Glyt-1 inhibitors and uses thereof

Abstract

The present application relates to compounds of Formula (I) and pharmaceutical compositions / formulations thereof. The present application also relates to methods of treating or preventing blood disorders.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 538,539, filed September 15, 2023, and U.S. Provisional Patent Application No. 63 / 658,642, filed June 11, 2024, the entirety of which is incorporated herein by reference. Background Technology

[0003] There are two main types of glycine transporters (GlyTs): glycine transporter-1 (GlyT-1) and glycine transporter-2 (GlyT-2). GlyT-1 shows widespread distribution in the brain, erythrocytes, and peripheral tissues. In contrast, GlyT-2 is found primarily in the spinal cord and brainstem and is involved in the regulation of glycine. Glycine transporter-1 is the main source of glycine for heme biosynthesis in developing erythrocytes. Therefore, inhibition of glycine transporter-1 could potentially reduce heme synthesis, thus providing new therapeutic approaches for conditions where excessive heme, accumulation of toxic intermediates in heme biosynthesis, or pathological increases in erythropoiesis lead to disease. For example, inhibiting erythrocyte glycine uptake can reduce the accumulation of protoporphyrin IX (PPIX), an intermediate in heme biosynthesis that accumulates and causes disease in erythropoietic protoporphyria and X-linked protoporphyria. This application provides novel compounds that inhibit glycine transporter 1 and are suitable for treating various hematological conditions, particularly those caused by excessive heme, accumulation of toxic intermediates in heme biosynthesis, or pathological increases in erythropoiesis. Summary of the Invention

[0004] This application provides a formula (I) (I) A compound or a pharmaceutically acceptable salt thereof, wherein: A is an aryl or heteroaryl ring system, wherein the aryl or heteroaryl ring system is optionally composed of R 1 Substitution once or multiple times; B is a 4- to 8-membered non-aromatic carbide ring or a 4- to 8-membered non-aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic carbide ring or heterocycle is optionally replaced by R. 2 Replace once or multiple times; R 1 Each occurrence is independently selected from OH, halogen, -CF3, -OCF3, -OCH2F, -OCHF2, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -CN, =O, -C(O)H, -(CH2)n NR a R b -(CH2) n NR aa C(O)R bb -C(O)NR a R b -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl, -NR a R b -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-NR a R b -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic, wherein -C 1-8 Alkyl, -OC 1-8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups may optionally be selected independently each time they appear, from halogen, CN, -C 1-8 Alkyl, -C 1-8 alkyl heterocyclic group, -C 1-8 Alkyl heteroaryl, -OC 1-8 Alkyl, aryl, and monocyclic heteroaryl substituents are substituted 1 to 3 times; R 2 Each occurrence is independently selected from OH, halogen, -CF3, -OCF3, -OCH2F, -OCHF2, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -CN, =O, -C(O)H, -(CH2) n NR a R b -(CH2) n NR aa C(O)R bb -C(O)NR a R b -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8Alkyl, -NHC(O)OC 1-8 Alkyl, -NR a R b -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-NR a R b -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic, wherein -C 1-8 Alkyl, -OC 1-8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups may optionally be selected independently each time they appear, from halogen, CN, -C 1-8 Alkyl, -C 1-8 alkyl heterocyclic group, -C 1-8 Alkyl heteroaryl, -OC 1-8 Alkyl, aryl, and monocyclic heteroaryl substituents are substituted 1 to 3 times; R 3 Selected from OH, -C 1-8 Alkyl, -OC 1-8 Alkyl, -O aryl, -O heteroaryl and -OC 0-8 Alkyl C 3-8 cycloalkyl, wherein -C 1-8 Alkyl and -OC 1-8 Alkyl groups may optionally be selected independently each time they appear from halogens, haloalkyl groups (e.g., CH2F, CHF2, CF3), aryl groups, heterocyclic groups, and -C groups. 3-8 The cycloalkyl group is substituted 1 to 3 times; R 4 It is H; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form cycloalkyl or heterocyclic groups, wherein the cycloalkyl and heterocyclic groups may optionally be independently selected from CN, -C in each occurrence. 1-8 Alkyl, aryl, and heterocyclic substituents are substituted once or twice, wherein -C 1-8 Alkyl, aryl, and heterocyclic groups may optionally be substituted 1 to 3 times, each time independently selected from halogens; R 5 Selected from H, -OH, -C 1-8 Alkyl groups and NH2; R 6 Selected from -C 1-8 Alkyl, aryl, and heteroaryl, wherein -C 1-8 Alkyl, aryl, and heteroaryl groups may optionally be selected independently of deuterium, H, or -C each time they appear. 1-8 The alkyl group is substituted 1 to 3 times, wherein -C 1-8Alkyl groups may optionally be replaced by -CONH2, -S(O)2NH2, or -S(O)2-C. 1-8 Alkyl, aryl, or heterocyclic substitution; or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted heterocyclic groups; R 7 It is deuterium; R a Is it H or -C 1-8 Alkyl; R b Is it H or -C 1-8 Alkyl, wherein -C 1-8 Alkyl groups may optionally be replaced by -CONH2, -S(O)2NH2, or -S(O)2-C. 1-8 Alkyl, aryl, or heterocyclic substitution; or R a and R b Together with the nitrogen atom to which they are attached, they form an atom optionally selected independently each time from OH, =O, halogen, CF3, -OCF3, -OCH2F, -OCHF2, -C(O)H, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NR a R b -CN, -C(O)OC 1-8 Alkyl group, -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl group, -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, -S(O)2NR a R b aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups are substituented 1 to 3 times by non-aromatic heterocyclic groups; R aa Is it H or -C 1-8 Alkyl; R bb It is -C 1-8 Alkyl, -C 4-8 Cycloalkylmethyl or monocyclic nonaromatic heterocyclic group, wherein -C 1-8 Alkyl and -C 4-8The cycloalkylmethyl group may optionally be substituted with NH2, halogen or CN; n is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4, 5 or 6; k is 0, 1, 2, 3, 4, 5 or 6; and l is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0005] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, A is selected from phenyl, pyrimidine, pyridine, and thiazole, wherein the phenyl, pyrimidine, pyridine, and thiazole are optionally replaced by R. 1 Replace once or multiple times.

[0006] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is halogen.

[0007] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is optionally replaced by R. 2 Replace one or more 5-membered non-aromatic carbon rings. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, B is optionally replaced by R. 2 The 6-membered non-aromatic carbon ring is replaced once or multiple times. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, B is a 5-membered non-aromatic heterocycle containing an oxygen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replacement once or multiple times. In certain embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, B is a 5-membered non-aromatic heterocycle containing a sulfur atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 The substitution may be made once or multiple times. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a 5-membered non-aromatic heterocycle containing a nitrogen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replacement once or multiple times. In certain embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, B is a 6-membered non-aromatic heterocycle comprising a nitrogen atom and an oxygen atom, wherein said non-aromatic heterocycle is optionally replaced by R. 2 Replacement once or multiple times. In certain embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, B is a 6-membered non-aromatic heterocycle containing a nitrogen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 The substitution may be made once or multiple times. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a 6-membered non-aromatic heterocycle comprising two nitrogen atoms, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replace once or multiple times.

[0008] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2Independently selected from halogens, =O, -C 1-8 Alkyl, C(O)OC 1-8 Alkyl groups and -S(O)2-NR a R b .

[0009] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 It is optionally selected independently each time it appears from halogens, CH2F, CHF2, CF3, aryl, heterocyclic and -C. 3-8 The cycloalkyl substituents are substituted 1 to 3 times with -OC 1-8 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 3 -OC is optionally substituted 1 to 3 times by substituents selected independently from halogens each time it appears. 1-8 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 3 It is -OCH(CH3)CF3. In some such implementations, R 3 It has an (S) configuration. In other such embodiments, R 3 It has an (R) configuration.

[0010] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 4 It is H.

[0011] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 5 It is H.

[0012] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 6 It is C 1-8 alkyl.

[0013] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 6 It's me.

[0014] This application provides a compound selected from compounds 1-60 and their pharmaceutically acceptable salts. In some embodiments, the compound is compound (1) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (11) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (17) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (52) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (53) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (54) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (55) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (56) or its pharmaceutically acceptable salt. In some embodiments, the compound is compound (57) or its pharmaceutically acceptable salt.

[0015] This application provides a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

[0016] This application provides a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament, said pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

[0017] This application provides a method for treating a blood disorder in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0018] This application provides a method for treating porphyria in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0019] This application provides a method for treating hepatic porphyria in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0020] This application provides a method for treating one or more complications of hepatic porphyria in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, the one or more complications of hepatic porphyria are selected from: acute photosensitivity, skin photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte disturbances, nausea, vomiting, constipation, diarrhea, dysuria, intestinal obstruction, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, seizures, neuropathic pain, muscle paralysis, quadriplegia, decreased respiration, respiratory arrest, hyponatremia, cardiac arrest. Tachycardia, hypertension, tachycardia, elevated 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 keratosis, bullae, lesions, scars, deformities, nail loss, finger / toe defects, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease.

