Compositions and methods for treatment of hepatoporphyrin with glycine transport inhibitors

Abstract

Embodiments of the present invention relate to methods of preventing or treating hepatic porphyrin and hepatic porphyrin-related syndromes 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

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 347,415, filed on May 31, 2022. The specification of the foregoing application is incorporated herein by reference in its entirety. Technical Field

[0003] Embodiments disclosed herein relate to methods and uses for preventing or treating hepatic porphyria with a glycine transporter inhibitor, such as but not limited to a GlyT1 inhibitor or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutical composition thereof. Background Art

[0004] Porphyria is a class of disorders caused by lack of activity of specific enzymes in the heme biosynthetic pathway (also referred to herein as the porphyrin pathway). Each porphyria is classified as hepatic or erythropoietic porphyria based on the organ system that overproduces heme precursors. They are also classified as acute or non-acute based on their clinical manifestations. The lack of enzymes in the porphyrin pathway leads to insufficient heme production and leads to the accumulation of porphyrin precursors (e.g., ALA and PBG) and porphyrins, which are toxic to tissues at high concentrations.

[0005] Acute hepatic porphyrias include acute intermittent porphyria (AIP), variable porphyria (VP), hereditary coproporphyria (HCP) and aminolevulinic acid dehydratase deficiency porphyria (ADP), and usually cause severe abdominal, mental, neurological or cardiovascular symptoms. Each acute hepatic porphyria is caused by a genetic defect that causes a deficiency in the enzyme of the heme synthesis pathway in the liver. Porphyria cutanea tarda (PCT) is a non-acute hepatic porphyria, in which patients usually show blisters, bullae, milia and hirsutism on the cheeks, temporal and eyebrows. In addition, there is also a rare homozygous recessive form of PCT, called hepatoerythropoietic porphyria (HEP).

[0006] In acute porphyrias (e.g., AIP, VP, HCP, and ADP), the corresponding enzyme deficiency causes the liver to produce and accumulate one or more substances (e.g., porphyrins, and / or porphyrin precursors such as ALA and / or PBG), which may be neurotoxic and may cause acute attacks to occur. If not properly treated, it may lead to quadriplegia, respiratory damage, and death. These hereditary disorders are rare and often difficult to diagnose. About 1 / 10,000 Europeans have a mutation in one of the genes that causes AIP, VP, or HCP. However, most (80%-90%) confirmed genetic carriers remain asymptomatic, and others experience one or several acute attacks in their lifetime.

[0007] Current treatments for acute neurological attacks include intravenous administration of hemin ( Lundbeck; or Orphan Europe), which provides exogenous hemin for negative feedback inhibition of ALAS1, thereby reducing the production of ALA and PBG. Hemin is used for treatment during acute attacks and for the prevention of attacks, particularly in women with acute porphyria who experience frequent attacks due to hormonal changes during the menstrual cycle. Although patients generally respond well, it is slow to act, often requiring two to four days or more for urinary ALA and PBG concentrations to return to normal levels. Because intravenous hemin is rapidly metabolized, three to four infusions are usually required to effectively treat or prevent an acute attack. In addition, repeated infusions may result in iron overload and phlebitis, which may compromise peripheral venous access.

[0008] Givosiran ), a small interfering ribonucleic acid (siRNA) against aminolevulinic acid synthase 1, is also used to treat patients with acute hepatic porphyria by targeting and degrading ALAS1 mRNA in hepatocytes using RNA interference. The risks associated with the use of Givosiran include allergic reactions, hepatotoxicity, and nephrotoxicity. For example, in the Givosiran clinical trial, 15% of patients showed an increase in transaminase (ALT) to 3 times the upper limit of normal. In addition, 15% of patients receiving Givosiran had kidney-related adverse reactions, including increased serum creatinine levels and decreased estimated glomerular filtration rate. The last treatment is orthotopic liver transplantation. Although orthotopic liver transplantation is curative, this procedure has significant morbidity and mortality, and the availability of liver donors is limited. Therefore, new methods and compositions for the treatment and / or prevention of hepatic porphyria are needed. The methods and uses of glycine transporter inhibitors (such as but not limited to GlyT1 inhibitors) described herein meet these and other needs. Summary of the invention

[0009] In certain aspects, the present disclosure provides a method of treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more GlyT1 inhibitors or salts thereof.

[0010] In certain aspects, the present disclosure provides a method for preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or prodrugs of the one or more GlyT1 inhibitors or salts thereof.

[0011] In certain aspects, the present disclosure provides a method for preventing, treating or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof. In some embodiments, the one or more complications of hepatic porphyria are selected from the group consisting of acute photosensitivity, skin photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte imbalance, nausea, vomiting, constipation, diarrhea, dysuria, intestinal obstruction, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, pain associated with neuropathy, muscle paralysis, quadriplegia, decreased respiration, respiratory arrest, hyponatremia, arrhythmia, dysur ... Tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive renal injury, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, bullae, lesions, scars, deformities, nail loss, finger / toe defects, cholestasis, cell lysis, cholelithiasis, cholestatic liver failure, cholelithiasis, mild liver disease, liver disease exacerbation and end-stage liver disease. In some embodiments, the hepatic porphyria is acute hepatic porphyria. In some embodiments, the acute hepatic porphyria is acute intermittent porphyria (AIP). In some embodiments, the acute hepatic porphyria is ALA dehydratase porphyria (ADP). In some embodiments, the acute hepatic porphyria is indeterminate porphyria (VP). In some embodiments, the acute hepatic porphyria is hereditary coproporphyria (HCP). In some embodiments, the acute hepatic porphyria is harderoporphyria. In some embodiments, the hepatic porphyria is non-acute hepatic porphyria. In some embodiments, the non-acute hepatic porphyria is familial and sporadic porphyria cutanea tarda (PCT). In some embodiments, the non-acute hepatic porphyria is hepatoerythropoietic porphyria (HEP). In some embodiments, the acute photosensitivity is due to sun exposure. In some embodiments, the method increases painless light exposure of the subject. In some embodiments, the method reduces the photosensitivity of the subject.

[0012] In certain aspects, the present disclosure provides a method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject suffers from hepatic porphyria.

[0013] In certain aspects, the present disclosure provides a method of inhibiting coproporphyrin III 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.

[0014] In certain aspects, the present disclosure provides a method of inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in a subject, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject has ALA dehydratase porphyria (ADP).

[0015] In certain aspects, the present disclosure provides a method of inhibiting porphobilinogen (PBG) 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.

[0016] In certain aspects, the present disclosure provides a method of inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) 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.

[0017] In certain aspects, the present disclosure provides a method of inhibiting hydroxymethylbendazole (HMB) 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.

[0018] In certain aspects, the present disclosure provides a method of inhibiting uroporphyrin III 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.

[0019] In certain aspects, the present disclosure provides a method of inhibiting heptacarboxyporphyrin 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.

[0020] In certain aspects, the present disclosure provides a method of inhibiting isocoproporphyrin 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.

[0021] In certain aspects, the present disclosure provides a method of inhibiting the synthesis of porphyrins or porphyrin precursors 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, wherein the porphyrin or porphyrin precursor is selected from: 5-ALA; PBG; hydroxymethylcholine; ZPPIX; uroporphyrinogen I; uroporphyrinogen III; heptacarboxyporphyrinogen I; heptacarboxyporphyrinogen III; hexacarboxyporphyrinogen I; hexacarboxyporphyrinogen III; pentacarboxyporphyrinogen I; pentacarboxyporphyrinogen III; coproporphyrinogen I; coproporphyrinogen III; isocoproporphyrin; porphobilinogen; and protoporphyrinogen IX.

[0022] In some embodiments, the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from 5-ALA, coproporphyrin III, zinc protoporphyrin IX (ZPPIX), porphobilinogen, uroporphyrin III, heptacarboxyporphyrin and isocoproporphyrin. In some embodiments, the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from: 5-ALA; PBG; hydroxymethyl bilirubin; ZPPIX; uroporphyrinogen I; uroporphyrinogen III; heptacarboxyporphyrinogen I; heptacarboxyporphyrinogen III; hexacarboxyporphyrinogen I; hexacarboxyporphyrinogen III; pentacarboxyporphyrinogen I; pentacarboxyporphyrinogen III; coproporphyrinogen I; coproporphyrinogen III; isocoproporphyrin; porphobilinogen; and protoporphyrinogen IX. In some embodiments, the accumulation of one or more heme intermediates is inhibited in a dose-dependent manner. 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.

[0023] In some embodiments, the subject suffers from or is at risk of developing hepatic porphyria, and suffers from pain (e.g., neuropathic pain, such as chronic neuropathic pain) or neuropathy (e.g., progressive neuropathy). In some embodiments, the subject has elevated levels of ALA and / or PBG, and suffers from chronic pain. In some embodiments, before the administration of the GlyT1 inhibitor, the subject's 5-ALA level is at least 10%, 20%, 30%, 40% or 50% higher than the 5-ALA level of a healthy subject. In some embodiments, before the administration of the GlyT1 inhibitor, the subject's HMB level is at least 10%, 20%, 30%, 40% or 50% higher than the HMB level of a healthy subject. In some embodiments, before the administration of the GlyT1 inhibitor, the subject's coproporphyrin III level is at least 10%, 20%, 30%, 40% or 50% higher than the coproporphyrin III level of a healthy subject. 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 the ZPPIX level of a healthy subject. In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's porphobilinogen level is at least 10%, 20%, 30%, 40%, or 50% higher than the porphobilinogen level of a healthy subject. In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's uroporphyrin III level is at least 10%, 20%, 30%, 40%, or 50% higher than the uroporphyrin III level of a healthy subject. In some embodiments, prior to administration of the GlyT1 inhibitor, the subject's heptacarboxyporphyrin level is at least 10%, 20%, 30%, 40%, or 50% higher than the heptacarboxyporphyrin level of a healthy subject. In some embodiments, before the administration of the GlyT1 inhibitor, the isocoproporphyrin level of the subject is at least 10%, 20%, 30%, 40% or 50% higher than the isocoproporphyrin level of a healthy subject. In some embodiments, the hemoglobin level of the subject is substantially maintained during treatment. In some embodiments, the treatment reduces the hemoglobin level of the subject 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 reduction in hemoglobin levels. In some embodiments, the 5-ALA level of the subject increases. In some embodiments, the 5-ALA level in the urine of the subject increases. In some embodiments, the 5-ALA level in the plasma of the subject increases. In some embodiments, the HMB level of the subject increases. In some embodiments, the coproporphyrin III level of the subject increases. In some embodiments, the coproporphyrin III level in the urine of the subject increases.In some embodiments, the level of coproporphyrin III in the feces of the subject is increased. In some embodiments, the level of porphobilinogen (PBG) in the subject is increased. In some embodiments, the level of porphobilinogen (PBG) in the urine of the subject is increased. In some embodiments, the plasma level or urine level of 5-ALA or PBG of the subject is greater than the reference value. In some embodiments, the reference value is two standard deviations higher than the average level in the sample of a healthy individual. In some embodiments, the plasma level or urine level of 5-ALA or PBG of the subject is greater than or equal to 2 times, 3 times, 4 times or 5 times the upper limit of the reference value. In some embodiments, the urine level of PBG of the subject is greater than or equal to 4.8mmol / mol creatinine. In some embodiments, the plasma PBG level of the subject is greater than or equal to 0.12μmol / L. In some embodiments, the urine PBG level of the subject is greater than or equal to 1.2mmol / mol creatinine. In some embodiments, the plasma 5-ALA level of the subject is greater than or equal to 0.12μmol / L. In some embodiments, the subject's urine 5-ALA level is greater than or equal to 3.1 mmol / mol creatinine. In some embodiments, the method reduces elevated 5-ALA and / or PBG levels. In some embodiments, the subject's uroporphyrin III level increases. In some embodiments, the subject's urine uroporphyrin III level increases. In some embodiments, the subject's feces protoporphyrin to coproporphyrin ratio increases. In some embodiments, the subject's heptacarboxyporphyrin level increases. In some embodiments, the subject's urine heptacarboxyporphyrin level increases. In some embodiments, the subject's feces heptacarboxyporphyrin level increases. In some embodiments, the subject's feces heptacarboxyporphyrin level increases. In some embodiments, the subject's isocoproporphyrin level increases. In some embodiments, the subject's feces isocoproporphyrin level increases. In some embodiments, the subject's erythrocytes ZPPIX level increases.

[0024] In some embodiments, the method reduces the 5-ALA level of the subject. In some embodiments, the method reduces the 5-ALA level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the HMB level of the subject. In some embodiments, the method reduces the HMB level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the coproporphyrin III level of the subject. In some embodiments, the method reduces the coproporphyrin III level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the PBG level of the subject. In some embodiments, the method reduces the PBG level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method effectively reduces the level of the 5-ALA and / or PBG. In some embodiments, the level of the 5-ALA and / or PBG is reduced so that it is below a reference value. In some embodiments, the reference value is an upper reference value limit. In some embodiments, the method reduces the urine porphyrin III level of the subject. In some embodiments, the method reduces the urine porphyrin III level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin of the subject. In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).In some embodiments, the method reduces the seven carboxy porphyrin levels of the subject. In some embodiments, the method reduces the seven carboxy porphyrin levels of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the isocoproporphyrin levels of the subject. In some embodiments, the method reduces the isocoproporphyrin levels of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the ZPPIX level of the subject. In some embodiments, the method reduces the ZPPIX 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%).

[0025] In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the plasma porphyrins of the subject fluoresce with a peak value between 615nm and 620nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the plasma porphyrins of the subject fluoresce with a peak value between 624nm and 627nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the skin porphyrins of the subject fluoresce with a peak value between 615nm and 620nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the skin porphyrins of the subject fluoresce with a peak value between 624nm and 627nm. In some embodiments, the subject has a deficiency in an enzyme selected from the group consisting of: ALA dehydratase; PBG deaminase; uroporphyrinogen III synthase; uroporphyrinogen decarboxylase; coproporphyrinogen oxidase; and protoporphyrinogen oxidase. In some embodiments, the subject has a mutation in a gene selected from the group consisting of: ALAD; HMBS; UROS; UROD; CPOX; and PPOX.

[0026] In some embodiments, the GlyT1 inhibitor is administered after an acute attack. In some embodiments, the GlyT1 inhibitor is administered during an acute attack. In some embodiments, the GlyT1 inhibitor is administered during prodromal symptoms. In some embodiments, the prodromal symptoms are characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the GlyT1 inhibitor is administered prophylactically to prevent acute attacks of hepatic porphyria. In some embodiments, the GlyT1 inhibitor is administered during a specific phase of the menstrual cycle, such as during the luteal phase. In some embodiments, the GlyT1 inhibitor improves or prevents the cyclical attacks of hepatic porphyria. In some embodiments, the cyclical attacks are associated with predisposing factors. In some embodiments, the predisposing factor is a specific phase of the menstrual cycle, such as the luteal phase. In some embodiments, the predisposing factor is premenstrual period. In some embodiments, the predisposing factor is exposure to chemicals. In some embodiments, the predisposing factor is exposure to lead. In some embodiments, the predisposing factor is selected from drugs, xenobiotics, steroid hormones, smoking, alcohol, reduced caloric or carbohydrate intake, fasting, metabolic stress, and psychological stress. In some embodiments, the method reduces pain or neuropathy. In some embodiments, the method prevents acute attacks of hepatic porphyria. In some embodiments, the method reduces or prevents nerve damage. In some embodiments, the GlyT1 inhibitor is administered prophylactically starting in adolescence. In some embodiments, the method further comprises administering an additional active agent and / or supportive therapy to the subject. In some embodiments, the additional active agent and / or supportive therapy is selected from: avoiding sunlight, topical sunscreen, skin protection, UVB light therapy, afamelanotide Bortezomib, heme infusion, adequate caloric support, givosiran, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of triggering factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes by viral vectors), hemodialysis, pharmacological chaperone therapy, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusions.

[0027] In certain embodiments, the GlyT1 inhibitor is a compound of Formula I, Formula I, wherein Ar is an unsubstituted or substituted aryl or a 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted aryl and the substituted heteroaryl are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR 7 R 8 、C(O)R 9 、SO2R 10 and -C(CH3)═NOR 7 , or is substituted by a 5-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N and O, the aromatic heterocyclic ring being optionally substituted by (C1-C6)-alkyl; R 1 is hydrogen or (C1-C6)-alkyl; R 2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C3-C7)-cycloalkyl, CH(CH3)-(C3-C7)-cycloalkyl, (CH2) n+1 -C(O)-R 9 、(CH2) n+1 -CN, bicyclo[2.2.1]heptyl, (CH2) n+1 -O-(C1-C6)-alkyl, (CH2) n -heterocycloalkyl, (CH2) n -aryl or (CH2) containing one, two or three heteroatoms selected from oxygen, sulfur or nitrogen n - 5-membered or 6-membered heteroaryl, wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy; R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl; R 5 NO2, CN, C(O)R 9 or SO2R 10 ; R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR 7 R8 ; R 10 is (C1-C6)-alkyl, (CH2) optionally substituted by halogen n -(C3-C6)-cycloalkyl, (CH2) n -(C3-C6)-alkoxy, (CH2) n -heterocycloalkyl or NR 7 R 8 ; n is 0, 1 or 2; or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0028] In certain embodiments, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula The compound bitopertin or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0029] In certain embodiments, the GlyT1 inhibitor is a compound of Formula II, wherein R1 represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolyl, isoxazolyl, pyrroloimidazolyl, and thiadiazole, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of -OH, -NR7R8, halogen, (C1-C8)alkyl, (C3-C 10 )cycloalkyl, (C1-C8)alkoxy, (C1-C 12 ) alkoxyalkyl, (C1-C8) hydroxyalkyl, (C6-C 14 )aryl and benzyl; R2, R3 and A independently represent H or (C1-C8)alkoxy, wherein the alkyl is optionally substituted by one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen; Q represents (CH2) n -, wherein n = 1, 2, 3 or 4, or (CH2) m -O-, wherein m = 2, 3 or 4; Z represents (C6-C 14 )aryl, (C1-C8)alkyl or (C3-C8)cycloalkyl; R4 and R5 each independently represent H, halogen, (C1-C8)alkyl, (C6-C 14 ) aryl, (C6-C 14 )aryloxy, (C1-C8)alkoxy, (3-10 membered)heterocycloalkyl 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, wherein o=1, 2 or 3; R6 represents H, (C6-C 14) aryl, (C 1-10 )alkyl, (C3-C 10 )cycloalkyl, (C5-C 18 ) bicycloalkyl, (C5-C 18 )tricycloalkyl, (3-10 membered)heterocycloalkyl, (5-10 membered)heteroaryl, C(=O)NR7R8, or -C(=O)OR7, wherein the R6 group may be optionally substituted by one or more X groups; wherein X=-OH, (C1-C8)alkoxy, -NR 11 R 12 、-SO2R 10 、-C(=O)R 10 , halogen, cyano, (C1-C8) alkyl, (C1-C 10 )alkoxyalkyl, (5-10 membered)heteroaryl, (C6-C 14 ) aryl, (C6-C 14 )aryloxy, benzyl, or (C1-C8)hydroxyalkyl; wherein R7 and R8 independently represent H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10 membered)heterocycloalkyl, (C1-C8)hydroxyalkyl, (5-10 membered)heteroaryl, or (C1-C8) 10 )alkoxyalkyl; wherein R7 and R8 may be optionally substituted by one or more X groups; or R7 and R8 together with the nitrogen to which they may be attached may form a (3-10 membered) heterocycloalkyl optionally substituted by one or more X groups; wherein R 10 represents (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl; wherein R 11 and R 12 independently represent H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10 membered)heterocycloalkyl, (C1-C8)hydroxyalkyl, (5-10 membered)heteroaryl or (C1-C 10 ) alkoxyalkyl; or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is a compound having the formula In other such embodiments, the GlyT1 inhibitor is a compound having the formula The compound PF-3463275 or a pharmaceutically acceptable salt thereof or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0030] In certain embodiments, the GlyT1 inhibitor is a compound of formula III, Formula III, wherein Z 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo 1-4 Alkyl, phenyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkylsulfonic acid oxygen, C 1-4 Alkylsulfonyl, bromine and chlorine; Z 2 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, phenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-6 Cycloalkyl; Z 3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo 1-4 Alkyl, halogenated C 1-4 Alkoxy, and C 3-6 Cycloalkyl; Z 4 Selected from hydrogen, halogen, C1-3 alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-6 Cycloalkyl; Z 5 Selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-6 Cycloalkyl; wherein if Z 1 To Z 5 If more than one of them is a methoxy group, then only Z 1 and Z 5 is methoxy, R 3 and R 4 independently selected from hydrogen and C optionally substituted by one or more groups Y 1-4 Alkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated A, 5-membered, 6-membered or 7-membered carbocyclic ring optionally substituted by a group Y'; Y is selected from C 1-4 Alkoxy, hydroxy, halogenated C 1-4 Alkoxy and C 3-5 Cycloalkyl; Y' is selected from C 1-4 Alkyl, C 1-4 Alkoxy, halogen, hydroxyl, halogenated C 1-4 Alkoxy, C 3-5 Cycloalkyl and C 5-10 Aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on A, a 5-membered, 6-membered or 7-membered carbon ring; R 5 and R 6 is independently C optionally substituted by one or more groups X 1-4 Alkyl; or R 5 and R 6 Together with the carbon atoms to which they are attached, they form a saturated 5- or 6-membered carbocyclic ring optionally substituted by one or more groups X', in which R 5 In the case where R and R6 together with the carbon atom to which they are attached form a 5-membered saturated carbocyclic ring, the ring may optionally further contain an additional heteroatom group selected from O, N and S(O)m; wherein m=0, 1 or 2; X is selected from halogen, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy and C 5-10 Aryl; and X' is selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy and C 5-10 Aryl; wherein R 3 , R 4 , R 5 and R 6 are not all unsubstituted methyl groups; provided that when Z 1 is propoxy, Z 3 It is chlorine, Z 2 =Z 4 =Z 5 =H, and R 5 and R 6 When both are methyl groups, then R 3 and R 4 do not form a 2-methylpyrrolidine group together with the nitrogen atom to which they are attached; when Z 1 It is methyl, Z 3 is methoxy, Z 2 = Z4 = Z5 = H, and R5 and R 6 When both are methyl groups, then R 3 and R 4 do not form a pyrrolidine group together with the nitrogen atom to which they are attached, or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is of the formula A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0031] In certain embodiments, the GlyT1 inhibitor is a compound of Formula IV, 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 the following: hydrogen, halogen, (C 1-6 ) alkoxy, (C 3-6 )cycloalkoxy, (C 6-12 ) aryloxy, (C 6-12 )aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6 and (C 1-4 )alkyl, which is optionally substituted with halogen, (C 6-12 ) aryl, (C 1-6 ) alkoxy or (C 6-12 ) aryloxy substitution; or two substituents at adjacent positions together represent a fused (C 5-6 ) aryl, condensed (C 5-6 )cycloalkyl ring or O-(CH2) m -O; m is 1 or 2; Y represents 1-3 independently selected from hydrogen, halogen, (C 1-4 ) alkoxy, SR6, NR6R6 and (C 1-4 )alkyl substituent, which is optionally substituted by halogen; R1 is COOR7 or CONR8R9; R2 and R6 are (C 1-4 ) alkyl; R3, R4 and R5 are independently hydrogen or (C 1-4 ) alkyl; R7, R8 and R9 are independently hydrogen, (C 1-4 ) alkyl, (C 6-12 ) aryl or arylalkyl, or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is a compound having the formula A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0032] In certain embodiments, the GlyT1 inhibitor is a compound of Formula V,

