-6 cycloalkyl ring;

[0342] A is selected from:

[0343] (1) -O-, and

[0344] (2) -NR10-;

[0345] m is 0 or 1, wherein when m is 0, R2 is directly attached to the carbonyl group;

[0346] and pharmaceutically acceptable salts thereof and their individual enantiomers and diastereomers, or pharmaceutically acceptable salts thereof or prodrugs of said compound or pharmaceutically acceptable salts thereof.

[0347] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula

[0348] , or a pharmaceutically acceptable salt thereof or a prodrug of said compound or pharmaceutically acceptable salt thereof.

[0349] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula:

[0350]

[0351] wherein:

[0352] R1 is a phenyl group independently substituted 1 to 5 times with a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, OR9, or SR10, wherein the C1-C3 alkyl group and the C3-C6 cycloalkyl group are optionally substituted 1 to 10 times with R7;

[0353] R2 is H;

[0354] R3 and R4 are each independently H or CH3;

[0355] R5 is selected from:

[0356] (1) hydrogen,

[0357] (2) a 1-C6 alkyl group optionally substituted 1 to 11 times with R7,

[0358] (3) a geminal dialkyl group, and

[0359] (4) a geminal dihalogenated group; or

[0360] Two R5 substituents on the same carbon atom, together with the carbon atom to which they are attached, can form a 3, 4, or 5-membered cycloalkyl group optionally substituted 1 to 10 times with R7; or

[0361] two R5 substituents on adjacent carbons of the ring to which they are attached can form a 3, 4, 5, or 6-membered cycloalkyl group optionally substituted 1 to 10 times with R7;

[0362] R6 is

[0363] wherein E, F, and G are each independently nitrogen or carbon, and R6a is a C1-C2 alkyl group optionally substituted 1 to 5 times with halogen or deuterium;

[0364] R7 is selected from:

[0365] (1) hydrogen,

[0366] (2) halogen,

[0367] (3) deuterium,

[0368] (4) geminal dialkyl,

[0369] (5) geminal dihalogen,

[0370] (6) -OR9, -NR11R12, -NR11C(O)pR10, -S(O)pR10, -CN, -NO2, -C(O)pR10, -C(O)NR11R12, or -NR11C(S)R10, and

[0371] (7) oxo or thio;

[0372] R8 is selected from:

[0373] (1) hydrogen, specification 39 / 97 pages 41 CN 121041437 A

[0374] (2) halogen,

[0375] (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each independently and optionally substituted by R7 1 to 11 times, or

[0376] (4) -OR9, -NR11R12, -NR11C(O)pR10, -S(O)pR10, -CN, -NO2, -C(O)pR10, -C(O)NR11R12, or - NR11C(S)R10;

[0377] R9 is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR11R12 and -C(O)pR10, wherein the C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally substituted by R7 1 to 11 times;

[0378] R10 is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein the C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally substituted by substituents as defined in R7 1 to 11 times, and the aryl or heteroaryl is optionally substituted by R8 1 to 10 times;

[0379] R11 and R12 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, wherein the C1-C4 alkyl, C3-C7 cycloalkyl, and C4-C7 cycloalkylalkyl are each optionally substituted 1 to 11 times by the substituents defined in R7, and the aryl or heteroaryl is optionally substituted 1 to 10 times by R8, or R11 and R12 together with the nitrogen to which they are attached form a saturated or partially saturated monocyclic or fused bicyclic heterocycle optionally substituted 1 to 11 times by R7;

[0380] A is

[0381] X is N;

[0382] Y is N;

[0383] p is 1 or 2; and

[0384] m is 0;

[0385] The condition is that R6 cannot be (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl;

[0386] or an oxide thereof, a pharmaceutically acceptable salt of said compound or an oxide thereof, or an enantiomer or diastereomer thereof.

[0387] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula: Specification 40 / 97 pages 42 CN 121041437 A

[0388] Specification 41 / 97 pages 43 CN121041437 A

[0389]

[0390] of the compound or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments of the methods and uses disclosed herein, the Gly T1 inhibitor is a compound having formula 42 / 97 pages 44 CN 121041437 A (ORG-24598) or (LY-2365109), or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0392] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula:

[0393]

[0394] wherein:

[0395] R1 represents a phenyl or a 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N, or S, wherein the phenyl or heteroaryl is optionally substituted by one or more R3s;

[0396] R2 represents an aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N, or S, wherein the aryl or heteroaryl is optionally substituted by one or more R4s;

[0397] R3 is a halogen, a C1-4-alkyl, or a C3-6-cycloalkyl, wherein the C1-4-alkyl or the C3-6-cycloalkyl is optionally substituted by one or more halogens; and

[0398] R4 is a halogen, -CN, C1-4-alkyl, C3-6-cycloalkyl, -C1-3-alkyl, -C3-6-cycloalkyl, or -O-C1-6-alkyl, wherein the C1-4-alkyl, C3-6-cycloalkyl, -C1-3-alkyl, -C3-6-cycloalkyl, or -O-C1-6-alkyl is optionally substituted with one or more halogens;

[0399] or a pharmaceutically acceptable salt thereof or a tautomer or stereoisomer of the compound thereof or a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0400] In some embodiments, a compound of formula IX may be represented by a compound of formula IX(a): or a pharmaceutically acceptable salt thereof or a tautomer of the compound thereof or a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0401] In some embodiments, a compound of formula IX may be represented by a compound of formula IX(b): or a pharmaceutically acceptable salt thereof, or a tautomer of said compound or a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0402] In some embodiments, a compound of formula IX is a compound selected from any of the following, whose stereoisomers are described in the specification.Pages 43 / 97, 45 CN 121041437 A: a mixture of solids or stereoisomers, or a pharmaceutically acceptable salt thereof:

[0403] Pages 44 / 97, 46 CN 121041437 A

[0404] Pages 45 / 97, 47 CN 121041437 A

[0405] Pages 46 / 97, 48 CN 121041437 A

[0406] Pages 47 / 97, ​​49 CN 121041437 A

[0407] Pages 48 / 97, 50 CN 121041437 A

[0408] Pages 49 / 97, 51 CN 121041437 A

[0409] Pages 50 / 97, 52 CN 121041437 A

[0410] Pages 51 / 97 Page 53 CN 121041437 A

[0411] Specification 52 / 97 Page 54 CN 121041437 A

[0412] Specification 53 / 97 Page 55 CN 121041437 A

[0413] Specification 54 / 97 Page 56 CN 121041437 A

[0414] Specification 55 / 97 Page 57 CN 121041437 A

[0415]

[0416] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound having the following formula: Specification 56 / 97 Page 58 CN 121041437 A

[0417]

[0418] wherein:

[0419] R1 is selected from:

[0420] a) a 5- or 6-membered monocyclic heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from O, N and S(O)r,

[0421] b) a 5- or 6-membered monocyclic partially saturated heterocyclic alkyl group having 1, 2, or 3 heteroatoms independently selected from O, N, and S(O)r, and

[0422] c) a 9- or 10-membered bicyclic heteroaryl group having 1, 2, or 3 heteroatoms independently selected from O, N, and S(O)r,

[0423] wherein r is 0, 1, or 2;

[0424] wherein each of the groups a), b) and c) is optionally substituted by one or more substituents independently selected from: C1-4-alkyl-, C1-4-alkyl-O-, oxobutyl, tetrahydrofuranyl, tetrahydropyranyl, C3-6-cycloalkyl-, and C3-6-cycloalkyl-O-, and where the substituent is attached to a nitrogen ring atom, the substituent is selected from C1-4-alkyl-, C1-4-alkyl-CO-, C3-6-cycloalkyl-, and C3-6-cycloalkyl-CO-,

[0425] And each of the C1-4-alkyl-, C1-4-alkyl-O-, C1-4-alkyl-CO-, oxetane-butyl, tetrahydrofuranyl, tetrahydropyranyl, C3-6-cycloalkyl-, C3-6-cycloalkyl-CO-, or C3-6-cycloalkyl-O- substituents may be substituted by one or more substituents independently selected from the following: fluorine, -CF3, -CHF2, -CH2F, and -CN;

[0426] R2 is selected from hydrogen, C1-4-alkyl-, C1-4-alkyl-O-, -CN, and C3-6-cycloalkyl-,

[0427] wherein each of the C1-4-alkyl-, C1-4-alkyl-O-, and C3-6-cycloalkyl- may optionally be substituted by one, two, three, or more substituents independently selected from the following: fluorine, -CF3, -CHF2, -CH2F, and -CN;

[0428] R3 is selected from C1-6-alkyl-O-, C3-6-cycloalkyl-O-, morpholino, pyrazolyl, and 4- to 7-membered monocyclic heterocyclic alkyl-O-, having one oxygen atom as a ring member and optionally one or two heteroatoms independently selected from O, N, and S(O)s, where s = 0, 1, or 2,

[0429] wherein the C1-6-alkyl-O- and the C3-6-cycloalkyl-O- may optionally be substituted by one, two, three, or more substituents independently selected from: fluorine, -CF3, -CHF2, -CH2F, -CN, C1-4-alkyl-, C3-6-cycloalkyl-, C1-6-alkyl-O-, and C3-6-cycloalkyl-O-;

[0430] R4 is hydrogen;

[0431] Alternatively, R3 and R4, together with the ring atoms of the phenyl group to which they are attached, can form a 4, 5, or 6-membered monocyclic partially saturated heterocyclic alkyl or heteroaryl group, each having 1, 2, or 3 heteroatoms independently selected from O, N, and S(O)s, where s = 0, 1, or 2, wherein in general formula (I) there must be one epoxy atom directly attached to the ring carbon atom of the phenyl group to which R3 is attached;

[0432] wherein the heterocyclic alkyl group may optionally be substituted with 1, 2, 3, or more substituents independently selected from: fluorine, -CF3, -CHF2, -CH2F, -CN, C1-4-alkyl-, C3-6-cycloalkyl-, C1-6-alkyl-O-, C3-6-cycloalkyl-O-, oxobutyryl-O-, tetrahydrofuranyl-O-, and tetrahydropyranyl-O-;

[0433] R5 is hydrogen;

[0434] R6 is selected from hydrogen, C1-4-alkyl-SO2-, C3-6-cycloalkyl-SO2-, and -CN; Specification 57 / 97 pages 59 CN 121041437 A

[0435] R7 is hydrogen;

[0436] or a) one of the pairs of R6 and R7 or b) one of the phenyl ring atoms to which they are bonded forms a ring with1, 2, or 3 heteroatoms independently selected from O, N, and S(O)u, a 5- or 6-membered partially saturated monocyclic heterocyclic alkyl group, wherein u = 0, 1, or 2, wherein in general formula (I) there must be one -SO2- member directly attached to the cyclic carbon atom of the phenyl group to which R6 is attached;

[0437] wherein the heterocyclic alkyl group may optionally be substituted by 1, 2, 3, or more substituents independently selected from: fluorine, -CF3, -CHF2, -CH2F, -CN, C1-4-alkyl-, C1-6-alkyl-O-, and C3-6-cycloalkyl-O- or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0438] In some embodiments, the compound of formula X is a compound selected from any of the following, its stereoisomers or mixtures of stereoisomers, or a pharmaceutically acceptable salt thereof:

[0439] Specification 58 / 97 pages 60 CN 121041437 A

[0440] Specification 59 / 97 pages 61 CN 121041437 A

[0441] Specification 60 / 97 pages 62 CN 121041437 A

[0442] Specification 61 / 97 pages 63 CN 121041437 A

[0443]

[0444] For example, the compound of formula X may be a mixture or a single diastereomer of any of the following, or a pharmaceutically acceptable salt thereof:

[0445] Specification 62 / 97 pages 64 CN 121041437 A

[0446] Specification 63 / 97 pages 65 CN 121041437 A

[0447] Specification 64 / 97 pages 66 CN 121041437 A

[0448] Specification 65 / 97 pages 67 CN 121041437 A

[0449] Specification 66 / 97 pages 68 CN 121041437 A

[0450] Specification 67 / 97 pages 69 CN 121041437 A

[0451]

[0452] In some of the methods and uses disclosed herein, the subject is a subject in need.