[0021] In some embodiments of the foregoing methods for treating hepatic porphyria or one or more complications of hepatic porphyria, hepatic porphyria is acute hepatic porphyria, acute intermittent porphyria (AIP), ALA dehydratase porphyria (ADP), mixed porphyria (VP), hereditary coprophyria (HCP), or Had porphyria. In some embodiments of the foregoing methods, hepatic porphyria is non-acute hepatic porphyria. In some such embodiments, non-acute hepatic porphyria is familial or sporadic porphyria cutanea (PCT) or hepatorepoliopathic porphyria (HEP).

[0022] This application provides a method for treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP) in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0023] This application provides a method for treating one or more complications of EPP, XLPP, or CEP in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some implementations, one or more complications of EPP, XLPP, or CEP are selected from: acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scarring, deformities, nail loss, finger / toe defects, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, end-stage liver disease, red teeth syndrome, myelocytic hyperplasia, thrombocytopenia, fetal hydrops, and / or intrauterine death.

[0024] This application provides a method for inhibiting the synthesis of protoporphyrin IX (PPIX) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0025] This application provides a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0026] This application provides a method for inhibiting the synthesis of coprophyrin III in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0027] This application provides a method for inhibiting the synthesis of zinc-protoporphyrin IX (ZPPIX) in a subject in need, the method comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0028] This application provides a method for inhibiting the synthesis of bilirubinogen (PBG) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0029] This application provides a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and bile pigment (PBG) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0030] This application provides a method for inhibiting the synthesis of hydroxymethylbilirubin (HMB) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0031] This application provides a method for inhibiting the synthesis of uroporphyrin III in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0032] This application provides a method for inhibiting the synthesis of heptacarboxy-porphyrin in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0033] This application provides a method for inhibiting the synthesis of isoflavone porphyrin in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0034] This application provides a method for inhibiting the synthesis of porphyrin or porphyrin precursor in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient, wherein the porphyrin or porphyrin precursor is selected from:

[0035] a.5-ALA

[0036] b.PBG

[0037] c. Hydroxymethylbiliflurane

[0038] d.PPIX

[0039] e.ZPPIX

[0040] f. Uroporphyrinogen I

[0041] g. Uroporphyrinogen III

[0042] h. Heptacarboxyporphyrinogen I

[0043] i. Heptacarboxyporphyrinogen III

[0044] j. Hexacarboxyporphyrinogen I

[0045] k. Hexacarboxyporphyrinogen III

[0046] l. Pentacarboxyporphyrinogen I

[0047] m. Pentacarboxyporphyrinogen III

[0048] n. coprophyrinogen I

[0049] o. coprophyrinogen III

[0050] p. isoflavones

[0051] q. Bile pigmentogen; and

[0052] r. protoporphyrin IX.

[0053] In some embodiments of the foregoing method, the accumulation of one or more heme intermediates is inhibited, and said one or more heme intermediates are selected from 5-ALA, coproporphyrin III, zinc-protoporphyrin IX (ZPPIX), bile pigmentogen, uroporphyrin III, heptacarboxy-porphyrin, and isofacoporphyrin. In some such embodiments, the accumulation of said one or more heme intermediates is inhibited in a dose-dependent manner.

[0054] In some embodiments of the aforementioned methods, the subject has EPP, XLPP, or CEP. In some embodiments of the aforementioned methods, the subject has hepatic porphyria. In some embodiments of the aforementioned methods, the subject has a mutation in UROS. In some embodiments of the aforementioned methods, the subject has a gene defect in the GATA-1 erythroid-specific transcription factor. In some embodiments of the aforementioned methods, the subject has liver disease associated with EPP, XLPP, or CEP.

[0055] In some embodiments of the foregoing method, the method further includes administering additional active agents and / or supportive therapies to the subject. In some such embodiments, the additional active agents and / or supportive therapies are selected from: sun avoidance, topical sunscreens, skin protection, UVB phototherapy, Scenesene® (afanotide), bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. In some embodiments, the additional active agents and / or supportive therapies are selected from: sun avoidance, topical sunscreens, skin protection, UVB phototherapy, afanotide (Scenesse®), bortezomib, heme infusion, adequate caloric support, gevorcilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of precipitating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venipuncture, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes via a viral vector), hemodialysis, pharmacological companion therapy, proteasome inhibitors, chemical companions, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0056] This application provides a method for treating anemia associated with ribosome dysfunction in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0057] This application provides a method for treating one or more complications of ribosomal dysfunction-related anemia in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, the one or more complications of ribosomal dysfunction-related anemia are selected from: thrombocytosis, megakaryocyte proliferation, infection, bleeding (e.g., from the nose or gums), contusion, splenomegaly, need for more frequent transfusions, need for increased glucocorticoid use, need for allogeneic hematopoietic stem cell transplantation, need for autologous gene therapy, bone marrow failure, leukemia, and acute myeloid leukemia.

[0058] In certain embodiments of the foregoing methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the anemia associated with ribosomal dysfunction is Diamond-Blackfan anemia. In some such embodiments, the subject has a haploinadequate dose of the following ribosomal proteins: 40S ribosomal protein S14 (RPS14), 40S ribosomal protein S19 (RPS19), 40S ribosomal protein S24 (RPS24), 40S ribosomal protein S17 (RPS17), 60S ribosomal protein L35a (RPL35a), 60S ribosomal protein L5 (RPL5), 60S ribosomal protein L11 (RPL11), and 40S ribosomal protein S7 (RPS7). In other such embodiments, the subject's ribosomal protein selected from the following is haplo-insufficient: 40S ribosomal protein S10 (RPS10), 40S ribosomal protein S26 (RPS26), 60S ribosomal protein L15 (RPL15), 60S ribosomal protein L17 (RPL17), 60S ribosomal protein L19 (RPL19), 60S ribosomal protein L26 (RPL26), 60S ribosomal protein L27 (RPL27), 60S ribosomal protein L31 (RPL31), 40S ribosomal protein S15a (RPS15a), 40S ribosomal protein S20 (RPS20), 40S ribosomal protein S27 (RPS27), 40S ribosomal protein S28 (RPS28), and 40S ribosomal protein S29 (RPS29). In other such embodiments, the subject has one or more mutations in a ribosomal protein gene. In other such embodiments, the subject has one or more mutations in a ribosomal protein gene selected from the following: RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28, and RPS29. In other such embodiments, the subject has one or more mutations in a non-ribosomal protein gene selected from the following: TSR2, GATA1, and EPO.

[0059] In some embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the anemia associated with ribosomal dysfunction is Schwarzman-Diamond syndrome. In some such embodiments, the subject has one or more mutations in the SBDS gene.

[0060] In some embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the anemia associated with ribosomal dysfunction is congenital dyskeratosis. In some such embodiments, the congenital dyskeratosis is X-linked congenital dyskeratosis. In other such embodiments, the subject has one or more mutations in the DKC1 gene.

[0061] In some embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the methods reduce the risk of bone marrow failure, pulmonary fibrosis, or liver fibrosis in the subject.

[0062] In some embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the anemia associated with ribosomal dysfunction is chondrodysplasia. In some such embodiments, the subject has one or more mutations in the RMRP gene.

[0063] In some embodiments of the aforementioned methods for treating anemia associated with ribosome dysfunction or for treating one or more complications of anemia associated with ribosome dysfunction, the methods reduce intracellular heme levels.

[0064] In some embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the methods increase the red blood cell count of the subject.

[0065] In certain embodiments of the foregoing methods for treating anemia associated with ribosomal dysfunction or for treating one or more complications of anemia associated with ribosomal dysfunction, the methods further include administering additional active agents and / or supportive therapies to the subject. In some such embodiments, the additional active agents and / or supportive therapies are selected from: trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotexip, rotezip, iron chelators, blood transfusions, and platelet transfusions.

[0066] This application provides a method for treating polycythemia in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

[0067] This application provides a method for treating one or more complications of polycythemia in a subject in need, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, the one or more complications of polycythemia are selected from: pulmonary embolism, transient ischemic attack, transient visual loss, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia.

[0068] In some embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, the polycythemia is essential polycythemia. In some such embodiments, essential polycythemia is polycythemia vera or pure polycythemia. In other such embodiments, essential polycythemia is essential familial polycythemia.

[0069] In certain embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, the polycythemia is secondary polycythemia. In some such embodiments, the secondary polycythemia is associated with a disorder selected from: hypoxia, central hypoxic processes, lung disease, right-to-left cardiopulmonary shunt (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, smoker polycythemia, high-altitude living, kidney disease, kidney transplantation, hemoglobinopathies with hyperoxygen affinity, decreased erythrocyte 2,3,-DPG levels, bisphosphoglycerate mutase deficiency, methemoglobinemia, hereditary ATP increase, gene mutations in oxygen sensing pathways, tumors, drug-induced secondary polycythemia, adrenocortical hypersecretion, and idiopathic polycythemia.