[0033] Formula V, wherein n is an integer from 1 to 3; R 1 and R 2 R is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the above ring is optionally independently selected from the following R a , R b or R c Substituted: alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino or disubstituted amino; or R 1 and R 2 When attached to the same carbon atom, they may combine to form a cycloalkyl or monocyclic saturated heterocyclic group to give a spirocycle, wherein the cycloalkyl or monocyclic saturated heterocyclic group may be optionally independently selected from the following R d , R c or R f Substituted: alkyl, alkoxy, fluorine, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino or disubstituted amino; or R 1 and R 2 When attached to the carbon atoms at positions 2 and 5 or 3 and 6 of the piperazine ring, they can combine to form a -C1-C3-alkylene chain, wherein one carbon atom in the alkylene chain is optionally replaced by -NR-, -O-, -S(O)n- (wherein R is hydrogen or alkyl and n is 0-2), and further wherein one or two hydrogen atoms in the alkylene chain can be optionally replaced by one or two alkyl groups; R 3 , R 4 and R 5 are independently hydrogen, alkyl, fluorine or fluoroalkyl; and Ar 1 and Ar 2 is independently aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of the above rings is optionally replaced by R g , R h or R i Substitution, where R g Alkyl, -C=CR 6 (where R 6 is aryl or heteroaryl), halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl or acylamino, and R h and R iare independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein R g , R h and R i The aromatic or alicyclic ring in j , R k or R l Substitution, the R j , R k or R l independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl or acylamino; or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof, provided that the compound of formula V is not 2-(4-diphenyl 2-((2R,5S)-4-((R)-(4-(1H-tetrazolyl-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. In certain such embodiments, the GlyT1 inhibitor is a compound having the formula A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0034] In certain embodiments, the GlyT1 inhibitor is a compound of Formula VI, wherein A represents a group of the general formula N-R1, a group of the general formula N+(O-)R1 or a group of the general formula N+(R′)R1, and wherein R1 represents a hydrogen atom, or a straight or branched (C1-C7)alkyl group optionally substituted with one or more fluorine atoms, or a (C4-C7)cycloalkyl group, or a (C3-C7)cycloalkyl (C1-C3)alkyl group, or a phenyl (C1-C3)alkyl group optionally substituted with one or two hydroxyl or methoxy groups, or a (C2-C4)alkenyl group, or a (C2-C4)alkynyl group; R′ represents a straight or branched (C1-C7)alkyl group; X represents a hydrogen atom or one or more selected from halogen atoms and trifluoromethane; 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 form a pyrrolidine, piperidine or morpholine ring together with the nitrogen atom carrying them, or a phenyl group optionally substituted by an atom or group as defined above for symbol X, or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is a compound having the formula A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0035] In certain embodiments, the GlyT1 inhibitor is a compound of Formula VII, Where R 1 Yes - (CH2) n -R 1a , wherein n is independently 0-6, and R 1a Selected from: (1) C 1-6 Alkyl, which is unsubstituted or substituted by 1-6 halogens, hydroxyl groups, (2) by R 2a , R 2b and R 2c Substituted phenyl, (3)C 3-6 Cycloallyl, which is unsubstituted or substituted by C 1-6 Alkyl, 1-6 halogens, hydroxyl or -NR 10 R 11 Substitution, (4)-OC 1-6 Alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl or -NR 10 R 11 Substitution, (5)-CO2R 9 , wherein R9 is independently selected from: (a) hydrogen, (b) -C 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 fluorine groups, (c) benzyl and (d) phenyl, (6)-NR10 R 11 , where R 10 and R 11 are independently selected from: (a) hydrogen, (b) -C 1-6 Alkyl, which is unsubstituted or substituted by hydroxy, 1-6 fluorine or -NR 12 R 13 Substitution, where R 12 and R 13 are independently selected from hydrogen and -C 1-6 Alkyl, (c)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by hydroxy, 1-6 fluorine or -NR 12 R 13 substituted, (d) benzyl, (e) phenyl and (7) -CONR 10 R 11 ; R2 is selected from: (1) phenyl, which is R 2a , R 2b and R 2c Replacement, (2) C 1-8 Alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, -NR 10 R 11 , phenyl or heterocyclic ring, wherein the phenyl or heterocyclic ring is replaced by R 2a , R 2b and R 2c Replacement, (3) C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1-6 halogen, hydroxy or -NR 10 R 11 Substitution, and (4)-C 1-6 Alkyl-(C 3-6 cycloalkyl), which is unsubstituted or substituted by 1-6 halogen, hydroxy or -NR 10 R 11 Replacement; R 2a , R 2b and R 2c are independently selected from: (1) hydrogen, (2) halogen, (3) -C 1-6 Alkyl, which is unsubstituted or substituted with (a) 1 to 6 halogens, (b) phenyl, (c) C 3-6 Cycloalkyl or (d)-NR 10 R 11 Substitution, (4)-OC 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 halogens, (5) hydroxy, (6) -SCF3, (7) -SCHF2, (8) -SCH3, (9) -CO2R 9 , (10)-CN, (11)-SO2R 9 , (12)-SO2-NR 10 R 11, (13)-NR 10 R 11 , (14)-CONR 10 R 11 , and (15)-NO2; R 3 Selected from: (1) C 1-6 Alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl or -NR 10 R 11 Replacement, (2) C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1-6 halogen, hydroxy or -NR 10 R 11 Replacement, R 4 and R 5 are independently selected from: (1) hydrogen, and (2) C 1-6 Alkyl, which is unsubstituted or substituted by halogen or hydroxy, or R 4 and R 5 Together they form C 3-6 Cycloalkyl ring; A is selected from: (1) -O- and (2) -NR 10 -; m is zero or one, wherein when m is zero, R 2 directly attached to the carbonyl group; and pharmaceutically acceptable salts of the compounds and individual enantiomers and diastereomers thereof, or pharmaceutically acceptable salts of the compounds or prodrugs of the compounds or pharmaceutically acceptable salts thereof. In certain such embodiments, the GlyT1 inhibitor is a compound having the formula A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0036] In certain embodiments, the GlyT1 inhibitor is a compound of Formula VIII, Where R 1 are independently halogen, C1-C3 alkyl, C3-C6 cycloalkyl, OR 9 or SR 10 Phenyl substituted 1 to 5 times, wherein C1-C3 alkyl and C3-C6 cycloalkyl are optionally replaced by R 7 Replaced 1 to 10 times; R 2 It is H; R 3 and R 4 are independently H or CH3; R 5 Selected from: (1) hydrogen, (2) optionally replaced by R 7 C1-C6 alkyl substituted 1 to 11 times, (3) geminal dialkyl, and (4) geminal dihalo; or two R on the same carbon 5 The substituents together with the carbon atom to which they are attached may form a 7 substituted 1 to 10 times 3-membered, 4-membered or 5-membered cycloalkyl; or two R5 Substituents on adjacent carbons of the ring to which they are attached may together form a 7 substituted 1 to 10 times 3-membered, 4-membered, 5-membered or 6-membered cycloalkyl; R 6 yes wherein E, F and G are each independently nitrogen or carbon, and R 6a is C1-C2 alkyl, which is optionally substituted 1 to 5 times by halogen or deuterium; R 7 Selected from: (1) hydrogen, (2) halogen, (3) deuterium, (4) geminal dialkyl, (5) geminal dihalogen, (6) -OR 9 、-NR 11 R 12 、-NR 11 C(O) p R 10 、-S(O) p R 10 、-CN、-NO2、-C(O) p R 10 、-C(O)NR 11 R 12 or -NR 11 C(S)R 10 , and (7) an oxo group or a thio group; R 8 is selected from: (1) hydrogen, (2) halogen, (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C4-C7 cycloalkylalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each independently and optionally replaced by R 7 Substitute 1 to 11 times, or (4)-OR 9 、-NR 11 R 12 、-NR 11 C(O) p R 10 、-S(O) p R 10 、-CN、-NO2、-C(O) p R 10 、-C(O)NR 11 R 12 or -NR 11 C(S)R 10 ; R 9 Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10, wherein C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally replaced by R 7 Substituted 1 to 11 times; R 10 is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally substituted by R 7 substituted 1 to 11 times by the substituents defined in 8 Replaced 1 to 10 times; R 11 and R 12 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally replaced by R 7 substituted 1 to 11 times by the substituents defined in 8 Replace 1 to 10 times, or R 11 and R 12 Together with the nitrogen to which they are attached, they form a 7 A is a saturated or partially saturated monocyclic or fused bicyclic heterocyclic ring substituted 1 to 11 times; X is N; Y is N; p is 1 or 2; and m is 0; and with the proviso that R 6 It cannot be (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl; or an oxide of said compound, a pharmaceutically acceptable salt of said compound or its oxide, or an individual enantiomer or diastereomer thereof.

[0037] In certain embodiments, the GlyT1 is a compound selected from any one of the following:

[0038]

[0039]

[0040]

[0041]

[0042] or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0043] In certain embodiments, the GlyT1 inhibitor is a compound of Formula IX, Where R 1represents a phenyl group or a 5-membered or 6-membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the phenyl group or the heteroaryl group is optionally substituted by one or more R 3 Replacement; R 2 represents an aryl group, a 5-membered or 6-membered monocyclic heteroaryl group or an 8-membered to 10-membered bicyclic heteroaryl group, the monocyclic or bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the aryl group or the heteroaryl group is optionally replaced by one or more R 4 Replacement; R 3 Halogen, C 1-4 -alkyl or C 3-6 -cycloalkyl, wherein the C 1-4 -alkyl or the C 3-6 - cycloalkyl is optionally substituted by one or more halogens; and R 4 It is halogen, -CN, C 1-4 -alkyl, C 3-6 -cycloalkyl, -C 1-3 -alkyl, -C 3-6 -cycloalkyl or -OC 1-6 Alkyl, wherein the C 1-4 -alkyl, C 3-6 -cycloalkyl, -C 1-3 -alkyl, -C 3-6 -cycloalkyl or -OC 1-6 -alkyl is optionally substituted with one or more halogens; or a pharmaceutically acceptable salt of the compound or a tautomer or stereoisomer of the compound or its pharmaceutically acceptable salt, or a mixture of any of the foregoing.

[0044] In certain embodiments, the GlyT1 inhibitor is a compound of formula X, Where R 1 is selected from a) a 5-membered or 6-membered monocyclic heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from O, N and S(O)r, b) a 5-membered or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from O, N and S(O)r, and c) a 5-membered or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from O, N and S(O)r. r wherein r is 0, 1 or 2; wherein the groups a), b) and c) are each optionally substituted by 1 or more substituents independently selected from the following: 1-4 -alkyl-, C 1-4 -alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3-6 -cycloalkyl- and C 3-6 -cycloalkyl-O-, and in the case where a substituent is attached to a nitrogen ring atom, the substituent is selected from C1-4 -alkyl-, C 1-4 -alkyl-CO-, C 3-6 -cycloalkyl- and C 3-6 -cycloalkyl-CO-, and wherein the C 1-4 -alkyl-, C 1-4 -alkyl-O-, C 1-4 -alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3-6 -cycloalkyl-, C 3-6 -cycloalkyl-CO- or C 3-6 The -cycloalkyl-O- substituents may each be substituted with one or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F, and -CN; R 2 Selected from hydrogen, C 1-4 -alkyl-, C 1-4 -alkyl-O-, -CN and C 3-6 -cycloalkyl-, wherein the C 1-4 -alkyl-, C 1-4 -alkyl-O- and C 3-6 -cycloalkyl- may each be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F and -CN; R 3 Selected from C 1-6 -alkyl-O-, C 3-6 -cycloalkyl-O-, morpholino, pyrazolyl and 4- to 7-membered monocyclic heterocycloalkyl-O- having 1 oxygen atom as a ring member and optionally 1 or 2 independently selected from O, N and S(O) s heteroatom, wherein s=0, 1 or 2, wherein the C 1-6 -alkyl-O- and the C 3-6 -cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F, -CN, C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -alkyl-O- and C 3-6 -cycloalkyl-O-; R 4 is hydrogen; or R 3 and R 4 Together with the ring atoms of the phenyl group to which they are attached, they can form a 4-, 5- or 6-membered monocyclic partially saturated heterocycloalkyl or heteroaryl group, each of which has 1, 2 or 3 independently selected from O, N and S(O) s wherein s=0, 1 or 2, of which in the general formula (I) there must be 1 directly attached to R 3wherein the heterocycloalkyl group may be optionally substituted by 1, 2, 3 or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F, -CN, C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -alkyl-O-, C 3-6 -cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-; R 5 is hydrogen; R 6 Selected from hydrogen, C 1-4 -alkyl-SO2-, C 3-6 -cycloalkyl-SO2 and -CN; R 7 is hydrogen; or a) R 6 and R 7 or b) R 6 and R 5 One of the pairs together with the ring atoms of the phenyl to which they are attached forms a ring having 1, 2 or 3 atoms independently selected from O, N and S(O) u 5-membered or 6-membered partially saturated monocyclic heterocycloalkyl containing 1, 2, 3, 4, 5-membered or 6-membered heteroatom, wherein u=0, 1 or 2, wherein in the general formula (I) there must be 1 directly attached to R 6 The -SO2- member of the ring carbon atom of the phenyl to which it is attached, wherein the heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F, -CN, C 1-4 -alkyl-, C 1-6 -alkyl-O- and C 3-6 -cycloalkyl-O-, or a pharmaceutically acceptable salt of said compound. In certain such embodiments, said GlyT1 inhibitor is a compound having the formula A compound or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the GlyT1 inhibitor is a compound of Formula XI, Where R 1 Is halogen, -OR 1′ 、-SR 1″ , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or a 5-membered or 6-membered heteroaryl group containing one, two or three heteroatoms selected from oxygen, sulfur and nitrogen; R 1′ and R 1″ are independently hydrogen, lower alkyl, lower alkyl substituted with halogen, -(CH2) x -cycloalkyl or -(CH2) x -aryl; R 2is -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; is an aromatic bicyclic amine or partially aromatic bicyclic amine having one or two additional N atoms, selected from

[0046] and wherein one additional N ring atom of the aromatic bicyclic amine or part of the aromatic bicyclic amine may be in the form of an oxide R3 to R10 are each independently hydrogen, hydroxyl, halogen, ═O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO2, NH2, aryl, 5-membered or 6-membered heteroaryl containing one, two or three heteroatoms selected from oxygen, sulfur and nitrogen, -NH-lower alkyl, -N(lower alkyl)2, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)2-lower alkyl, halogenated substituted by halogen, substituted by halogen lower alkyl, substituted by hydroxy lower alkyl, -O-(CH2)y-lower alkoxy, -O(CH2)yC(O)N(lower alkyl)2, -C(O)-lower alkyl, -O-(CH2)x-aryl, -O-(CH2)x-cycloalkyl, -O-(CH2)x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl R, R', R" and R'" are each independently hydrogen or lower alkyl; or R' and R'" in group e) together with -(CH2)4- form a six-membered ring; and wherein as for R1, R1', R1" and R3 to R10 All aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5-membered or 6-membered heteroaryl groups as defined are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, ═O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen, and lower alkoxy; n, m, o, p, q, r, s, and t are each independently 1 or 2; x is 0, 1 or 2; and y is 1 or 2; or a pharmaceutically acceptable salt of the compound.

[0047] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0048] In certain embodiments, the subject is a subject in need thereof.

[0049] In certain embodiments, 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 Shown is the expression of GlyT1 in various liver-derived cell lines compared to the expression in the erythropoietic cell line K562.

[0051] Figure 2 The expression of GlyT1 and other components of the heme synthesis pathway (e.g., ALAS1, ALAS2, ALAD, FECH, CPOX, HMBS, UROD, UROS, and GlyT2) in 26 liver cancer cell lines is shown.

[0052] Figure 3 shows that phenobarbital induces ALAS1 in HepG2 cells ( Figure 3A ) and GlyT1( Figure 3B ). In this figure, "*" indicates p value < 0.05, and "****" indicates p value < 0.0001.

[0053] FIG. 4 shows that bitopertin inhibits glycine uptake in HepG2 cells overexpressing GlyT1. Figure 4A represents HepG2 pLenti6.3-GlyT1 (unlabeled), and Figure 4B Indicates HepG2 pLenti6.3-GlyT1-HA-Flag.

[0054] FIG5 shows that in HepG2 cells transduced with shHMBS, GlyT1, and ALAS1, the toxic metabolite 5-ALA ( Figure 5A ) and PBG( Figure 5B ).

[0055] FIG6 shows that in the presence of different concentrations of glycine in the culture medium, in HepG2 cells transduced with shHMBS, GlyT1, and ALAS1, the toxic metabolite 5-ALA ( Fig. 6A ) and PBG( Figure 6B ). In this figure, “*” indicates p-value < 0.05, “**” indicates p-value < 0.01, and “***” indicates p-value < 0.001. DETAILED DESCRIPTION

[0056] Unless defined otherwise, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0057] As used herein, "a" or "an" means "at least one" or "one or more" unless the context clearly indicates otherwise.

[0058] As used herein, the term "about" means that the numerical value is approximate and that small variations will not significantly affect the practice of the disclosed embodiments. Where numerical limitations are used, unless the context indicates otherwise, "about" means that the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0059] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0060] As used herein, the term "acylamino" means an amino group substituted with an acyl group (e.g., -OC(=O)-H or -OC(=O)-alkyl). Examples of acylamino groups are -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" means an amino group substituted with a lower acyl group (e.g., -OC(=O)-H or -OC(=O)-C 1-6 Examples of lower acylamino groups are -NHC(=O)H or -NHC(=O)CH3.

[0061] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0062] As used herein, the term "alkenyl" means a straight or branched chain alkyl group having one or more carbon-carbon double bonds and 2-20 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In some embodiments, the alkenyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0063] The terms "alkoxy", "phenoxy", "benzyloxy" and "pyrimidinyloxy" refer to an optionally substituted alkyl, phenyl, benzyl or pyrimidinyl group, respectively, bonded through an oxygen atom. For example, the term "alkoxy" means a straight or branched-O-alkyl group of 1 to 20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like. In some embodiments, the alkoxy chain is 1 to 10 carbon atoms in length, 1 to 8 carbon atoms in length, 1 to 6 carbon atoms in length, 1 to 4 carbon atoms in length, 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0064] As used herein, the term "alkyl" means a straight or branched saturated hydrocarbon group. The alkyl group 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.

[0065] As used herein, the term "alkylamino" means an amino group substituted by an alkyl group having 1 to 6 carbon atoms. An example of an alkylamino group is -NHCH2CH3.

[0066] As used herein, the term "alkylene" or "alkylenyl" means a divalent alkyl linking group. An example of an alkylene group is methylene (methylene or methylenyl) (-CH2-).

[0067] As used herein, the term "alkylthio" means an -S-alkyl group having 1 to 6 carbon atoms. An example of an alkylthio group is -SCH2CH3.

[0068] As used herein, the term "alkynyl" means a straight or branched chain alkyl group having one or more carbon-carbon triple bonds and 2-20 carbon atoms, including but not limited to acetylene, 1-propylene, 2-propylene, etc. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0069] As used herein, the term "amide" refers to a group

[0070]

[0071] Each R 30 independently represent hydrogen or a hydrocarbon group, or two R 30 Together with the N atom to which they are attached they form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0072] As used herein, the term "amidino" refers to -C(=NH)NH2.

[0073] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines and salts thereof, for example, the moiety represented by:

[0074]

[0075] Each R 30 independently represent hydrogen or a hydrocarbon group, or two R 30 Together with the N atom to which they are attached they form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0076] As used herein, the term "aminoalkoxy" refers to an alkoxy group substituted with an amino group. An example of an aminoalkoxy group is -OCH2CH2NH2.

[0077] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group. An example of an aminoalkyl group is -CH2CH2NH2.

[0078] As used herein, the term "aminosulfonyl" refers to -S(=O)2NH2.

[0079] As used herein, the term "aminoalkylthio" refers to an alkylthio group substituted with an amino group. An example of an aminoalkylthio group is -SCH2CH2NH2.

[0080] As used herein, the term "amphiphilic" means a three-dimensional structure having discrete hydrophobic and hydrophilic regions. Amphiphilic compounds suitably have both hydrophobic and hydrophilic elements present.

[0081] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates, such as wild animals, domestic animals, and farm animals.

[0082] As used herein, the term "aryl" means a monocyclic, bicyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon. In some embodiments, the aryl group has 6 to 20 carbon atoms or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, etc. Examples of aryl groups include, but are not limited to:

[0083]

[0084]

[0085] As used herein, the term "arylalkyl" refers to a C 1-6 alkyl.

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

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

[0088] The term "carbamate" is art-recognized and refers to a group

[0089]

[0090] Where R 29 and R 30 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R 29 and R 30 Together with one or more intervening atoms a heterocyclic ring is formed having 4 to 8 atoms in the ring structure.

[0091] As used herein, the term "carbamoyl" refers to -C(=O)-NH2.

[0092] As used herein, the term "carbocycle" means a 5- or 6-membered saturated or unsaturated ring, optionally containing O, S or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the above heterocycles.

[0093] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl group.

[0094] The term "carbonate" is art-recognized and refers to the group -OCO2-R 30 , where R 30 It represents a hydrocarbon group.

[0095] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0096] As used herein, the term "carrier" means a diluent, adjuvant or excipient with which the compound is administered. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants can be used.

[0097] As used herein, the term "compound" refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0098] As used herein, the terms "comprising" (and any form of comprising, such as "comprise," "comprises," and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0099] As used herein, the term "contacting" means bringing two elements together in an in vitro system or an in vivo system. For example, "contacting" a GlyT1 transporter inhibitor with a 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 preparation (containing a GlyT1 transporter).

[0100] As used herein, the term "cyano" refers to -CN.

[0101] As used herein, the term "cycloalkyl" means a non-aromatic cyclic hydrocarbon, including cyclized alkyl, alkenyl and alkynyl containing up to 20 ring-forming carbon atoms.Cycloalkyl can include monocyclic or polycyclic systems, such as condensed ring systems, bridged ring systems and spirocyclic systems.In some embodiments, polycyclic systems include 2, 3 or 4 condensed rings.Cycloalkyl can contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5 or 5 or 6 ring-forming carbon atoms.The ring-forming carbon atoms of cycloalkyl can be optionally replaced by oxo or sulfido.The example of cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarboxyl, adamantyl etc. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused (having a common bond) to a cycloalkyl ring, such as benzo or thienyl derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-on-1-yl).

[0102] As used herein, the term "cycloalkylalkyl" refers to a C 1-6 alkyl.

[0103] As used herein, the term "dialkylamino" means an amino group substituted with two alkyl groups each having 1 to 6 carbon atoms.

[0104] As used herein, the term "diazoamino" means -N(NH2)2.

[0105] As used herein, the term "ester" refers to the group -C(O)OR 30 , where R 30 It represents a hydrocarbon group.

[0106] As used herein, the term "ether" refers to a hydrocarbon group connected to another hydrocarbon group through an oxygen. Thus, an ether substituent of a hydrocarbon group may be hydrocarbon-O-. An ether may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyls," which may be represented by the general formula alkyl-O-alkyl.

[0107] As used herein, the term "facially amphiphilic" or "facialamphiphilicity" refers to compounds having polar (hydrophilic) and nonpolar (hydrophobic) side chains that adopt one or more conformations that result in the separation of the polar and nonpolar side chains into opposite faces or separate regions of a structure or molecule.

[0108] As used herein, the term "glycine transporter" or "GlyT" refers to a membrane protein that facilitates the transport of glycine across the plasma membrane of a cell. Non-limiting examples of glycine transporters include glycine transporter 1 (GlyT1) and glycine transporter 2 (GlyT2).

[0109] As used herein, the term "GlyT1" or "GlyT1 transporter" means sodium and chloride-dependent glycine transporter 1 (also known as glycine transporter 1), which is 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 situ hybridization". Cytogenet Cell Genet. 71(3):211), which are hereby incorporated by reference in their entirety.

[0110] 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 are hereby incorporated by reference in their entirety.

[0111] 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 isoform. Non-limiting examples of GlyT1 inhibitors are provided herein. In some embodiments, the GlyT1 inhibitor is a specific GlyT1 inhibitor, which means that the inhibitor has greater inhibitor activity on GlyT1 compared to GlyT2. In some embodiments, the inhibitor inhibits GlyT1 with at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity compared to GlyT2. In some embodiments, the GlyT1 inhibitor inhibits GlyT1 but does not inhibit or significantly inhibits the activity of GlyT2. If the GlyT1 inhibitor inhibits the activity of GlyT2 by less than 5%, 4%, 3%, 2% or 1%, 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 a published journal article (BN Atkinson, SC Bell, M. De Vivo, LR Kowalski, SM Lechner, VIOgnyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and MA Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is incorporated in its entirety.

[0112] 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 isoform. In some embodiments, the GlyT2 inhibitor is a nonspecific inhibitor, which means that it can also inhibit or block the activity of GlyT1. In some embodiments, the GlyT2 inhibitor is a specific GlyT2 inhibitor, which means that compared with GlyT1, the inhibitor has greater inhibitor activity to GlyT2. In some embodiments, compared with GlyT1, the inhibitor inhibits GlyT2 with at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity. In some embodiments, the GlyT2 inhibitor inhibits GlyT2 activity but does not inhibit or significantly inhibits the activity of GlyT1. A GlyT2 inhibitor does not significantly inhibit the activity of GlyT1 if the GlyT2 inhibitor inhibits the activity of GlyT1 by less than 5%, 4%, 3%, 2% or 1%. The selectivity of a GlyT2 inhibitor is determined based on assays known in the art, such as those described in a published journal article (BN Atkinson, SC Bell, M. De Vivo, LR Kowalski, SM Lechner, VIO gnyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and MA Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is incorporated in its entirety.