[0453] In some embodiments of the uses and methods disclosed herein, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount; or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a pharmaceutically acceptable salt thereof.

[0454] In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof is selected from those described herein.The compounds described herein. Any compound provided herein may be prepared as a pharmaceutically acceptable salt, solvate, or prodrug and / or as part of a pharmaceutical composition as described in the patent or patent application publication cited herein.

[0455] Although the compounds described herein may be shown having a particular stereochemistry around certain atoms, such as cis or trans, the compounds may also be prepared in opposite directions or racemic mixtures. Such isomers or racemic mixtures are included in this disclosure. Additionally, although the compounds are collectively shown in the table, any compound or its pharmaceutically acceptable salt, solvate, or prodrug may be selected from the table and used in the embodiments provided herein.

[0456] The compounds described herein may be prepared according to the methods described in the patent or patent application publication cited herein.

[0457] The compounds may be used to inhibit the GlyT1 transporter. Thus, in some embodiments, the compounds may be referred to as GlyT1 transporter inhibitory compounds or GlyT1 inhibitors.

[0458] The compounds described herein may be administered in any conventional manner by any route through which they are made active. Administration may be systemic, local, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ocular routes, or vaginal, by inhalation, by reservoir injection, or by implant. The route of administration may depend on the condition or disease to be targeted or treated. The specific route of administration may be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.

[0459] In some embodiments, it may be desirable to apply one or more compounds or their pharmaceutically acceptable salts, solvates, or prodrugs topically to the area requiring treatment. This can be achieved, for example, but not limited to, local infusion during surgery, topical application (e.g., in combination with a wound dressing after surgery), by injection, by catheter, by suppository, or by implant (instructions for use 68 / 97 pages 70 CN 121041437 A), wherein the implant is a porous, non-porous, or gel-like material, including membranes, such as silicone rubber membranes or fibers.

[0460] The compounds described herein can be administered alone or in combination with other drugs (simultaneously or sequentially). For example, the compound may be administered in combination with other drugs used to treat EPP, XLPP, or CEP, etc. Examples of other drugs or agents are known to those skilled in the art and include, but are not limited to, those described herein.

[0461] The means and methods of administration are known to those skilled in the art, and those skilled in the art may 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).

[0462] The amount of the compound to be administered is a therapeutically effective amount. The dose to be administered will depend on the characteristics of the subject being treated, such as the specific animal being treated, age, weight, health status, type of concurrent treatment (if any), and frequency of treatment, and can be readily determined by someone skilled in the art (e.g., a clinician). The standard dose of protamine can be used and adjusted (i.e., increased or decreased) based on the factors described above. The 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.

[0463] The amount of the compound described herein that is effective in treating and / or preventing a specific disease, condition, or disorder will depend on the nature and severity of the disease, condition, or disorder and can be determined by standard clinical techniques. Additionally, in vitro or in vivo assays may optionally be used to help identify the optimal dose range. The exact dose to be used in the composition will also depend on the route of administration and the severity of the disorder, and should be determined based on the practitioner's judgment and the individual patient's situation. However, suitable dose ranges for oral administration are typically about 0.001 mg to about 200 mg / kg body weight, about 0.01 mg to about 100 mg / kg body weight, about 0.01 mg to about 70 mg / kg body weight, about 0.1 mg to about 50 mg / kg body weight, 0.5 mg to about 20 mg / kg body weight, or about 1 mg to about 10 mg / kg body weight. In some embodiments, the oral dose is about 5 mg / kg body weight.

[0464] In some embodiments, suitable dose ranges for intravenous (i.v.) administration are about 0.01 mg to about 500 mg / kg body weight, about 0.1 mg to about 100 mg / kg body weight, about 1 mg to about 50 mg / kg body weight, or about 10 mg to about 35 mg / kg body weight. Suitable dose ranges for other administration methods can be calculated based on the above doses known to those skilled in the art. For example, recommended doses for intranasal, mucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal, or inhalation administration are about 0.001 mg to about 200 mg / kg body weight, about 0.01 mg to about 100 mg / kg body weight, about 0.1 mg to about 50 mg / kg body weight, or about 1 mg to about 20 mg / kg body weight. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model testing systems. Such animal models and systems are well known in the art.

[0465] The compounds described herein can be formulated for parenteral administration by injection, such as by bolus or...Continuous infusion. In some embodiments, the compound can be administered by continuous subcutaneous infusion over a period of about 15 minutes to about 24 hours. The injectable formulation can be presented in unit dosage forms, such as in ampoules or multi-dose containers, and optionally with added preservatives. The composition can take the form of suspensions, solutions, or emulsions in oily or aqueous media and can contain formulations such as suspending agents, stabilizers, and / or dispersants. In some embodiments, the injectable is in the form of short-acting, reservoir, or implant and pellet for subcutaneous or intramuscular injection. In some embodiments, the parenteral dosage form is in the form of a solution, suspension, emulsion, or dry powder.

[0466] 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 can formulate compounds into tablets, pills, sugar-coated pills, capsules, emulsions, liquids, gels, syrups, granules, pellets, powders, granules, liquids, lozenges, aqueous or oily suspensions, etc., for oral ingestion by the patient. Orally administered pharmaceutical formulations can be obtained, for example, by adding a solid excipient (see page 69 / 97 of CN 121041437 A), optionally grinding the resulting mixture, and, if necessary, processing the granular mixture after adding suitable excipients to obtain tablets or sugar-coated pill cores. Suitable excipients include, but are not limited to, fillers such as sugars, including but not limited to lactose, sucrose, mannitol, and sorbitol; and cellulose formulations such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrants such as, but not limited to, croscarmellose, agar, or alginate or salts thereof, such as sodium alginate, may be added.

[0467] Orally administered compositions may contain one or more optional pharmaceutical 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 a pharmaceutically palatable formulation. Furthermore, in the case of tablets or pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over an extended period of time. Selective permeable membranes surrounding permeation-driven compounds are also suitable for orally administered compounds. Oral compositions may contain standard mediators such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such mediators are preferably pharmaceutical grade.

[0468] Sugar-coated pellet cores may have a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution.and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the coating of tablets or sugar-coated pills for identification or characterization of different combinations of active compound dosages.

[0469] Orally usable pharmaceutical formulations include, but are not limited to, push-fit capsules made of gelatin, and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules may contain the active ingredient mixed with fillers 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 may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added.

[0470] For buccal administration, the composition may be in the form of tablets or lozenges, such as those formulated in a conventional manner.

[0471] For inhalation administration, the compounds described herein may be delivered in the form of an aerosol spray from a pressurized package or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metering amount. Capsules and cartridges, such as those for inhalers or blowpipes, may be formulated containing a mixture of the compound with a suitable powder matrix such as lactose or starch.

[0472] The compounds described herein may also be formulated into rectal compositions, such as suppositories or retention enemas, such as those containing a conventional suppository matrix, such as cocoa butter or other glycerides. The compounds described herein may also be formulated into vaginal compositions, such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine devices.

[0473] In transdermal administration, the compounds may be applied as ointments or may be applied via a transdermal therapeutic system and subsequently delivered to the organism. In some embodiments, the compound is present in creams, solutions, powders, fluid emulsions, fluid suspensions, semi-solid preparations, ointments, pastes, gels, jelly preparations, and foams, or in patches containing any of them.

[0474] The compounds described herein can also be formulated into reservoir formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Reservoir injections can be administered at intervals of about 1 to about 6 months or longer. Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or formulated as a slightly soluble derivative (e.g., formulated as a slightly soluble salt).

[0475] In some embodiments, the compound can be delivered in a controlled-release system. In one embodiment, a pump (see Langer, ibid.; Sefton, CRC) can be used.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 implementations, polymeric materials may be used (see Medical Applications of Controlled Release, Langer and Wise (ed.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (ed.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, the controlled-release system may be placed near the target of the compound described herein, such as the liver, thus requiring only a portion of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115–138 (1984)). Other controlled-release systems discussed in the review in Langer, Science, 1990, 249, 1527–1533 may be used.

[0476] It is also known in the art that compounds may be included in such formulations along with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic carriers, water-soluble carriers, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives, etc. Pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In some embodiments, the compounds described herein can be used in conjunction with pharmaceutical agents, including but not limited to local analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or irrigants (e.g., Caphosol).

[0477] In some embodiments, the compounds described herein can be delivered in vesicles, particularly liposomes (see Langer, Science, 1990, 249, 1527-1533; Treat et al., 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; generally see ibid.).

[0478] Suitable compositions include, but are not limited to, orally non-absorbable compositions. Suitable compositions also include, but are not limited to, saline, water, cyclodextrin solutions, and buffer solutions with pH 3-9.

[0479] The compounds described herein, or their pharmaceutically acceptable salts, solvates, or prodrugs, can be formulated with a variety of excipients, including but not limited to purified water, propylene glycol, PEG 400, glycerol, DMA, ethanol, benzyl alcohol, citric acid / sodium citrate (pH 3), citric acid / sodium citrate (pH 5), tris(hydroxymethyl)aminomethane HCl (pH 7.0), 0.9% saline, and 1.2% saline, and any combination thereof. In some embodiments, the excipients are selected from propylene glycol, purified water, and glycerol.

[0480] In some embodiments, the formulation can be lyophilized into a solid and reconstituted with, for example, water before use.

[0481] When administered to mammals (e.g., to animals for veterinary use or to humans for clinical use), the compounds can be administered in an isolated form.