[0070] In some embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, polycythemia is relative polycythemia. In some such embodiments, relative polycythemia is selected from Gaisbock's syndrome, pseudopolycythemia, or stress-induced polycythemia.

[0071] In some embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, polycythemia is Chuvash polycythemia.

[0072] This application provides a method for inhibiting heme synthesis in a subject suffering from polycythemia, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, heme synthesis is inhibited in a dose-dependent manner.

[0073] This application provides a method for inhibiting hemoglobin synthesis in a subject suffering from polycythemia, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, hemoglobin synthesis is inhibited in a dose-dependent manner.

[0074] This application provides a method for inhibiting erythrocyte synthesis in a subject suffering from polycythemia, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, erythrocyte synthesis is inhibited in a dose-dependent manner.

[0075] This application provides a method for reducing the red blood cell count in a subject suffering from polycythemia, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. In some embodiments, the red blood cell count is reduced in a dose-dependent manner.

[0076] In some embodiments of the aforementioned method, the method reduces the incidence of iron deficiency by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0077] In some embodiments of the foregoing method, the method further includes administering additional active agents and / or supportive therapies to the subject. In some such embodiments, the additional active agents and / or supportive therapies are selected from: hydroxyurea (e.g., Droxia®, Hydrea®), interferon alpha, interferon alpha-2b (e.g., Intron® A), ruxotinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiation therapy, hepcidin mimics (e.g., PTG-300), membrane-type serine protease (matriptase)-2 inhibitors, iron transporter inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors. Attached Figure Description

[0078] Figure 1 This study demonstrates the procedure for evaluating the efficacy of GlyT1 inhibitors in EPP phototoxicity assays.

[0079] Figure 2 Compound 11 (“GlyT1 inhibitor”) was shown to reduce Fech m1Pas / Fech m1Pas PPIX levels in the RBCs of homozygous mice, as measured by flow cytometry on days 14 and 18.

[0080] Figure 3 Compound 11 (“GlyT1 inhibitor”) is shown to treat reduced Fech m1Pas / Fech m1Pas Skin lesions in homozygous mice after light exposure.

[0081] Figure 4 Compound 11 (“GlyT1 inhibitor”) is shown to treat reduced Fech m1Pas / Fech m1Pas Percentage of skin lesions in homozygous mice after light exposure.

[0082] Figure 5 Fech treated with mediator or compound 11 (“GlyT1 inhibitor”) is shown. m1Pas / Fech m1Pas Correlation between the quantification of skin lesions on day 14 and PPIX levels in homozygous mice. Detailed Implementation

[0083] The compounds and pharmaceutical compositions thereof of this application can be used as inhibitors of GlyT-1 or its mutants. Without wishing to be bound by any particular theory, it is believed that the compounds and pharmaceutical compositions thereof of this application can inhibit the activity of GlyT-1 or its mutants, and thus treat certain diseases, disorders (such as various blood disorders, particularly those caused by iron overload) and / or regulate heme synthesis through GlyT-1 inhibition. Inhibition of heme synthesis by inhibiting PPIX synthesis can be used to treat a variety of blood disorders, such as erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP). Inhibiting heme synthesis with glycine transporter inhibitors also holds promise for treating iron overload disorders and hemoglobinopathies such as polycythemia (e.g., essential polycythemia, polycythemia vera, pure polycythemia, essential familial polycythemia, relative polycythemia, secondary polycythemia, Gasbock syndrome, pseudopolycythemia, stress-induced polycythemia, Chuvash polycythemia); and anemia associated with ribosome dysfunction (…). For example, Diamond-Blackfan anemia, Schwarzman-Diamond syndrome, chondrodysplasia, and congenital keratosis; hepatic porphyria (e.g., acute hepatic porphyria, acute intermittent porphyria, ALA dehydrase porphyria, mixed porphyria, hereditary coprophyria, Had porphyria, non-acute hepatic porphyria, familial or sporadic porphyria cutanea, hepatorepoietin porphyria); thalassemia; and other blood-related disorders.

[0084] It has now been found that the compounds of this application and pharmaceutically acceptable compositions thereof are effective as GlyT-1 inhibitors. This application provides a compound of formula (I). (I), or a pharmaceutically acceptable salt thereof, wherein:

[0085] A is an aryl or heteroaryl ring system, wherein the aryl or heteroaryl ring system is optionally composed of R 1 Replace one or more times;

[0086] B is a 4- to 8-membered non-aromatic carbon ring or a 4- to 8-membered non-aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic carbon ring or heterocycle is optionally composed of R. 2 Replace one or more times;

[0087] R 1 Each occurrence is independently selected from OH, halogen, -CF3, -OCF3, -OCH2F, -OCHF2, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8Alkyl, -CN, =O, -C(O)H, -(CH2) n NR a R b -(CH2) n NR aa C(O)R bb -C(O)NR a R b -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl, -NR a R b -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-NR a R b -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic, wherein -C 1-8 Alkyl, -OC 1-8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups may optionally be selected independently each time they appear, from halogen, CN, -C 1-8 Alkyl, -C 1-8 alkyl heterocyclic group, -C 1-8 Alkyl heteroaryl, -OC 1-8 Alkyl, aryl, and monocyclic heteroaryl substituents are substituted 1 to 3 times;

[0088] R 2 Each occurrence is independently selected from OH, halogen, -CF3, -OCF3, -OCH2F, -OCHF2, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -CN, =O, -C(O)H, -(CH2) n NR a R b -(CH2) n NR aa C(O)R bb -C(O)NR a R b -C(O)OH, -(CH2) k COC1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl, -NR a R b -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-NR a R b -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic, wherein -C 1-8 Alkyl, -OC 1-8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups may optionally be selected independently each time they appear, from halogen, CN, -C 1-8 Alkyl, -C 1-8 alkyl heterocyclic group, -C 1-8 Alkyl heteroaryl, -OC 1-8 Alkyl, aryl, and monocyclic heteroaryl substituents are substituted 1 to 3 times;

[0089] R 3 Selected from OH, -C 1-8 Alkyl, -OC 1-8 Alkyl, -O aryl, -O heteroaryl and -OC 0-8 Alkyl C 3-8 cycloalkyl, wherein -C 1-8 Alkyl and -OC 1-8 Alkyl groups can optionally be selected independently, each time they appear, from halogens, haloalkyl groups (e.g., CH2F, CHF2, CF3), aryl groups, heterocyclic groups, and -C groups. 3-8 The cycloalkyl substituents are substituted 1 to 3 times;

[0090] R 4 It is H; or

[0091] R 3 and R 4 Together with the carbon atoms to which they are attached, they form cycloalkyl or heterocyclic groups, wherein the cycloalkyl and heterocyclic groups may optionally be independently selected from CN, -C in each occurrence. 1-8 Alkyl, aryl, and heterocyclic substituents are substituted once or twice, wherein -C 1-8 Alkyl, aryl, and heterocyclic groups may optionally be substituted 1 to 3 times with substituents selected independently of halogens each time they appear;

[0092] R 5 Selected from H, -OH, -C 1-8Alkyl groups and NH2;

[0093] R 6 Selected from -C 1-8 Alkyl, aryl, and heteroaryl, wherein -C 1-8 Alkyl, aryl, and heteroaryl groups may optionally be selected independently of deuterium, H, or -C each time they appear. 1-8 The alkyl group is substituted 1 to 3 times, wherein -C 1-8 Alkyl groups may optionally be replaced by -CONH2, -S(O)2NH2, or -S(O)2-C. 1-8 Alkyl, aryl, or heterocyclic substitution; or

[0094] R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted heterocyclic groups;

[0095] R 7 It is deuterium;

[0096] R a Is it H or -C 1-8 alkyl;

[0097] R b Is it H or -C 1-8 Alkyl, wherein -C 1-8 Alkyl groups may optionally be replaced by -CONH2, -S(O)2NH2, or -S(O)2-C. 1-8 Alkyl, aryl, or heterocyclic substitution; or

[0098] R a and R b Together with the nitrogen atoms to which they are attached, they form non-aromatic heterocyclic groups, which are optionally selected independently each time they appear from OH, =O, halogens, CF3, -OCF3, -OCH2F, -OCHF2, -C(O)H, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NR a R b -CN, -C(O)OC 1-8 Alkyl group, -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl group, -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-C1-8 Alkyl, -S(O)2-aryl, -S(O)2NR a R b Substituents of aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups are substituted 1 to 3 times;

[0099] R aa Is it H or -C 1-8 alkyl;

[0100] R bb It is -C 1-8 Alkyl, -C 4-8 Cycloalkylmethyl or monocyclic nonaromatic heterocyclic group, wherein -C 1-8 Alkyl and -C 4-8 The cycloalkylmethyl group may optionally be replaced by NH2, halogen or CN;

[0101] n is 0, 1, 2, 3, 4, 5, or 6;

[0102] m is 0, 1, 2, 3, 4, 5, or 6;

[0103] k is 0, 1, 2, 3, 4, 5, or 6; and

[0104] l can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0105] Those skilled in the art will readily understand Formula I. This indicates a ring system in which rings A and B are fused. Those skilled in the art will further understand that the aforementioned ring system is bonded to the adjacent piperazine ring system in Formula I through ring A (i.e., a designated nitrogen atom of the piperazine ring is directly bonded to one of the atoms of ring A).