[0113] As used herein, the term "guanidino" refers to -NH(=NH)NH2.

[0114] As used herein, the term "halo" refers to halogen groups including, but not limited to, fluoro, chloro, bromo, and iodo.

[0115] As used herein, the term "haloalkoxy" means -O-haloalkyl. An example of a haloalkoxy group is OCF3.

[0116] As used herein, the term "haloalkyl" refers to a C 1-6 Alkyl. Examples of haloalkyl include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.

[0117] As used herein, the term "heteroaryl" means an aromatic heterocycle having up to 20 ring atoms (e.g., C) and having at least one heteroatom ring member (ring atoms), such as sulfur, oxygen or nitrogen. In some embodiments, heteroaryl has at least one or more heteroatom ring atoms, each of which is independently sulfur, oxygen or nitrogen. In some embodiments, heteroaryl has 3 to 20 ring atoms, 3 to 10 ring atoms, 3 to 6 ring atoms or 3 to 5 ring atoms. In some embodiments, heteroaryl contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, heteroaryl has 1 to 4 heteroatoms, 1 to 3 heteroatoms or 1 or 2 heteroatoms. Heteroaryl includes monocyclic and polycyclic (e.g., having 2, 3 or 4 condensed rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (e.g., indol-3-yl), pyrrolyl, oxazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiophenyl, purinyl, carbazolyl, benzothiophene, imidazolyl, dihydroindole, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, piperidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl and the like. Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine and 2-aminopyridine.

[0118] As used herein, the term "heteroarylalkyl" refers to a C 1-6 alkyl.

[0119] As used herein, the term "heteroarylamino" means an amino group substituted by a heteroaryl group. An example of a heteroarylamino group is -NH-(2-pyridyl).

[0120] As used herein, the term "heteroarylene" means a heteroaryl linking group, ie, a heteroaryl group that links one group to another group in a molecule.

[0121] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0122] As used herein, the term "heterocycle" or "heterocyclic ring" means a 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring system, wherein any ring may be saturated or unsaturated, and which consists of carbon atoms and one to three heteroatoms selected from N, O and S, and wherein the N and S heteroatoms may be optionally oxidized, and the N heteroatom may be optionally quaternized, and includes any bicyclic group in which any of the above-defined heterocycles is fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur in combination with one or two nitrogen atoms. The heterocycle may 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-oxopiperazinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepanyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiaminyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

[0123] As used herein, the term "heterocycloalkyl" means a non-aromatic heterocycle with up to 20 ring atoms, including cyclized alkyl, alkenyl and alkynyl, wherein one or more ring carbon atoms are replaced by heteroatoms such as O, N or S atoms. Heterocycloalkyl can be monocyclic or polycyclic (e.g., fused, bridged or spirocyclic systems). In some embodiments, heterocycloalkyl has 1 to 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, heterocycloalkyl contains 3 to 14 ring atoms, 3 to 7 ring atoms, or 5 or 6 ring atoms. In some embodiments, heterocycloalkyl has 1 to 4 heteroatoms, 1 to 3 heteroatoms or 1 or 2 heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 triple bonds. Examples of heterocycloalkyl include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, etc. In addition, the ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally substituted with oxo or thio-negative groups. For example, the ring-forming S atoms can be substituted with 1 or 2 oxo groups (forming S(O) or S(O)2). For another example, the ring-forming C atoms can be substituted with oxo (forming carbonyl). Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (having a common bond) to a non-aromatic heterocycle, including, but not limited to, pyridyl, thienyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles, such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3-yl. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl may be optionally substituted with oxo or thioxanthyl.

[0124] As used herein, the term "heterocycloalkylalkyl" refers to a C 1-6 alkyl.

[0125] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0126] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl group substituted with a hydroxy group. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH and -CH2CH2OH.

[0127] As used herein, the terms "subject" or "patient," which are used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, such as humans.

[0128] As used herein, the phrase "inhibiting an activity" such as enzyme activity or transporter activity means reducing the activity of the enzyme or transporter (such as GlyT1 transporter) by any measurable amount.

[0129] As used herein, the phrase "in need thereof" means that an animal or mammal has been identified as being in need of a particular method or treatment. In some embodiments, identification can 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 an environment where a particular disease, disorder, or condition is prevalent or is traveling to such an environment.

[0130] As used herein, the phrase "in situ gellable" is meant to include not only low viscosity liquids that form gels upon contact with tear fluid in the eye or outside the eye, but also more viscous liquids such as semifluids and thixotropic gels that exhibit a significant increase in viscosity or gel stiffness when applied to the eye.

[0131] As used herein, the phrase "integer from X to Y" means any integer including the endpoints. For example, the phrase "integer from X to Y" means 1, 2, 3, 4 or 5.

[0132] 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 there are ten or less, preferably six or less non-hydrogen atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or less, preferably six or less carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are respectively low acyl, low acyloxy, low alkyl, low alkenyl, low alkynyl or low alkoxy, whether they occur alone or in combination with other substituents, such as the hydroxyalkyl and aralkyl groups listed (in this case, for example, when counting the carbon atoms in the alkyl substituent, the atoms in the aryl are not counted).

[0133] As used herein, the term "mammal" means a rodent (ie, mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0134] As used herein, the term "N-alkyl" refers to an alkyl chain substituted with an amine group. Non-limiting examples include, but are not limited to The alkyl chain can be linear, branched, cyclic, or any combination thereof. In some embodiments, the alkyl group contains 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 carbons.

[0135] As used herein, the term "nitro" means -NO2.

[0136] As used herein, the term "n-membered" (where n is an integer) typically describes the number of ring atoms in a moiety, where the number of ring 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.

[0137] As used herein, the phrase "ophthalmologically acceptable" means having no persistent detrimental effects on the treated eye or its function, or on the general health of the treated subject. However, it is recognized that transient effects such as mild irritation or a "stinging" sensation are common for topical ocular administration of drugs, and the presence of such transient effects is not inconsistent with the composition, formulation, or ingredient (e.g., excipient) in question being "ophthalmologically acceptable" as defined herein.

[0138] As used herein, the phrase "optionally substituted" means that substitution is optional, and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the specified atom or moiety can be replaced by a selection from a specified substituent, provided that the normal valence of the specified atom or moiety is not exceeded and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced by a substituent.

[0139] As used herein, the phrase "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0140] "Pharmaceutically acceptable salts" are intended to mean salts of free acids or bases of the compounds represented herein that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without excessive toxicity, irritation, or allergic reaction. 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 therefore react with a variety of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0141] For compounds described herein that contain a basic group (e.g., an amine), pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, sesquiterpene acid, succinic acid, valeric acid, succinic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, succinic acid, pyruvic acid, succinic acid, succinic acid, hydroxyethyl sulfonic ... Cinnamic acid, pyranosidic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as mandelic acid, citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acid (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid); or any compatible acid mixture, such as those given as examples herein; and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes according to the ordinary skill in the art.

[0142] For compounds described herein containing acidic groups (such as carboxylic acid groups), 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 (neat 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 tetraalkyl ammonium salts.

[0143] Other examples of pharmaceutically acceptable salts include, but are not limited to, camphorsulfonate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate Pharmaceutically acceptable salts include, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985.

[0144] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but in other respects the salts are equivalent to the parent form of the compound for the purposes of this application.

[0145] As used herein, the term "phenyl" means -C6H5. A phenyl group may be unsubstituted or substituted with one, two or three suitable substituents.

[0146] The terms "polycyclic group", "polycyclic" and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10 atoms in the ring, preferably 5 to 7.

[0147] As used herein, the term "prodrug" means a derivative of a known direct-acting drug, which has enhanced delivery characteristics and therapeutic value compared to the drug, and is converted into an active drug by enzymatic or chemical methods. A common method for preparing a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to produce the desired molecule. In certain embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, a prodrug with a nitro group on 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, a functional group such as a hydroxyl, carbonate or carboxylic acid in the parent compound is presented as an ester, which can be cut by an esterase. In addition, 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," Molecules, (2008), 13: 519-547). In certain embodiments, some or all of the compounds described herein in the formulations represented above can be replaced with corresponding suitable prodrugs.

[0148] As used herein, the term "purified" means that when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% of a compound described herein by weight of the isolate.

[0149] As used herein, the phrase "quaternary ammonium salt" means a derivative of the disclosed compounds having one or more tertiary amine moieties, wherein at least one tertiary amine moiety in the parent compound is alkylated (and the cation is substituted by an anion such as Cl). - 、CH3COO - and CF3COO - The tertiary amine moiety is modified by converting it to a quaternary ammonium cation (e.g., methylation or ethylation).

[0150] As used herein, the term "semicarbazone" means =NNHC(=O)NH2.

[0151] As used herein, the phrase "solubilizer" means an agent that results in the formation of a micellar solution or a true solution of the drug.

[0152] As used herein, the term "solution / suspension" means a liquid composition wherein a first portion of the active agent is present in solution and a second portion of the active agent is present in suspension in the form of particles in a liquid matrix.

[0153] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it was formed or detected.

[0154] The term "substituted" refers to a substituent having a substituent of hydrogen on one or more carbons of the main chain. It should be understood that "replacement" or "substituted by ... " includes implicit conditions, i.e., such substitution is consistent with the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, the stable compound will not spontaneously transform as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all allowed substituents of organic compounds. In a broad aspect, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, allowed substituents can be one or more and are the same or different. For the purposes of this application, heteroatoms such as nitrogen can have hydrogen substituents and / or any allowed substituents of organic compounds that meet heteroatom valence as described herein.

[0155] Substituents may include any substituent described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that substituents themselves may be substituted if appropriate. Unless specifically stated as "unsubstituted", chemical moieties referred to herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0156] The term "sulfate" is art-recognized and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0157] The term "sulfonamide" is art-recognized and refers to a group represented by the following general formula:

[0158]

[0159] Where R 29 and R 30 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R 29 and R 30 Together with one or more intervening atoms a heterocyclic ring is formed having 4 to 8 atoms in the ring structure.

[0160] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 30 , where R 30 It represents a hydrocarbon group.

[0161] The term "sulfonate" is art-recognized and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0162] The term "sulfone" is art-recognized and refers to the group -S(O)2-R 30 , where R 30 It represents a hydrocarbon group.

[0163] As used herein, the phrase "therapeutically 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 being that a researcher, veterinarian, physician, or other clinician is seeking. The therapeutic effect depends on the disorder being treated or the desired biological effect. Therefore, the therapeutic effect can be a reduction in the severity of symptoms associated with the disorder and / or inhibition of the progression of the disorder (partial or complete), or treatment, cure, prevention, or elimination of an improvement in the disorder or side effect. The amount required to elicit a therapeutic response can be determined based on the age, health, size, and sex of the subject. The optimal amount can also be determined based on monitoring the subject's response to treatment.

[0164] As used herein, the term "alkylthio" refers to an alkyl group substituted with a thiol group.

[0165] As used herein, the term "thioester" refers to the group -C(O)SR 30 or -SC(O)R 30 , where R 30 It represents a hydrocarbon group.

[0166] As used herein, the term "thioether" is equivalent to an ether in which the oxygen is replaced by sulfur.

[0167] As used herein, the term "treat, treated or treating" means therapeutic treatment and preventive measures, wherein the purpose is to slow down (mitigate) an undesirable physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, relief of symptoms; relief of the extent of a condition, disorder or disease; a stable (i.e., non-worsening) state of a condition, disorder or disease; a delay or slowing of the onset of a condition, disorder or disease progression; an improvement or alleviation (whether partial or complete) of a detectable or undetectable condition, disorder or disease state; an improvement in at least one measurable physical parameter, which is not necessarily discernible by the patient; or an enhancement or improvement of a condition, disorder or disease. Treatment includes causing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival time compared to the expected survival time if not receiving treatment. Therefore, "treating hepatic porphyria" means an activity that alleviates or improves any primary phenomenon or secondary symptoms associated with hepatic porphyria or other conditions described herein.

[0168] The term "urea" is art-recognized and can be represented by the general formula

[0169]

[0170] Where R 29 and R 30 independently represents hydrogen or a hydrocarbon group, such as an alkyl group, or any occurrence of R 29 With R 30 Together with one or more intervening atoms, a heterocyclic ring is formed having 4 to 8 atoms in the ring structure.

[0171] At various places in this specification, substituents of compounds may be disclosed in groups or ranges. In particular, it is intended that the embodiments include every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to disclose individually methyl, ethyl, propyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0172] For compounds in which a variable appears more than once, each variable may be a different part selected from the Markush group defining the variable. For example, where a 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 a 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. When the form specifies optional multiple substituents, it is understood that the substituent R can appear s times on the ring, and R can be a different moiety at each occurrence. 1 is defined to include hydrogen, such as when T 1 When it is CH2, NH, etc., any H may be replaced by a substituent.

[0173] It should also be understood that certain features described herein, which are described in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

[0174] It should be understood that embodiments of the present invention include stereoisomers, diastereomers and optical stereoisomers and mixtures thereof of compounds used where applicable. In addition, it should be understood that stereoisomers, diastereomers and optical stereoisomers and mixtures thereof of compounds are within the scope of the embodiments. As non-limiting examples, mixtures can be racemates or mixtures can contain unequal proportions of a particular stereoisomer relative to another. In addition, compounds can be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).

[0175] 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 embodiment. Compounds containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by splitting racemic mixtures or preparing by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in compounds described herein, and all such stable isomers are provided herein. The cis and trans geometric isomers of the compound are also included in the present embodiment, and they can be separated as a mixture of isomers or as separate isomeric forms. When specifying a compound capable of stereoisomerism or geometric isomerism in its structure or name without mentioning a specific R / S or cis / trans configuration, it is intended to cover all such isomers.

[0176] In some embodiments, the composition comprises a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof that is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure, meaning that the ratio of one enantiomer to the other in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or is entirely in the form of one enantiomer over the other. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means, for example, that the substance in question comprises 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, it would be said to contain 98 mol% of the first enantiomer and only 2% of the second enantiomer.

[0177] In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means, for example, that the substance in question comprises 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 a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol% of the first enantiomer and only 2% of the second enantiomer.

[0178] The resolution of the racemic mixture of a compound 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 resolution acid, which is an optically active salified organic acid. Suitable resolution agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid, in the form of D and L. Other resolution agents suitable for fractional crystallization methods include, but are not limited to, α-methylbenzylamine (e.g., S and R forms or diastereoisomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of a racemic mixture can also be carried out by eluting on a column filled with an optically active resolution agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0179] Compounds can also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, including but not limited to 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into a form by appropriate substitution.

[0180] Glycine transporter inhibitors, such as GlyT1 inhibitors, including pharmaceutically acceptable salts thereof (e.g., GlyT1 inhibitors as disclosed herein) can also exist as hydrates and solvates, as well as anhydrous and non-solvated forms. "Hydrates" are compounds present in a composition together with water molecules. The composition may contain a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may contain a random amount of water. "Solvates" are similar compositions, except that solvents other than water are used, such as methanol, ethanol, dimethylformamide, diethyl ether, etc. replace water. For example, methanol or ethanol can form "alcoholates", which can also be stoichiometric or non-stoichiometric. Mixtures of such solvates or hydrates can also be prepared. The source of such solvates or hydrates can be from the crystallization solvent, inherent in the preparation or crystallization solvent, or exogenous to such solvents.

[0181] The compounds of the present application, including pharmaceutically acceptable salts and prodrugs thereof, can 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. Due to the different stacking of molecules in the lattice caused by changes in temperature, pressure or changes in the crystallization process, different crystalline polymorphs have different crystal structures. The physical properties of polymorphs are different from each other, such as X-ray diffraction characteristics, stability, melting point, solubility or dissolution rate in certain solvents. Therefore, crystalline polymorphs are an important aspect of developing suitable dosage forms in the pharmaceutical industry.

[0182] Compounds can also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms with the same atomic number but different mass numbers. For example, isotopes of tritium include tritium and deuterium.

[0183] In some embodiments, the compound or its salt is substantially separated. Partial separation can include, for example, a composition rich in the compound. Substantial separation can include a composition 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% of the compound or its salt by weight. Methods for separating compounds and their salts are routine in the art.

[0184] Although the disclosed compounds are suitable, other functional groups can be introduced into the compounds, and similar results are expected. In particular, it is expected that thioamides and thioesters have very similar characteristics. The distance between the aromatic rings may affect the geometric pattern of the compound, and this distance can be changed by incorporating aliphatic chains of different lengths, which can be optionally substituted or can contain amino acids, dicarboxylic acids or diamines. The distance and relative orientation between monomers in the compound can also be changed by replacing the amide bond with a substitute with an additional atom. Therefore, replacing the carbonyl with a dicarbonyl changes the distance between the monomers and the tendency of the dicarbonyl unit to adopt the anti-arrangement of two carbonyl parts and change the periodicity of the compound. Pyromellitic anhydride represents another alternative to simple amide bonds, which can change the conformation and physical properties of the compound. Modern methods of solid phase organic chemistry (E.Atherton and RCSheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of uniformly dispersed compounds with molecular weights close to 5,000 daltons. Other substitution patterns are equally effective.

[0185] The compounds also include derivatives known as prodrugs.

[0186] Compounds containing amine functional groups can also form N-oxides. Compounds containing amine functional groups mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide. Examples of N-oxides include N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience).

[0187] By hereby retaining the right to limit or exclude any individual member of any such group that can be claimed according to scope or in any similar manner (including any sub-range or combination of sub-ranges in the group), less than the full scope of the present disclosure may be claimed for any reason. In addition, by hereby retaining the right to limit or exclude any individual substituent, analog, compound, ligand, structure or any member of the group claimed, less than the full scope of the present disclosure may be claimed for any reason. Throughout the present disclosure, multiple patents, patent applications and publications are mentioned. The disclosures of these patents, patent applications and publications are incorporated into the present disclosure by reference in their entirety to more fully describe the prior art known to those skilled in the art as of the date of the present disclosure. In the event of any inconsistency between the cited patents, patent applications and publications and the present disclosure, the present disclosure shall prevail.

[0188] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0189] Various embodiments of compounds and salts thereof are provided. Where a variable is not specifically enumerated, the variable may be any of the options described herein unless otherwise stated or indicated by the context.

[0190] In some embodiments, the compound is as described in the accompanying exemplary non-limiting claims, or is a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

[0192]

[0193] in:

[0194] Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted aryl and the substituted heteroaryl are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR 7 R 8 、C(O)R 9 、SO2R 10 and -C(CH3)=NOR 7 , or is substituted by a 5-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N and O, the aromatic heterocyclic ring being optionally substituted by (C1-C6)-alkyl;

[0195] R 1 is hydrogen or (C1-C6)-alkyl;

[0196] R 2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C3-C7)-cycloalkyl, CH(CH3)-(C3-C7)-cycloalkyl, (CH2) n+1 -C(O)-R 9 、(CH2) n+1 -CN, bicyclo[2.2.1]heptyl, (CH2) n+1 -O-(C1-C6)-alkyl, (CH2) n -heterocycloalkyl, (CH2) n -aryl or (CH2) containing one, two or three heteroatoms selected from oxygen, sulfur or nitrogen n - 5- or 6-membered heteroaryl, wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;

[0197] R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl;

[0198] R 5 NO2, CN, C(O)R 9 or SO2R 10 ;

[0199] R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl;

[0200] R 9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR 7 R 8 ;

[0201] R 10 is (C1-C6)-alkyl, (CH2) optionally substituted by halogen n -(C3-C6)-cycloalkyl, (CH2) n -(C3-C6)-alkoxy, (CH2) n -heterocycloalkyl or NR 7 R 8 ;

[0202] n is 0, 1, or 2;

[0203] or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula The compound is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula II,

[0206]

[0207] in:

[0208] R1 represents a heteroaryl group selected from the group consisting of imidazolyl, thiazolyl, pyridinyl, oxazolyl, pyrazolyl, triazolyl, oxadiazolyl, quinolyl, isoxazolyl, pyrroloimidazolyl, and thiadiazole, wherein the heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of -OH, -NR7R8, halogen, (C1-C8)alkyl, (C3-C 10 )cycloalkyl, (C1-C8)alkoxy, (C1-C 12 ) alkoxyalkyl, (C1-C8) hydroxyalkyl, (C6-C 14 ) aryl and benzyl;

[0209] R2, R3 and A independently represent H or (C1-C8)alkoxy, wherein the alkyl is optionally substituted with one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen;

[0210] Q stands for -(CH2) n -, wherein n = 1, 2, 3 or 4, or -(CH2) m -O-, wherein m=2, 3 or 4;

[0211] Z represents (C6-C 14 )aryl, (C1-C8)alkyl or (C3-C8)cycloalkyl;

[0212] R4 and R5 each independently represent H, halogen, (C1-C8) alkyl, (C6-C 14 ) aryl, (C6-C 14 )aryloxy, (C1-C8)alkoxy, (3-10 membered)heterocycloalkyl or (C3-C8)cycloalkoxy; wherein R4 and R5 are optionally substituted by one or more -OH, (C1-C8)alkoxy, -NR7R8 or halogen;

[0213] Y represents -R6, -(CH2)o-R6, -C(R6)3 or -CH(R6)2, wherein 0=1, 2 or 3;

[0214] R6 represents H, (C6-C 14 ) aryl, (C 1-10 )alkyl, (C3-C 10 )cycloalkyl, (C5-C 18 ) bicycloalkyl, (C5-C 18 )tricycloalkyl, (3-10 membered)heterocycloalkyl, (5-10 membered)heteroaryl, -C(=O)NR7R8 or -C(=O)OR7, wherein the R6 group may be optionally substituted by one or more X groups;

[0215] Where X = -OH, (C1-C8) alkoxy, -NR 11 R 12 、-SO2R 10 、-C(=O)R 10 , halogen, cyano, (C1-C8) alkyl, (C1-C 10 )alkoxyalkyl, (5-10 membered)heteroaryl, (C6-C 14 ) aryl, (C6-C 14 )aryloxy, benzyl or (C1-C8)hydroxyalkyl;

[0216] wherein R7 and R8 independently represent H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10 membered)heterocycloalkyl, (C1-C8)hydroxyalkyl, (5-10 membered)heteroaryl or (C1-C8) 10 ) alkoxyalkyl; wherein R7 and R8 may be optionally substituted with one or more X groups;

[0217] or R7 and R8 together with the nitrogen to which they may be attached may form a (3-10 membered) heterocycloalkyl optionally substituted with one or more X groups;

[0218] Where R 10 represents (C1-C8) alkyl, (C3-C8) cycloalkyl, (3-10 membered) heterocycloalkyl, (C1-C8) hydroxyalkyl, (5-10 membered) heteroaryl or (C1-C 10 ) alkoxyalkyl;

[0219] Where R 11 and R 12 independently represent H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10 membered)heterocycloalkyl, (C1-C8)hydroxyalkyl, (5-10 membered)heteroaryl or (C1-C 10 ) alkoxyalkyl; or a pharmaceutically acceptable salt of the compound 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 GlyT1 inhibitor having the formula

[0221] A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula

[0223] The compound PF-3463275, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula III,

[0225]

[0226] in:

[0227] Z 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4Alkoxy, C 1-4 Alkylthio, halo 1-4 Alkyl, phenyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkylsulfonic acid oxygen, C 1-4 alkylsulfonyl, bromine and chlorine;

[0228] Z 2 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, phenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-6 Cycloalkyl;

[0229] Z 3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo 1-4 Alkyl, halogenated C 1-4 Alkoxy and C 3-6 Cycloalkyl;

[0230] Z 4 Selected from hydrogen, halogen, C1-3 alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-6 Cycloalkyl;

[0231] Z 5 Selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, phenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated phenyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-6 Cycloalkyl;

[0232] If Z 1 To Z 5 If more than one of them is a methoxy group, then only Z 1 and Z 5 is methoxy, R 3 and R 4 independently selected from hydrogen and C optionally substituted by one or more groups Y1-4 Alkyl; or R 3 and R4 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated A, 5-membered, 6-membered or 7-membered carbocyclic ring optionally substituted by a group Y';

[0233] Y is selected from C 1-4 Alkoxy, hydroxy, halogenated C 1-4 Alkoxy and C 3-5 Cycloalkyl;

[0234] Y' is selected from C 1-4 Alkyl, C 1-4 Alkoxy, halogen, hydroxyl, halogenated C 1-4 Alkoxy, C 3-5 Cycloalkyl and C 5-10 Aryl, or Y' forms a -CH2- or -CH2-CH2- bridge between two atoms on A, a 5-membered, 6-membered or 7-membered carbon ring;

[0235] R 5 and R 6 is independently C optionally substituted by one or more groups X 1-4 Alkyl; or R 5 and R 6 Together with the carbon atoms to which they are attached, they form a saturated 5- or 6-membered carbocyclic ring which is optionally substituted by one or more groups X', in which R 5 In case R6 and R6 together with the carbon atom to which they are attached form a 5-membered saturated carbocyclic ring, the ring may optionally further contain an additional heteroatom group selected from O, N and S(O)m; wherein m=0, 1 or 2.