[0482] When administered to humans, the compounds can be sterile. Water is a suitable carrier when administering compounds of formulas I-VIII intravenously. Saline solutions and aqueous solutions of dextran and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable drug carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, etc. If desired, the compositions of the present invention may also contain small amounts of wetting agents or emulsifiers or pH buffers.

[0483] The compositions described herein may be in the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquid, powders, sustained-release formulations, suppositories, aerosols, sprays, or any other suitable form. Examples of suitable drug carriers are described in Remington's Pharmaceutical Sciences, ARGennaro (editor) specification 71 / 97 pages 73 CN 121041437 A Mack

[0484] In some embodiments, the compound is formulated into a pharmaceutical composition suitable for human administration according to conventional procedures. Typically, the compound is a solution in a sterile isotonic buffer solution. If necessary, the composition may also contain a solubilizer. Compositions for intravenous administration may optionally contain a local anesthetic such as lidocaine to relieve pain at the injection site. Typically, the components are provided separately or mixed together in unit dosage forms, for example, as a dried lyophilized powder or anhydrous concentrate in an airtight container, such as an ampoule or capsule indicating the amount of active agent. When administering the compound by infusion, it may be prepared, for example, with an infusion bottle containing sterile pharmaceutical-grade water or saline. When administering the compound by injection, an ampoule of sterile water for injection or saline may be provided so that the components can be mixed before administration.

[0485] The pharmaceutical composition may be a unit dosage form. In this form, the composition may be divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as powder in packaged tablets, capsules, vials, or ampoules. The unit dosage form can also be the capsule, sac, or tablet itself, or it can be any of these packaging forms in appropriate quantities.

[0486] In some embodiments, the composition is in liquid form, wherein the active agent (i.e., one of the surface-amphiphilic polymers or oligomers disclosed herein) is present in the form of a solution, suspension, emulsion, or solution / suspension. In some embodiments, the liquid composition is in gel form. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in ointment form.

[0487] In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, the ophthalmic composition is a solid article that can be inserted into a suitable location in the eye, such as between the eye and the eyelid or in the conjunctival sac, where it releases an active agent, as described, for example, in U.S. Patent Nos. 3,863,633; 3,867,519; 3,868,445; 3,960,150; 3,963,025; 4,186,184; 4,303,637; 5,443,505; and 5,869,079. Typically, from such an article, the solid article is released onto the cornea via tears that soak the corneal surface, or directly onto the cornea itself, and is usually in close contact with the cornea. Solid articles suitable for implantation into the eye in this manner are typically composed primarily of polymers and can be bio-eroded or non-bio-eroded. Bioeroable polymers that can be used to prepare ocular implants carrying one or more compounds include, but are not limited to, aliphatic polyesters, such as poly(glycolic acid), poly(lactide), poly(ε-caprolactone), and poly(hydroxybutyric acid).Polymers and copolymers of esters and poly(hydroxyvalerates), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates, and polyether lactones. Suitable non-biodegradable polymers include silicone elastomers.

[0488] The compositions described herein may contain preservatives. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercuric salts (e.g., phenylmercuric acetate, phenylmercuric borate, and phenylmercuric nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridine chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben and their salts; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenethyl alcohol; disodium EDTA; and sorbic acid and their salts.

[0489] Optionally, the compositions may contain one or more stabilizers to enhance chemical stability when needed. Suitable stabilizers include, but are not limited to, chelating or complexing agents, such as the calcium complexing agent ethylenediaminetetraacetic acid (EDTA). For example, the composition may contain an appropriate amount of EDTA or a salt thereof, such as disodium EDTA, to complex excess calcium ions and prevent gel formation during storage. A suitable amount of EDTA or a salt thereof may be from about 0.01% to about 0.5%. In those embodiments containing preservatives other than EDTA, EDTA or a salt thereof, more particularly disodium EDTA, may be present in an amount from about 0.025% by weight to about 0.1% by weight. Specification 72 / 97 pages 74 CN 121041437 A

[0490] The composition may also contain one or more antioxidants. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenethyl 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% by weight to about 1.0% by weight.

[0491] In some embodiments, the compound is at least partially dissolved by an acceptable solubilizer. Certain acceptable nonionic surfactants (e.g., polysorbate 80) can be used as solubilizers, as can ophthalmologically acceptable glycols, polyethylene glycols (e.g., polyethylene glycol 400 (PEG-400)) and glycol ethers.

[0492] Suitable solubilizers for solutions and solution / suspension compositions are cyclodextrins. Suitable cyclodextrins may be selected from α-cyclodextrin, β-cyclodextrin,

[0493] γ-cyclodextrin, alkylcyclodextrins (e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin), hydroxyalkylcyclodextrins (e.g., hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), carboxyl-alkylcyclodextrins (e.g.,Carboxymethyl-β-cyclodextrin), sulfonyl ether cyclodextrin (e.g., sulfobutyl ether-β-cyclodextrin), etc. The ophthalmic applications of cyclodextrin are reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.

[0494] In some embodiments, the composition optionally contains a suspending agent. For example, in those embodiments where the composition is an aqueous suspension or solution / suspension, the composition may 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 hydroxypropyl methylcellulose, and water-insoluble polymers such as crosslinked carboxyl-containing polymers.

[0495] The composition may contain one or more acceptable pH adjusters and / or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers such as citrate / glucose, sodium bicarbonate, and ammonium chloride. The amount required to maintain the pH of the composition within an acceptable range includes such acids, bases, and buffer solutions.

[0496] One or more acceptable salts, solvates, or prodrugs may be included in the composition in the amount required to achieve an acceptable osmolality of the composition. Such salts include, but are not limited to, those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions. In some embodiments, the salt includes sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate. In some embodiments, the salt is sodium chloride.

[0497] Optionally, the composition may contain one or more acceptable surfactants, such as, but not limited to, nonionic surfactants or cosolvents, to improve the solubility of the composition components or 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 alkylphenyl ethers, such as octylphenyl polyol 10, octylphenyl polyol 40; polysorbates 20, 60 and 80; polyoxyethylene / polyoxypropylene surfactants (e.g., F-68, F84 and P-103); cyclodextrins; or other agents known to those skilled in the art. Typically, these cosolvents or surfactants are used in the composition in amounts from about 0.01% by weight to about 2% by weight.

[0498] In some embodiments, pharmaceutical packaging or kits are provided comprising one or more containers filled with one or more compounds described herein. Optionally associated with such one or more containers may be those presented by a controlled pharmaceutical orA notification in the form prescribed by a government agency for the manufacture, use, or sale of a biological product, reflecting the approval of the manufacturing, using, or selling agency for human administration to treat the conditions, diseases, or disorders described herein. In some embodiments, the kit contains more than one compound described herein. In some embodiments, the kit contains a single dose of the compound described herein in a single injectable dosage form, such as in an injectable device (such as a syringe with a needle). Specification 73 / 97 pages 75 CN 121041437 A

[0499] In some embodiments, the method includes administering to a subject one or more of the compounds described herein or pharmaceutically acceptable salts, solvates, or prodrugs thereof, or pharmaceutical compositions 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.

[0500] In some embodiments, one or more of the above-described compounds, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, or pharmaceutical compositions comprising one or more of the above-described compounds, are also provided for use in preparing a medicament for treating and / or preventing EPP, XLPP, or CEP, or related syndromes of a subject, including but not limited to the conditions described herein, such as those described herein. In some embodiments, the subject is a subject in need.

[0501] This embodiment also provides the use of one or more of the above-described compounds, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, or pharmaceutical compositions comprising one or more of the above-described compounds, in inhibiting GlyT1 transporters (such as those present on cell surfaces). In some embodiments, the compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof inhibit the internalization, transport, and / or degradation of GlyT1 transporters.

[0502] As used herein, “inhibition” can refer to inhibition of a specific activity. The activity of GlyT1 transporters can be measured by any method known in the art, including but not limited to the methods described herein.

[0503] The compounds described herein are inhibitors of GlyT1 transporters. The ability of a compound to inhibit GlyT1 transporter activity can be measured using any assay known in the art.

[0504] Typically, assays used to test for the inhibition of GlyT1 transporter activity involve determining any parameters, such as functional, physical, or chemical effects, that are indirectly or directly affected by the GlyT1 transporter.

[0505] A sample or assay containing 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 the inhibitor) is designated as 100% of the relative GlyT1 transporter activity value. Inhibition of the GlyT1 transporter is achieved when the GlyT1 transporter activity value relative to the control is about 80%, 50%, or 25%.

[0506] The binding of the ligand to the GlyT1 transporter can be tested in a variety of forms. Binding can occur in solution, in a bilayer, attached to a solid phase, in a lipid monolayer, or in vesicles. For example, in an assay, the binding of the native ligand to its transporter is measured in the presence of a candidate regulator (such as the compounds described herein). Alternatively, the binding of the candidate regulator can be measured in the presence of the native ligand. Typically, a competitive assay is used, which measures the ability of the compound to competitively bind to the transporter against the native ligand. Binding can be tested by measuring changes in, for example, spectral characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic changes (e.g., shape), or chromatographic or solubility properties.

[0507] Once the transporter is expressed in cells, the cells can be grown in a suitable cell plate in a suitable culture medium. Cells can be seeded, for example, at 5,000–10,000 cells / well in a 384-well plate. In some embodiments, cells are plated at approximately 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 cells / well. The plate may have any number of wells, and the number of cells may be varied accordingly.

[0508] Any agent that is effective in the applications described herein may be used for co-treatment, co-administration, or co-formulation with the compositions described above. Thus, the compounds described herein may be administered before, simultaneously with, or after administration of such therapeutic agents to a subject.

[0509] Additional agents may be administered in co-treatment (including co-formulation) with one or more compounds described herein.

[0510] In some embodiments, the response of the disease or disorder to treatment is monitored, and the treatment regimen is adjusted based on such monitoring if necessary.

[0511] The frequency of administration typically results in dosing intervals, for example, during the conscious period, the time between one dose and the next dose being 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 daily. Those skilled in the art will understand that an appropriate dosing interval depends to some extent on the length of time that the selected composition can maintain concentrations of one or more compounds (e.g., above EC50 (the minimum compound concentration that inhibits transporter activity by 90%)) in the subject and / or target tissues. Ideally, the concentration is maintained above EC50 for at least 100% of the dosing interval. When this is not possible, it is desirable that the concentration be maintained above EC50 for at least about 60% of the dosing interval, or for at least about 40% of the dosing interval.

[0512] Method of Use

[0513] This application provides a method for preventing or treating a subject's impairment related to PPIX accumulation, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In some embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as the GlyT1 inhibitors disclosed herein. For example, this application provides a method for preventing or treating a subject's impairment related to PPIX accumulation, the method comprising administering to the subject bitopertin, or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof.