[0106] In some embodiments, A is a monocyclic aryl or heteroaryl ring system, wherein the monocyclic aryl or heteroaryl ring system is fused with ring B, and wherein the monocyclic aryl or heteroaryl ring system is optionally fused with R. 1 Replacement once or multiple times. In some embodiments, A is selected from phenyl, pyrimidine, pyridine, and thiazole, wherein the phenyl, pyrimidine, pyridine, and thiazole are optionally replaced by R. 1 Replace once or multiple times.

[0107] In some implementations, R 1 It is a halogen (e.g., fluorine or chlorine) or -C 1-8 Alkyl group. In some embodiments, R 1 It is a halogen (e.g., fluorine or chlorine).

[0108] In some embodiments, B is a 5- or 6-membered non-aromatic carbide ring or a 5- or 6-membered non-aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic carbide ring or heterocycle is optionally composed of R2 Replace one or more times. In some implementations, B is optionally replaced by R. 2 Replace one or more 5-membered non-aromatic carbon rings. In some embodiments, B is optionally replaced by R. 2 The 6-membered non-aromatic carbon ring is replaced once or multiple times. In some embodiments, B is a 5-membered non-aromatic heterocycle containing an oxygen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 The substitution can be performed once or multiple times. In some embodiments, B is a 5-membered non-aromatic heterocycle containing a nitrogen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replacement once or multiple times. In some embodiments, B is a 5-membered non-aromatic heterocycle containing a sulfur atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Substitution occurs once or multiple times (e.g., sulfur is substituted twice with =O, such that the 5-membered non-aromatic heterocycle contains sulfone). In some embodiments, B is a 5-membered non-aromatic heterocycle containing nitrogen and sulfur atoms, wherein the non-aromatic heterocycle is optionally substituted with R. 2 Substitution occurs once or multiple times (e.g., sulfur is substituted twice with =O, such that the 5-membered non-aromatic heterocycle comprises a sulfonamide). In some embodiments, B is a 6-membered non-aromatic heterocycle comprising a nitrogen atom, an oxygen atom, and a sulfur atom, wherein said non-aromatic heterocycle is optionally substituted with R. 2 Substitution can occur once or multiple times (e.g., sulfur is substituted twice with =O, such that the 6-membered non-aromatic heterocycle comprises a sulfone, an oxygen atom, and a nitrogen atom). In some embodiments, B is a 6-membered non-aromatic heterocycle containing an oxygen atom, wherein the non-aromatic heterocycle is optionally substituted with R. 2 Replacement once or multiple times. In some embodiments, B is a 6-membered non-aromatic heterocycle comprising nitrogen and oxygen atoms, wherein the non-aromatic heterocycle is optionally replaced by R. 2 The substitution can be performed once or multiple times. In some embodiments, B is a 6-membered non-aromatic heterocycle containing a nitrogen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 The substitution can be performed once or multiple times. In some embodiments, B is a 6-membered non-aromatic heterocycle containing two nitrogen atoms, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replace once or multiple times.

[0109] In some implementations, R 2 Independently selected from =O and -C 1-8 Alkyl groups (e.g., methyl) and C(O)OC 1-8 alkyl.

[0110] In some implementations, Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In which the aryl or heteroaryl ring system of ring A is optionally R 1 (For example, halogens (such as fluorine or chlorine) or -C 1-8 Alkyl groups (such as methyl) are substituted once or multiple times, and the 5- or 6-membered non-aromatic carbon ring or heterocycle of ring B is optionally further replaced by R. 2 (For example, alkyl groups (such as methyl) or -(CH2)) m C(O)OC 1-8 Alkyl groups (such as C(O)OtBu) are substituted once or multiple times. In some embodiments, yes The aryl or heteroaryl ring system of ring A is optionally replaced by R. 1 (e.g., halogens (such as fluorine or chlorine) or -C) 1-8 Alkyl groups (such as methyl) are substituted once or multiple times, and the 5- or 6-membered non-aromatic carbon ring or heterocycle of ring B is optionally further replaced by R. 2 (For example, alkyl groups (such as methyl) or -(CH2)) m C(O)OC1-8 Alkyl groups (such as C(O)OtBu) are substituted once or multiple times. In some embodiments, Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, yes .

[0111] In some implementations, R a and R bTogether with the nitrogen atom to which they are attached, they form optionally substituted monocyclic nonaromatic heterocyclic groups containing 3-9 atoms, having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. These monocyclic nonaromatic heterocyclic groups may optionally be independently selected, each time appearing, from OH, =O, halogens, CF3, -OCF3, -OCH2F, -OCHF2, -C(O)H, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -CN, -C(O)OC 1-8 Alkyl group, -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl group, -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-C 1-8 The substituents of alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups are substituted 1 to 3 times. In some embodiments, R a and R b Together with the nitrogen atom to which they are attached, they form morpholino, oxazolyl, thiazinyl, imidazoyl, piperidinyl, pyrrolyl, piperazinyl, or thiomorpholino, wherein the morpholino, oxazolyl, thiazinyl, imidazoyl, piperidinyl, pyrrolyl, piperazinyl, or thiomorpholino may optionally be independently selected from =O, -C in each occurrence. 1-8 Alkyl groups, OH groups, and -C(O)OC 1-8 The alkyl substituents are substituted 1 to 3 times. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form , , , , , , or Groups, each of which may optionally be independently selected from =O, -C, etc., each time it appears. 1-8 Alkyl groups, OH groups, and -C(O)OC 1-8 The alkyl substituents are substituted 1 to 3 times. In some embodiments, R a and R b Together with the nitrogen atoms to which they are attached, they form oxazolidinyl or oxazolidinyl groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form thiazinyl or thiazinyl groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form imidazoalkyl or imidazoalkyl groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form piperazine or piperazine groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form pyrrolidinyl or pyrrolidinyl groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form thiomorpholino or thiomorpholino groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form piperidinyl or piperidinyl groups: In some implementations, R a and R b Together with the nitrogen atoms to which they are attached, they form morpholino groups or morpholino groups: .

[0112] In some implementations, R 3 Selected from OH, -OC 1-8 Alkyl, -O aryl, -O heteroaryl and -OC 0-8 Alkyl C 3-8 cycloalkyl, wherein -C 1-8 Alkyl and -OC 1-8 Alkyl groups can optionally be selected independently, each time they appear, from halogens, haloalkyl groups (e.g., CH2F, CHF2, CF3), aryl groups, heterocyclic groups, and -C groups. 3-8 The cycloalkyl substituents are substituted 1 to 3 times. In some embodiments, R 3 It is optionally selected independently each time it appears from halogens, CF3, aryl, heterocyclic groups, and -C. 3-8 The cycloalkyl substituents are substituted 1 to 3 times with -OC 1-8 Alkyl group. In some embodiments, R 3 -OC is optionally substituted 1 to 3 times by a substituent selected independently from halogens (e.g., fluorine) each time it appears. 1-8 Alkyl group. In some embodiments, R 3 It is -OCH(CH3)CF3.

[0113] In some implementations, R 4 It is H.

[0114] In some implementations, R 3 and R 4 Together with the carbon atoms to which they are attached, they form 4-8 membered heterocyclic groups, wherein the 4-8 membered heterocyclic groups may optionally be converted to -C 1-8 Alkyl, aryl, and heterocyclic substituents are substituted once or twice, wherein -C 1-8 Alkyl, aryl, and heterocyclic groups may optionally be substituted 1 to 3 times, each time independently selected from halogens. In some embodiments, R 3 and R 4 Together with the carbon atoms to which they are attached, they form tetrahydrofuranyl or dihydrofuranyl, wherein the tetrahydrofuranyl and dihydrofuranyl may optionally be converted to -C 1-8 Alkyl substitution once or twice, wherein -C 1-8 The alkyl group may optionally be substituted 1 to 3 times with a substituent selected independently of a halogen each time it appears. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form optionally substituted 4-8 membered heterocyclic groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form tetrahydrothiophene 1,1-dioxide or dihydrothiophene 1,1-dioxide.

[0115] In some implementations, R 3 and R 4 Together with the carbon atoms to which they are attached, they form optionally -C 1-8 Alkyl-substituted tetrahydrofuranyl group, wherein -C 1-8 The alkyl group may optionally be substituted 1 to 3 times with a substituent selected independently of a halogen (e.g., Cl or F) each time it appears. Therefore, the compound of formula (I) has the following structure:

[0116] .