[0236] X is selected from halogen, hydroxyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy and C 5-10 Aryl; and

[0237] X' is selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy and C 5-10 Aryl;

[0238] Where R 3 , R 4 , R 5 and R 6 Not all are unsubstituted methyl groups;

[0239] The condition is that when Z 1 is propoxy, Z 3 It is chlorine, Z2 =Z 4 =Z 5 =H, and R 5 and R 6 When both are methyl groups, then R 3 and R 4 do not form a 2-methylpyrrolidine group together with the nitrogen atom to which they are attached; when Z 1 It is methyl, Z 3 is methoxy, Z 2 = Z4 = Z5 = H, and R 5 and R 6 When both are methyl groups, then R 3 and R 4 Do not form, together with the nitrogen atom to which they are attached, a pyrrolidine group, or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

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

[0241] A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula IV,

[0243]

[0244] in:

[0245] Z is (CH2) n , O, S, SO, SO2 or N-R5;

[0246] n is 0, 1, or 2;

[0247] X represents 1-3 substituents independently selected from the following: hydrogen, halogen, (C 1-6 ) alkoxy, (C 3-6 )cycloalkoxy, (C 6-12 ) aryloxy, (C 6-12 )aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6 and (C 1-4 )alkyl, which is optionally substituted with halogen, (C 6-12 ) aryl, (C 1-6 ) alkoxy or (C 6-12 ) aryloxy substituted; or two substituents at adjacent positions together represent a fused (C 5-6 ) aryl, condensed (C5-6 )cycloalkyl ring or O-(CH2) m -O; m is 1 or 2;

[0248] Y represents 1-3 independently selected from hydrogen, halogen, (C 1-4 ) alkoxy, SR6, NR6R6 and (C 1-4 ) a substituent of an alkyl group, which is optionally substituted with halogen;

[0249] R1 is COOR7 or CONR8R9;

[0250] R2 and R6 are (C 1-4 )alkyl;

[0251] R3, R4 and R5 are independently hydrogen or (C 1-4 )alkyl;

[0252] R7, R8 and R9 are independently hydrogen, (C 1-4 ) alkyl, (C 6-12 ) aryl or aralkyl, or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula

[0254] The compound ORG-25935, 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 of Formula V,

[0256]

[0257] in:

[0258] n is an integer from 1 to 3;

[0259] R 1 and R 2 R is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the above ring is optionally independently selected from the following R a , R b or R c Substituted: alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino; or

[0260] R 1 and R 2When attached to the same carbon atom, they may combine to form a cycloalkyl or monocyclic saturated heterocyclic group to give a spirocycle, wherein the cycloalkyl or monocyclic saturated heterocyclic group may be optionally independently selected from the following R d , R c or R f Substituted: alkyl, alkoxy, fluorine, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino or disubstituted amino; or

[0261] R 1 and R 2 When attached to the carbon atoms at positions 2 and 5 or 3 and 6 of the piperazine ring, they can combine to form a -C1-C3-alkylene chain, wherein one carbon atom in the alkylene chain is optionally replaced by -NR-, -O-, -S(O)n- (wherein R is hydrogen or alkyl and n is 0-2), and further wherein one or two hydrogen atoms in the alkylene chain can be optionally replaced by one or two alkyl groups;

[0262] R 3 , R 4 and R 5 are independently hydrogen, alkyl, fluorine or fluoroalkyl; and Ar 1 and Ar 2 is independently aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of the above rings is optionally replaced by R g , R h or R i Substitution, where R g Alkyl, -C=CR 6 (where R 6 is aryl or heteroaryl), halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl or acylamino, and R h and R i are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein R g , R h and R i The aromatic or alicyclic ring in is optionally replaced by R j , R k or R l Substitution, the R j , R k or Rl independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl or acylamino; or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof, provided that the compound of formula V is not 2-(4-diphenyl 2-((2R,5S)-4-((R)-(4-(lH-tetrazol-5-yl)phenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-l-yl)acetic acid or 2-((2R,5S)-4-((R)-(4-cyanophenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-l-yl)acetic acid or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula

[0264] A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of Formula VI,

[0266]

[0267] in:

[0268] A represents a group of the general formula N-R1, a group of the general formula N+(O-)R1 or a group of the general formula N+(R')R1, and wherein R1 represents a hydrogen atom, or a straight or branched (C1-C7)alkyl group optionally substituted by one or more fluorine atoms, or a (C4-C7)cycloalkyl group, or a (C3-C7)cycloalkyl (C1-C3)alkyl group, or a phenyl (C1-C3)alkyl group optionally substituted by one or two hydroxyl or methoxy groups, or a (C2-C4)alkenyl group, or a (C2-C4)alkynyl group,

[0269] R' represents a linear or branched (C1-C7) alkyl group;

[0270] X represents a hydrogen atom or one or more substituents selected from a halogen atom and a trifluoromethyl group, a linear or branched (C1-C4) alkyl group and a (C1-C4) alkoxy group;

[0271] R2 represents a hydrogen atom, or one or more substituents selected from a halogen atom and a trifluoromethyl group, a (C1-C4) alkyl group or a (C1-C4) alkoxy group, or an amino group of the general formula NR3R4, wherein R3 and R4 each independently represent a hydrogen atom or a (C1-C4) alkyl group, or together with the nitrogen atom carrying them form a pyrrolidine, piperidine or morpholine ring, or a phenyl group optionally substituted by an atom or group as defined above for symbol X, or a pharmaceutically acceptable salt of the compound 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 GlyT1 inhibitor having the formula

[0273] A compound, SSR-504734, or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula VII,

[0275]

[0276] in:

[0277] R 1 Yes - (CH2) n -R 1a , wherein n is independently 0-6, and R 1a Selected from:

[0278] (1)C 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 halogens, hydroxyl groups,

[0279] (2) R 2a , R 2b and R 2c Substituted phenyl,

[0280] (3)C 3-6 Cycloallyl, which is unsubstituted or substituted by C 1-6 Alkyl, 1-6 halogens, hydroxyl or -NR 10 R 11 replace,

[0281] (4)-OC 1-6 Alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl or -NR 10 R 11 replace,

[0282] (5)-CO2R 9 ,

[0283] Wherein R9 is independently selected from:

[0284] (a) hydrogen,

[0285] (b)-C 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 fluorine atoms,

[0286] (c) benzyl, and

[0287] (d) phenyl,

[0288] (6)-NR 10 R 11 ,

[0289] Where R 10 and R 11 Independently selected from:

[0290] (a) hydrogen,

[0291] (b)-C 1-6 Alkyl, which is unsubstituted or substituted by hydroxy, 1-6 fluorine or -NR 12 R 13 Substitution, where R 12 and R 13 are independently selected from hydrogen and -C 1-6 alkyl,

[0292] (c)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by hydroxy, 1-6 fluorine or -NR 12 R 13 replace,

[0293] (d) benzyl,

[0294] (e) phenyl, and

[0295] (7)-CONR 10 R 11 ;

[0296] R 2 Selected from:

[0297] (1) phenyl, which is R 2a , R 2b and R 2c replace,

[0298] (2)C 1-8 Alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, -NR 10 R 11 , phenyl or heterocyclic ring, wherein the phenyl or heterocyclic ring is replaced by R 2a , R 2b and R 2c replace,

[0299] (3)C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1-6 halogen, hydroxy or -NR 10 R 11 Replace, and

[0300] (4)-C 1-6 Alkyl-(C 3-6 cycloalkyl), which is unsubstituted or substituted by 1-6 halogen, hydroxy or -NR 10 R 11 replace;

[0301] R 2a , R 2b and R 2c Independently selected from:

[0302] (1) Hydrogen,

[0303] (2) Halogen,

[0304] (3)-C 1-6 Alkyl, which is unsubstituted or substituted with:

[0305] (a) 1 to 6 halogens,

[0306] (b) phenyl,

[0307] (c)C 3-6 Cycloalkyl, or

[0308] (d)-NR 10 R 11 ,

[0309] (4)-OC 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 halogens,

[0310] (5) hydroxyl group,

[0311] (6)-SCF3,

[0312] (7)-SCHF2,

[0313] (8)-SCH3,

[0314] (9)-CO2R 9 ,

[0315] (10)-CN,

[0316] (11)-SO2R 9 ,

[0317] (12)-SO2-NR 10 R 11 ,

[0318] (13)-NR 10 R 11 ,

[0319] (14)-CONR 10 R 11 ,and

[0320] (15)-NO2;

[0321] R 3 Selected from:

[0322] (1)C 1-6 Alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl or -NR 10 R 11 replace,

[0323] (2)C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1-6 halogen, hydroxy or -NR 10 R 11 replace,

[0324] R 4 and R 5 Independently selected from:

[0325] (1) hydrogen, and

[0326] (2)C 1-6 Alkyl, which is unsubstituted or substituted by halogen or hydroxy, or R 4 and R 5 Together they form C 3-6 Cycloalkyl ring;

[0327] A is selected from:

[0328] (1) -O-, and

[0329] (2)-NR 10 -;

[0330] m is zero or one, wherein when m is zero, R 2 Directly attached to the carbonyl group;

[0331] and pharmaceutically acceptable salts of the compounds and individual enantiomers and diastereomers thereof, or pharmaceutically acceptable salts thereof or prodrugs of the compounds or pharmaceutically acceptable salts thereof.

[0332] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula

[0333] A compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula VIII,

[0335]

[0336] in:

[0337] R 1 are independently halogen, C1-C3 alkyl, C3-C6 cycloalkyl, OR 9 or SR 10 Phenyl substituted 1 to 5 times, wherein C1-C3 alkyl and C3-C6 cycloalkyl are optionally replaced by R 7 Replace 1 to 10 times;

[0338] R 2 It is H;

[0339] R 3 and R 4 Each independently is H or CH3;

[0340] R 5 Selected from:

[0341] (1) Hydrogen,

[0342] (2) Optionally R 7 C1-C6 alkyl substituted 1 to 11 times,

[0343] (3) a geminal dialkyl group, and

[0344] (4) geminal dihalide; or

[0345] Two R's on the same carbon 5 The substituents together with the carbon atom to which they are attached may form a 7 3-membered, 4-membered or 5-membered cycloalkyl substituted 1 to 10 times; or

[0346] Two R on adjacent carbons of the ring to which they are attached 5 The substituents together may form an optionally R 7 3-membered, 4-membered, 5-membered or 6-membered cycloalkyl substituted 1 to 10 times;

[0347]

[0348] wherein E, F and G are each independently nitrogen or carbon, and R 6a is C1-C2 alkyl, which is optionally substituted 1 to 5 times by halogen or deuterium;

[0349] R 7 Selected from:

[0350] (1) Hydrogen,

[0351] (2) Halogen,

[0352] (3) Deuterium,

[0353] (4) geminal dialkyl,

[0354] (5) Geminal dihalide,

[0355] (6)-OR 9 、-NR 11 R 12 、-NR 11 C(O) p R 10 、-S(O) p R 10 、-CN、-NO2、-C(O) p R 10 、-C(O)NR 11 R 12 , or -NR 11 C(S)R 10 ,and

[0356] (7) oxo or thio;

[0357] R 8 Selected from:

[0358] (1) Hydrogen,

[0359] (2) Halogen,

[0360] (3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C4-C7 cycloalkylalkyl,

[0361] wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each independently and optionally replaced by R 7 Replace 1 to 11 times, or

[0362] (4)-OR 9 、-NR 11 R 12 、-NR 11 C(O) p R 10 、-S(O) p R 10 、-CN、-NO2、-C(O) p R 10 、-C(O)NR 11 R 12 , or -NR 11 C(S)R 10 ;

[0363] R 9 Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)NR 11 R 12 and -C(O) p R 10 , wherein C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally replaced by R 7 Replace 1 to 11 times;

[0364] R 10 is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally substituted 1 to 11 times with substituents as defined in R7, and aryl or heteroaryl is optionally substituted with R 8 Replace 1 to 10 times;

[0365] R 11 and R 12 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, aryl and heteroaryl, wherein C1-C4 alkyl, C3-C7 cycloalkyl and C4-C7 cycloalkylalkyl are each optionally replaced by R 7 substituted 1 to 11 times by the substituents defined in 8 Replace 1 to 10 times, or R 11 and R 12 Together with the nitrogen to which they are attached, they form a 7 a saturated or partially saturated monocyclic or fused bicyclic heterocyclic ring substituted 1 to 11 times;

[0366] A is

[0367] X is N;

[0368] Y is N;

[0369] p is 1 or 2; and

[0370] m is 0;

[0371] The following conditions apply: R 6 cannot be (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl;

[0372] or an oxide of the compound, a pharmaceutically acceptable salt of the compound or its oxide, or an individual enantiomer or diastereomer thereof.

[0373] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is selected from any one of the following:

[0374]

[0375]

[0376]

[0377] or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0378] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a GlyT1 inhibitor having the formula (ORG-24598) or (LY-2365109), or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0379] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula IX,

[0380]

[0381] in:

[0382] R 1 represents phenyl or a 5-membered 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 R 3 replace;

[0383] R 2 represents an aryl group, a 5-membered or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the monocyclic or bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the aryl or heteroaryl group is optionally replaced by one or more R 4 replace;

[0384] R 3 Halogen, C 1-4 -alkyl or C 3-6 -cycloalkyl, wherein the C 1-4 -alkyl or the C 3-6 - cycloalkyl is optionally substituted by one or more halogens; and

[0385] R 4 It is halogen, -CN, C 1-4 -alkyl, C 3-6 -cycloalkyl, -C1-3 -alkyl, -C 3-6 -cycloalkyl or -OC 1-6 Alkyl, wherein the C 1-4 -alkyl, C 3-6 -cycloalkyl, -C 1-3 -alkyl, -C 3-6 -cycloalkyl or -OC 1-6 - alkyl is optionally substituted with one or more halogens;

[0386] or a pharmaceutically acceptable salt of the compound or a tautomer or stereoisomer of the compound or its pharmaceutically acceptable salt, or a mixture of any of the foregoing.

[0387] In certain embodiments, the compound of Formula IX can be represented by a compound of Formula IX(a): or a pharmaceutically acceptable salt thereof or a tautomer of the compound or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0388] In certain embodiments, the compound of Formula IX can be represented by a compound of Formula IX(b): or a pharmaceutically acceptable salt thereof or a tautomer of the compound or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0389] In certain embodiments, the compound of Formula IX is a compound selected from any one of the following, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula X,

[0412]

[0413] in:

[0414] R 1 Selected from:

[0415] 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,

[0416] b) a 5- or 6-membered monocyclic partially saturated heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from O, N and S(O)r, and

[0417] c) having 1, 2 or 3 independently selected from O, N and S(O) r A 9-membered or 10-membered bicyclic heteroaryl group having a heteroatom

[0418] Where r is 0, 1 or 2;

[0419] wherein the groups a), b) and c) are each optionally substituted by one or more substituents independently selected from the following: 1-4 -alkyl-, C 1-4 -alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3-6 -cycloalkyl- and C 3-6-cycloalkyl-O-, and in the case where a substituent is attached to a nitrogen ring atom, the substituent is selected from C 1-4 -alkyl-, C 1-4 -alkyl-CO-, C 3-6 -cycloalkyl- and C 3-6 -cycloalkyl-CO-,

[0420] And wherein the C 1-4 -alkyl-, C 1-4 -alkyl-O-, C 1-4 -alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 3-6 -cycloalkyl-, C 3-6 -cycloalkyl-CO- or C 3-6 -cycloalkyl-O-substituents may each be substituted with one or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F, and -CN;

[0421] R 2 Selected from hydrogen, C 1-4 -alkyl-, C 1-4 -alkyl-O-, -CN and C 3-6 -cycloalkyl-,

[0422] Wherein C 1-4 -alkyl-, C 1-4 -alkyl-O- and C 3-6 -cycloalkyl- each may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F and -CN;

[0423] R 3 Selected from C 1-6 -alkyl-O-, C 3-6 -cycloalkyl-O-, morpholino, pyrazolyl and 4- to 7-membered monocyclic heterocycloalkyl-O- having 1 oxygen atom as a ring member and optionally 1 or 2 independently selected from O, N and S(O) s heteroatom, wherein s=0, 1 or 2,

[0424] Wherein C 1-6 -alkyl-O- and the C 3-6 -cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluorine, -CF3, -CHF2, -CH2F, -CN, C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -alkyl-O- and C 3-6 -cycloalkyl-O-;

[0425] R 4 It is hydrogen;

[0426] or R 3 and R 4 Together with the ring atoms of the phenyl group to which they are attached, they can form a 4-, 5- or 6-membered monocyclic partially saturated heterocycloalkyl or heteroaryl group, each of which has 1, 2 or 3 independently selected from O, N and S(O) s wherein s=0, 1 or 2, of which in the general formula (I) there must be 1 directly attached to R 3 a ring oxygen atom of a ring carbon atom of the phenyl group to which it is attached;

[0427] wherein the heterocycloalkyl group may be optionally substituted by 1, 2, 3 or more substituents independently selected from the following: fluorine, -CF3, -CHF2, -CH2F, -CN, C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -alkyl-O-, C 3-6 -cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, and tetrahydropyranyl-O-;

[0428] R 5 It is hydrogen;

[0429] R 6 Selected from hydrogen, C 1-4 -alkyl-SO2-, C 3-6 -cycloalkyl-SO2 and -CN;

[0430] R 7 It is hydrogen;

[0431] or a) R 6 and R 7 or b) R 6 and R 5 One of the pairs together with the ring atoms of the phenyl to which they are attached forms a ring having 1, 2 or 3 atoms independently selected from O, N and S(O) u 5-membered or 6-membered partially saturated monocyclic heterocycloalkyl containing 1, 2, 3, 4, 5-membered or 6-membered heteroatom, wherein u=0, 1 or 2, wherein in the general formula (I) there must be 1 directly attached to R 6 a -SO2- member of a ring carbon atom of the phenyl group to which it is attached;

[0432] wherein the heterocycloalkyl group may be optionally substituted by 1, 2, 3 or more substituents independently selected from the following: fluorine, -CF3, -CHF2, -CH2F, -CN, C 1-4 -alkyl-, C 1-6 -alkyl-O- and C 3-6 -cycloalkyl-O-

[0433] or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0434] In certain embodiments, the compound of Formula X is a compound selected from any one of the following, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445] For example, the compound of formula X may be a diastereomeric mixture or a single diastereoisomer of any of the following, or a pharmaceutically acceptable salt thereof:

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460] In certain embodiments, the compound of formula X is a compound having the formula A compound or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is a compound of formula XI,

[0462]

[0463] in:

[0464] R 1 Is halogen, -OR 1′ 、-SR 1″ , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or a 5-membered or 6-membered heteroaryl containing one, two or three heteroatoms selected from oxygen, sulfur and nitrogen;

[0465] R 1′ and R 1″ are independently hydrogen, lower alkyl, lower alkyl substituted with halogen, -(CH2) x -cycloalkyl or -(CH2) x - aryl;

[0466] R 2 is -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN;

[0467] is an aromatic bicyclic amine or partially aromatic bicyclic amine having one or two additional N atoms, selected from

[0468]

[0469]

[0470] and wherein one additional N ring atom of the aromatic bicyclic amine or part of the aromatic bicyclic amine may be in the form of an oxide exists in the form of;

[0471] R3 to R10 are each independently hydrogen, hydroxy, halogen, ═O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO2, NH2, aryl, 5-membered or 6-membered heteroaryl containing one, two or three heteroatoms selected from oxygen, sulfur and nitrogen, -NH-lower alkyl, -N(lower alkyl)2, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)2-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-( -C(O)-lower alkyl, -O(CH2)y-lower alkoxy, -O(CH2)yC(O)N(lower alkyl), -C(O)-lower alkyl, -O-(CH2)x-aryl, -O-(CH2)x-cycloalkyl, -O-(CH2)x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl), 2-oxo-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl;

[0472] R, R', R" and R'" are each independently hydrogen or lower alkyl; or

[0473] R' and R'" in group e) together with -(CH2)4- form a six-membered ring;

[0474] and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5-membered or 6-membered heteroaryl groups as defined for R1, R1′, R1″ and R3 to R10 are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, ═O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen and lower alkoxy;

[0475] n, m, o, p, q, r, s and t are each independently 1 or 2;

[0476] x is 0, 1, or 2; and

[0477] y is 1 or 2;

[0478] or a pharmaceutically acceptable salt of the compound.

[0479] In certain embodiments, the compound of Formula XI or a pharmaceutically acceptable salt thereof is a compound of Formula XI(a), or a pharmaceutically acceptable salt thereof; a compound of formula XI(b), or a pharmaceutically acceptable salt thereof; a compound of formula XI(c), or a pharmaceutically acceptable salt thereof; a compound of formula XI(d), or a pharmaceutically acceptable salt thereof; a compound of formula XI(e), or a pharmaceutically acceptable salt thereof; a compound of formula XI(f), or a pharmaceutically acceptable salt thereof; a compound of formula XI(g), or a pharmaceutically acceptable salt thereof; or a compound of formula XI(h), or a pharmaceutically acceptable salt thereof.

[0480] In certain embodiments, the compound of Formula XI is a compound selected from any one of the following, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

[0481]

[0482]

[0483]

[0484] In certain methods and uses disclosed herein, the subject is a subject in need. In some embodiments of the uses and methods as 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 glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a prodrug of a pharmaceutically acceptable salt thereof.

[0485] In some embodiments, the compound or its pharmaceutically acceptable salt, solvate or prodrug is selected from the compounds as described herein. Any compound provided herein can be prepared as a pharmaceutically acceptable salt, solvate or prodrug and / or prepared as part of a pharmaceutical composition described in a patent or patent application publication cited herein.

[0486] Although the compounds described herein can be shown as having specific stereochemistry around certain atoms, such as cis or trans, the compounds can also be prepared in the opposite orientation or as racemic mixtures. Such isomers or racemic mixtures are included in the present disclosure. In addition, although the compounds are collectively shown in the table, any compound or its pharmaceutically acceptable salt, solvate or prodrug can be selected from the table and used in the embodiments provided herein.

[0487] The compounds described herein can be prepared according to the methods described in the patents or patent application publications cited herein.

[0488] The compounds can be used to inhibit the GlyT1 transporter. Thus, in some embodiments, the compounds can be referred to as GlyT1 transporter inhibiting compounds or GlyT1 inhibitors.

[0489] The compounds described herein can be administered in any conventional manner by any route that makes them active. Administration can be systemic, topical or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual or ocular, or intravaginal, by inhalation, by reservoir injection, or by implant. The mode of administration can depend on the condition or disease to be targeted or treated. The choice of a specific route of administration can be selected or adjusted by a clinician according to methods known to clinicians to obtain a desired clinical response.

[0490] In some embodiments, it may be desirable to administer one or more compounds or pharmaceutically acceptable salts, solvates or prodrugs thereof topically to the area in need of treatment. This can be achieved, for example but not limited to, by local infusion during surgery, topical application (e.g., in conjunction with a wound dressing after surgery), by injection, by means of a catheter, by means of a suppository, or by means of an implant, wherein the implant is a porous, non-porous or gel-like material, including a membrane, such as a silicone rubber membrane or fiber.

[0491] The compounds described herein can be administered alone or in combination (simultaneously or continuously) with other drugs. For example, the compounds can be administered in combination with other drugs used to treat hepatic porphyria, etc. Examples of other drugs or medicaments are known to those skilled in the art and include, but are not limited to, those described herein.

[0492] Means and methods of administration are known in the art, and the skilled artisan can consult various pharmacology references for guidance (see, e.g., Modern Pharmaceutics, Banker and Rhodes, Marcel Dekker, Inc. (1979); and Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980)).

[0493] The amount of the compound to be administered is a therapeutically effective amount. The dosage to be administered will depend on the characteristics of the subject being treated, such as the specific animal being treated, age, body weight, health status, the type (if any) of simultaneous treatment and the frequency of treatment, and can be easily determined by those skilled in the art (e.g., clinicians). The standard dose of protamine can be used and adjusted (i.e., increase or decrease) according to the above factors. The selection of a specific dosage regimen can be selected or adjusted or titrated by a clinician according to methods known to clinicians to obtain the desired clinical response.