[0514] In part, this disclosure relates to methods for treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP), the methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a salt thereof. In some embodiments, this disclosure provides methods 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 methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof. These methods are particularly directed for therapeutic and prophylactic treatment in animals and more specifically in humans. The terms “subject,” “individual,” or “patient” are interchangeable throughout the specification and refer to a human or a non-human animal. These terms include mammals such as humans, non-human primates, laboratory animals, livestock (including cattle, pigs, camels, etc.), companion animals (e.g., dogs, cats, other domestic animals, etc.), and rodents (e.g., mice and rats). In a particular embodiment, the patient, subject, or individual is a human.

[0515] This application provides a method for preventing or treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP) or a related syndrome (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome), the method comprising administering to the subject one or more glycine transporter inhibitors or a pharmaceutically acceptable salt thereof, or the one or more glycine transporter inhibitors or the drug information leaflet 75 / 97 pages 77 CN 121041437 AThis application also 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 a prodrug of the one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. For example, this 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 a prodrug of the one or more 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, such as one or more GlyT1 inhibitors disclosed herein. For example, this application provides a method for preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof.

[0516] This application also provides a method for preventing or treating EPP, XLPP, or CEP or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or a prodrug of the one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. This application also provides a method for preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or a prodrug of the one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. For example, this application provides a method for treating EPP, XLPP, or CEP in a subject, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or a prodrug of the one or more 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, such as one or more GlyT1 inhibitors disclosed herein. In some of the above embodiments, the pharmaceutical composition further comprises pharmaceutically acceptable...The carrier of the subject. For example, this application provides a method for preventing or treating EPP, XLPP or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising bitopertin or a pharmaceutically acceptable salt thereof or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0517] Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLPP) are erythropoietic cutaneous porphyria characterized by acute non-blistering photosensitivity, sun intolerance and significantly reduced quality of life. EPP is caused by a partial deficiency of ferrous chelate (FECH), which catalyzes the final step in the heme biosynthesis pathway. FECH deficiency increases the level 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 lead to the accumulation of both metal-free PPIX and zinc-bound PPIX. Both EPP and XLPP lead to the accumulation of PPIX in erythrocytes and other tissues or biological fluids (e.g., skin, liver, bile, or feces). PPIX is lipophilic and eliminated via bile, and is hepatotoxic at high concentrations.

[0518] Patients with EPP or XLPP typically develop photosensitivity in early childhood. Patients frequently present with symptoms of burning, itching, painful erythema, and edema in sun-exposed areas. Skin symptoms are sometimes associated with abnormal liver enzyme activity, hepatobiliary damage such as jaundice and cirrhosis, iron deficiency, and corresponding microcytic anemia.

[0519] The diagnosis of EPP and XLPP can be determined by measuring the levels of total erythrocytes, free protoporphyrin IX, and zinc-protoporphyrin IX in hemolyzed and anticoagulated whole blood. The diagnosis of EPP and / or XLPP can be based on an increase in the level of free protoporphyrin IX in the blood, as described on pages 76 / 97 of the specification, CN 121041437 A. 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%).

[0520] The diagnosis of EPP can also be determined by measuring the level of ferrochelatase activity in the subject. Ferrochelatase is a mitochondrial enzyme that catalyzes the insertion of ferrous iron into PPIX to form heme. Ferrochelatase also catalyzes the insertion of zinc to form zinc protoporphyrin IX (ZPPIX) from any PPIX remaining after heme synthesis is complete. In EPP, free PPIX accumulates in bone marrow reticulocytes because the formation of both heme and ZPPIX is impaired. In some embodiments, this disclosure relates to a method of treating a subject whose ferrochelatase activity level is reduced to that observed in normal subjects.The ferrochelate activity level is between 10% and 35%. In some embodiments, this disclosure relates to a method of treating a subject whose ferrochelate activity level is reduced to less than 50% of the ferrochelate activity level observed in normal subjects.

[0521] XLPP has a similar phenotype to EPP and can be distinguished based on genetic analysis of ALAS2 or by determining the enzyme activity level of ALAS2. In some embodiments, this disclosure relates to a method of treating a subject with a gain-of-function mutation in ALAS2. In some embodiments, the subject's ALAS2 enzyme activity is increased. Since ferrochelate is not lacking in XLPP, some of the excess PPIX measured in erythrocytes is ZPPIX, and a low percentage (e.g., 50%–85%) is metal-free. In some embodiments, the subject's zinc-protoporphyrin IX level is increased in erythrocytes. In some embodiments, the method reduces the zinc-protoporphyrin IX level in the subject's erythrocytes. In some embodiments, the method reduces zinc protoporphyrin IX levels in the erythrocytes of 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%).

[0522] In some aspects, this disclosure relates to a method of treating a subject with erythropoietic protoporphyrin (EPP) and / or X-linked protoporphyrin (XLPP), 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 a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has increased PPIX levels. In some embodiments, the method involves subjects having PPIX levels at least 10%, 20%, 30%, 40%, or 50% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having PPIX levels at least 10% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having PPIX levels at least 20% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having PPIX levels at least 10% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor).Subjects with PPIX levels at least 30% higher than those in healthy subjects. In some embodiments, the method involves subjects with PPIX levels at least 40% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects with PPIX levels at least 50% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the subject has increased protoporphyrin IX levels in feces. In some embodiments, the subject has increased protoporphyrin IX levels in skin. In some embodiments, the subject has increased levels of free protoporphyrin IX in erythrocytes. In some embodiments, the subject has protoporphyrin IX levels greater than 31 μmol L⁻¹ in erythrocytes. In some embodiments, the subject has protoporphyrin IX levels from 31 μmol L⁻¹ to 53 μmol L⁻¹ in erythrocytes. In some embodiments, the subject has protoporphyrin IX levels greater than 53 μmol L⁻¹ in erythrocytes.

[0523] This application also provides a method for inhibiting PPIX synthesis in vivo, the method comprising administering to a subject a glycine transporter inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In some aspects, this disclosure relates to a method for inhibiting PPIX synthesis in vivo, the method comprising administering to a subject 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, this 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, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 20%. In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 30%. In some embodiments, this disclosure relates to a method for inhibiting at least 40% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 50% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 60% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 70% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to inhibiting at least...80% method. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of PPIX synthesis in vivo. This application also provides a method for reducing the rate of PPIX synthesis in vivo, the method comprising administering to a subject a glycine transporter inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In some embodiments of the methods and uses disclosed herein, PPIX accumulation is inhibited directly or indirectly. In some such embodiments, PPIX accumulation is inhibited in a dose-dependent manner. In some embodiments of the foregoing methods, the glycine transporter inhibitor is a GlyT1 inhibitor, such as the GlyT1 inhibitor disclosed herein. For example, this application provides a method for inhibiting PPIX synthesis in vivo, reducing the rate of PPIX synthesis in vitro, and / or inhibiting PPIX accumulation in vivo, the method comprising administering to a subject bitopertin or a pharmaceutically acceptable salt thereof or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject. In some embodiments, the method involves reducing the level of free protoporphyrin IX in the erythrocytes of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the erythrocytes of a subject to below 53 μmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the erythrocytes of a subject to below 31 μmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the erythrocytes of a subject to below 15 μmol L⁻¹. In some embodiments, the method involves 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 involves 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 involves reducing the level of free protoporphyrin IX in a subject by at least 15%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 20%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 25%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least...A 30% method. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 35%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 40%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 45%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 50%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 55%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 60%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 65%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 70%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 75%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 80%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 85%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 90%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 95%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 100%.

[0525] In some aspects, this disclosure relates to a method of treating a subject with X-linked protoporphyria (XLPP), 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 a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has increased zinc-protoporphyrin IX (ZPPIX) levels. In some embodiments, the method relates to a subject having ZPPIX levels at least 10%, 20%, 30%, 40%, or 50% higher than ZPPIX levels in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method relates to a subject having ZPPIX levels at least 10% higher than ZPPIX levels in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some...In some embodiments, the method involves subjects having ZPPIX levels at least 20% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having ZPPIX levels at least 30% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having ZPPIX levels at least 40% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having ZPPIX levels at least 50% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the subject's ZPPIX levels are increased in red blood cells.

[0526] In some aspects, this disclosure relates to a method of treating a subject with X-linked protoporphyria (XLPP), 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 a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has an increased ratio of zinc-protoporphyrin IX (ZPPIX) to free protoporphyrin IX (ZPPIX / PPIX ratio) compared to a subject with 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 involves a subject having a ZPPIX / PPIX ratio of at least 30%. In some embodiments, the method involves a subject having a ZPPIX / PPIX ratio of at least 35%. In some embodiments, the method involves a subject having a ZPPIX / PPIX ratio of at least 40%. In some embodiments, the method involves a subject having a ZPPIX / PPIX ratio of at least 45%.

[0527] In some aspects, this disclosure relates to a method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or the GlyT1 inhibitor or its pharmaceutically acceptable labeling. (Pages 79 / 97, 81 CN)121041437 A An acceptable salt prodrug. In some embodiments, this 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, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 20%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 30%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 40%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 50%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 60%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 70%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 80%. In some embodiments, this disclosure relates to a method of inhibiting ZPPIX synthesis in vivo by at least 90%. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of ZPPIX synthesis in vivo.

[0528] In some aspects, this disclosure relates to a method for treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP), 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 a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has increased 5-aminolevulinic acid (5-ALA) levels. In some embodiments, the method relates to a subject having 5-ALA levels at least 10%, 20%, 30%, 40%, or 50% higher than 5-ALA levels in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having 5-ALA levels at least 10% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having 5-ALA levels at least 20% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having 5-ALA levels at least [missing information - likely a percentage] higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor).30% of subjects with 5-ALA levels. In some embodiments, the method involves subjects having 5-ALA levels at least 40% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having 5-ALA levels at least 50% higher than those in healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor).

[0529] In some aspects, this disclosure relates to a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for 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, this disclosure relates to a method for inhibiting at least 20% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 30% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 40% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 50% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 60% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 70% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of 5-ALA synthesis in vivo.

[0530] This application also provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of such one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, as described on pages 80 / 97 of CN 121041437 A, in the preparation of formulations for treating subjects with EPP, XLPP, CEP, or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome). In some embodiments, this application provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of such one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, in the preparation of formulations for treating subjects with EPP, XLPP, or CEP. In some embodimentsIn this application, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors disclosed herein. In some 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 some of the foregoing embodiments, the formulation is administered in a therapeutically effective amount.

[0531] This application provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof or prodrugs thereof in the preparation of a pharmaceutical composition for treating a subject with EPP, XLPP, or CEP or a related syndrome (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome). In some embodiments, this application provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof or prodrugs thereof in the preparation of a pharmaceutical composition for treating a subject with EPP, XLPP, or CEP. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors disclosed herein. In some 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 some of the above embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0532] Congenital erythropoietic porphyria (CEP) is an erythropoietic cutaneous porphyria characterized by blistering photosensitivity of the skin. Severe cases of CEP can occur in utero with fetal hydrops or shortly after birth with severe blistering photosensitivity, hematuria, splenomegaly, hemolysis, and transfusion dependence. Milder cases and later-onset forms typically present with hematuria, severe blistering, and hemolytic anemia.