[0117] In some implementations, R 3 and R 4 Together with the carbon atoms to which they are attached, they form optionally -C 1-8 Alkyl-substituted dihydrofuranyl group, wherein -C 1-8 The alkyl group may optionally be substituted 1 to 3 times with a substituent selected independently of a halogen (e.g., Cl or F) each time it appears. Therefore, the compound of formula (I) has the following structure:

[0118]

[0119] In some implementations, R 5 It is H. In some implementations, R 5 Selected from H and NH2.

[0120] In some implementations, R 6 It is C 1-8 Alkyl group. In some embodiments, R 6 It's me.

[0121] In some implementations, R 5 and R 6 Together with the atoms to which they are attached, they form tetrahydrothiophene 1,1-dioxide. Therefore, the compound of formula (I) has the following structure:

[0122] .

[0123] In some implementations, R 5 and R 6 They form dihydrothiophene 1,1-dioxide with the atoms to which they are attached. Therefore, the compound of formula (I) has the following structure:

[0124] .

[0125] In some implementations, l is 0. In some implementations, l is 8.

[0126] This application provides compounds selected from any one of compounds 1-60 and their pharmaceutically acceptable salts: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (twenty one), (twenty two), (twenty three), (twenty four), (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43)

[0127] (44)

[0128] (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) (59) and (60)

[0129] In some embodiments, the compound is selected from any one of compounds 1-51 and their pharmaceutically acceptable salts. In some embodiments, the compound is selected from any one of compounds 1-57 and their pharmaceutically acceptable salts. In embodiments of this application in which compounds (e.g., compounds of formula (I) or their pharmaceutically acceptable salts, such as any one of compounds 1-60 and their pharmaceutically acceptable salts) are disclosed herein as particular enantiomers, this application further contemplates compounds in their racemic or other enantiomeric forms. For example, for any one of compounds 1-60 shown as (S) enantiomers, this application further provides compounds in their racemic or (R) enantiomeric forms and their pharmaceutically acceptable salts. Similarly, for any one of compounds 1-60 shown as (R) enantiomers, this application further provides compounds in their racemic or (S) enantiomeric forms and their pharmaceutically acceptable salts.

[0130] In certain embodiments in which alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclic, or oxime are substituted, they are substituted by one or more substituents selected from the following, where the valence allows: substituted or unsubstituted alkyl (e.g., perfluoroalkyl (e.g., trifluoromethyl)), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, haloyl, alkoxy (e.g., perfluoroalkoxy (e.g., trifluoromethoxy)), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl (e.g., perfluoroacylaminoalkyl (e.g., trifluoromethylacylaminoalkyl)), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclic, heterocyclic, heterocyclic Cycloalkyl, heterocyclooxy, heterocycloalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocycloaminoalkyl, heterocycloaminoalkoxy, amide, amamide alkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl, including perfluoroacyl (e.g., C(O)CF3)), carbonylalkyl (such as carboxylalkyl, alkoxycarbonylalkyl, formylalkyl or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(O)CF3)), urethane, urethane alkyl, urea, ureyl alkyl, sulfate, sulfonate, aminosulfonyl, sulfonamide, sulfonamide alkyl, cyano, nitro, azide, mercapto, alkylthio, thiocarbonyl (such as thioester, thioacetate or thiocarbamate), phosphoryl, phosphate, phosphonate or hypophosphonate.

[0131] When a substituent is shown to cross a bond between two atoms in the linking ring, such a substituent can bond to any atom in the ring. When a substituent is listed without indicating which atom it bonds to the rest of the compound in the given formula, the substituent can bond to any atom in that substituent. Such combinations are only permitted if they result in a chemically stable compound.

[0132] As used in this application, the term "optionally substituted" means that the substitution is optional, and therefore the specified atom or portion may be unsubstituted.

[0133] The compounds of this application containing one or more asymmetrically substituted atoms can be isolated in optically active or racemic form. The preparation of optically active forms is well known in the art, such as by resolving the racemic form, by synthesis from optically active starting materials, or by using optically active reagents.

[0134] In some embodiments, the compounds of this application may be racemic. For example, in embodiments of this application in which the compounds (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) are disclosed herein as specific enantiomers, the racemic form of the compounds is further considered. In some embodiments, the compounds of this application may be enriched with one enantiomer. For example, the compounds of this application may have an ee greater than 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 95% or greater.

[0135] In some embodiments, the therapeutic agent may be enriched to primarily provide one enantiomer of the compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). The enantiomer-enriched mixture may contain, for example, at least 60 mol% of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol% of one enantiomer. In some embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means, for example, that the substance in question accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% of the amount of the other enantiomer in the composition or compound mixture. For example, if the 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.

[0136] In some embodiments, the compounds of this application may have more than one stereocenter. In some such embodiments, the compounds of this application may be rich in one or more diastereomers. For example, the compounds of this application may have greater than 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 95% or more of de.

[0137] In some embodiments, the therapeutic agent may be enriched to primarily provide a diastereomer of the compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). The diastereomer-enriched mixture may contain, for example, at least 60 mol percent of a diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent of a diastereomer.

[0138] The various compounds described in this application may exist in specific geometric or stereoisomeric forms. All such compounds, including their tautomers, cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures, are considered within the scope of this application. This application covers all tautomeric forms. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. Unless specifically indicated by stereochemistry or isomerism, all such isomers and mixtures thereof are intended to be included in this application.

[0139] This application also includes all pharmaceutically acceptable isotopically labeled compounds (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof). An "isotopically labeled" or "radiolabeled" compound is one in which one or more atoms are replaced or substituted with atoms of atomic mass or atomic number different from those normally found in nature (i.e., naturally occurring). For example, in some embodiments, in a compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), hydrogen atoms are replaced or substituted with one or more deuterium or tritium atoms (e.g., C32-C4 ... 1-6 Alkyl or C 1-6 The hydrogen atom on the alkoxy group is replaced by deuterium, such as d3-methoxy or 1,1,2,2-d4-3-methylbutyl.

[0140] In this application, certain isotope-labeled compounds (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), such as those doped with radioactive isotopes, can be used for tissue distribution studies of drugs and / or substrates. Given their ease of incorporation and readily available detection methods, radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Specifically for this purpose.

[0141] Using heavier isotopes such as deuterium (i.e., 2 Substitution of H) can impart certain therapeutic advantages due to better metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases.

[0142] Using positron emission isotopes (such as...) 11 C 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0143] Isotope-labeled compounds (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using a suitable isotope-labeled reagent in place of the previously used unlabeled reagent. Suitable isotopes that can be incorporated into the compounds of this application include, but are not limited to, those that are not included in the present application. 2 H (also written as D, deuterium), 3 H (also written as T, tritium) 11 C 13 C, 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 18 F, 35 S, 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I and 131 I.

[0144] In some embodiments, this application provides a pharmaceutical formulation suitable for human patients, said pharmaceutical formulation comprising any of the compounds shown above (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical formulation may be used to treat or prevent a condition or disease as described herein. In some embodiments, the pharmaceutical formulation has sufficiently low pyrogenic activity to be suitable for use in human patients.

[0145] In some embodiments, compounds disclosed herein (e.g., compounds according to formula (I) or pharmaceutically acceptable salts thereof) exhibit reduced brain penetration (e.g., compared to compounds known to cross the blood-brain barrier, such as metoprolol). In some embodiments, compounds disclosed herein (e.g., compounds according to formula (I) or pharmaceutically acceptable salts thereof) cannot cross the blood-brain barrier (i.e., the compounds are peripherally confined). In some embodiments, compounds disclosed herein (e.g., compounds according to formula (I) or pharmaceutically acceptable salts thereof) are substrates of the human efflux transporter P-glycoprotein (P-gp). In some embodiments, compounds disclosed herein (e.g., compounds according to formula (I) or pharmaceutically acceptable salts thereof) have an efflux ratio greater than about 1.75, 1.8, 1.9, 2.0, 5.0, 10, 15, 20, 25, 30, 35, or 40, wherein And P app (B-A) The apparent permeability coefficient is indicated from the outer side of the substrate to the top, and P app (A-B) The apparent permeability coefficient is indicated from the tip to the outer side of the substrate. In some such embodiments, the efflux ratio is determined in the absence of a P-gp inhibitor. In other such embodiments, when measured in the presence of a known P-gp inhibitor, a reduction in the efflux ratio of at least 50%, 60%, 70%, 80%, 90%, or 95% is demonstrated.

[0146] Any compound with the above-described structure may be used to manufacture a medicament for treating any of the diseases or conditions disclosed herein.

[0147] Use of compounds

[0148] The compounds of this application can be administered orally, parenterally, orally, vaginally, rectally, by inhalation, by blowing in, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intraventricularly, and by injection into joints.