[0494] The amount of the compound described herein for effectively treating and / or preventing a particular disease, illness or disorder will depend on the nature and degree of the disease, illness or disorder, and can be determined by standard clinical techniques. In addition, in vitro or in vivo determinations can be optionally used to help identify the optimal dose range. The exact dosage to be used in the composition will also depend on the severity of the route of administration and the disorder, and should be determined according to the judgment of the practitioner and the situation of each patient. However, the suitable dosage range for oral administration is generally about 0.001 milligram to about 200 milligrams / kg body weight, about 0.01 milligram to about 100 milligrams / kg body weight, about 0.01 milligram to about 70 milligrams / kg body weight, about 0.1 milligram to about 50 milligrams / kg body weight, 0.5 milligram to about 20 milligrams / kg body weight or about 1 milligram to about 10 milligrams / kg body weight. In some embodiments, the oral dose is about 5 milligrams / kg body weight.

[0495] In some embodiments, the suitable dosage for intravenous (iv) use is about 0.01mg to about 500mg / kg body weight, about 0.1mg to about 100mg / kg body weight, about 1mg to about 50mg / kg body weight or about 10mg to about 35mg / kg body weight. Suitable dosage ranges for other modes of administration can be calculated based on the above-mentioned dosages known to those skilled in the art. For example, the scope of the recommended dose for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration or inhalation administration is about 0.001mg to about 200mg / kg body weight, about 0.01mg to about 100mg / kg body weight, about 0.1mg to about 50mg / kg body weight or about 1mg to about 20mg / kg body weight. Effective dose can be extrapolated from the dose-response curve derived from in vitro or animal model test system. Such animal models and systems are well known in the art.

[0496] In certain embodiments, the glycine transporter inhibitor to be administered is a GlyT1 inhibitor, such as a GlyT1 inhibitor as disclosed herein. In some embodiments, the suitable dosage range of the GlyT1 inhibitor is about 5 mg / day to 200 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 5 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 10 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 15 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 20 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 25 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 30 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 35 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 40 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 45 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 50 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 55 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 60 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 65 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 70 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 75 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 80 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 85 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 90 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 95 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 100 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 105 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 110 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 115 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 120 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 125 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 130 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 135 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 140 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 145 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 150 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 155 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 160 mg / day.In some embodiments, the GlyT1 inhibitor is administered at 165 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 170 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 175 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 180 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 185 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 190 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 195 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 200 mg / day.

[0497] In certain embodiments, the glycine transporter inhibitor to be administered is a GlyT1 inhibitor, such as Bitopertin, a pharmaceutically acceptable salt thereof, or a prodrug of Bitopertin or a pharmaceutically acceptable salt thereof. In some embodiments, the GlyT1 inhibitor is Bitopertin. In some embodiments, a suitable dosage range of Bitopertin is about 5 mg / day to 200 mg / day. In some embodiments, Bitopertin is administered at 5 mg / day. In some embodiments, Bitopertin is administered at 10 mg / day. In some embodiments, Bitopertin is administered at 15 mg / day. In some embodiments, Bitopertin is administered at 20 mg / day. In some embodiments, Bitopertin is administered at 25 mg / day. In some embodiments, Bitopertin is administered at 30 mg / day. In some embodiments, Bitopertin is administered at 35 mg / day. In some embodiments, Bitopertin is administered at 40 mg / day. In some embodiments, Bitopertin is administered at 45 mg / day. In some embodiments, Bitopertin is administered at 50 mg / day. In some embodiments, Bitopertin is administered at 55 mg / day. In some embodiments, Bitopertin is administered at 60 mg / day. In some embodiments, Bitopertin is administered at 65 mg / day. In some embodiments, Bitopertin is administered at 70 mg / day. In some embodiments, Bitopertin is administered at 75 mg / day. In some embodiments, Bitopertin is administered at 80 mg / day. In some embodiments, Bitopertin is administered at 85 mg / day. In some embodiments, Bitopertin is administered at 90 mg / day. In some embodiments, Bitopertin is administered at 95 mg / day. In some embodiments, Bitopertin is administered at 100 mg / day. In some embodiments, Bitopertin is administered at 105 mg / day. In some embodiments, Bitopertin is administered at 110 mg / day. In some embodiments, Bitopertin is administered at 115 mg / day. In some embodiments, Bitopertin is administered at 120 mg / day. In some embodiments, Bitopertin is administered at 125 mg / day. In some embodiments, Bitopertin is administered at 130 mg / day. In some embodiments, Bitopertin is administered at 135 mg / day. In some embodiments, Bitopertin is administered at 140 mg / day. In some embodiments, Bitopertin is administered at 145 mg / day. In some embodiments, Bitopertin is administered at 150 mg / day. In some embodiments, Bitopertin is administered at 155 mg / day. In some embodiments, Bitopertin is administered at 160 mg / day. In some embodiments, Bitopertin is administered at 165 mg / day. In some embodiments, Bitopertin is administered at 170 mg / day. In some embodiments, Bitopertin is administered at 175 mg / day.In some embodiments, bitopertin is administered at 180 mg / day. In some embodiments, bitopertin is administered at 185 mg / day. In some embodiments, bitopertin is administered at 190 mg / day. In some embodiments, bitopertin is administered at 195 mg / day. In some embodiments, bitopertin is administered at 200 mg / day.

[0498] The compounds described herein can be formulated for parenteral administration by injection, such as by push injection or continuous infusion. In some embodiments, the compound can be administered by subcutaneous continuous infusion within a time period of about 15 minutes to about 24 hours. Injectable preparations can be presented in unit dosage form, such as in ampoules or multi-dose containers, and are optionally added with preservatives. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and can contain formulations such as suspending agents, stabilizers and / or dispersants. In some embodiments, injectables are short-acting, depots or implants and pellets for subcutaneous or intramuscular injection. In some embodiments, parenteral dosage forms are in the form of solutions, suspensions, emulsions or dry powders.

[0499] For oral administration, the compounds described herein can be formulated by combining the compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds to be formulated into tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, cachets, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, etc., for oral ingestion by patients to be treated. Pharmaceutical preparations for oral use can be obtained by, for example, adding solid excipients, optionally grinding the resulting mixture, and, if necessary, processing the granular mixture after adding suitable adjuvants to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers, such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations, such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0500] Orally administered compositions may contain one or more optional agents, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, wintergreen oil or cherry; coloring agents; and preservatives to provide pharmaceutically palatable preparations. In addition, in the case of tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. Selectively permeable membranes surrounding osmotically active driving compounds are also suitable for orally administered compounds. Oral compositions may contain standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are suitably pharmaceutical grade.

[0501] The dragee core may have a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coating for identification or characterization of different combinations of active compound dosages.

[0502] Pharmaceutical preparations that can be used orally include, but are not limited to, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate and, optionally, a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or a liquid polyethylene glycol. In addition, a stabilizer may be added.

[0503] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0504] For administration by inhalation, the compounds described herein can be delivered in the form of an aerosol spray from a pressurized pack 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 can be determined by providing a valve to deliver a metered amount. Capsules and cartridges such as gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0505] The compounds described herein may also be formulated into rectal compositions such as suppositories or retention enemas, such as containing conventional suppository bases 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.

[0506] In transdermal administration, the compound can be applied to a plaster, or can be applied through a transdermal therapeutic system and then provided to the organism. In some embodiments, the compound is present in a cream, solution, powder, fluid emulsion, fluid suspension, semisolid, ointment, paste, gel, jelly and foam, or in a patch containing any of them.

[0507] Compounds described herein can also be formulated into depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months or longer. Therefore, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or formulated into a slightly soluble derivative (e.g., formulated into a slightly soluble salt).

[0508] In some embodiments, the compound can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J. Med., 1989, 321, 574). In some embodiments, polymeric materials may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, a controlled release system can be placed near a target of the compounds described herein, such as the liver, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138 (1984)). Other controlled release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533 can be used.

[0509] It is also known in the art that the compound can be included in such a formulation together with a pharmaceutically acceptable diluent, filler, disintegrant, binder, lubricant, surfactant, hydrophobic carrier, water-soluble carrier, emulsifier, buffer, wetting agent, moisturizer, solubilizer, preservative, etc. The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In some embodiments, the compounds described herein may be used together with a medicament, including, but not limited to, an external analgesic (e.g., lidocaine), a barrier device (e.g., GelClair), or an irrigant (e.g., Caphosol).

[0510] In some embodiments, the compounds described herein can be delivered in vesicles, particularly liposomes (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, supra, pp. 317-327; see generally supra).

[0511] Suitable compositions include, but are not limited to, oral non-absorbable compositions. Suitable compositions also include, but are not limited to, saline, water, cyclodextrin solutions, and buffer solutions of pH 3-9.

[0512] The compounds described herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, 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 excipient is selected from propylene glycol, purified water, and glycerol.

[0513] In some embodiments, the formulation can be lyophilized to a solid and reconstituted with, for example, water, prior to use.

[0514] When administered to mammals (eg, to animals for veterinary use or to humans for clinical use), the compound can be administered in isolated form.

[0515] When applied to humans, the compound can be sterile. When the compound of formula I-VIII is administered intravenously, water is a suitable carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talcum powder, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, etc. If necessary, the composition of the present invention can also contain a small amount of wetting agent or emulsifier or pH buffer.

[0516] The compositions described herein can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, aerosols, sprays, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A.R. Gennaro (ed.) Mack Publishing Co.

[0517] In some embodiments, the compound is formulated into a pharmaceutical composition suitable for administration to a human being according to conventional procedures. Typically, the compound is a solution in a sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent. The composition for intravenous administration may optionally include a local anesthetic such as lidocaine to relieve pain at the injection site. Typically, the components are separated or mixed together to provide in a unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate in an airtight sealed container, the airtight sealed container being, for example, an ampoule or a small sachet indicating the amount of the active agent. When the compound is administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the components may be mixed before administration.

[0518] The pharmaceutical composition may be in unit dosage form. In this form, the composition is divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, cachet, or tablet itself, or it may be the appropriate number of any of these packaged forms.

[0519] 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 the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

[0520] In some embodiments, the composition is in the form of a solid product. For example, in some embodiments, the ocular composition is a solid product that can be inserted into a suitable position in the eye (such as between the eye and the eyelid or in the conjunctival sac), and the ocular composition releases the active agent at the suitable position, as described below: for example, U.S. Patent No. 3,863,633; U.S. Patent No. 3,867,519; U.S. Patent No. 3,868,445; U.S. Patent No. 3,960,150; U.S. Patent No. 3,963,025; U.S. Patent No. 4,186,184; U.S. Patent No. 4,303,637; U.S. Patent No. 5,443,505; and U.S. Patent No. 5,869,079. Usually released from such a product to the cornea via tears soaking the corneal surface, or directly released to the cornea itself, the solid product is usually in close contact with the cornea. Solid products suitable for implantation in the eye in this way are usually mainly composed of polymers and can be bioerodible or non-bioerodible. Bioerodible polymers that can be used to prepare ocular implants carrying one or more compounds include, but are not limited to, aliphatic polyesters such as polymers and copolymers of poly(glycolide), poly(lactide), poly(ε-caprolactone), poly(hydroxybutyrate), and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates, and polyether lactones. Suitable non-bioerodible polymers include silicone elastomers.

[0521] 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, cetyltrimethylammonium bromide, and cetylpyridinium chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben and their salts; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDTA; and sorbic acid and its salts.

[0522] Optionally, one or more stabilizers may be included in the composition to enhance chemical stability when needed. Suitable stabilizers include, but are not limited to, chelating agents or complexing agents, such as calcium complexing agent ethylenediaminetetraacetic acid (EDTA). For example, an appropriate amount of EDTA or its salt, such as disodium salt, may be included in the composition to complex excessive calcium ions and prevent gel formation during storage. The appropriate amount of EDTA or its salt may be about 0.01% to about 0.5%. In those embodiments containing a preservative other than EDTA, EDTA or its salt, more particularly disodium EDTA, may be present in an amount of about 0.025 % by weight to about 0.1 % by weight.

[0523] One or more antioxidants may also be included in the composition. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium pyrosulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, or other agents known to those skilled in the art. Such preservatives are typically used at a level of about 0.001% by weight to about 1.0% by weight.

[0524] In some embodiments, the compound is at least partially solubilized by an acceptable solubilizing agent. Certain acceptable nonionic surfactants (e.g., polysorbate 80) can be used as solubilizing agents, as can ophthalmologically acceptable glycols, polyglycols (e.g., polyethylene glycol 400 (PEG-400)) and glycol ethers.

[0525] Solubilizers suitable for solutions and solution / suspension compositions are cyclodextrins. Suitable cyclodextrins can be selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alkylcyclodextrin (e.g., methyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin, diethyl-beta-cyclodextrin), hydroxyalkylcyclodextrin (e.g., hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin), carboxyl-alkylcyclodextrin (e.g., carboxymethyl-beta-cyclodextrin), sulfoalkyl ether cyclodextrin (e.g., sulfobutyl ether-beta-cyclodextrin), etc. The ophthalmic application of cyclodextrins is reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.

[0526] 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 (e.g., hydroxypropyl methylcellulose), and water-insoluble polymers such as cross-linked carboxyl-containing polymers.

[0527] The composition may include 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(hydroxymethylaminomethane); and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0528] One or more acceptable salts, solvates or prodrugs can be included in the composition in an amount required to bring the osmolality of the composition to an acceptable range. 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, salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In some embodiments, the salt is sodium chloride.

[0529] Optionally, one or more acceptable surfactants, such as but not limited to nonionic surfactants or cosolvents, may be included in the composition to improve the solubility of the composition components or to impart physical stability, or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10, octoxynol 40; polysorbates 20, 60 and 80; polyoxyethylene / polyoxypropylene surfactants (e.g., F-68, F84 and P-103); cyclodextrin; or other agents known to those skilled in the art. Typically, these co-solvents or surfactants are used in the composition in an amount of about 0.01% to about 2% by weight.

[0530] In some embodiments, a pharmaceutical package or kit is provided, comprising one or more containers filled with one or more compounds described herein. Optionally associated with one or more such containers may be instructions in a form prescribed by a government agency that manages the manufacture, use or sale of drugs or biological products, the instructions reflecting the manufacture, use or sales agency approved 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 comprises a compound described herein in a single injectable dosage form, such as a single dose in an injectable device (such as a syringe with a needle).

[0531] In some embodiments, the method comprises administering to a subject one or more compounds described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is a subject in need of such treatment. As described herein, in some embodiments, the subject is a mammal, such as, but not limited to, a human.

[0532] In some embodiments, one or more of the above compounds, or pharmaceutically acceptable salts, solvates or prodrugs thereof, or pharmaceutical compositions comprising one or more of the above compounds are provided for use in the manufacture of a medicament for treating and / or preventing a subject's hepatic porphyria or a method of treating a syndrome associated therewith, including but not limited to the conditions described herein, such as those described herein. In some embodiments, the subject is a subject in need thereof.

[0533] This embodiment also provides one or more of the above compounds or their pharmaceutically acceptable salts, solvates or prodrugs or pharmaceutical compositions comprising one or more of the above compounds for use in inhibiting the GlyT1 transporter (such as the presence on the cell surface). In some embodiments, the compound, its pharmaceutically acceptable salt or its pharmaceutical composition inhibits the internalization, transport and / or degradation of the GlyT1 transporter.

[0534] As used herein, "inhibition" may refer to the inhibition of a specific activity. The activity of the GlyT1 transporter may be measured by any method known in the art, including but not limited to the methods described herein.

[0535] The compounds described herein are inhibitors of the GlyT1 transporter.The ability of a compound to inhibit the activity of the GlyT1 transporter can be measured using any assay known in the art.

[0536] Generally, assays for testing compounds that inhibit GlyT1 transporter activity include determining any parameter that is indirectly or directly affected by the GlyT1 transporter, such as a functional, physical or chemical effect.

[0537] The sample or determination comprising the GlyT1 transporter treated with a potential inhibitor is compared with a control sample without an inhibitor to check the degree of inhibition. The control sample (not treated with an inhibitor) is assigned a relative GlyT1 transporter activity value of 100%. When the GlyT1 transporter activity value relative to the control is about 80%, 50% or 25%, the inhibition of the GlyT1 transporter is achieved.

[0538] The binding of the ligand to the GlyT1 transporter can be tested in various forms. The binding can be carried out in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer or in a vesicle. For example, in a determination, the binding of a natural ligand to its transporter is measured in the presence of a candidate modulator (compound as described herein). Alternatively, the binding of a candidate modulator can be measured in the presence of a natural ligand. Typically, a competitive assay is used, which measures the ability of a compound to compete with a natural ligand for binding to a transporter. Binding can be tested by measuring, for example, changes in spectral characteristics (e.g., fluorescence, absorbance, refractive index), changes in fluid dynamics (e.g., shape) or changes in chromatograms or solubility characteristics.

[0539] After the transporter is expressed in the cell, the cell can be grown in a suitable culture medium in a suitable cell plate. The cell can be, for example, plated in a 384-well plate with 5000-10000 cells / well. In some embodiments, the cell is plated with about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 cells / well. The plate can have any number of holes, and the number of cells can be changed accordingly.

[0540] Any agent having utility in the uses described herein can be used for co-treatment, co-administration or co-formulation with the compositions described above. Thus, the compounds described herein can be administered before, simultaneously with or after such therapeutic agents are administered to the subject.

[0541] Additional agents may be administered in co-therapy (including co-formulation) with one or more of the compounds described herein.

[0542] In some embodiments, the response of the disease or disorder to treatment is monitored, and if necessary, the treatment regimen is adjusted based on such monitoring.

[0543] The frequency of administration is typically such that the dosing interval, e.g., the time period between one dosing and the next dosing during waking hours, is about 1 to about 24 hours, about 2 to about 12 hours, about 3 to about 8 hours, or about 4 to about 6 hours. In some embodiments, the dose is administered 1, 2, 3, or 4 times per day. It will be appreciated by those skilled in the art that the appropriate dosing interval depends, to some extent, on the ability of the selected composition to maintain a concentration of one or more compounds (e.g., above the EC 50 (the minimum compound concentration that inhibits transporter activity by 90%) for a period of time. Ideally, concentrations above the EC are maintained for at least 100% of the dosing interval. 50 When this is not achievable, the desired concentration should be maintained above the EC for at least about 60% of the dosing interval. 50, or should be maintained above the EC for at least about 40% of the dosing interval 50 .

[0544] How to use

[0545] The present application provides a method for preventing or treating hepatic porphyria in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as a GlyT1 inhibitor as disclosed herein. For example, the present application provides a method for preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject bitopertin, or a pharmaceutically acceptable salt thereof or a prodrug of bitoperetin or a pharmaceutically acceptable salt thereof.

[0546] In part, the present disclosure relates to a method for treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.

[0547] In some embodiments, hepatic porphyria is acute hepatic porphyria. In some embodiments, hepatic porphyria is non-acute hepatic porphyria. In some embodiments, hepatic porphyria is acute intermittent porphyria (AIP). In some embodiments, hepatic porphyria is ALA dehydratase porphyria (ADP). In some embodiments, hepatic porphyria is indeterminate porphyria (VP). In some embodiments, hepatic porphyria is hereditary coproporphyria (HCP). In some embodiments, hepatic porphyria is Harder porphyria. In some embodiments, hepatic porphyria is porphyria cutanea tarda (PCT). In some embodiments, PCT is familial or sporadic PCT. In some embodiments, hepatic porphyria is hepatoerythropoietic porphyria (HEP).

[0548] The terms "subject", "individual" or "patient" are interchangeable throughout the specification and refer to humans or non-human animals. 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 certain embodiments, the patient, subject or individual is a human.

[0549] The present application provides a method for preventing, treating hepatic porphyria or reducing the rate of progression and / or severity of hepatic porphyria, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof or prodrugs 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 as disclosed herein. In certain embodiments above, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. For example, the present application provides a method for preventing, treating hepatic porphyria of a subject or reducing the rate of progression and / or severity of hepatic porphyria of a subject, 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.

[0550] The application further provides one or more glycine transporter inhibitors or their pharmaceutically acceptable salts or the one or more glycine transporter inhibitors or their pharmaceutically acceptable salts The use of a prodrug of the preparation for treating hepatic porphyria in a subject. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors as disclosed herein. In certain such embodiments, the GlyT1 inhibitor is Bitopertin or its pharmaceutically acceptable salt or a prodrug of Bitopertin or its pharmaceutically acceptable salt. In certain of the foregoing embodiments, the preparation is administered in a therapeutically effective amount.

[0551] Hepatic porphyria

[0552] Porphyrias include eight inherited metabolic disorders of heme biosynthesis, in which various enzymes in the complex heme biosynthetic pathway are destroyed. Porphyrias are widely classified as acute and non-acute porphyrias or hepatic and erythropoietic porphyrias based on their clinical manifestations. Acute hepatic porphyrias include acute intermittent porphyria (AIP), variable porphyria (VP), hereditary coproporphyria (HCP) and aminolevulinic acid dehydratase deficiency porphyria (ADP), and usually cause severe abdominal, mental, neurological or cardiovascular symptoms. AIP, HCP and VP are autosomal dominant porphyrias, and ADP is an autosomal recessive porphyria. In rare cases, AIP, HCP and VP appear in homozygous dominant form. Porphyria cutanea tarda (PCT) is a non-acute hepatic porphyria in which patients typically present with vesicles, bullae, milia, and hirsutism on the cheeks, temporal area, and eyebrows. In addition, there is a rare homozygous recessive form of PCT called hepatoerythropoietic porphyria (HEP). The clinical and laboratory features of these porphyrias are described in Table 1 below.

[0553] Table 1: Symptoms and diagnostic strategies for hepatic porphyria and lead poisoning

[0554]

[0555] NV: cerebrospinal sympathetic nervous system symptoms; C: skin symptoms; A: anemia; LD: liver damage; 1 Clinical features variables at presentation; ALA: 5-aminolevulinic acid; Copro: coproporphyrin; PBG: porphobilinogen; Uro: uroporphyrin; Hepta: heptacarboxyporphyrin; Proto: protoporphyrin; Isocopro: isocoproporphyrin;

[0556] Porphyria is a class of hereditary or acquired disorders caused by the lack of activity of specific enzymes in the heme biosynthetic pathway (also referred to herein as the porphyrin pathway). Porphyrin is the main precursor of heme. Porphyrins and porphyrin precursors include 5-aminolevulinic acid (ALA), porphobilinogen (PBG), hydroxymethylbilin (HMB), uroporphyrinogen I or III, coproporphyrinogen I or III, protoporphyrinogen IX and protoporphyrin IX. Heme is an essential part of hemoglobin, myoglobin, catalase, peroxidase and cytochrome, the latter including respiratory cytochromes and P450 liver cytochromes. Heme is synthesized in most or all human cells. About 85% of heme is produced in erythroid cells, mainly for hemoglobin. Most of the remaining heme is produced in the liver, of which 80% is used to synthesize cytochromes. Deficiencies in specific enzymes in the porphyrin pathway result in insufficient heme production and also in the accumulation of porphyrin precursors and / or porphyrins, which at high concentrations can be toxic to cellular or organ function.

[0557] Porphyria can be classified by the main part of excessive production and accumulation of porphyrin or its precursor. In hepatic porphyria, porphyrin and porphyrin precursor are mainly excessively produced in liver, and in erythropoietic porphyria, porphyrin is excessively produced in erythroid cells in bone. Acute or hepatic porphyria causes dysfunction and neurological manifestation of nervous system, and it may affect both central and peripheral nervous system, causes for example as following symptom: pain (for example, abdominal pain and / or chronic neuropathic pain), vomiting, neuropathy (for example, acute neuropathy progressive neuropathy), muscle weakness, epilepsy, mental disorder (for example, hallucination, depression anxiety, paranoia), arrhythmia, tachycardia, constipation and diarrhea. Skin or erythropoietic porphyria mainly affect skin, cause such as light sensitive symptom, described symptom can be pain, blister, necrosis, itching, swelling and hair growth increase on the area such as forehead. Subsequent infection of the skin lesions may result in bone and tissue loss, as well as scarring, disfigurement, and digital (eg, finger, toe) loss.Most porphyrias are caused by mutations in enzymes encoded in the heme biosynthetic pathway.

[0558] Not all porphyrias are hereditary. For example, a patient with liver disease may develop porphyria due to liver dysfunction. A patient with PCT may have deficient uroporphyrinogen decarboxylase (URO-D) due to the formation of an ORO-D enzyme with lower than normal enzymatic activity.

[0559] Acute intermittent porphyria (AIP), also known as porphobilinogen (PBG) deaminase deficiency or hydroxymethylbilin synthase (HMBS) deficiency, is the most common type of acute hepatic porphyria. Other types of acute hepatic porphyria include hereditary coproporphyria (HCP), variable porphyria (VP), and ALA dehydratase deficiency porphyria (ADP). Non-acute hepatic porphyrias include porphyria cutanea tarda (PCT), a disease in which patients usually present with blisters, bullae, milia, and hirsutism on the cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT, called hepatoerythropoietic porphyria (HEP). The clinical and laboratory features of these porphyrias are described in Table 1.