[0533] Individuals with CEP are typically homozygous or compound heterozygous for UROS mutations. Some cases of CEP are caused by mutations in the gene encoding the transcriptional regulator GATA1. These mutations lead to reduced activity of uroporphyrinogen III synthase (UROIII-S), the fourth enzyme in the heme biosynthesis pathway. Reduced UROIII-S activity results in decreased hydroxyl...Accumulation of methylcholine, spontaneous formation of uroporphyrinogen I from hydroxymethylcholine, and further metabolism of uroporphyrinogen I to coproporphyrinogen I. Uroporphyrinogen I and coproporphyrinogen I accumulate in tissues.

[0534] Diagnosis of CEP can be determined by analyzing the enzymatic activity of uroporphyrinogen III synthase (UROIII-S), by assessing mutations in the UROS gene, by assessing the function of the GATA-1 erythroid-specific transcription factor, by assessing mutations in GATA1, and by 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 gene defect in the GATA-1 erythroid-specific transcription factor. In some embodiments, the method relates to a method of treating a subject, wherein the subject has reduced uroporphyrinogen III synthase activity. In some embodiments, increased levels of uroporphyrin I and / or coproporphyrin I are measured in the subject's urine or red blood cells. In some embodiments, increased levels of coprophytic I are measured in the subject's stool.

[0535] In some aspects, this disclosure relates to a method of treating a subject with congenital erythropoietic porphyria (CEP), 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 a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject has increased levels of uroporphytic I and / or coprophytic I. In some embodiments, the subject has increased levels of uroporphytic I and / or coprophytic I. In some embodiments, the method involves subjects having uroporphyrin I levels at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having uroporphyrin I levels at least 10% higher than those of healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having uroporphyrin I levels at least 20% higher than those of healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having uroporphyrin I levels at least 30% higher than those of healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves subjects having uroporphyrin I levels at least 10% higher than those of healthy subjects prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor).Subjects who, prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor), have uroporphyrin I levels at least 40% higher than those of healthy subjects. In some embodiments, the method relates to subjects who, prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor), have uroporphyrin I levels at least 50% higher than those of healthy subjects.

[0536] In some embodiments, this disclosure relates to a method for treating subjects who, prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor), have coproporphyrin I levels at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects. In some embodiments, the method relates to subjects who, prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor), have coproporphyrin I levels at least 10% higher than those of healthy subjects. In some embodiments, the method involves a subject having a coprophytic I level at least 20% higher than that of a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves a subject having a coprophytic I level at least 30% higher than that of a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves a subject having a coprophytic I level at least 40% higher than that of a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor). In some embodiments, the method involves a subject having a coprophytic I level at least 50% higher than that of a healthy subject prior to administration of a glycine transporter inhibitor (e.g., a GlyT1 inhibitor).

[0537] In some aspects, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin I and / or coproporphyrin I in vivo, the method comprising administering to a subject 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, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin I in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin I in vivo by at least 20%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin I in vivo by at least 30%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin I in vivo by at least 40%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin I in vivo by at least 50%.In some embodiments, this disclosure relates to a method for inhibiting at least 60% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 70% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of the synthesis of uroporphyrin I in vivo.

[0538] In some embodiments, this disclosure relates to a method for inhibiting at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%) of the synthesis of coproporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 20% of the synthesis of coproporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 30% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 40% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 50% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 60% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 70% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of coproporphyrin I synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of coproporphyrin I synthesis in vivo.

[0539] Porphyrins (e.g., PPIX, ZPPIX, uroporphyrin I, and coproporphyrin I) can be found in a variety of biological samples, including skin, urine, feces, plasma, and red blood cells. In some embodiments, porphyrins can be extracted from biological samples into solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., 400–420 nm). Porphyrins have a maximum absorption wavelength near 400–420 nm, with their highest absorption peak appearing at 415 nm. The maximum emission of porphyrins is typically around 600 nm and varies slightly depending on the type of porphyrin and the solvent used for analysis. In some embodiments, the diagnosis of EPP, XLPP, and CEP can 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.

[0540] In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's plasma porphyrins fluoresce at a peak of 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's plasma porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's skin porphyrins fluoresce at a peak of 632 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's skin porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, the level of protoporphyrin IX in the subject's skin is greater than 0.2 fluorescent units (FDU). In some embodiments, the protoporphyrin IX level in the subject's skin is greater than 1.0 FDU. In some embodiments, the protoporphyrin IX level in the subject's skin is between 1.0 FDU and 2.5 FDU. In some embodiments, the protoporphyrin IX level in the subject's skin is greater 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, using plasma porphyrin fluorescence analysis, the subject has a peak between 615 nm and 620 nm.

[0541] In some aspects, this disclosure relates to 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, said 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 a prodrug of said 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: acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, spleenHyperfunction, palmar keratosis, bullae, lesions, scars, deformities, nail loss, toe loss, cholelithiasis, cholestasis, cell lysis, gallstones, cholestatic liver failure, red teeth syndrome, high cellularity bone marrow, spinal dysplasia, thrombocytopenia, fetal hydrops and / or intrauterine death. In some embodiments, this disclosure considers a method for treating one or more complications of EPP, XLPP, or CEP (e.g., acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scars, malformations, nail loss, toe loss, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic liver failure, red teeth syndrome, high-cytosis bone marrow, spinal dysplasia, thrombocytopenia, fetal hydrops, and / or intrauterine death), said method comprising administering a pharmaceutical composition to the subject, said pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, one or more complications are indirectly improved. In some embodiments, this disclosure contemplates methods for preventing one or more complications of EPP, XLPP, or CEP, the methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, this disclosure contemplates methods for reducing the progression rate of one or more complications of EPP, XLPP, or CEP, the methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, this disclosure contemplates methods for reducing the severity of one or more complications of EPP, XLPP, or CEP, said methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.

[0542] Optionally, the methods disclosed herein 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 may further comprise administering to the patient one or more medications for treatingSupportive therapy or additional active agents of EPP, XLPP, or CEP may also be administered to the patient, for example, one or more of the following: avoidance of sunlight, local sun protection, skin protection, UVB phototherapy, afanotide 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 include administration of afanotide

[0543] to the patient. Porphyrin photosensitization in EPP, XLPP, and CEP produces two distinct clinical syndromes: (1) acute photosensitivity under sun exposure with erythema and edema, and (2) a syndrome of subepidermal bullae appearing in sun-exposed areas of the skin. In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of EPP, XLPP, or CEP in a subject, said methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, said method increasing the subject's painless light exposure. In some embodiments, said method increases the subject's painless light exposure by at least 10%, 20%, 30%, 40%, or 50% compared to painless light exposure prior to administration of the GlyT1 inhibitor. In some embodiments, said method reduces the subject's photosensitivity. In some embodiments, said method reduces the subject's photosensitivity 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, child, infant, or pregnant woman.

[0544] Glycine is one of the key starting substrates for heme and globin synthesis. Therefore, a decrease in glycine levels due to GlyT1 inhibition may lead to a decrease in heme synthesis. In some aspects, this disclosure relates to a method of treating a subject with an EPP, XLPP, or CEP, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a pharmaceutically acceptable salt thereof, or a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a salt thereof, wherein the subject's heme level decreases by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, this disclosure relates to a method of treating a subject with an EPP, XLPP, or CEP, wherein the subject's heme level decreases by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%).More than 15%. In some embodiments, this disclosure relates to a method of treating a subject with EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 20%. In some embodiments, this disclosure relates to a method of treating a subject with EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 25%. In some embodiments, this disclosure relates to a method of treating a subject with EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 30%.

[0545] In some aspects, this disclosure relates to a method of treating a subject with EPP, XLPP, or CEP, 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 a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the subject's PPIX level is reduced while the patient's heme level is significantly maintained. In some embodiments, the patient's PPIX level is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the patient's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient's PPIX level is reduced by at least 85% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 80% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 75% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 70% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 65% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 60% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 55% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 50% and the patient's heme level is reduced by no more than 15%.

[0546] In some aspects, this disclosure relates to a method of treating a subject with EPP, XLPP, or CEP, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a pharmaceutically acceptable salt thereof, or one or more glycine transporter inhibitors.(e.g., a GlyT1 inhibitor) or a prodrug of a salt thereof, wherein the dose of said pharmaceutical composition does not cause a significant decrease in heme levels. In some embodiments, the patient's PPIX level 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 patient's PPIX level is reduced by at least 55%. In some embodiments, the patient's PPIX level is reduced by at least 60%. In some embodiments, the patient's PPIX level is reduced by at least 65%. In some embodiments, the patient's PPIX level is reduced by at least 70%. In some embodiments, the patient's PPIX level is reduced by at least 75%. In some embodiments, the patient's PPIX level is reduced by at least 80%. In some embodiments, the patient's PPIX level is reduced by at least 85%. In some embodiments, the patient's PPIX level is reduced by at least 90%. In some embodiments, the patient's PPIX level is reduced by at least 95%. In some embodiments, the PPIX level is reduced by at least 100% as per the patient's instructions for use (page 85 / 97, CN 121041437 A). In some embodiments, the patient's heme level decreases by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient's heme level decreases by no more than 15%. In some embodiments, the patient's heme level decreases by no more than 20%. In some embodiments, the patient's heme level decreases by no more than 25%. In some embodiments, the patient's heme level decreases by no more than 30%.

[0547] In some embodiments, the accumulation of one or more of the following heme intermediates is inhibited, wherein the one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some embodiments, this disclosure relates to a method of inhibiting PPIX accumulation, 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 a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX accumulation, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I accumulation, the method comprising...The method includes administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a salt thereof. In some embodiments, this disclosure relates to a method for inhibiting coprophyrin I accumulation, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a salt thereof. In some embodiments, this disclosure relates to a method for inhibiting 5-ALA accumulation, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or a salt 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, Figure 7.

[0548] When the liver load exceeds the tubular excretory capacity, the accumulation of protoporphyrins in EPP, XLPP, and CEP can cause liver injury. The accumulation of PPIX in hepatocytes and bile tubules can lead to cell damage, cholestasis, cell lysis, and further retention of protoporphyrins. Excessive protoporphyrins can exert a cholestatic effect, leading to changes in the hepatobiliary system ranging from mild inflammation to fibrosis and cirrhosis (e.g., cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease). Between 3% and 5% of EPP or XLPP patients develop protoporphyrin liver disease, a serious liver disease that can progress rapidly and require liver transplantation. Approximately 2% of patients will develop severe liver disease.