[0149] The dosage will depend on the route of administration, the severity of the disease, the patient's age and weight, and other factors that the attending physician typically considers when determining the most suitable individual regimen and dosage level for a particular patient. The amount of compound to be administered will vary depending on the patient being treated and will range from about 100 ng / kg body weight per day to 100 mg / kg body weight per day. For example, a person skilled in the art can readily determine the dosage based on this disclosure and knowledge in the art. Therefore, a skilled person can readily determine the amount of compounds and optional additives, mediators, and / or carriers in the compositions administered in the methods of this application. In some embodiments, this application relates to compounds of formula (I) used as medicaments (e.g., any one of compounds 1-60) or pharmaceutically acceptable salts thereof, said medicaments being used, for example, to treat any of the disorders disclosed herein.

[0150] In some embodiments, the compounds and compositions described herein are generally used to inhibit GlyT-1 or its mutants. The activity of compounds used as inhibitors of GlyT-1 or its mutants in this disclosure can be determined in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of GlyT-1 or its mutants. Alternative in vitro assays quantify the ability of the inhibitor to bind to GlyT-1 or its mutants. Detailed conditions for determining the compounds used as inhibitors of GlyT-1 or its mutants in this disclosure are set forth in the following examples.

[0151] In some embodiments, this application relates to a compound of formula (I) used as a medicament (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0152] This application provides a method for preventing or treating a disorder related to a condition in which excessive heme, accumulation of toxic intermediates in heme biosynthesis, or a pathological increase in erythropoiesis leads to a disease in a subject. The method comprises administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or a prodrug of said one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In some aspects, the disorder is porphyria (e.g., erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP)), hepatic porphyria (e.g., acute hepatic porphyria, acute intermittent porphyria, ALA dehydratase porphyria, mixed porphyria, hereditary coprophyria, Had porphyria, non-acute hepatic porphyria, familial or sporadic late-onset cutaneous porphyria, hepatorenal erythropoiesis), and related to ribosome disorders. This includes anemias related to PPIX accumulation (e.g., Diamond-Black Fan anemia, Schwarzman-Diamond syndrome, chondrodysplasia, and congenital keratosis), polycythemia (e.g., essential polycythemia, polycythemia vera, pure polycythemia, essential familial polycythemia, relative polycythemia, secondary polycythemia, Gasbock syndrome, pseudopolycythemia, stress-induced polycythemia, Chuvash polycythemia), thalassemia, or other blood-related disorders. In some embodiments, the glycine transporter inhibitor is a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. For example, this application provides a method for preventing or treating a subject with a disorder related to PPIX accumulation, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0153] In the treatment of any disorder disclosed herein, the different compounds of this application may be administered in combination with one or more other compounds of this application (e.g., compounds of formula (I) (e.g., any one of compounds 1-60) or their pharmaceutically acceptable salts) (e.g., in combination). Furthermore, any one or more compounds of formula (I) (e.g., any one of compounds 1-60) or their pharmaceutically acceptable salts may be administered in combination with other conventional therapeutic agents to treat one or more of the conditions mentioned herein.

[0154] In some embodiments, the compounds of this application may be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., both compounds are effective simultaneously in the patient, which may include a synergistic effect between the two compounds). For example, the different therapeutic compounds may be administered simultaneously, sequentially, or by separately administering individual components of the treatment in the same formulation or in separate formulations. In some embodiments, the different therapeutic compounds may be administered at intervals of 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic compounds.

[0155] In some embodiments, the combined administration of the compound of this application with one or more other therapeutic agents provides improved efficacy relative to the individual administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof or one or more other therapeutic agents. In some such embodiments, the combined administration provides an additive effect, wherein the additive effect refers to the sum of the effects of the individual administration of the compound of this application and one or more other therapeutic agents.

[0156] Such combination products use compounds of this application within the dosage range described herein and one or more other pharmaceutically active compounds within the approved dosage range and / or the dosage range described in the published references.

[0157] Porphyria

[0158] Porphyria is a group of inherited or acquired disorders caused by a deficiency of activity of specific enzymes in the heme biosynthetic pathway (also referred to herein as the porphyrin pathway). Porphyrins are the major precursors of heme. Porphyrins and porphyrin precursors include 5-aminolevulinic acid (ALA), bile pigmentogen (PBG), hydroxymethylbilirubin (HMB), uroporphyrinogen I or III, coproporphyrinogen I or III, protoporphyrinogen IX, and protoporphyrin IX. Heme is an essential component of hemoglobin, myoglobin, catalase, peroxidase, and cytochromes, the latter including respiratory cytochromes and P450 hepatocyte cytochromes. Heme is synthesized in most or all human cells. Approximately 85% of heme is produced in erythroid cells, primarily for hemoglobin production. The majority of the remaining heme is produced in the liver, with 80% used for cytochrome synthesis. A deficiency of specific enzymes in the porphyrin pathway leads to insufficient heme production and also results in the accumulation of porphyrin precursors and / or porphyrins, which may be toxic to cell or organ function at high concentrations.

[0159] Porphyria can be classified by the primary site of overproduction and accumulation of porphyrins or their precursors. In hepatic porphyria, porphyrins and their precursors are primarily overproduced in the liver, while in erythropoietic porphyria, porphyrins are overproduced in erythroid cells in the bone. Acute or hepatic porphyria leads to neurological dysfunction and neurological manifestations, which may affect both the central and peripheral nervous systems, resulting in symptoms such as: pain (e.g., abdominal pain and / or chronic neuropathic pain), vomiting, neuropathy (e.g., acute neuropathy and progressive neuropathy), muscle weakness, seizures, mental disorders (e.g., hallucinations, depression, anxiety, paranoia), arrhythmias, tachycardia, constipation, and diarrhea. Cutaneous or erythropoietic porphyria primarily affects the skin, causing symptoms such as photosensitivity, which may include pain, blisters, necrosis, itching, swelling, and increased hair growth in areas such as the forehead. Subsequent infections of skin lesions can lead to bone and tissue loss, as well as scarring, disfigurement, and loss of fingers / toes (e.g., fingers, toes). Most porphyria are caused by mutations in enzymes encoding the heme biosynthesis pathway. However, not all porphyria are hereditary. For example, patients with liver disease may develop porphyria due to impaired liver function. Patients with PCT may acquire inactive uroporphyrinogen decarboxylase (URO-D) due to the formation of ORO-D enzymes with lower than normal enzyme activity.

[0160] Acute hepatic porphyria

[0161] Porphyria encompasses eight inherited metabolic disorders of heme biosynthesis, in which various enzymes in the complex heme biosynthesis pathway are disrupted. Porphyria is broadly classified based on its clinical presentation as acute and non-acute porphyria or hepatic and erythropoietic porphyria. Acute hepatic porphyria includes acute intermittent porphyria (AIP), mixed porphyria (VP), hereditary coprophyria (HCP), and aminolevulinic acid dehydratase deficiency porphyria (ADP), and typically causes severe abdominal, psychiatric, neurological, or cardiovascular symptoms. Each type of acute hepatic porphyria is caused by a genetic defect that results in a deficiency of one of the enzymes in the heme biosynthesis pathway in the liver. AIP, HCP, and VP are autosomal dominant porphyria, while ADP is autosomal recessive porphyria. In rare cases, AIP, HCP, and VP occur in homozygous dominant forms. Porphyria cutanea tarda (PCT) is a non-acute hepatic porphyria in which patients typically present with vesicles, bullae, milia, and hirsutism on the cheeks, temples, and eyebrows. Additionally, there is a rare homozygous recessive form of PCT called hepatic erythropoietic porphyria (HEP). The clinical and laboratory features of these porphyria are described in Table 1 below.

[0162] Table 1: Symptoms and Diagnostic Strategies for Hepatic Porphyria and Lead Poisoning

[0163]

[0164] NV: Symptoms of the sympathetic nervous system in the brain and spinal cord; C: Skin symptoms; A: Anemia; LD: Liver damage; 1 Clinical characteristic variables at the time of presentation; ALA: 5-aminolevulinic acid; Copro: coprophyrin; PBG: bilirubinogen; Uro: uroporphyrin; Hepta: heptacarboxy-porphyrin; Proto: protoporphyrin; Isocopro: isoflavoneporphyrin;

[0165] Acute intermittent porphyria (AIP) (also known as bilirubinogen (PBG) deaminase deficiency or hydroxymethylbilirubin synthase (HMBS) deficiency) is the most common type of acute hepatic porphyria. Other types of acute hepatic porphyria include hereditary coprophyria (HCP), mixed porphyria (VP), and ALA dehydratase deficiency porphyria (ADP). Non-acute hepatic porphyria includes porphyria cutanea (PCT), a condition in which patients typically present with vesicles, bullae, milia, and hirsutism on the cheeks, temples, and eyebrows. Additionally, there is a rare homozygous recessive form of PCT called hepatoerythropoietic porphyria (HEP). The clinical and laboratory characteristics of these porphyria are described in Table 1.