[0560] AIP has been found to have a prevalence of up to 1 / 10,000 in certain populations (e.g., in northern Sweden). In the general population of the United States and Europe (excluding the United Kingdom), the prevalence of mutations is estimated to be about 1 / 10,000 to 1 / 20,000. Only about 10%-15% of individuals carrying mutations known to be associated with AIP show clinical disease. However, in individuals with certain mutations (e.g., W198X mutations), the penetrance is as high as 40%. Before puberty, AIP is typically latent. Symptoms are more common in women than in men. Due to the incomplete penetrance and long-term latency of the disease, its prevalence may be underestimated. In the United States, it is estimated that approximately 2,000 patients have suffered at least one attack. It is estimated that there are approximately 150 active recurrences in France, Sweden, the United Kingdom, and Poland; these patients are mainly young women with a median age of 30 years.

[0561] AIP affects, for example, the visceral, peripheral, autonomic, and central nervous systems. Symptoms of AIP are variable and include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, intestinal obstruction), urinary symptoms (dysuria, urinary retention / incontinence, or dark urine), neurological symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting cranial nerves and / or causing weakness in the arms or legs), seizures, neuropathic pain (e.g., pain associated with a progressive neuropathy, such as chronic neuropathic pain), neuropsychiatric symptoms (e.g., confusion, anxiety, agitation, hallucinations, hysteria, delirium, apathy, depression, panic disorder, psychosis, insomnia, drowsiness, coma), autonomic nervous system involvement (causing, for example, cardiovascular Symptoms (such as tachycardia, hypertension and / or arrhythmia) and other symptoms, such as increased circulating catecholamine levels, sweating, restlessness and / or tremor), dehydration and electrolyte abnormalities. The most common symptoms are abdominal pain and tachycardia. In addition, patients often suffer from chronic neuropathic pain and develop progressive neuropathy. Patients with recurrent attacks usually have prodromal symptoms. Permanent paralysis may occur after a severe attack. Recovery from a severe attack that is not treated in time may take weeks or months. Acute attacks can be fatal, such as respiratory muscle paralysis or cardiovascular failure due to electrolyte imbalance. Before hemin treatment was available, up to 20% of AIP patients died from the disease.

[0562] The risk of hepatocellular carcinoma is increased in individuals who carry the AIP gene. The risk of hepatocellular carcinoma is particularly severe in those with recurrent episodes: after age 50, the risk is almost 100 times that of the general population.

[0563] Acute porphyria attacks may be triggered by endogenous or exogenous factors. The mechanism by which such factors induce attacks may include, for example, increased demand for hepatic P450 enzymes and / or induction of ALAS1 activity in the liver. Increased demand for hepatic P450 enzymes leads to a decrease in free heme in the liver, thereby inducing hepatic ALAS1 synthesis.

[0564] Predisposing factors include fasting (or other forms of reduced or inadequate caloric intake due to crash dieting, long-distance athletics, etc.), metabolic stress (e.g., infection, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), smoking, fat-soluble exogenous chemicals (including, for example, chemicals present in tobacco smoke, certain prescription drugs, organic solvents, antimicrobials, components of alcoholic beverages), endocrine factors (e.g., reproductive hormones (women may experience exacerbations during the premenstrual period), synthetic estrogens, progesterone, ovulation stimulants, and hormone replacement therapy).

[0565] Over 1000 drugs are contraindicated in acute hepatic porphyrias (e.g., AIP, HCP, ADP, and VP), including, for example, alcohol, barbiturates, carbamazepine, carisoprodol, clonazepam (high doses), danazol, diclofenac and possibly other NSAIDS, ergots, estrogens, ethclorvynol, doxepin, griseofulvin, mephenytoin, meprobamate (also known as mebutamate and tybutamate), metoprolol, metodopramide, phenytoin, primidone, progesterone and synthetic progestins, pyrazinamide, pyrazolones (aminopyrine and antipyrine), rifampin, succinimides (ethosuximide and methsuximide), sulfonamide antibiotics, and valproic acid.

[0566] Objective signs of AIP include urine discoloration (urine may appear red or reddish brown) and increased concentrations of PBG and ALA in the urine during acute attacks. Molecular genetic testing identifies mutations in the PBG deaminase (also known as HMBS) gene in more than 98% of affected individuals.

[0567] The differential diagnosis of porphyria can involve determining the type of porphyria by measuring individual levels of porphyrins or porphyrin precursors (e.g., ALA, PBG) in urine, feces, and / or plasma during an attack (e.g., by chromatography and fluorometry). The diagnosis of AIP can be confirmed by determining that erythrocyte PBG deaminase activity is 50% or less of normal levels. DNA testing for mutations can be performed on patients and at-risk family members. The diagnosis of AIP is typically confirmed by DNA testing to identify specific pathogenic gene mutations (e.g., HMBS mutations).

[0568] Treatment of acute attacks typically requires hospitalization to control and treat acute symptoms, including, for example, abdominal pain, seizures, dehydration / hyponatremia, nausea / vomiting, tachycardia / hypertension, urinary retention / ileus. For example, abdominal pain can be treated, for example, with narcotic analgesics, seizures can be treated with seizure prevention measures and possible medications (although many anti-seizure medications are contraindicated), nausea / vomiting can be treated, for example, with phenothiazines, and tachycardia / hypertension can be treated, for example, with beta blockers. Treatment may include discontinuation of unsafe medications, monitoring of respiratory function, and muscle strength and neurological status. Mild attacks (e.g., attacks without paresis or hyponatremia) can be treated with at least 300 g of intravenous 10% dextrose per day, although increasingly, hemin is provided immediately. Severe attacks should be treated as soon as possible with intravenous hemin (3-4 mg / kg daily for 4-14 days) and with intravenous glucose while waiting for the intravenous hemin to take effect. Typically, attacks are treated with IV hemin for 4 days and with IV glucose while awaiting administration of IV hemin.

[0569] Hemin ( or hemin for injection, formerly known as methemoglobin) is the only heme product approved for use in the United States and was the first drug approved under the Orphan Drug Act. It is hemin derived from processed red blood cells (PRBC) and is a protoporphyrin IX containing a ferric iron ion (heme B) and a chloride ligand. Heme acts to limit the synthesis of porphyrins by the liver and / or myeloid. The exact mechanism by which hemin produces symptomatic improvement in patients with acute hepatic porphyria has not been elucidated; however, its effect may be due to (feedback) inhibition of delta-aminolevulinic acid (ALA) synthase, which limits the rate of the porphyrin / heme biosynthetic pathway. Inhibition of ALA synthase should result in reduced production of ALA and PBG, as well as porphyrins and porphyrin intermediates.

[0570] Disadvantages of hemin include its delayed effect on clinical symptoms, and its inability to prevent recurrence of attacks. Adverse reactions associated with hemin administration may include thrombophlebitis, anticoagulation, thrombocytopenia, renal arrest, or iron overload, which is particularly likely in patients who require multiple courses of hemin treatment for recurrent attacks. Patients with recurrent attacks require indwelling intravenous catheters to prevent phlebitis. Infrequently reported side effects include fever, aches, fatigue, hemolysis, allergic reactions, and circulatory collapse.

[0571] Heme is difficult to prepare in a stable form for intravenous administration. It is insoluble at neutral pH, but can be prepared as heme hydroxide at pH 8 or higher. is a freeze-dried preparation of hemin. When freeze-dried hemin is dissolved for intravenous administration, degradation products are rapidly formed; these degradation products cause transient anticoagulation and phlebitis at the infusion site. Heme albumin and heme arginine salt (Normosang, the European form of hemin) are more stable and may potentially cause less thrombophlebitis. However, heme arginine salt is not approved for use in the United States. It can be administered by Dissolved in 30% human albumin rather than sterile water for steady infusion; however, since albumin is isolated from human blood, it increases the intravascular volume expansion effect and increases the cost of treatment as well as the risk of pathogens.

[0572] Successful treatment of acute attacks does not prevent or delay recurrences. There is a question whether hemin itself triggers recurrent attacks due to induction of heme oxygenase. Nevertheless, in some areas (particularly France), young women with multiple recurrent attacks are being treated with weekly hemin with the goal of prevention.

[0573] Givaudan A small interfering RNA (siRNA) against aminolevulinic acid synthase 1 is also used to treat patients with acute hepatic porphyria by using RNA interference to target and degrade ALAS1 mRNA in hepatocytes. Risks associated with the use of Givosiran include allergic reactions, hepatotoxicity, and nephrotoxicity. For example, in Givosiran clinical trials, 15% of patients showed elevations in transaminases (ALT) up to 3 times the upper limit of normal. In addition, 15% of patients receiving Givosiran had kidney-related adverse reactions, including increased serum creatinine levels and decreased estimated glomerular filtration rate.

[0574] Limited experience with liver transplantation suggests that, if successful, it is an effective treatment for AIP. In Europe, approximately 12 human patients have been transplanted, with either curative or variable effects. Liver transplantation can restore normal excretion of ALA and PBG and prevent acute attacks. In addition, if a liver from a patient with AP is transplanted into another patient (a "domino transplant"), the recipient patient may develop AIP. Although orthotopic liver transplantation is curative, this procedure has significant morbidity and mortality, and the availability of liver donors is limited.

[0575] One of the long-term clinical effects of acute porphyria is chronic neuropathic pain, which may be caused by progressive neuropathy caused by, for example, the neurotoxic effects of elevated porphyrin precursors (e.g., ALA and / or PBG). Patients may suffer from neuropathic pain before or during an acute attack. Elderly patients may experience increased neuropathic pain as they age, and various narcotic drugs are often prescribed. In patients with acute hepatic porphyria, electromyographic abnormalities and shortened conduction times have been recorded. In patients with acute porphyria (e.g., ADP, AIP, HCP or VP), porphyrin precursor (ALA and PBG) levels are typically elevated between attacks in asymptomatic and symptomatic patients. Therefore, by reducing ALAS1 expression and / or activity levels to reduce porphyrin precursors and restore normal heme biosynthesis, it is expected that the development of chronic and progressive neuropathy can be prevented and / or minimized. Treatment, e.g., chronic treatment (e.g., regular treatment with an iRNA as described herein; e.g., treatment according to a dosing regimen as described herein; e.g., treatment once a week or once every two weeks) can provide a sustained reduction in ALAS1 expression in an acute porphyria patient with elevated levels of a porphyrin precursor, porphyrin, porphyrin product, or other metabolite. Such treatment can be provided as needed to prevent symptoms in an individual patient or to reduce the frequency or severity of symptoms in an individual patient (e.g., pain and / or neuropathy) and / or to reduce the level of a porphyrin precursor, porphyrin, porphyrin product, or metabolite.

[0576] There is a need to identify novel therapeutic agents that can be used to treat porphyria. As discussed above, existing treatments such as hemin, givosiran, and liver transplantation have many disadvantages. For example, the effect of hemin on clinical symptoms is delayed, it is expensive, and it may have side effects (e.g., thrombophlebitis, anticoagulation, thrombocytopenia, iron overload, renal arrest).

[0577] Treatment of hepatic porphyria

[0578] In some embodiments, the disclosure provides a method for preventing or treating hepatic porphyria in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as a GlyT1 inhibitor as disclosed herein.

[0579] In some embodiments, the subject suffers from or is at risk of suffering from a hepatic porphyria (e.g., AIP, HCP, VP, ADP, PCT, and HEP). In some embodiments, the hepatic porphyria is an acute hepatic porphyria (e.g., AIP, HCP, VP, and ADP). In some embodiments, the hepatic porphyria is a non-acute hepatic porphyria (e.g., PCT and HEP). In some embodiments, the hepatic porphyria is a dual hepatic porphyria, such as at least two hepatic porphyrias. In some embodiments, the dual hepatic porphyria comprises two or more hepatic porphyrias selected from the following: AIP, HCP, VP, ADP, PCT, and HEP.

[0580] In some embodiments, hepatic porphyria is caused by a heterozygous mutation that results in reduced enzyme activity. In some embodiments, hepatic porphyria is caused by a homozygous mutation that results in reduced enzyme activity. In some embodiments, hepatic porphyria is an autosomal recessive disease (e.g., ADP). In some embodiments, the subject carries a genetic change (e.g., mutation), but is otherwise asymptomatic.

[0581] Mutations associated with hepatic porphyria include mutations in genes encoding certain enzymes in the heme biosynthetic pathway (porphyrin pathway) or genes that alter gene expression in the heme biosynthetic pathway (e.g., ALAD, HMBS, UROD, UROS, CPOX, and PPOX). In many embodiments, the subject carries one or more mutations in enzymes of the porphyrin pathway (e.g., ALA dehydratase, PBG deaminase, uroporphyrinogen III synthase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase).

[0582] In some embodiments, patients with acute hepatic porphyria (e.g., AIP) or patients with mutations associated with acute hepatic porphyria (e.g., AIP) but asymptomatic have elevated ALA and / or PBG levels compared to healthy individuals. In such cases, ALA and / or PBG levels may also be elevated even when the patient has no episodes or has never had an episode. In some such cases, the patient is otherwise completely asymptomatic. In some such cases, the patient suffers from pain (e.g., neuropathic pain), which may be chronic pain (e.g., chronic neuropathic pain). In some cases, the patient suffers from neuropathy. In some cases, the patient suffers from progressive neuropathy.

[0583] In some embodiments, the subject suffers from an acute attack of hepatic porphyria. In some embodiments, the patient suffers from a non-acute attack of hepatic porphyria. In some embodiments, the subject has never experienced an acute attack of hepatic porphyria. In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject suffers from nerve damage. In some embodiments, the subject has EMG changes and / or changes in nerve conduction velocity. In some embodiments, the subject is asymptomatic. In some embodiments, the subject is at risk of suffering from hepatic porphyria (e.g., carrying a mutation associated with hepatic porphyria), and is asymptomatic. In some embodiments, the subject previously suffered from an acute attack of hepatic porphyria, but was asymptomatic during treatment.

[0584] In some embodiments, the subject is at risk of developing hepatic porphyria and is treated prophylactically to prevent the development of hepatic porphyria. In some embodiments, the subject has an elevated level of porphyrin or porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, prophylactic treatment begins during adolescence. In some embodiments, treatment reduces the level (e.g., plasma level or urine level) of porphyrin or porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, treatment prevents the development of elevated levels of porphyrin or porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, treatment prevents the development of symptoms (e.g., pain or nerve damage) associated with hepatic porphyria or reduces the frequency or severity of symptoms (e.g., pain or nerve damage) associated with hepatic porphyria.

[0585] In some embodiments, the subject treated according to the method suffers from pain, such as chronic pain. In some embodiments, the method is effective in treating the pain (e.g., by reducing the severity of the pain or curing the pain). In some embodiments, the method is effective in reducing or preventing nerve damage.

[0586] In some embodiments, the subject treated according to the methods described herein (a) has elevated levels of ALA and / or PBG, and (b) suffers from pain (e.g., chronic pain). In some embodiments, the methods are effective in reducing elevated ALA and / or PBG levels, and / or treating the pain (e.g., by reducing the severity of the pain or curing the pain).

[0587] In some embodiments, the subject is a subject who has suffered one or more acute attacks of one or more hepatic porphyrin symptoms. In other embodiments, the subject is a subject who has long suffered from one or more symptoms of hepatic porphyria (e.g., pain; e.g., neuropathic pain and / or neuropathy; e.g., progressive neuropathy). In some embodiments, the subject treated according to the methods described herein has recently experienced or is experiencing prodromal symptoms.

[0588] As used herein, "prodrome" includes any symptoms that an individual subject previously experienced immediately before an acute attack occurs. Typical symptoms of prodrome include, for example, abdominal pain, nausea, headache, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the subject experiences pain (e.g., abdominal pain and / or headache) during the prodrome. In some embodiments, the subject experiences nausea during the prodrome. In some embodiments, the subject experiences psychological symptoms (e.g., anxiety) during the prodrome. In some embodiments, the subject becomes restless and / or suffers from insomnia during the prodrome.

[0589] An acute "attack" of hepatic porphyria involves the onset of one or more symptoms of hepatic porphyria, typically in patients carrying a mutation associated with hepatic porphyria (eg, a mutation in a gene encoding an enzyme in the porphyrin pathway).

[0590] In some embodiments, the GlyT1 inhibitor is administered after an acute attack of hepatic porphyria. In some embodiments, the GlyT1 inhibitor is administered during an acute attack of hepatic porphyria. In some embodiments, the administration of the GlyT1 inhibitor effectively reduces the severity of the attack (e.g., by improving one or more signs or symptoms associated with the attack). In some embodiments, the administration of the GlyT1 inhibitor effectively shortens the duration of the attack. In some embodiments, the administration of the GlyT1 inhibitor effectively stops the attack. In some embodiments, the GlyT1 inhibitor is administered prophylactically to prevent acute attacks of hepatic porphyria. In some embodiments, prophylactic administration is performed before, during, or after exposure to or the occurrence of a predisposing factor. In some embodiments, the subject is at risk of developing porphyria.

[0591] As used herein, "predisposing factors" refer to endogenous or exogenous factors that may induce acute attacks of one or more symptoms associated with porphyria. Predisposing factors include fasting (or other forms of reduced or insufficient caloric intake caused by fast-acting diets, long-distance athletics, etc.), metabolic stress (e.g., infection, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), smoking, fat-soluble foreign chemicals (including, for example, chemicals present in tobacco smoke, certain prescription drugs, organic solvents, antimicrobials, components in alcoholic beverages), endocrine factors (e.g., reproductive hormones (women may experience aggravation during the premenstrual period), synthetic estrogens, progesterone, ovulation stimulants, and hormone replacement therapy) and lead. Other common predisposing factors include drugs and phenobarbital that induce cytochrome P450.

[0592] In some embodiments, the GlyT1 inhibitor is administered during the prodrome. In some embodiments, the prodrome is characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the GlyT1 inhibitor is administered during a specific phase of the menstrual cycle, such as during the luteal phase.

[0593] In some embodiments, the administration of a GlyT1 inhibitor is effective in preventing attacks (e.g., recurrent attacks associated with prodromal symptoms and / or predisposing factors (e.g., a specific phase of the menstrual cycle, such as the luteal phase)). In some embodiments, the administration of a GlyT1 inhibitor is effective in reducing the frequency of attacks. In some embodiments, the administration of a GlyT1 inhibitor is effective in reducing the severity of an attack (e.g., by improving one or more signs or symptoms associated with an attack). In some embodiments, the administration of a GlyT1 inhibitor is effective in shortening the duration of an attack. In some embodiments, the administration of a GlyT1 inhibitor is effective in stopping an attack.

[0594] In some embodiments, the administration of a GlyT1 inhibitor is effective to prevent pain (e.g., neuropathic pain) or reduce the frequency or severity of pain (e.g., neuropathic pain). In some embodiments, the administration of a GlyT1 inhibitor is effective to prevent neuropathy or reduce the frequency or severity of neuropathy. In some embodiments, the subject suffers from or is at risk of developing hepatic porphyria and suffers from pain (e.g., neuropathic pain, such as chronic neuropathic pain) or neuropathy (e.g., progressive neuropathy). In some embodiments, the subject has elevated levels of ALA and / or PBG and suffers from chronic pain.

[0595] The administration effect of GlyT1 inhibitor can be determined, for example, by comparing with appropriate controls. For example, the reduction of acute attack frequency, and the reduction of one or more porphyrins or porphyrin precursor levels can be determined as, for example, the frequency reduced in a group of patients suffering from AIP compared with an appropriate control group. A control group (for example, a group of similar individuals or the same group of individuals in a crossover design) can include, for example, an untreated population, a population treated with conventional treatments for hepatic porphyria (for example, conventional treatments for AIP can include glucose, hemin chloride or both); a population treated with placebo or GlyT1 inhibitor (optionally combined with one or more conventional treatments for hepatic porphyria (for example, glucose, such as intravenous glucose)).

[0596] As used herein, subjects "at risk" for developing hepatic porphyria include subjects with a family history of hepatic porphyria and / or a history of one or more recurrent or chronic hepatic porphyria symptoms, and / or subjects carrying genetic alterations (e.g., mutations) in genes encoding enzymes in the heme biosynthetic pathway, as well as subjects carrying genetic alterations (e.g., mutations) known to be associated with hepatic porphyria.

[0597] In some embodiments, the alteration (e.g., mutation) predisposes the individual to an acute attack (e.g., after exposure to a trigger (e.g., a drug, diet, or other trigger, such as disclosed herein). In some embodiments, the alteration (e.g., mutation) is associated with elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the alteration (e.g., mutation) is associated with chronic pain (e.g., chronic neuropathic pain) and / or neuropathy (e.g., progressive neuropathy). In some embodiments, the alteration (e.g., mutation) is associated with changes in EMG and / or nerve conduction velocity.

[0598] In some embodiments, the change is a mutation in a gene selected from: ALAD, HMBS, UROD, CPOX and PPOX. In some embodiments, the change is a change (e.g., mutation) in a gene encoding an enzyme in a heme biosynthetic pathway. In some embodiments, the subject has a genetic change, but does not suffer from acute attacks. In some embodiments, the subject has a mutation associated with AIP, HCP, VP, ADP, PCT or HEP.

[0599] In some embodiments, the hepatic porphyria is AIP. In some such embodiments, the subject has an alteration, such as at least one mutation, in PBGD (a gene encoding a PBG deaminase). Many PBGD mutations are known in the art. In some embodiments, the subject is heterozygous for a PBGD mutation. In other embodiments, the subject is homozygous for a PBGD mutation. A homozygous subject may carry two identical mutations or two different mutations in the PBGD gene. In some embodiments, the hepatic porphyria is HCP. In some embodiments, the subject has an alteration, such as at least one mutation, in CPOX (i.e., a gene encoding the enzyme coproporphyrinogen III oxidase). In some embodiments, the hepatic porphyria is VP. In some embodiments, the subject has an alteration, such as at least one mutation, in PPOX (i.e., a gene encoding protoporphyrinogen oxidase). In some embodiments, the hepatic porphyria is ADP (e.g., autosomal recessive ADP). In some embodiments, the subject has an alteration, such as at least one mutation, in ALAD (a gene encoding an ALA dehydratase). In some embodiments, the hepatic porphyria is PCT. In some embodiments, the subject has an alteration, such as at least one mutation, in UROD (a gene encoding uroporphyrinogen decarboxylase). In some embodiments, the hepatic porphyria is CEP. In some embodiments, the subject has an alteration, such as at least one mutation, in UROS (a gene encoding uroporphyrinogen III synthase).

[0600] In some embodiments, the increase in porphyrin precursor levels is due to lead poisoning. Lead poisoning inhibits the activity of each of the enzymes ALAD, CPOX, and FECH involved in heme biosynthesis. Patients with lead poisoning are often misdiagnosed as ADP or other acute porphyrias. In some embodiments, the ALAD enzyme activity of a subject suffering from lead poisoning is reduced. In some embodiments, the CPOX enzyme activity of a subject suffering from lead poisoning is reduced. In some embodiments, the FECH enzyme activity of a subject suffering from lead poisoning is reduced. In some embodiments, the lead level in the blood and / or urine of a subject suffering from lead poisoning is increased. In some embodiments, the ALA level of a subject suffering from lead poisoning is increased. In some embodiments, the levels of ALA and PBG of a subject suffering from lead poisoning are increased. In some embodiments, the ALA level of a subject suffering from lead poisoning is increased by at least 10 times compared to a reference value. In some embodiments, the ALA level of a subject suffering from lead poisoning is increased by at least 5 times compared to a reference value. In some embodiments, the disclosure relates to a method of treating lead poisoning in a subject, the method comprising administering to the 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, a chelating agent is further administered to the subject. In some embodiments, the chelating agent is 2,3-dimercaptosuccinic acid. In some embodiments, the chelating agent is calcium disodium ethylenediaminetetraacetate.

[0601] Porphyrins (e.g., 5-ALA, PBG, uroporphyrins and coproporphyrins) can be found in various biological samples including skin, urine, feces, blood plasma and red blood cells. In some embodiments, porphyrins can be extracted from biological samples (e.g., blood plasma) into a solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct inspection using long wavelength ultraviolet light (e.g., 400-420nm light). Porphyrins have a maximum absorption wavelength near 400-420nm, and their highest absorption peak appears at 415nm. The emission maximum of porphyrins is typically about 600nm, and varies slightly based on the type of porphyrin and the solvent used for analysis. In some embodiments, the diagnosis of hepatic porphyria can be performed using fluorescence analysis. In some embodiments, skin porphyrin levels can be measured by calculating the difference before and after the complete photobleaching of skin porphyrins using controlled illumination. See, e.g., Heerfordt IM. Br J Dermatol. 2016; 175(6): 1284-1289.