[0549] In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of liver disease associated with EPP, XLPP, or CEP in a subject, said methods comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or a prodrug of said one or more 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 severe liver disease.In some embodiments, the liver disease associated with EPP, XLPP, or CEP is end-stage liver disease.

[0550] Liver function in patients with EPP, XLPP, and CEP can be assessed 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 aspartate aminotransferase levels, alkaline phosphatase, or gamma-glutamyl transferase levels). In some embodiments, histopathology of a liver biopsy can be used to assess one or more parameters of the subject (e.g., protoporphyrin deposition, fibrosis, infiltration, portal fibrosis, and periportal fibrosis). In some embodiments, ultrastructural studies of the biopsy specimen can be used to determine the presence of crystalline vacuoles in the subject. As liver function deteriorates, urinary comatose porphyrin excretion increases. In some embodiments, urinary comatose porphyrin excretion can be analyzed to assess the subject's liver function. In some embodiments, ultrasound or magnetic resonance elastography can be used to measure the subject's liver stiffness.

[0551] In certain embodiments of the methods and uses disclosed herein, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as 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 as disclosed herein) or a pharmaceutically acceptable salt thereof, exhibits PPIX inhibition, wherein the EC50 is 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 this application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as 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 as disclosed herein) or a pharmaceutically acceptable salt thereof, exhibits PPIX inhibition, wherein the EC50 is less than 100 nM. In certain embodiments of this application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as 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 as disclosed herein) or a pharmaceutically acceptable salt thereof, exhibits PPIX inhibition, wherein the EC50 is less than 50 nM. In some such embodiments, the EC50 is measured in a flow cytometry assay. In some 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.

[0552] In some embodiments of the methods and uses disclosed herein, cell viability is maintained at at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. In some such embodiments, cell viability is maintained at at least 90%.

[0553] This disclosure also provides the following non-limiting embodiments:

[0554] Examples are provided below to facilitate a more efficient understanding of the embodiments disclosed herein. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the embodiments in any way. Unless otherwise stated, throughout these examples, molecular cloning reactions and other standard recombinant DNA techniques described may be present, performed using commercially available reagents according to the methods described in Maniatis et al., Molecular Cloning—A Laboratory Manual, 2nd edition, Cold Spring Harbor Press (1989).

[0555] The following examples illustrate, but do not limit, the methods and compositions described herein. Other suitable modifications and adjustments to various conditions and parameters commonly encountered in the therapeutic, synthetic, and other embodiments disclosed herein are within the spirit and scope of the embodiments.

[0556] Examples

[0557] Example 1: Synthesis of Compounds

[0558] The compounds disclosed herein can be prepared according to well-known procedures and by methods known and disclosed in the art. For example, compounds of Formula I, such as bitopertin, can be prepared according to the synthetic methods 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. In addition, compounds of Formula II, such as PF-3463275, can be prepared according to the synthetic method provided in U.S. Patent No. 8,124,639, the contents of which are incorporated herein by reference in their entirety.

[0559] Example 2: GlyT1 inhibitor for treating subjects with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP) and congenital erythropoietic protoporphyria (CEP). (Predictive Example)

[0560] To support the production of large amounts of hemoglobin, the synthesis of large amounts of heme is a fundamental requirement for developing erythrocytes. In this cell lineage, the amount of heme required to meet this requirement is far greater than in any other cell type. Heme synthesis is initiated by the condensation of glycine with succinyl-CoA via the ALAS enzyme. This is the rate-limiting step in heme biosynthesis to ensure that heme intermediates do not accumulate and cause toxicity. Erythroid cells have acquired an erythroid-specific form of ALAS (ALAS2).And the glycine transporter GlyT1 to increase glycine availability, thereby meeting this high demand for heme.

[0561] Animal and human studies that have eliminated GlyT1 activity through gene deletion (Garcia-Santos et al., 2017) or reduced GlyT1 activity through the administration of specific GlyT1 inhibitors (Pinard et al., 2018) have shown reduced heme synthesis in erythroid cells, resulting in moderate microglobulinous hypochromic anemia as a result of impaired hemoglobin production. These findings suggest that regulation of glycine uptake in erythrocytes can modulate the heme biosynthetic pathway.

[0562] In patients with erythropoietic protoporphyria or congenital erythropoietic porphyria, specific mutations in a single gene encoding an enzyme in the heme biosynthetic pathway result in altered enzyme activity and accumulation of heme intermediates upstream of the affected enzyme. The accumulation of these metabolites occurs because the mutant enzyme becomes the rate-limiting step in the pathway, and its activity is insufficient to completely convert the upstream metabolite into the next step in the pathway. Three diseases are of particular concern:

[0563] 1. EPP caused by mutations in the ferrochelase gene, which leads to reduced enzyme activity and accumulation of the upstream metabolite protoporphyrin IX (PPIX). Acquired forms of EPP are rarely observed in older adults who have developed new clones containing ferrochelase mutations as a characteristic of spinal dysplasia.

[0564] 2. XLPP caused by mutations in the ALAS2 gene, resulting in high levels of PPIX. In this case, because the excessive production of ferrochelase cannot be completely converted into heme even at normal levels, the metabolite accumulates downstream of the affected enzyme.

[0565] 3. CEP caused by mutations in the uroporphyrinogen synthase gene, resulting in reduced enzyme activity and accumulation of the upstream metabolite comatose porphyrin I.

[0566] These heme intermediates can escape from red blood cells and cause toxicity through hemolysis (in CEP) or by active transport out of cells (in EPP and XLPP). A consistent feature of all three diseases is a severe, painful, blistering skin reaction following sun exposure, leading to permanent scarring and deformities. This is caused by the local production of active intermediates from the effects of sunlight on PPIX or coproporphyrin I, triggering a severe inflammatory response. PPIX is hydrophobic and therefore excreted via the bile duct. High bile concentrations can lead to cholelithiasis, cholestasis, and severe liver damage, resulting in liver failure. In the case of CEP, the accumulation of coproporphyrin in mature erythrocytes can lead to severe hemolytic anemia.

[0567] These disease manifestations of EPP, XLPP, and CEP are caused by an overproduction of intermediate heme metabolites due to genetic abnormalities in the heme biosynthesis pathway. The accumulated metabolites accumulate in the skin and have an effect on erythrocytes after sun exposure.Toxicity, or due to bile excretion by the liver. GlyT1 controls the availability of one of the initial substrates in the heme biosynthesis pathway and has been shown to downregulate heme production in humans or animals with a normal heme pathway as described above. Unbound by any particular theory, GlyT1 is able to reduce the production of intermediate metabolites of heme in the same way, especially when those intermediates accumulate due to abnormal enzyme activity. Therefore, treatment of subjects with EPP, XLPP, or CEP with GlyT1 will reduce the production of toxic metabolites in erythroid cells in such subjects and result in reduced skin accumulation of these metabolites, reduced hepatobiliary excretion, or, in the case of CEP, reduced hemolysis, and in all cases, reduced disease severity. Thus, the disease is treated.

[0568] Example 3: Met GlyT1 inhibitors effectively reduce heme metabolite levels in erythroleukemia cell lines containing pathogenic mutations of EPP, XLPP, or CEP. Instructions for Use, pages 88 / 97, 90 CN 121041437 A

[0569] Erythroleukemia cells were genetically modified to obtain cell lines containing pathogenic mutations in EPP, XLPP, or CEP. These genetically modified cell lines were treated with a GlyT1 inhibitor, and the production of heme metabolites was evaluated by spectrophotometric, biochemical, or radiolabeled studies. The level of photohemolysis caused by PPIX was evaluated in these cell lines, and it was found to be reduced in the presence of a GlyT1 inhibitor.

[0570] Example 4: GlyT1 inhibitors effectively reduce the level of heme metabolites in erythrocytes containing pathogenic mutations in EPP, XLPP, or CEP. (Prognostic Example)

[0571] Erythroid cells were obtained from the bone marrow or peripheral blood of animals with pathogenic mutations in specific genes that cause EPP, XLPP, or CEP. These cell lines were treated with a GlyT1 inhibitor, and the production of heme metabolites was evaluated by spectrophotometric, biochemical, or radiolabeled studies. The levels of photohemolysis induced by PPIX were assessed in these cell lines, and a reduction was found in the presence of a GlyT1 inhibitor.

[0572] Example 5: GlyT1 inhibitors effectively reduced the levels of heme metabolites in erythrocytes of patients with pathogenic mutations in EPP, XLPP, or CEP. (Prognostic Example)

[0573] Erythroid cells (reticulocytes and erythrocytes) were obtained from patients with EPP, XLPP, and CEP (if available). Cells from patients were treated with a GlyT1 inhibitor, and the production of heme metabolites was assessed by spectrophotometric, biochemical, or radiolabeled studies. The levels of photohemolysis induced by PPIX were assessed in these cell lines, and a reduction was found in the presence of a GlyT1 inhibitor.

[0574] Example 6: GlyT1 inhibitors effectively reduced the severity of EPP or XLPP in animals. (Prognostic Example)

[0575] Animals with EPP and XLPP were treated with different doses of one or more GlyT1 inhibitors over a period of time. A reduction in the level of toxic heme intermediates was observed in these animals, and an improvement was found in the severity of symptoms of these diseases such as skin reactions, hepatobiliary disease, and / or hemolysis.

[0576] 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.

[0577] Example 7: EPP Cell Model

[0578] Knockout guide sequences were designed to target exon 3 of the ferrochelase gene. The guide sequences tested are shown in Table 1.

[0579] Table 1: Guide Sequences Tested

[0580]

[0581] K562 cells were cultured in Iscove modified Durbecco medium (IMDM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (PS). Electroporation was performed on the CRISPR Cas9 RNP-guide RNA complex in K562 cells. Genomic DNA was isolated from the merged cells, amplified by PCR, and sequenced by Sanger sequencing to determine knockout efficiency. Single-cell clones were isolated by fluorescence-assisted cell sorting (FACS). TA cloning and Sanger sequencing were used to confirm single-cell clones and genotypes. Five clones (clone IDs: clones 1-7; clones 1-9; clones 1-10, clones 1-32; clones 1-51; and K562 WT) were selected for further characterization by Western blotting (Figure 1) to determine FECH protein expression levels (antibody: FECH antibody rabbit polyclonal, Proteintech, 14466-1-AP) and PPIX levels by flow cytometry (Figure 2). LC / MS / MS confirmed PPIX accumulation in clones 1-9 compared to WT K562 cells (Figure 3). The genotypic characteristics of the five clones are provided in Table 2.