[0166] AIP has been found to have a prevalence as high as 1 in 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 the mutation is estimated to be between 1 in 10,000 and 1 in 20,000. Only about 10%–15% of individuals carrying mutations known to be associated with AIP exhibit clinical disease. However, penetrance can be as high as 40% in individuals with certain mutations (e.g., the W198X mutation). AIP is typically latent before puberty. Symptoms are more common in women than in men. Its prevalence may be underestimated due to the incomplete penetrance and long latency of the disease. In the United States, it is estimated that approximately 2,000 patients have experienced at least one episode. An estimated 150 cases of active relapse have been reported in France, Sweden, the United Kingdom, and Poland; these patients are primarily young women with a median age of 30 years.

[0167] AIP affects systems such as the visceral nervous system, peripheral nervous system, autonomic nervous system, and central nervous system. 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 progressive neuropathy, such as chronic neuropathic pain), neuropsychiatric symptoms (e.g., confusion, anxiety, agitation, hallucinations, hysteria, delirium, emotional blunting, depression, panic disorder, psychosis, insomnia, somnolence, coma), and autonomic nervous system involvement (leading to, for example, cardiovascular disease). Symptoms include tachycardia, hypertension, and / or arrhythmias, as well as other symptoms such as increased circulating catecholamine levels, sweating, restlessness, and / or tremors, dehydration, and electrolyte abnormalities. The most common symptoms are abdominal pain and tachycardia. Additionally, patients often suffer from chronic neuropathic pain that can develop into progressive neuropathy. Patients with recurrent episodes usually have prodromal symptoms. Permanent paralysis may occur after a severe episode. Recovery from a severe episode that is not treated promptly can take weeks or months. Acute episodes can be fatal, for example, due to respiratory muscle paralysis or cardiovascular failure caused by electrolyte imbalances. Before the availability of heme chloride therapy, up to 20% of patients with AIP died from the disease.

[0168] Individuals carrying the AIP gene have an increased risk of hepatocellular carcinoma. The risk is particularly severe in those with recurrent episodes: after age 50, the risk is almost 100 times that of the general population.

[0169] Acute porphyria attacks can be triggered by endogenous or exogenous factors. Mechanisms by which such factors induce attacks may include, for example, increased demand for hepatic P450 enzymes and / or induction of hepatic ALAS1 activity. Increased demand for hepatic P450 enzymes leads to a decrease in free hemoglobin in the liver, thereby inducing the synthesis of hepatic ALAS1.

[0170] Triggering factors include fasting (or other forms of reduced or insufficient calorie intake such as rapid dieting, long-distance track and field, 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, antimicrobial agents, and components in alcoholic beverages), and endocrine factors (e.g., reproductive hormones (which women may experience exacerbations during the premenstrual period), synthetic estrogens, progesterone, ovulation stimulants, and hormone replacement therapy).

[0171] More than 1,000 drugs are contraindicated in acute hepatic porphyria (e.g., AIP, HCP, ADP, and VP), including, for example, alcohol, barbiturates, carbamazepine, carisoprodol, clonazepam (high dose), danazol, diclofenac and possibly other NSAIDs, ergot, estrogens, ethclovulvinol, dapoxetine, griseofulvin, mephenytoin, tybutamate (also known as mebuprofen and tybutamate), methylphenidate, metoclopramide, phenytoin, primidone, progesterone and synthetic progestins, pyrazinamide, pyrazolone (aminopyrine and antipyrine), rifampin, succinimide (ethosuximide and mesuximide), sulfonamide antibiotics, and valproic acid.

[0172] Objective signs of acute inflammatory bowel disease (AIP) include discoloration of urine during an acute attack (urine may appear red or reddish-brown), and increased concentrations of PBG and ALA in the urine during an acute attack. Molecular genetic testing has identified mutations in the PBG deaminase (also known as HMBS) gene in more than 98% of affected individuals.

[0173] 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 fluorescence assays). Diagnosis of AIP can be confirmed by determining that erythrocyte PBG deaminase activity is 50% or lower than normal. Mutated DNA testing can be performed on the patient and at-risk family members. Diagnosis of AIP is typically confirmed by DNA testing to identify a specific pathogenic gene mutation (e.g., HMBS mutation).

[0174] Treatment of acute seizures typically requires hospitalization to control and treat acute symptoms, including, for example, abdominal pain, seizures, dehydration / hyponatremia, nausea / vomiting, tachycardia / hypertension, urinary retention / intestinal obstruction. For instance, abdominal pain can be treated with narcotic analgesics, seizures with seizure prophylaxis and possible medications (although many anti-seizure drugs are contraindicated), nausea / vomiting can be treated with phenothiazines, and tachycardia / hypertension can be treated with beta-blockers. Treatment may include discontinuing unsafe medications, monitoring respiratory function, and muscle strength and neurological status. Mild seizures (e.g., seizures without hemiparesis or hyponatremia) can be treated with at least 300 g of intravenous 10% glucose daily, although in increasingly more cases heme chloride is administered immediately. Severe seizures should be treated as soon as possible with intravenous heme chloride (3-4 mg / kg daily for 4-14 days) and with intravenous glucose while waiting for the heme chloride to take effect. Typically, the attack is treated with intravenous heme chloride for 4 days, and intravenous glucose is administered while waiting for the intravenous heme chloride to be administered.

[0175] Panhematin® (or heme chloride 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. Panhematin® is heme chloride derived from treated red blood cells (PRBCs) and is a protoporphyrin IX containing ferric ions (heme B) and chloride ligands. Heme acts to limit the synthesis of porphyrins in the liver and / or myeloid. The exact mechanism by which heme chloride produces symptom improvement in patients with acute hepatic porphyria is not fully understood; however, its effect is likely due to (feedback) inhibition of δ-aminolevulinic acid (ALA) synthase, which limits the rate of porphyrin / heme biosynthesis. Inhibition of ALA synthase should result in a reduction in the production of ALA and PBG, as well as porphyrin and porphyrin intermediates.

[0176] The disadvantages of heme chloride include its delayed effect on clinical symptoms and its inability to prevent recurrence of attacks. Adverse reactions associated with heme chloride administration may include thrombophlebitis, anticoagulation, thrombocytopenia, renal arrest, or iron overload, which are particularly likely to occur in patients requiring multiple courses of heme chloride therapy for recurrent attacks. To prevent phlebitis, patients with recurrent attacks require indwelling intravenous catheters. Less frequently reported side effects include fever, aches, fatigue, hemolysis, allergic reactions, and circulatory failure.

[0177] Heme is difficult to prepare into a stable form for intravenous administration. It is insoluble at neutral pH but can be prepared as heme hydroxide at pH 8 or higher. Panhematin® is a lyophilized heme chloride formulation. When lyophilized heme chloride is dissolved for intravenous administration, degradation products rapidly form; these degradation products lead to transient anticoagulation and phlebitis at the infusion site. Heme albumin and heme arginine (Normosang, the European form of heme chloride) are more stable and may potentially cause less thrombophlebitis. However, heme arginine is not approved for use in the United States. Stable infusion can be achieved by dissolving Panhemin® in 30% human albumin instead of sterile water; however, because albumin is separated from human blood, it increases the intravascular volume expansion effect and increases treatment costs and the risk of pathogens.

[0178] Successful treatment of acute attacks does not prevent or delay relapses. One question remains whether heme chloride itself can trigger relapses due to the induction of heme oxygenase. Nevertheless, in some regions (particularly France), young women with multiple relapses are receiving weekly heme chloride treatment as a preventative measure.

[0179] Current treatments for acute neurological attacks include intravenous administration of heme chloride (Panhematin®, Lundbeck; or Normosang®, Orphan Europe), which provides exogenous heme for negative feedback inhibition of ALAS1, thereby reducing ALA and PBG production. Heme chloride is used for the treatment and prevention of acute attacks, particularly in women with acute porphyria who experience frequent attacks due to hormonal changes during their menstrual cycle. While patients generally respond well, its effects are slow, typically requiring two to four days or longer for urinary ALA and PBG concentrations to normalize. Due to the rapid metabolism of intravenously administered heme chloride, three to four infusions are usually required for effective treatment or prevention of acute attacks. Furthermore, repeated infusions can lead to iron overload and phlebitis, which may impair peripheral venous access.

[0180] Givosiran (Givlaari®), a small interfering RNA (siRNA) targeting aminolevulinic acid synthase 1, is also used to treat patients with acute hepatic porphyria by targeting and degrading ALAS1 mRNA in hepatocytes through RNA interference. Related risks associated with the use of Givosiran include allergic reactions, hepatotoxicity, and nephrotoxicity. For example, in Givosiran clinical trials, 15% of patients showed elevated transaminase (ALT) levels up to three times the upper limit of normal. Additionally, 15% of patients receiving Givosiran experienced renal-related adverse events, including elevated serum creatinine levels and an estimated decrease in glomerular filtration rate. The final treatment option is orthotopic liver transplantation. While 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 are needed for the treatment and / or prevention of hepatic porphyria. Glycine transporter inhibitors, such as, but not limited to, compounds of formula (I) (e.g., any one of compounds 1-60) or their pharmaceutically acceptable salts, are used in methods and applications that meet these and other needs.