[0602] In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the plasma porphyrins of the subject fluoresce with a peak value of 634nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the plasma porphyrins of the subject fluoresce with a peak value of 626nm and 634nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the skin porphyrins of the subject fluoresce with a peak value of 632nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the skin porphyrins of the subject fluoresce with a peak value of 626nm and 634nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), the sample (e.g., plasma or skin) containing porphyrins or porphyrin precursors from the subject fluoresces with a peak value of 615nm and 620nm. In some embodiments, when irradiated with blue light (e.g., 400-420nm light), a sample (e.g., plasma or skin) containing porphyrin or porphyrin precursor from a subject fluoresces with a peak value between 624nm and 627nm. In some embodiments, a 405nm laser is used to excite the subject's plasma. In some embodiments, the subject has red fluorescent urine.

[0603] Heme and heme intermediates

[0604] Glycine is one of the key starting substrates for the synthesis of heme and globin. Therefore, the reduction in glycine levels due to GlyT1 inhibition may lead to reduced heme synthesis. In certain aspects, the present disclosure relates to a method for treating hepatic porphyria in a subject, 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 the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the heme level of the subject is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25% and 30%). In some embodiments, the present disclosure relates to a method for treating hepatic porphyria in a subject, wherein the heme level of the subject is reduced by no more than 15%. In some embodiments, the present disclosure relates to a method for treating hepatic porphyria in a subject, wherein the heme level of the subject is reduced by no more than 20%. In some embodiments, the present disclosure relates to a method for treating hepatic porphyria in a subject, wherein the heme level of the subject is reduced by no more than 25%. In some embodiments, the disclosure relates to a method for treating hepatic porphyria in a subject, wherein the subject's hemoglobin level is reduced by no more than 30%. In certain aspects, the disclosure relates to a method for treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or a prodrug of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the dosage of the pharmaceutical composition does not cause a significant reduction in hemoglobin levels.

[0605] In some embodiments, the synthesis of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, wherein the one or more heme intermediates are selected from 5-ALA, PBG, hydroxymethyl bilirubin, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isocoproporphyrin, porphobilinogen; and protoporphyrinogen IX. In some embodiments, the present disclosure relates to a method of inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in a subject, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject suffers from hepatic porphyria. In some embodiments, the present disclosure relates to a method of inhibiting the synthesis of coproporphyrin III 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, the present disclosure relates to a method of inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in a subject, 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, wherein the subject suffers from ALA dehydratase porphyria (ADP). In some embodiments, the present disclosure relates to a method of inhibiting the synthesis of porphobilinogen (PBG) 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, the present disclosure relates to a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) 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, the present disclosure relates to a method for inhibiting the synthesis of hydroxymethyl biline (HMB) 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, the present disclosure relates to a method for inhibiting the synthesis of uroporphyrin III 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, the present disclosure relates to a method for inhibiting the synthesis of heptacarboxyporphyrin 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, the disclosure relates to a method of inhibiting the synthesis of isocoproporphyrin 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, the synthesis of one or more heme intermediates (e.g., 5-ALA, coproporphyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxyl porphyrin, and isocoproporphyrin) is inhibited in a dose-dependent manner.

[0606] In some embodiments, one or more of the following heme intermediates (e.g., porphyrin precursors) are inhibited, wherein the one or more heme intermediates are selected from 5-ALA, PBG, hydroxymethylbilinin, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isocoproporphyrin, porphobilinogen; and protoporphyrinogen IX. In some embodiments, the accumulation of the one or more heme intermediates (e.g., 5-ALA, coproporphyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxyporphyrin, and isocoproporphyrin) is inhibited in a dose-dependent manner.

[0607] In some embodiments, the subject treated according to the methods described herein has an elevated level of porphyrin or porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, before administering the GlyT1 inhibitor, the subject's porphyrin precursor level is at least 10%, 20%, 30%, 40% or 50% higher than the porphyrin precursor level of a healthy subject. In some embodiments, the subject's porphyrin precursor level increases. In some embodiments, the porphyrin precursor is selected from 5-ALA, HMB, coproporphyrin III, ZPPIX, porphobilinogen, uroporphyrin III, heptacarboxyl porphyrin and isocoproporphyrin. In some embodiments, the subject's uroporphyrin III level increases (e.g., the uroporphyrin III level in urine increases). In some embodiments, the subject's 5-ALA level increases (e.g., the 5-ALA level in urine or plasma increases). In some embodiments, the subject's HMB level increases. In some embodiments, the subject's coproporphyrin III level increases (e.g., the coproporphyrin III level in urine and feces increases). In some embodiments, the subject's PBG level increases (e.g., the PBG level in urine increases). In some embodiments, the ratio of protoporphyrin to coproporphyrin in the feces of the subject increases. In some embodiments, the subject's heptacarboxyporphyrin level increases (e.g., the heptacarboxyporphyrin level in urine or feces increases). In some embodiments, the subject's isocoproporphyrin level increases (e.g., the isocoproporphyrin level in feces increases). In some embodiments, the ZPPIX level in the red blood cells of the subject increases.

[0608] The level of porphyrin or porphyrin precursor can be assessed using methods known in the art or methods described herein. In some embodiments, the level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in the subject is assessed based on the absolute level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in the sample from the subject. In some embodiments, the level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in the subject is assessed based on the relative level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in the sample from the subject. In some embodiments, the relative level is relative to the level of another protein or compound (e.g., the level of creatinine) in the sample from the subject. In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a fecal sample.

[0609] An elevated level of a porphyrin or porphyrin precursor (e.g., ALA and / or PBG) can be determined by showing that the subject's porphyrin or porphyrin precursor level (e.g., plasma or urine level of ALA and / or PBG) is greater than or greater than or equal to a reference value. A physician with expertise in treating porphyrias will be able to determine whether the level of a porphyrin or porphyrin precursor (e.g., ALA and / or PBG) is elevated, for example for the purpose of diagnosing hepatic porphyria or for determining whether a subject is at risk for developing a hepatic porphyria, such as a subject may be susceptible to acute attacks or conditions associated with porphyrias, such as, for example, chronic pain (e.g., neuropathic pain) and neuropathy (e.g., progressive neuropathy).

[0610] As used herein, "reference value" refers to a value from a subject when the subject is not in a disease state, or a value from a normal or healthy subject, or a value from a reference sample or population, e.g., a group of normal or healthy subjects (e.g., a group of subjects who do not carry a mutation associated with hepatic porphyria and / or a group of subjects who do not suffer from symptoms associated with hepatic porphyria).

[0611] In some embodiments, the reference value is the pre-disease level in the same individual. In some embodiments, the reference value is the level in a reference sample or a population. In some embodiments, the reference value is the mean or median in a reference sample or a population. In some embodiments, the reference value is a value that is two standard deviations higher than the mean value in a reference sample or a population. In some embodiments, the reference value is a value that is 2.5, 3, 3.5, 4, 4.5, or 5 standard deviations higher than the mean value in a reference sample or a population.

[0612] In some embodiments, the subject's plasma level or urine level of ALA or PBG is greater than a reference value. In some embodiments, where the subject has an elevated level of a porphyrin or porphyrin precursor (e.g., ALA and / or PBG), the subject's ALA and / or PBG level is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than the reference value. In some embodiments, the subject's porphyrin or porphyrin precursor (e.g., ALA and / or PBG) level is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the reference value.

[0613] In some embodiments, the reference value is an upper reference value limit. As used herein, "upper reference value limit" refers to the upper limit level of a 95% confidence interval of a reference sample or population (e.g., a group of normal (e.g., wild type) or healthy individuals, such as individuals who do not carry a genetic mutation associated with porphyria and / or individuals who do not suffer from hepatic porphyria). Therefore, the lower reference value limit refers to the lower limit level of the same 95% confidence interval.

[0614] In some embodiments, the subject has an elevated level (e.g., plasma level or urine level) of porphyrin or porphyrin precursor that is greater than or equal to 2, 3, 4, or 5 times of a reference value (e.g., an upper limit of a reference value). In some embodiments, the subject's urine level of porphyrin or porphyrin precursor is greater than 4 times of the upper limit of a reference value.

[0615] In some embodiments, the subject's urine level of PBG is greater than or equal to 1.4 mmol / mol creatinine. In some embodiments, the subject's urine level of PBG is greater than or equal to 4.8 mmol / mol creatinine. In certain embodiments, the subject's urine level of PBG is greater than or equal to about 3, 4, 5, 6, 7, or 8 mmol / mol creatinine.

[0616] In some embodiments, the reference value of plasma PBG is 0.12 μmol / L. In some embodiments, the subject's PBG level is greater than or equal to 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject's plasma PBG level is greater than or equal to 0.48 μmol / L.

[0617] In some embodiments, the reference value of urine PBG is 1.2 mmol / mol creatinine. In some embodiments, the reference value of urine PBG is 1.4 mmol / mol creatinine. In some embodiments, the subject's urine PBG level is greater than or greater than or equal to 1.0 mmol / mol creatinine, 1.2 mmol / mol creatinine, 2.4 mmol / mol creatinine, 3.6 mmol / mol creatinine, 4.8 mmol / mol creatinine, or 6.0 mmol / mol creatinine. In some embodiments, the subject's urine PBG level is greater than or greater than or equal to 4.8 mmol / mol creatinine.

[0618] In some embodiments, the reference value of plasma ALA is 0.12 μmol / L. In some embodiments, the subject's plasma ALA level is greater than or equal to 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject's plasma ALA level is greater than or equal to 0.48 μmol / L.

[0619] In some embodiments, the reference value of urine ALA is 3.1 mmol / mol creatinine. In some embodiments, the reference value of urine ALA is 6.3 mmol / mol creatinine. In some embodiments, the subject's urine ALA level is greater than or equal to 2.5 mmol / mol creatinine, 3.1 mmol / mol creatinine, 6.2 mmol / mol creatinine, 6.3 mmol / mol creatinine, 9.3 mmol / mol creatinine, 12.4 mmol / mol creatinine, or 15.5 mmol / mol creatinine.

[0620] In some embodiments, the reference value of urine uroporphyrin is less than 4.5 μmol / mol creatinine. In some embodiments, the subject's urine uroporphyrin level is greater than or equal to 4.5 μmol / mol creatinine, 9.0 μmol / mol creatinine, 13.5 μmol / mol creatinine, 18.0 μmol / mol creatinine, 22.5 μmol / mol creatinine, 27 μmol / mol creatinine or 31.5 μmol / mol creatinine.

[0621] In some embodiments, the reference value of urine coproporphyrin is less than 20.7 μmol / mol creatinine. In some embodiments, the urine coproporphyrin level of the subject is greater than or equal to 20.7 μmol / mol creatinine, 41.4 μmol / mol creatinine, 62.1 μmol / mol creatinine, 82.8 μmol / mol creatinine, 103.5 μmol / mol creatinine, 124.2 μmol / mol creatinine or 144.9 μmol / mol creatinine.

[0622] In some embodiments, the reference value of plasma porphyrin is 10nmol / L. In some embodiments, the plasma porphyrin level of the subject is greater than or greater than or equal to 10nmol / L. In some embodiments, the plasma porphyrin level of the subject is greater than or greater than or equal to 8, 10, 15, 20, 25, 30, 35, 40, 45 or 50nmol / L. In some embodiments, the plasma porphyrin level of the subject is greater than or greater than or equal to 40nmol / L.

[0623] In some embodiments, the reference value of urine porphyrin is 25 μmol / mol creatinine. In some embodiments, the reference value of urine porphyrin is less than 28.4 μmol / mol creatinine. In some embodiments, the urine porphyrin level of the subject is greater than or equal to 25 μmol / mol creatinine. In some embodiments, the urine porphyrin level of the subject is greater than or equal to 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80 μmol / mol creatinine.

[0624] In some embodiments, the subject has a level (eg, plasma level or urine level) of a porphyrin or porphyrin precursor that is greater than 99% of individuals in a sample of healthy individuals.

[0625] In some embodiments, the subject's level of ALA or PBG (eg, plasma level or urine level) is a level that is greater than two standard deviations above the mean level in a sample of healthy individuals.

[0626] In some embodiments, the subject's urine level of ALA is 1.6 times or more higher than the average level of a normal subject (e.g., a subject that does not carry a mutation associated with porphyria). In some embodiments, the subject's plasma level of ALA is 2 or 3 times higher than the average level of a normal subject. In some embodiments, the subject's urine level of PBG is four or more times higher than the average level of a normal subject. In some embodiments, the subject's plasma level of PBG is four or more times higher than the average level of a normal subject.

[0627] In certain embodiments, as described herein, administration of a GlyT1 inhibitor results in a reduction in the level of one or more porphyrins or porphyrin precursors (e.g., ALA and / or PBG). The reduction can be measured relative to any appropriate control or reference value. For example, a reduction in the level of one or more porphyrins or porphyrin precursors can be determined in an individual subject, such as a reduction of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the level before treatment (e.g., immediately before treatment). The reduction in the level of a porphyrin precursor, a porphyrin, or a porphyrin metabolite can be measured using any method known in the art.

[0628] In some embodiments, administration of a GlyT1 inhibitor is effective to reduce the level of ALA and / or PBG in a subject. The level of ALA or PBG in a subject can be assessed, for example, based on the absolute level of ALA or PBG in a sample from the subject, or based on the relative level of ALA or PBG in a sample from the subject (e.g., relative to another protein or compound, such as the level of creatinine). In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample.

[0629] In some embodiments, the method reduces the 5-ALA level of the subject. In some embodiments, the method reduces the 5-ALA level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the HMB level of the subject. In some embodiments, the method reduces the HMB level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the coproporphyrin III level of the subject. In some embodiments, the method reduces the subject's coproporphyrin III level by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's PBG level. In some embodiments, the method reduces the subject's PBG level by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's urinary porphyrin III level. In some embodiments, the method reduces the level of urinary porphyrin III in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in the subject. In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%). In some embodiments, the method reduces heptacarboxyporphyrin levels in the subject.In some embodiments, the method reduces the level of heptacarboxyporphyrin in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of isocoproporphyrin in a subject. In some embodiments, the method reduces the level of isocoproporphyrin in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of ZPPIX in a subject. In some embodiments, the method reduces the ZPPIX level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of a porphyrin or porphyrin precursor (e.g., ALA or PBG) in the subject to a normal level. In some embodiments, the normal level is a reference value for a porphyrin or porphyrin precursor as described herein (e.g., urine ALA levels <6.3 mmol / mol creatine and urine PBG levels <1.4 mmol / mol creatine).

[0630] Complications of hepatic porphyria

[0631] In certain aspects, the present disclosure relates to a method for preventing, treating or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, one or more complications of hepatic porphyria are selected from the group consisting of acute photosensitivity, skin photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte imbalance, nausea, vomiting, constipation, diarrhea, dysuria, intestinal obstruction, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, pain associated with neuropathy, muscle paralysis, quadriplegia, decreased respiration, respiratory arrest, hyponatremia, tachycardia, In some embodiments, the present invention provides a method for preventing one or more complications of hepatic porphyria, 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 a pharmaceutically acceptable salt thereof or a prodrug thereof. In some embodiments, the present disclosure contemplates a method for reducing the rate of progression of one or more complications of hepatic porphyria, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure contemplates a method for reducing the severity of one or more complications of hepatic porphyria, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.

[0632] The treatment methods provided herein can be used to improve one or more symptoms associated with hepatic porphyria or reduce the risk of developing a porphyria-related condition (e.g., neuropathy (e.g., progressive neuropathy), hepatocellular carcinoma). Symptoms associated with hepatic porphyria can include abdominal pain or cramps, headaches, effects caused by abnormalities of the nervous system, and light sensitivity, causing rashes, blisters, and scars on the skin (photodermatitis). In certain embodiments, the hepatic porphyria is AIP. Symptoms of AIP include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (dysuria, urinary retention / incontinence, or dark urine), neurologic symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting cranial nerves and / or causing weakness in the arms or legs), seizures, neuropathic pain, progressive neuropathy, headaches, neuropsychiatric symptoms (e.g., confusion, anxiety, agitation, hallucinations, hysteria, delirium, apathy, depression, panic disorder, psychosis, insomnia, lethargy, coma), autonomic nervous system involvement (leading to, for example, cardiovascular symptoms (such as tachycardia, hypertension, and / or arrhythmias) and other symptoms such as, for example, increased circulating catecholamine levels, sweating, restlessness, and / or tremor), dehydration, and electrolyte abnormalities.

[0633] In some embodiments, the GlyT1 inhibitor is administered with a treatment that can be used to alleviate one or more of the above symptoms (e.g., before, after, or simultaneously with the treatment). For example, abdominal pain can be treated, for example, with narcotic analgesics, epilepsy can be treated, for example, with anti-epileptic seizure drugs, nausea / vomiting can be treated, for example, with phenothiazines, and tachycardia / hypertension can be treated, for example, with beta blockers.

[0634] Photosensitization of porphyrins in certain hepatic porphyrias (e.g., VP, HCP, PCT, and HEP) can produce two distinct clinical syndromes: (1) acute photosensitivity to sun exposure with erythema and edema, and (2) a syndrome in which subepidermal bullae appear in sun-exposed areas of the skin. In certain aspects, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of a hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof or prodrugs of the one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the method increases the subject's pain-free light exposure. In some embodiments, the method increases the subject's pain-free light exposure by at least 10%, 20%, 30%, 40%, or 50% more than the pain-free light exposure prior to administration of the GlyT1 inhibitor. In some embodiments, the method reduces the subject's photosensitivity. In some embodiments, the method reduces the subject's photosensitivity by at least 10%, 20%, 30%, 40%, or 50% more than the photosensitivity prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a history of phototoxic reactions from hepatic porphyria. In some embodiments, the subject is an adult, child, infant, or pregnant woman.

[0635] EC50 and administration

[0636] 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 glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a prodrug of a pharmaceutically acceptable salt thereof, exhibits porphyrin precursor (e.g., 5-ALA or PBG) inhibition with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the present application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a pharmaceutically acceptable salt thereof; or a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a prodrug of a pharmaceutically acceptable salt thereof, exhibits porphyrin precursor (e.g., 5-ALA or PBG) inhibition with an EC50 of less than 100 nM. In certain embodiments of the present application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a pharmaceutically acceptable salt thereof; or a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor as disclosed herein) or a prodrug of a pharmaceutically acceptable salt thereof, exhibits porphyrin precursor (e.g., 5-ALA or PBG) inhibition, wherein the EC50 is less than 50 nM. In certain embodiments, the EC50 is measured in a flow cytometry assay. In certain embodiments, the EC50 is measured in an LC-MS / MS assay. In certain of the foregoing embodiments, the GlyT1 inhibitor is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof.

[0637] In certain embodiments, a GlyT1 inhibitor is administered to prevent recurrent attacks (e.g., cyclical attacks associated with a predisposing factor) or to reduce the severity or frequency of recurrent attacks (e.g., cyclical attacks associated with a predisposing factor). In some embodiments, the predisposing factor is the menstrual cycle. In some embodiments, a GlyT1 inhibitor is administered repeatedly (e.g., at regular intervals) to prevent recurrent attacks (e.g., cyclical attacks associated with a predisposing factor (e.g., a menstrual cycle, such as a specific phase of the menstrual cycle, such as the luteal phase)) or to reduce the severity or frequency of recurrent attacks (e.g., cyclical attacks associated with a predisposing factor (e.g., a menstrual cycle, such as a specific phase of the menstrual cycle, such as the luteal phase). In some embodiments, a GlyT1 inhibitor is administered during a specific phase of the menstrual cycle or based on the hormone levels of the patient being treated (e.g., based on the hormone levels associated with a specific phase of the menstrual cycle). In some embodiments, the GlyT1 inhibitor is administered on one or more specific days of the menstrual cycle, for example, on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, or day 28 (or a later day for subjects with longer menstrual cycles) of the menstrual cycle. In some embodiments, the GlyT1 inhibitor is administered during the luteal phase (e.g., one or more days between day 14-day 28 of the menstrual cycle (or a later day in subjects with a menstrual cycle longer than 28 days)). In some embodiments, the ovulation of the subject is assessed (e.g., using a blood or urine test that detects hormones associated with ovulation (e.g., LH)), and the GlyT1 inhibitor is administered at predetermined intervals after ovulation. In some embodiments, the GlyT1 inhibitor is administered immediately after ovulation. In some embodiments, the GlyT1 inhibitor is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 days after ovulation. Any of these schedules can be optionally repeated for one or more iterations. The number of iterations can depend on the achievement of a desired effect, such as the achievement of a therapeutic effect or a preventive effect, such as reducing or preventing one or more symptoms associated with hepatic porphyria to reduce the frequency of attacks associated with hepatic porphyria.

[0638] In some embodiments, an initial dose of a GlyT1 inhibitor is administered, and the level of ALA or PBG is tested, for example, 1-48 hours (e.g., 2, 4, 8, 12, or 24 hours) after the initial dose is administered. In some embodiments, if the level of ALA and / or PBG is reduced (e.g., a predetermined reduction is achieved, such as normalization) and / or if the symptoms associated with hepatic porphyria (e.g., pain) are improved (e.g., the patient is asymptomatic), no further dose is administered, and if the level of ALA and / or PBG is not reduced (e.g., a predetermined reduction has not yet been achieved, such as normalization), a further dose of the GlyT1 inhibitor is administered. In some embodiments, a further dose is administered 12, 24, 36, 48, 60, or 72 hours after the initial dose. In some embodiments, if the initial dose does not effectively reduce the level of ALA and / or PBG, the further dose is modified, such as increased to achieve the desired reduction (e.g., a predetermined reduction, such as normalization) of the ALA or PBG level.

[0639] In some embodiments, the predetermined reduction is a decrease of at least 10%, 20%, 30%, 40% or 50%. In some embodiments, the predetermined reduction is a reduction effective to prevent or improve symptoms (eg, pain, prodromal symptoms or recurrent attacks).

[0640] In some embodiments, the predetermined reduction is a reduction of at least 1, 2, 3, or more standard deviations, wherein the standard deviations are determined based on values ​​from a reference sample (eg, a reference sample as described herein).

[0641] In some embodiments, the predetermined reduction is a reduction in the level of a porphyrin or porphyrin precursor to a level less than a reference value (e.g., a reference value as described herein) or to a level less than or equal to a reference value (e.g., a reference value as described herein).

[0642] As used herein, "normalization" of ALA or PBG levels (or "normal" or "normalized" levels) refers to levels of ALA or PBG or both (e.g., urine and / or plasma levels) within the expected range for healthy individuals, asymptomatic individuals (e.g., individuals who do not experience pain and / or do not suffer from neuropathy), or individuals who do not have mutations associated with porphyria. For example, in some embodiments, the normalized level is within two standard deviations of the normal mean. In some embodiments, the normalized level is within the normal reference value limit, such as within the 95% confidence interval of an appropriate control sample (e.g., a sample of a healthy individual or an individual who does not carry a genetic mutation associated with porphyria). In some embodiments, the subject's ALA and / or PBG levels (e.g., urine and / or plasma ALA and / or PBG levels) are monitored at intervals, and when the level increases above the reference value, a further dose of the GlyT1 inhibitor is administered.

[0643] Administration of a GlyT1 inhibitor can, for example, reduce the level of porphyrin or porphyrin precursor in a patient's cells, tissues, blood, urine or other compartment by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% or more. Administration of a GlyT1 inhibitor can also reduce porphyrin or porphyrin precursor levels during an acute attack of AIP.

[0644] Combination therapy

[0645] Optionally, the methods disclosed herein for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject may further comprise administering to the patient one or more supportive therapies or additional active agents for treating hepatic porphyria. For example, the patient may also be administered one or more supportive therapies or active agents selected from the group consisting of: avoiding sunlight, topical sunscreen, skin protection, UVB light therapy, afamelanotide, Bortezomib, heme infusion, adequate caloric support, givosiran, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of triggering factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes by viral vectors), hemodialysis, pharmacological chaperone therapy, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusions.

[0646] In some embodiments, a subject is administered a combination therapy, e.g., a GlyT1 inhibitor as described herein and one or more additional therapies known to be effective for hepatic porphyria (e.g., glucose and / or heme products such as hemin as described herein) or symptoms associated therewith.