[0582] Table 2: Genotypic characteristics of clones

[0583] Clone ID Genotype K562WT WT / WT 1-7 KO / KO 1-9 KO / Missense T81H 1-10 KO / WT 1-32 KO / WT 1-51 KO / WT

[0584] 900 μL of K562 clone-9 cells at 2 x 10⁵ cells / mL in IMDM medium containing 10% FBS and 1% PS were plated into 24-well plates. After incubation for 24 hours, 100 μL of the compound in DMSO / medium medium at different concentrations was added. The final concentration of DMSO was 0.1%. The compound was incubated at 37°C for 96 hours. Cell counts were measured using the Vi-CELL XR complete system.Cell viability and cell count. Finally, the effect of the compounds on PPIX levels was determined by flow cytometry. Figure 4 shows that both bitopertin and PF-03463275 showed dose-dependent inhibition of PPIX accumulation by flow cytometry, up to 50%. Bitopertin showed an EC50 of 7 nM, and PF-03463275 showed an EC50 of 46 nM. Figure 5 shows that bitopertin and PF-03463275 had no negative effect on cell viability. Importantly, LC / MS / MS methods showed that bitopertin reduced 5-aminolevulinic acid (5-ALA) and PPIX levels in the EPP K562 cell model and had minimal effect on heme formation (Figures 6, 7, and 8).

[0585] Other GlyT1 inhibitors also showed dose-dependent inhibition of PPIX accumulation, while the GlyT2 inhibitor ORG-25543 did not show any inhibition at the highest tested concentration of 10 μM (Table 3).

[0586] Table 3: EC50 of test compounds in EPP cell model

[0587]

[0588]

[0589] Example 8: GlyT1 inhibitor effectively reduces PPIX levels in human hematopoietic stem cells transduced with lentivirus expressing FECH small interfering RNA (shRNA)

[0590] To investigate the effect of GlyT1 inhibitor in human hematopoietic stem cells with EPP phenotype, a lentiviral vector expressing FECH shRNA (Table 4) was constructed and transduced into human umbilical cord blood CD34+ cells purchased from Stemexpress at 25 MOI.

[0591] Table 4: Oligonucleotides used to construct lentiviral vectors with FECH shRNA sequences

[0592]

[0593] RT-qPCR of the resulting CD34+ cells showed a 60% reduction in FECH mRNA levels compared to cells treated with the control lentiviral vector (Figure 9). Transduced CD34+ cells differentiated into erythroid cells within 9 days in StemSpan SFEMII medium supplemented with StemSpan erythroid amplification supplement, in the presence of bitopertin (100 nM) or DMSO control. Erythroid cell antigen profiles were analyzed using a cellular fluorescence strategy employing the following surface-labeled antigens: CD71 (PE mouse anti-human CD71, BD Biosciences), glycoprotein A (APC mouse anti-human CD235a, BD Biosciences). Cell viability was greater than 60% in all samples after 9 days of differentiation culture, as confirmed by flow cytometry, and was achieved by lentiviral transfection with FECH-expressing shRNA.More than 80% of the cells treated showed an increase in PPIX (Figure 10). Treatment with Biotopertin (100 nM) had no negative effect on erythroid cell surface markers and reduced PPIX accumulation by 60% (Figure 11).

[0594] Although preferred embodiments of the present application have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, alterations and substitutions will now occur to those skilled in the art without departing from the present application. It should be understood that various alternatives to the embodiments of the present application described herein may be used in the practice of the present application. The following claims are intended to define the scope of the present application and thereby cover the methods and structures within the scope of these claims and their equivalents.

[0595] In summary, the present invention includes, but is not limited to, the following:

[0596] 1. A method for treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP), 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 a prodrug of one or more GlyT1 inhibitors or a salt thereof.

[0597] 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 a prodrug of one or more GlyT1 inhibitors or a pharmaceutically acceptable salt thereof.

[0598] 3. The method according to item 2, wherein one or more complications of said EPP, XLPP or CEP are selected from: acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scars, deformities, nail loss, toe loss, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, end-stage liver disease, red teeth syndrome, high cellularity bone marrow, spinal dysplasia, thrombocytopenia, fetal hydrops and / or intrauterine death.

[0599] 4. A method for preventing or treating EPP, XLPP or CEP in a subject, wherein said method comprises administering to said subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of said one or more GlyT1 inhibitors or a pharmaceutically acceptable salt thereof. Instructions for Use, pages 91 / 97, 93 CN 121041437 A

[0600] 5. A method for preparing a pharmaceutical agent for treating a subject with EPP, XLPP or CEP, the method comprising:6. A method for preparing a medicament for inhibiting the synthesis of protoporphyrin IX (PPIX) in vivo, the method comprising administering to a 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.

[0601] 7. The method according to any one of claims 1-6, wherein the subject has EPP.

[0603] 8. The method according to any one of claims 1-6, wherein the subject has XLPP.

[0604] 9. The method according to any one of claims 1-6, wherein the subject has CEP.

[0605] 10. The method according to claim 3, wherein the acute photosensitivity is due to sun exposure.

[0606] 11. The method according to any one of claims 1-10, wherein the method increases the subject's painless light exposure.

[0607] 12. The method according to any one of claims 1-10, wherein the method reduces the photosensitivity of the subject.

[0608] 13. A method for inhibiting the synthesis of PPIX in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0609] 14. A method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0610] 15. A method for inhibiting the synthesis of uroporphyrin I and / or coproporphyrin I in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0611] 16. A method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0612] 17. The method according to any one of claims 1-16, wherein the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA.

[0613] 18. The method according to claim 17, wherein the accumulation of the one or more heme intermediates is inhibited in a dose-dependent manner.

[0614] 19. The method according to any one of the preceding claims, wherein the GlyT1 inhibitor exhibits an EC50 of less than 500 nM.

[0615] 20. The method according to any one of the preceding items, wherein the GlyT1 inhibitor exhibits an EC50 of less than 100 nM.

[0616] 21. The method according to any one of the preceding items, wherein at least 50% cell viability is maintained.

[0617] 22. The method according to any one of the preceding items, wherein at least 90% cell viability is maintained.

[0618] 23. The method according to any one of items 1-22, wherein prior to administration of the GlyT1 inhibitor, the subject's PPIX level is at least 10%, 20%, 30%, 40%, or 50% higher than the PPIX level of a healthy subject.

[0619] 24. The method according to any one of items 1-22, wherein prior to administration of the GlyT1 inhibitor, the subject's ZPPIX level is at least 10%, 20%, 30%, 40%, or 50% higher than the ZPPIX level of a healthy subject.

[0620] 25. The method according to any one of items 1-22, wherein the subject has an increased ratio of ZPPIX to free protoporphyrin IX (ZPPIX / PPIX ratio) compared to a subject with EPP.

[0621] 26. The method according to any one of items 1-22, wherein prior to administration of the GlyT1 inhibitor, the subject's uroporphyrin I and / or coprophyrin I levels are at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects.

[0622] 27. The method according to any one of items 1-22, wherein prior to administration of the GlyT1 inhibitor, the subject's 5-ALA levels are at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects.

[0623] 28. The method according to any one of items 1-27, wherein the subject's PPIX level is reduced while the patient's heme level is significantly maintained.

[0624] 29. The method according to any one of items 1-28, wherein the patient's PPIX level is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the patient's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%).

[0625] 30. The method according to item 28 or 29, wherein the patient's PPIX level is reduced by at least 85% and the patient's heme level is reduced by no more than 15%.

[0626] 31. The method according to any one of items 1-29, wherein the heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%).

[0627] 32. The method according to any one of items 1-31, wherein the dose of said pharmaceutical composition does not cause a significant decrease in heme levels.

[0628] 33. The method according to any one of items 1-8, 10-15, 17-25, and 27-32, wherein the level of free protoporphyrin IX in the erythrocytes of said subject increases.

[0629] 34. The method according to any one of items 1-8, 10-15, 17-25, and 27-33, wherein said method decreases the level of free protoporphyrin IX in said subject.

[0630] 35. The method according to any one of items 1-8, 10-15, 17-25, and 27-34, wherein the method reduces the free protoporphyrin IX level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0631] 36. The method according to any one of items 1-8, 10-15, 17-25, and 27-35, wherein the protoporphyrin IX level in the feces of the subject increases.

[0632] 37. The method according to any one of items 1-8, 10-15, 17-25, and 27-36, wherein the method reduces the protoporphyrin IX level in the feces of the subject.

[0633] 38. The method according to any one of items 1-8, 10-15, 17-25 and 27-37, wherein the method reduces the level 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%).

[0634] 39. The method according to any one of items 1-38, wherein when irradiated with blue light (e.g., 400-420 nm light), the plasma porphyrins of the subject fluoresce at a peak of 634 nm.

[0635] 40. The method according to any one of claims 1-39, wherein when irradiated with blue light (e.g., 400-420 nm light), the plasma porphyrins of the subject fluoresces at a peak between 626 nm and 634 nm.

[0636] 41. The method according to any one of claims 1-38, wherein when irradiated with blue light (e.g., 400-420 nm light), the skin porphyrins of the subject fluoresces at a peak of 632 nm.

[0637] 42. The method according to any one of claims 1-38, wherein when irradiated with blue light (e.g., 400-420 nm light), the skin porphyrins of the subject fluoresces at a peak between 626 nm and 634 nm.

[0638] 43. The method according to any one of items 1-8, 10-15, 17-25 and 27-42, wherein the level of protoporphyrin IX in the skin of the subject is increased. Specification 93 / 97 pages 95 CN 121041437 A

[0639] 44. The method according to any one of items 1-8, 10-15, 17-25 and 27-43, wherein the method reduces the level of protoporphyrin IX in the skin of the subject.

[0640] 45. The method according to any one of items 1-8, 10-15, 17-25, and 27-44, 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%).

[0641] 46. The method according to any one of items 1-8, 10-15, 17-25, and 27-45, wherein the protoporphyrin IX level in the skin of the subject is greater than 0.2 fluorescent units (FDU).

[0642] 47. The method according to any one of items 1-8, 10-15, 17-25, and 27-45, wherein the protoporphyrin IX level in the skin of the subject is greater than 1.0 FDU.

[0643] 48. The method according to any one of items 1-8, 10-15, 17-25, and 27-45, wherein the protoporphyrin IX level in the skin of the subject is between 1.0 FDU and 2.5 FDU.

[0644] 49. The method according to any one of items 1-8, 10-15, 17-25, and 27-45, wherein the protoporphyrin IX level in the skin of the subject is greater than 2.5 FDU.

[0645] 50. The method according to any one of items 1-8, 10-15, 17-25, and 27-49, wherein the method reduces the protoporphyrin IX level in the skin of the subject to less than 0.5 FDU.

[0646] 51. The method according to any one of items 1-8, 10-15, 17-25, and 27-49, wherein the method reduces the protoporphyrin IX level in the skin of the subject to less than 1.0 FDU.

[0647] 52. The method according to any one of items 1-8, 10-15, 17-25, and 27-49, wherein the method reduces the protoporphyrin IX level in the skin of the subject to less than 1.5 FDU.

[0648] 53. The method according to any one of items 1-8, 10-15, 17-25, and 27-49, wherein the method reduces the protoporphyrin IX level in the skin of the subject to less than 2.0 FDU.

[0649] 54. The method according to any one of items 1-8, 10-15, 17-25, and 27-49, wherein the method reduces the protoporphyrin IX level in the skin of the subject to less than 2.5 FDU.

[0650] 55. The method according to any one of items 1-8, 10-15, 17-25, and 27-54, wherein the protoporphyrin IX level in the erythrocytes of the subject increases.

[0651] 56. The method according to any one of items 1-8, 10-15, 17-25, and 27-55, wherein the method reduces the protoporphyrin IX level in the erythrocytes of the subject.

[0652] 57. The method according to any one of items 1-8, 10-15, 17-25, and 27-56, wherein the method reduces the level of protoporphyrin IX 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%).

[0653] 58. The method according to any one of items 1-8, 10-15, 17-25, and 27-57, wherein the level of protoporphyrin IX in the erythrocytes of the subject is greater than 31 μmol L⁻¹.

[0654] 59. The method according to any one of items 1-8, 10-15, 17-25, and 27-58, wherein the protoporphyrin IX level in the erythrocytes of the subject is between 31 μmol L⁻¹ and 53 μmol L⁻¹.

[0655] 60. The method according to any one of items 1-8, 10-15, 17-25, and 27-58, wherein the protoporphyrin IX level in the erythrocytes of the subject is greater than 53 μmol L⁻¹.

[0656] 61. The method according to any one of items 1-8, 10-15, 17-25, and 27-58, wherein the method reduces the protoporphyrin IX level in the erythrocytes of the subject to a level below 53 μmol L⁻¹.

[0657] 62. The method according to any one of items 1-8, 10-15, 17-25, and 27-58, wherein the method reduces the level of protoporphyrin IX in the erythrocytes of the subject to below 31 μmol L⁻¹.

[0658] 63. The method according to any one of items 1-8, 10-15, 17-25, and 27-58, wherein the method reduces the level of protoporphyrin IX in the erythrocytes of the subject to below 15 μmol L⁻¹.

[0659] 64. The method according to any one of items 1-7, 10-14, 17-25, and 27-63, wherein the subject's sub-The iron chelate activity level is reduced to between 10% and 35% of the iron chelate activity level observed in normal subjects.

[0660] 65. The method according to any one of items 1-7, 10-14, 17-25, and 27-64, wherein the iron chelate activity level of the subject is reduced to less than 50% of the iron chelate activity level observed in normal subjects.

[0661] 66. The method according to any one of items 1-6, 8, 10-15, 17-25, and 27-63, wherein the subject has a gain-of-function mutation in ALAS2.

[0662] 67. The method according to any one of items 1-6, 8, 10-15, 17-25, 27-63, and 66, wherein the ALAS2 enzyme activity of the subject is increased.

[0663] 68. The method according to any one of items 1-6, 8, 10-15, 17-25, 27-63, 66 and 67, wherein the level of zinc protoporphyrin IX in the erythrocytes of the subject is increased.

[0664] 69. The method according to any one of items 1-6, 8, 10-15, 17-25, 27-63 and 66-68, wherein the method reduces the level of zinc protoporphyrin IX in the erythrocytes of the subject.

[0665] 70. The method according to any one of items 1-6, 8, 10-15, 17-25, 27-63 and 66-69, wherein the method reduces the level of zinc protoporphyrin IX 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%).

[0666] 71. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32 and 39-42, wherein the uroporphyrinogen III synthase activity of the subject is reduced.

[0667] 72. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42, and 71, wherein the subject's uroporphyrin I and / or coprophyrin I levels are increased.

[0668] 73. The method according to item 72, wherein increased uroporphyrin I and / or coprophyrin I levels are measured in the subject's urine or red blood cells.

[0669] 74. The method according to item 72, wherein increased coprophyrin I levels are measured in the subject's feces.

[0670] 75. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42, and 71-74, wherein the method reduces the subject's uroporphyrin I and / or coprophyrin I levels.

[0671] 76. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42 and 71-74, wherein the method reduces the uroporphyrin I level of the subject.

[0672] 77. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42 and 71-76, wherein the method reduces the uroporphyrin I level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%).

[0673] 78. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42 and 71-77, wherein the method reduces the coprophyte I level of the subject.

[0674] 79. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42 and 71-78, wherein the method described in the specification on pages 95 / 97 of CN 121041437 A reduces the coprophyte I level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%).

[0675] 80. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42, and 71-79, wherein the subject has a mutation in UROS.

[0676] 81. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42, and 71-80, wherein the subject has a gene defect in the GATA-1 erythroid-specific transcription factor.

[0677] 82. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42, and 71-81, wherein the subject has red fluorescent urine.

[0678] 83. The method according to any one of items 1-5, 9-13, 16-23, 26, 27, 31, 32, 39-42 and 71-82, wherein plasma porphyrin fluorescence analysis is used, and the subject has a peak between 615 nm and 620 nm.

[0679] 84. The method according to any one of items 1-83, wherein the subject suffers from liver disease associated with EPP, XLPP or CEP.

[0680] 85. The method according to any one of items 1-75, wherein the liver disease associated with EPP, XLPP, or CEP is cholelithiasis.

[0681] 86. The method according to any one of items 1-75, wherein the liver disease associated with EPP, XLPP, or CEP is mild liver disease.

[0682] 87. The method according to any one of items 1-75, wherein the liver disease associated with EPP, XLPP, or CEP is severe liver disease.

[0683] 88. The method according to any one of items 1-75, wherein the liver disease associated with EPP, XLPP, or CEP is end-stage liver disease.

[0684] 89. The method according to any one of items 1-88, further comprising administering additional active agents and / or supportive therapy to the subject.

[0685] 90. The method according to claim 89, wherein the additional active agent and / or supportive therapy is selected from: sun avoidance, topical sun protection, skin protection, UVB phototherapy, afanotide bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0686] 91. The method according to any one of claims 1-90, wherein the GlyT1 inhibitor is a compound having the following formula

[0687]

[0688] wherein:

[0689] Ar is an unsubstituted or substituted aryl group or a 6-membered heteroaryl group containing 1, 2, or 3 nitrogen atoms, wherein the substituted aryl group and the substituted heteroaryl group are substituted by one or more substituents selected from: hydroxyl, halogen, NO2, CN, (C1-C6)-alkyl, halogen-substituted (C1-C6)-alkyl, hydroxyl-substituted (C1-C6)-alkyl, (CH2)n-(C1- C6)-alkoxy, halogen-substituted (C1-C6)-alkoxy, NR7R8, C(O)R9, SO2R10 and -C(CH3)=NOR7, or substituted with a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, said aromatic heterocycle optionally substituted with (C1-C6)-alkyl; Specification 96 / 97 pages 98 CN 121041437 A R1 is hydrogen or (C1-C6)-alkyl;

[0690] R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen-substituted (C1-C6)-alkyl, hydroxyl-substituted (C1-C6)-alkyl, optionally (C1-C6)-alkoxy or halogen-substituted (CH2)n-(C3-C7)-cycloalkyl, CH(CH3)- (C3-C7)-cycloalkyl, (CH2)n+1-C(O)-R9, (CH2)n+1-CN, bicyclo[2.2.1]heptyl, (CH2)n+1-O-(C1-C6)-alkaneR3, R4, and R6 are each independently hydrogen, hydroxyl, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, or (C3-C6)-cycloalkyl; R5 is NO2, CN, C(O)R9, or SO2R10; R7 and R8 are each independently hydrogen or (C1-C6)-alkyl; R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, or NR7R8;

[0695] R10 is optionally halogen-substituted (C1-C6)-alkyl, (CH2)n-(C3-C6)-cycloalkyl, (CH2)n-(C3-C6)-alkoxy, (CH2)n-heterocyclic alkyl, or NR7R8;

[0696] n is 0, 1, or 2;

[0697] or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0698] 92. The method according to claim 91, wherein the GlyT1 inhibitor is a compound having the formula bitopertin or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0699] 93. The method according to any one of claims 1-92, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0700] 94. The method according to any one of items 1-93, wherein the subject is a subject in need.

[0701] 95. The method according to any one of items 1-94, wherein the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0702] Incorporated by Reference

[0703] All references cited in this application and their references thereof are incorporated herein by reference in their entirety where suitable to impart additional or alternative details, features and / or technical background. Specification 97 / 97 pages 99 CN 121041437 A Figure 1 Specification Figure 1 / 9 pages 100 CN 121041437 A Figure 2 Specification Figure 2 / 9 pages 101 CN 121041437 A Figure 3 Figure 4 Specification Figure 3 / 9 pages 102 CN 121041437 A Figure 5 Figure 6 Specification Figure 4 / 9 pages 103CN 121041437 A Figure 7 Appendix 5 / 9, Page 104 CN 121041437 A Figure 8 Appendix 6 / 9, Page 105 CN 121041437 A Figure 9 Appendix 7 / 9, Page 106 CN 121041437 A Figure 10 Appendix 8 / 9, Page 107 CN 121041437 A Figure 11 Appendix 9 / 9, Page 108 CN 121041437 A Record of treatment of erythropoietic protoporphyria, X Methods for treating erythropoietic protoporphyria or congenital erythropoietic porphyria: Embodiments of the present invention relate to methods for preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), and / or congenital erythropoietic porphyria (CEP) and related syndromes using glycine transporter inhibitors such as GlyT1 inhibitors or pharmaceutically acceptable salts, solvates, or prodrugs thereof or pharmaceutical compositions thereof. Abstract METHODS OF TREATING ERYTHROPOIETIC PROTOPORPHYRIA, X-LINKED PROTOPORPHYRIA, OR CONGENITAL ERYTHROPOIETIC PORPHYRIA WITH GLYCINE TRANSPORT INHIBITORS. compositions thereof, for preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), and / or congenital erythropoietic porphyria (CEP), and related syndromes thereof. Abstract

Claims

1. A method for inhibiting PPIX synthesis in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

2. A method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

3. A method for inhibiting the synthesis of uroporphyrin I and / or comatoporphyrin I in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

4. A method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in vivo, the method comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

5. The method according to any one of claims 1-4, wherein the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, comatoporphyrin I and / or 5-ALA.

6. The method of claim 5, wherein the accumulation of the one or more heme intermediates is inhibited in a dose-dependent manner.

7. The method according to any one of the preceding claims, wherein the GlyT1 inhibitor exhibits an EC50 of less than 500 nM.

8. The method according to any one of the preceding claims, wherein the GlyT1 inhibitor exhibits an EC50 of less than 100 nM.

9. The method according to any one of the preceding claims, wherein at least 50% cell viability is maintained.

10. The method according to any one of the preceding claims, wherein at least 90% cell viability is maintained.

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