[0647] In one embodiment, GlyT1 inhibitor as described herein is administered in combination with glucose or dextrose. For example, 10%-20% dextrose in normal saline can be provided intravenously. Typically, when glucose is administered, 10% glucose of at least 300g is administered intravenously daily. GlyT1 inhibitor can also be administered intravenously, as part of the same infusion for administering glucose or dextrose, or as a separate infusion administered before, simultaneously or afterwards administering glucose or dextrose. In some embodiments, GlyT1 inhibitor is administered via different routes of administration (e.g., subcutaneously). In yet another embodiment, GlyT1 inhibitor is administered in combination with total parenteral nutrition. GlyT1 inhibitor can be administered before, simultaneously or afterwards administering total parenteral nutrition.

[0648] In certain embodiments, the GlyT1 inhibitor is administered in combination with one or more additional treatments (e.g., another treatment known to be effective for treating porphyria or the symptoms of porphyria). In one embodiment, the GlyT1 inhibitor is administered in combination with a heme product (e.g., hemin, heme arginine salt, or heme albumin). In other embodiments, the GlyT1 inhibitor is administered in combination with a heme product and glucose, a heme product and dextrose, or a heme product and total parenteral nutrition. One or more additional treatments can be administered before, after, or simultaneously with the administration of the GlyT1 inhibitor. The GlyT1 inhibitor and additional therapeutic agents can be administered in combination (e.g., intravenously) in the same composition, or additional therapeutic agents can be administered as a part of a separate composition or by another method described herein. In some embodiments, as described herein, the subject has previously been treated with a heme product (e.g., hemin, heme arginine salt, or heme albumin).

[0649] In some embodiments, administration of a GlyT1 inhibitor or administration of a GlyT1 inhibitor in combination with one or more additional treatments (e.g., glucose, dextrose, etc.) reduces the frequency of acute attacks (e.g., by preventing acute attacks so that they no longer occur, or by reducing the number of attacks that occur within a certain period of time, such as fewer attacks per year). In some such embodiments, the GlyT1 inhibitor is administered according to a conventional dosing regimen, such as twice daily, once daily, once weekly, once every two weeks, or once monthly.

[0650] Example

[0651] Having now generally described the invention, the same will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain embodiments of the invention and are not intended to limit the invention.

[0652] Example 1: Synthesis of compounds

[0653] 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 synthesis schemes 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 synthesis schemes provided in U.S. Patent No. 8,124,639, the contents of which are incorporated herein by reference in their entirety.

[0654] Example 2: Expression of GlyT1 in hepatocytes

[0655] The liver is responsible for synthesizing 15%-20% of the heme in the human body, and therefore, enzymes of the heme synthesis pathway are generally expressed at high levels in the liver. Evaluation of GlyT1 expression in normal liver tends to show no expression of GlyT1, and therefore, it is generally believed that hepatocytes obtain glycine from internal metabolic sources and do not require an exogenous source of glycine that GlyT1 expression would provide. Nevertheless, Applicants evaluated the expression of GlyT1 in a variety of cell lines and surprisingly found significant GlyT1 expression in cell lines of liver origin. See Figure 1 This level is higher than that observed in the erythropoietic cell line K562. Same as above. GlyT1 is known to be an important source of glycine to support the induction of heme synthesis associated with erythroid maturation. These data indicate that GlyT1 may be transiently expressed in hepatocytes, potentially supporting elevated heme synthesis requirements, such as those characteristic of hepatic porphyria. Therefore, administration of GlyT1 inhibitors has the potential to treat hepatic porphyria.

[0656] Cells were cultured under the conditions described in Table 2 below, and GlyT1 mRNA levels were determined by standard methods.

[0657] Table 2: Cell lines and cell culture conditions

[0658]

[0659]

[0660] Applicants further evaluated GlyT1 expression as reported in the Cancer Cell Database and determined that GlyT1 was expressed in many of the 26 liver cancer cell lines analyzed. Figure 2 This data supports the initial conclusion that GlyT1 expression may be induced under certain conditions in normal hepatocytes. As positive controls, we noted that other components of the heme synthesis pathway were almost uniformly expressed in hepatoma cell lines. Same as above. A second glycine transporter, GlyT2, was not expressed in the liver cancer cell lines, suggesting that GlyT2 is unlikely to play a role in heme synthesis in the liver. Generally speaking, GlyT2 is thought to be restricted to neural tissue.

[0661] Example 3: Phenobarbital induces overexpression of ALAS1 and GlyT1 in HepG2 cells

[0662] Phenobarbital is used to activate the heme synthesis pathway and induce AIP symptoms in the AIP mouse model. Phenobarbital is known to stimulate the expression of ALAS1. The liver-derived cell line HepG2 was treated with phenobarbital for 24 and 48 hours. The expression of ALAS1 and GlyT1 was examined by qPCR. ALAS1( Figure 3A ) and GlyT1( Figure 3B ) mRNA increased 3-fold at 24 h after phenobarbital treatment and increased 6-fold at 48 h after phenobarbital treatment. The results suggest that GlyT1 overexpression induced by phenobarbital treatment may increase intracellular glycine levels and subsequent heme pathway intermediates, thereby contributing to phenobarbital-induced AIP symptoms.

[0663] Example 4: Effects of GlyT1 inhibitors on glycine uptake in liver cell lines.

[0664] HepG2 cells, a liver-derived cell line, were engineered to overexpress untagged GlyT1 ( Figure 4A ) or HA-Flag-tagged GlyT1( Figure 4B As described in Example 3, overexpression of GlyT1 was used to mimic the phenobarbital-induced AIP symptoms observed in HepG2. Overexpression of GlyT1 protein was confirmed by Western blot using HA-Flag-tagged constructs. Overexpression of untagged constructs was confirmed by qPCR. Cells were incubated at room temperature for 60 min in the presence of the GlyT1 inhibitor bitoperitone and then incubated with 20 nM glycine in the presence of 25 μM untagged glycine. 3H-labeled glycine was incubated for 60 min. Glycine uptake was measured by detecting the radioisotope level. In the presence of bitopertin, glycine uptake in engineered HepG2 cells was significantly reduced, with an IC50 range of 0.71 to 1.54 μM (Figure 4). The results suggest that GlyT1 inhibition reduces glycine uptake in liver cells, which can reduce intermediates in the heme synthesis pathway.

[0665] Example 5: Effect of GlyT1 inhibitor on 5-ALA and PBG in AIP cell model The impact of accumulation

[0666] The liver-derived cell line HepG2 was engineered to express shRNA against HMBS, a gene in the heme biosynthesis pathway whose loss-of-function mutations cause hepatic porphyria. The shRNA reduced HMBS mRNA by 50% and HMBS protein by 70%. Hepatic porphyria is a dormant disease that is activated by increased ALAS1 expression. To establish a cellular model that resembles the pathological state of hepatic porphyria, HMBS-knockdown HepG2 cells were also transduced by lentivirus to overexpress ALAS1 and GlyT1. By demonstrating that the toxic heme pathway metabolite 5-ALA ( Figure 5A ) and PBG( Figure 5B ), confirming that the genetically modified HepG2 cells mimic the pathological state of hepatic porphyria. The modified HepG2 cells treated with the GlyT1 inhibitor bitoperatin showed a significant reduction in the production of toxic metabolites.

[0667] Normal plasma glycine concentrations in adults range from 0.12 to 0.55 mM. To confirm that GlyT1 inhibitors such as bitopertin can reduce the production of toxic metabolites under physiological conditions, modified HepG2 cells were treated with bitopertin in the presence of different concentrations of glycine (0.1-1 mM). Bitopertin treatment showed that the toxic metabolite 5-ALA ( Fig. 6A ) and PBG( Figure 6B ) is consistently reduced.

[0668] Taken together, these data demonstrate that inhibition of glycine uptake suppresses the production of heme and its metabolic intermediates. Thus, GlyT1 inhibitors such as bitopertin may have utility in controlling the production of toxic metabolites in patients with hepatic porphyrias.

[0669] Incorporated by Reference

[0670] All publications and patents mentioned herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0671] Although specific embodiments of the subject matter have been discussed, the above description is illustrative rather than restrictive. Many variations will become clear to those skilled in the art upon reviewing this specification and the following claims. The full scope of the invention should be determined by reference to the full scope of the claims and their equivalents as well as the specification and such variations.

Claims

1. A method for treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more GlyT1 inhibitors or salts thereof.

2. A method for preventing, treating or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more GlyT1 inhibitors or their salts.

3. A method for preventing, treating or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof or prodrugs of the one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof.

4. The method of claim 3, wherein the one or more complications of hepatic porphyria are selected from the group consisting of acute photosensitivity, skin photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte imbalance, nausea, vomiting, constipation, diarrhea, dysuria, intestinal obstruction, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, pain associated with neuropathy, muscle paralysis, quadriplegia, respiratory depression, respiratory arrest, hyponatremia symptoms, tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive kidney injury, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, bullae, lesions, scars, deformities, nail loss, digital defects, cholestasis, cytolysis, cholelithiasis, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease.

5. The method according to any one of claims 1 to 4, wherein the hepatic porphyria is acute hepatic porphyria.

6. The method of claim 5, wherein the acute hepatic porphyria is acute intermittent porphyria (AIP).

7. The method of claim 5, wherein the acute hepatic porphyria is ALA dehydratase porphyria (ADP).

8. The method of claim 5, wherein the acute hepatic porphyria is porphyria vulgaris (VP).

9. The method of claim 5, wherein the acute hepatic porphyria is hereditary coproporphyria (HCP).

10. The method of claim 5, wherein the acute hepatic porphyria is Harder's porphyria.

11. The method according to any one of claims 1-4, wherein the hepatic porphyria is a non-acute hepatic porphyria.

12. The method of claim 11, wherein the non-acute hepatic porphyria is familial and sporadic porphyria cutanea tarda (PCT).

13. The method of claim 11, wherein the non-acute hepatic porphyria is hepatoerythropoietic porphyria (HEP).

14. The method of claim 4, wherein the acute photosensitivity is due to sun exposure.

15. The method of any one of claims 4, 13 or 14, wherein the method increases pain-free light exposure in the subject.

16. The method of any one of claims 1-15, wherein the method reduces photosensitivity in the subject.

17. A method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject suffers from hepatic porphyria.

18. A method of inhibiting coproporphyrin III 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.

19. A method of inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in a subject, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject suffers from ALA dehydratase porphyria (ADP).

20. A method of inhibiting porphobilinogen (PBG) 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.

21. A method of inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) 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.

22. A method of inhibiting the synthesis of hydroxymethylbendazole (HMB) 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.

23. A method of inhibiting uroporphyrin III 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.

24. A method of inhibiting heptacarboxyporphyrin 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.

25. A method of inhibiting isocoproporphyrin 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.

26. A method for inhibiting the synthesis of porphyrin or porphyrin precursor 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, wherein the porphyrin or porphyrin precursor is selected from: a.5-ALA b.PBG c. Hydroxymethylcholine d.ZPPIX e. Uroporphyrinogen I f. Uroporphyrinogen III g. Heptacarboxyporphyrinogen I h. Heptacarboxylporphyrinogen III i. Hexacarboxyporphyrinogen I j. Hexacarboxyporphyrinogen III k. Pentacarboxyporphyrinogen I 1. Pentacarboxyporphyrinogen III m. Coproporphyrinogen I n. Coproporphyrinogen III o. Isocoproporphyrin p. porphobilinogen; and q. Protoporphyrinogen IX.

27. The method of any one of claims 1-26, wherein the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from 5-ALA, coproporphyrin III, zinc protoporphyrin IX (ZPPIX), porphobilinogen, uroporphyrin III, heptacarboxyporphyrin, and isocoproporphyrin.

28. The method of any one of claims 1-26, wherein the accumulation of one or more heme intermediates is inhibited, and wherein the one or more heme intermediates are selected from: a.5-ALA b.PBG c. Hydroxymethylcholine d.ZPPIX e. Uroporphyrinogen I f. Uroporphyrinogen III g. Heptacarboxyporphyrinogen I h. Heptacarboxylporphyrinogen III i. Hexacarboxyporphyrinogen I j. Hexacarboxyporphyrinogen III k. Pentacarboxyporphyrinogen I 1. Pentacarboxyporphyrinogen III m. Coproporphyrinogen I n. Coproporphyrinogen III o. Isocoproporphyrin p. porphobilinogen; and q. Protoporphyrinogen IX.

29. The method of claim 27 or claim 28, wherein the accumulation of the one or more heme intermediates is inhibited in a dose-dependent manner.

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

31. The method of any preceding claim, wherein the GlyT1 inhibitor exhibits an EC50 of less than 100 nM.

32. The method of any one of claims 1-31, wherein the subject has or is at risk for developing hepatic porphyria and has pain (e.g., neuropathic pain, such as chronic neuropathic pain) or neuropathy (e.g., progressive neuropathy).

33. The method of any one of claims 1-32, wherein the subject has elevated levels of ALA and / or PBG and suffers from chronic pain.

34. The method of any one of claims 1-33, 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 5-ALA levels in healthy subjects.

35. The method of any one of claims 1-34, wherein prior to administration of the GlyT1 inhibitor, the subject's HMB levels are at least 10%, 20%, 30%, 40%, or 50% higher than HMB levels in healthy subjects.

36. The method of any one of claims 1-35, wherein prior to administration of the GlyT1 inhibitor, the subject's coproporphyrin III levels are at least 10%, 20%, 30%, 40% or 50% higher than the coproporphyrin III levels of healthy subjects.

37. The method of any one of claims 1-36, wherein prior to administration of the GlyT1 inhibitor, the subject's ZPPIX level is at least 10%, 20%, 30%, 40%, or 50% greater than the ZPPIX level of a healthy subject.

38. The method of any one of claims 1-37, wherein prior to administration of the GlyT1 inhibitor, the subject's porphobilinogen level is at least 10%, 20%, 30%, 40% or 50% higher than the porphobilinogen level of a healthy subject.

39. The method of any one of claims 1-38, wherein prior to administration of the GlyT1 inhibitor, the subject's urinary porphyrin III levels are at least 10%, 20%, 30%, 40% or 50% higher than those of healthy subjects.

40. The method of any one of claims 1-39, wherein prior to administration of the GlyT1 inhibitor, the subject's heptacarboxyporphyrin levels are at least 10%, 20%, 30%, 40% or 50% higher than the heptacarboxyporphyrin levels of healthy subjects.

41. The method of any one of claims 1-40, wherein prior to administration of the GlyT1 inhibitor, the subject's isocoproporphyrin levels are at least 10%, 20%, 30%, 40% or 50% higher than the isocoproporphyrin levels of healthy subjects.

42. The method of any one of claims 1-41, wherein during the treatment period, the subject's hemoglobin level is substantially maintained.

43. The method of any one of claims 1-41, wherein the treatment reduces the subject's hemoglobin levels by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%).

44. The method of any one of claims 1-41, wherein the dose of the pharmaceutical composition does not cause a significant decrease in hemoglobin levels.

45. The method of any one of claims 1-44, wherein the subject has increased levels of 5-ALA.

46. ​​The method of any one of claims 1-45, wherein the subject has increased levels of 5-ALA in the urine.

47. The method of any one of claims 1-46, wherein the subject has increased levels of 5-ALA in plasma.

48. The method of any one of claims 1-47, wherein the subject has increased levels of HMB.

49. The method of any one of claims 1-48, wherein the subject has increased coproporphyrin III levels.

50. The method of any one of claims 1-49, wherein the subject has increased levels of coproporphyrin III in the urine.

51. The method of any one of claims 1-50, wherein the subject has increased levels of coproporphyrin III in feces.

52. The method of any one of claims 1-51, wherein the subject has increased levels of porphobilinogen (PBG).

53. The method of any one of claims 1-52, wherein the subject has increased levels of porphobilinogen (PBG) in the urine.

54. The method of any one of claims 1-53, wherein the subject's plasma level or urine level of 5-ALA or PBG is greater than a reference value.

55. The method of claim 54, wherein the reference value is two standard deviations above the mean level in a sample of healthy individuals.

56. The method of any one of claims 1-55, wherein the subject's plasma level or urine level of 5-ALA or PBG is greater than or equal to 2, 3, 4, or 5 times the upper limit of a reference value.

57. The method of any one of claims 1-55, wherein the subject has a urine level of PBG greater than or equal to 4.8 mmol / mol creatinine.

58. The method of any one of claims 1-55, wherein the subject has a plasma PBG level greater than or equal to 0.12 μmol / L.

59. The method of any one of claims 1-55, wherein the subject has a urine PBG level greater than or equal to 1.2 mmol / mol creatinine.

60. The method of any one of claims 1-55, wherein the subject has a plasma 5-ALA level greater than or equal to 0.12 μmol / L.

61. The method of any one of claims 1-55, wherein the subject has a urine 5-ALA level greater than or equal to 3.1 mmol / mol creatinine.

62. The method of any one of claims 1-55, wherein the method reduces elevated 5-ALA and / or PBG levels.

63. The method of any one of claims 1-62, wherein the subject has increased urinary porphyrin III levels.

64. The method of any one of claims 1-63, wherein the subject has increased levels of uroporphyrin III in the urine.

65. The method of any one of claims 1-64, wherein the ratio of protoporphyrin to coproporphyrin in the feces of the subject is increased.

66. The method of any one of claims 1-65, wherein the subject has increased levels of heptacarboxyporphyrin.

67. The method of any one of claims 1-66, wherein the subject has increased levels of heptacarboxyporphyrin in the urine.

68. The method of any one of claims 1-67, wherein the subject has increased levels of heptacarboxyporphyrin in feces.

69. The method of any one of claims 1-68, wherein the subject has increased levels of isocoproporphyrin.

70. The method of any one of claims 1-69, wherein the subject has increased levels of isocoproporphyrin in feces.

71. The method of any one of claims 1-70, wherein the subject has increased levels of ZPPIX in red blood cells.

72. The method of any one of claims 1-71, wherein the method reduces 5-ALA levels in the subject.

73. The method of any one of claims 1-72, wherein the method reduces the subject's 5-ALA 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%).

74. The method of any one of claims 1-73, wherein the method reduces HMB levels in the subject.

75. The method of any one of claims 1-74, wherein the method reduces the subject's HMB 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%).

76. The method of any one of claims 1-75, wherein the method reduces the subject's coproporphyrin III level.

77. The method of any one of claims 1-76, wherein the method reduces the subject's coproporphyrin III 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%).

78. The method of any one of claims 1-77, wherein the method reduces PBG levels in the subject.

79. The method of any one of claims 1-78, wherein the method reduces the subject's PBG 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%).

80. The method of any one of claims 1-79, wherein the method is effective to reduce the level of 5-ALA and / or PBG.

81. The method of any one of claims 1-80, wherein the level of 5-ALA and / or PBG is reduced such that it is below a reference value.

82. The method according to claim 81, wherein the reference value is an upper reference value limit.

83. The method of any one of claims 1-82, wherein the method reduces the subject's urinary porphyrin III levels.

84. The method of any one of claims 1-83, wherein the method reduces the subject's urinary porphyrin III 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%).

85. according to the method described in any one of claims 1-84, wherein said method reduces the ratio of protoporphyrin to coproporphyrin in said experimenter.

86. The method of any one of claims 1-85, wherein the method reduces the ratio of protoporphyrin to coproporphyrin 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%).

87. The method of any one of claims 1-86, wherein the method reduces the subject's heptacarboxyporphyrin levels.

88. The method of any one of claims 1-87, wherein the method reduces the subject's heptacarboxyporphyrin 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%).

89. The method of any one of claims 1-88, wherein the method reduces isocoproporphyrin levels in the subject.

90. The method of any one of claims 1-89, wherein the method reduces the subject's isocoproporphyrin 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%).

91. The method of any one of claims 1-90, wherein the method reduces the level of ZPPIX in the subject.

92. The method of any one of claims 1-91, wherein the method reduces the subject's ZPPIX 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%).

93. The method of any one of claims 1-92, wherein the subject's plasma porphyrins fluoresce with a peak between 615 nm and 620 nm when illuminated with blue light (e.g., 400-420 nm light).

94. The method of any one of claims 1-92, wherein the subject's plasma porphyrins fluoresce with a peak between 624 nm and 627 nm when illuminated with blue light (e.g., 400-420 nm light).

95. The method of any one of claims 1-92, wherein the subject's skin porphyrins fluoresce with a peak between 615 nm and 620 nm when illuminated with blue light (e.g., 400-420 nm light).

96. The method of any one of claims 1-92, wherein the subject's skin porphyrins fluoresce with a peak between 624 nm and 627 nm when illuminated with blue light (e.g., 400-420 nm light).

97. The method of any one of claims 1-96, wherein the subject has a deficiency in an enzyme selected from: a.ALA dehydratase b.PBG deaminase c. Uroporphyrinogen III synthase d. Uroporphyrinogen decarboxylase e. coproporphyrinogen oxidase; and f. Protoporphyrinogen oxidase.

98. The method of any one of claims 1-97, wherein the subject has a mutation in a gene selected from: a.ALAD b.HMBS c.UROS d.UROD e. CPOX; and f.PPOX.

99. The method of any one of claims 1-98, wherein the GlyT1 inhibitor is administered after an acute attack.

100. The method of any one of claims 1-98, wherein the GlyT1 inhibitor is administered during an acute attack.

101. The method of any one of claims 1-98, wherein the GlyT1 inhibitor is administered during a prodromal period.

102. The method of claim 101, wherein the prodrome is characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness, and / or insomnia.

103. The method of any one of claims 1-98, wherein the GlyT1 inhibitor is administered prophylactically to prevent an acute attack of hepatic porphyria.

104. The method of any one of claims 1-98, wherein the GlyT1 inhibitor is administered during a specific phase of the menstrual cycle, such as during the luteal phase.

105. The method of any one of claims 1-98, wherein the GlyT1 inhibitor ameliorates or prevents cyclical attacks of hepatic porphyria.

106. The method of claim 105, wherein the periodic attacks are associated with a precipitating factor.

107. The method of claim 106, wherein the predisposing factor is a specific phase of the menstrual cycle, such as the luteal phase.

108. The method of claim 106, wherein the predisposing factor is the premenstrual period.

109. The method of claim 106, wherein the predisposing factor is exposure to a chemical.

110. The method of claim 106, wherein the predisposing factor is exposure to lead.

111. The method of claim 106, wherein the predisposing factor is selected from the group consisting of drugs, xenobiotics, steroid hormones, smoking, alcohol, reduced caloric or carbohydrate intake, fasting, metabolic stress, and psychological stress.

112. The method of any one of claims 1-111, wherein the method reduces pain or neuropathy.

113. The method of any one of claims 1-112, wherein the method prevents an acute attack of hepatic porphyria.

114. The method of any one of claims 1-113, wherein the method reduces or prevents nerve damage.

115. The method of any one of claims 1-114, wherein the GlyT1 inhibitor is administered prophylactically starting in adolescence.

116. The method of any one of claims 1-115, comprising further administering to the subject an additional active agent and / or supportive therapy.

117. The method of claim 116, wherein the additional active agent and / or supportive therapy is selected from the group consisting of: sun avoidance, topical sunscreen, skin protection, UVB phototherapy, afamelanotide Bortezomib, heme infusion, adequate caloric support, givosiran, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of triggering factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes by viral vectors), hemodialysis, pharmacological chaperone therapy, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusions.

118. The method according to any one of claims 1-117, wherein the GlyT1 inhibitor is a compound having the formula in: Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted aryl and the substituted heteroaryl are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR 7 R 8 、C(O)R 9 、SO2R 10 and -C(CH3)=NOR 7 , or is substituted by a 5-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N and O, the aromatic heterocyclic ring being optionally substituted by (C1-C6)-alkyl; R 1 is hydrogen or (C1-C6)-alkyl; R 2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C3-C7)-cycloalkyl, CH(CH3)-(C3-C7)-cycloalkyl, (CH2) n+1 -C(O)-R 9 、(CH2) n+1 -CN, bicyclo[2.2.1]heptyl, (CH2) n+1 -O-(C1-C6)-alkyl, (CH2) n -heterocycloalkyl, (CH2) n -aryl or (CH2) containing one, two or three heteroatoms selected from oxygen, sulfur or nitrogen n - 5- or 6-membered heteroaryl, wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy; R 3 , R 4 and R 6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl; R 5 NO2, CN, C(O)R 9 or SO2R 10 ; R 7 and R 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR 7 R 8 ; R 10 is (C1-C6)-alkyl, (CH2) optionally substituted by halogen n -(C3-C6)-cycloalkyl, (CH2) n -(C3-C6)-alkoxy, (CH2) n -heterocycloalkyl or NR 7 R 8 ; n is 0, 1, or 2; or a pharmaceutically acceptable salt of the compound or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

119. The method of claim 118, wherein the GlyT1 inhibitor is of the formula The compound is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

120. The method of any one of claims 1-119, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

121. The method of any one of claims 1-120, wherein the subject is a subject in need thereof.

122. The method of any one of claims 1-121, 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.

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