[0181] Limited experience with liver transplantation suggests it is an effective treatment for AIP if successful. In Europe, approximately 12 patients have received transplants with curative or varying outcomes. Liver transplantation can restore normal excretion of ALA and PBG and prevent acute attacks. Furthermore, if a liver from a patient with AP is transplanted into another patient (“domino transplant”), the recipient may develop AIP. While orthotopic liver transplantation is curative, this procedure has significant morbidity and mortality, and the availability of liver donors is limited.

[0182] One of the long-term clinical effects of acute porphyria is chronic neuropathic pain, which may be caused by progressive neuropathy resulting from the neurotoxic effects of elevated porphyrin precursors, such as ALA and / or PBG. Patients may experience neuropathic pain before or during acute attacks. Older patients may experience increased neuropathic pain with age, and therefore are often prescribed various anesthetic medications. Electromyography abnormalities and shortened conduction times have been recorded in patients with acute hepatic porphyria. In patients with acute porphyria (e.g., ADP, AIP, HCP, or VP), porphyrin precursor (ALA and PBG) levels are typically elevated between asymptomatic and symptomatic attacks. Therefore, reducing porphyrin precursors and restoring normal heme biosynthesis by decreasing ALAS1 expression and / or activity levels is expected to prevent and / or minimize the development of chronic and progressive neuropathy. Treatments, such as chronic treatment (e.g., regular treatment with iRNA as described herein; e.g., treatment according to a dosing regimen as described herein; e.g., treatment once weekly or every two weeks), can persistently reduce ALAS1 expression in patients with acute porphyria who have elevated levels of porphyrin precursors, porphyrins, porphyrin products, or other metabolites. 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 levels of porphyrin precursors, porphyrins, porphyrin products, or metabolites.

[0183] There is a need to identify novel therapeutic agents for the treatment of porphyria. As discussed above, existing treatments such as heme chloride, gevoceline, and liver transplantation have many drawbacks. For example, the effect of heme chloride on clinical symptoms is delayed, it is expensive, and it may have side effects (e.g., thrombophlebitis, anticoagulation, thrombocytopenia, iron overload, renal arrest).

[0184] In some aspects, this application provides the use of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating hepatic porphyria in a subject of need. In some embodiments, this disclosure provides a method for preventing or treating hepatic porphyria in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. For example, this 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 a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0185] Optionally, the methods disclosed herein for preventing or treating one or more complications of hepatic porphyria (e.g., AIP, HCP, VP, HARPO, ADP, PCT, and HEP) in subjects, or for reducing its rate of progression and / or severity, may further include administering to the patient one or more supportive therapies or additional active agents for the treatment of porphyria (e.g., AIP, HCP, VP, HARPO, ADP, PCT, and HEP). For example, patients may also be given one or more supportive therapies or active agents selected from the following: avoidance of sunlight, topical sunscreen, skin protection, UVB phototherapy, afanotide (Scenesse®), bortezomib, heme infusion, adequate caloric support, gevorcilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of precipitating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venipuncture, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes via viral vector), hemodialysis, pharmacological companion therapy, proteasome inhibitors, chemical companions, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0186] In some implementations, the subject is given a combination therapy, such as a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, with one or more other treatments known to be effective against AIP, HCP, VP, HARPO, ADP, PCT and HEP or their associated symptoms (e.g., glucose and / or heme products such as heme chloride as described herein).

[0187] In one embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with glucose or dextrose. For example, 10%-20% dextrose in physiological saline may be administered intravenously. Typically, when glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. A compound selected from formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof may also be administered intravenously as part of the same infusion for the administration of glucose or dextrose, or as a separate infusion administered before, concurrently with, or after the administration of glucose or dextrose. In some embodiments, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered via a different route of administration (e.g., subcutaneously). In yet another embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with total parenteral nutrition. A compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be administered before, concurrently with, or after total parenteral nutrition.

[0188] In some embodiments, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other treatments (e.g., another known effective treatment for hepatic porphyria or symptoms of hepatic porphyria). In one embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product (e.g., heme chloride, heme arginine salt, or heme albumin). In another embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product and glucose, a heme product and dextran, or a heme product and total parenteral nutrition. One or more other treatments may be administered before, after, or concurrently with the administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof. A compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be administered in combination with an additional therapeutic agent in the same composition (e.g., intravenously), or the additional therapeutic agent may be administered as 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., heme chloride, heme arginine salt, or heme albumin).

[0189] In some embodiments, administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof, or administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof, in combination with one or more other treatments (e.g., glucose, dextrose), may reduce the frequency of acute attacks (e.g., by preventing acute attacks from occurring again, or by reducing the number of attacks occurring within a certain period of time, e.g., fewer attacks per year). In some such embodiments, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered according to a regular dosing regimen, such as twice daily, once daily, once weekly, once every two weeks, or once monthly.

[0190] In some embodiments, the subject has or is at risk of developing hepatic porphyria (e.g., AIP, HCP, VP, ADP, PCT, HARPO, and HEP). In some embodiments, the hepatic porphyria is acute hepatic porphyria (e.g., AIP, HCP, VP, and ADP). In some embodiments, the hepatic porphyria is non-acute hepatic porphyria (e.g., PCT and HEP). In some embodiments, the hepatic porphyria is dual hepatic porphyria, such as at least two types of hepatic porphyria. In some embodiments, dual hepatic porphyria includes two or more types of hepatic porphyria selected from: AIP, HCP, VP, ADP, HARPO, PCT, and HEP.

[0191] In some embodiments, hepatic porphyria is caused by a heterozygous mutation that results in decreased enzyme activity. In some embodiments, hepatic porphyria is caused by a homozygous mutation that results in decreased enzyme activity. In some embodiments, hepatic porphyria is an autosomal recessive disease (e.g., ADP). In some embodiments, the subject carries a genetic alteration (e.g., a mutation) but is otherwise asymptomatic.

[0192] Mutations associated with hepatic porphyria include mutations in genes encoding certain enzymes in the heme biosynthesis pathway (porphyrin pathway) or in genes that alter gene expression in the heme biosynthesis 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).

[0193] 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 mixed porphyria (VP). In some embodiments, hepatic porphyria is hereditary coprophyria (HCP). In some embodiments, hepatic porphyria is Had porphyria (HARPO). In some embodiments, hepatic porphyria is delayed-onset cutaneous porphyria (PCT). In some embodiments, PCT is familial or sporadic PCT. In some embodiments, hepatic porphyria is hepatorepologenic porphyria (HEP). In some implementations, patients with acute hepatic porphyria (e.g., AIP) or asymptomatic patients carrying mutations associated with acute hepatic porphyria (e.g., AIP) have elevated ALA and / or PBG levels compared to healthy individuals. In such cases, ALA and / or PBG levels may 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 has neuropathy. In some cases, the patient has progressive neuropathy.

[0194] In some embodiments, the subject experiences an acute exacerbation of hepatic porphyria. In some embodiments, the patient experiences a non-acute exacerbation of hepatic porphyria. In some embodiments, the subject has never experienced an acute exacerbation of hepatic porphyria. In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject has neurological 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 developing hepatic porphyria (e.g., carrying a mutation associated with hepatic porphyria) and is asymptomatic. In some embodiments, the subject previously experienced an acute exacerbation of hepatic porphyria but was asymptomatic at the time of treatment.

[0195] 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 elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, prophylactic treatment begins in adolescence. In some embodiments, the treatment lowers the levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG) (e.g., plasma or urine levels). In some embodiments, the treatment prevents the development of elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the treatment prevents the development of symptoms associated with hepatic porphyria (e.g., pain or nerve damage) or reduces the frequency or severity of symptoms associated with hepatic porphyria (e.g., pain or nerve damage).

[0196] This application further provides the use of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof in the manufacture of a preparation for treating hepatic porphyria in a subject.

[0197] In some embodiments, the subject treated according to the method suffers from pain, such as chronic pain. In some embodiments, the method effectively treats the pain (e.g., by reducing the severity of the pain or curing the pain). In some embodiments, the method effectively reduces or prevents nerve damage.

[0198] 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 effectively reduce elevated ALA and / or PBG levels, and / or treat the pain (e.g., by reducing the severity of the pain or curing the pain).

[0199] In some embodiments, the subject is a subject who has experienced one or more acute episodes of one or more symptoms of hepatic porphyria. In other embodiments, the subject is a subject with a long-term history of 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.

[0200] As used herein, “prodromal symptoms” include any symptoms that an individual subject experiences immediately prior to the onset of an acute attack. Typical symptoms of prodromal symptoms 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 prodromal symptoms. In some embodiments, the subject experiences nausea during the prodromal symptoms. In some embodiments, the subject experiences psychological symptoms (e.g., anxiety) during the prodromal symptoms. In some embodiments, the subject becomes restless and / or suffers from insomnia during the prodromal symptoms.

[0201] Typically, in patients carrying mutations associated with hepatic porphyria (e.g., mutations in genes encoding enzymes in the porphyrin pathway), an acute “attack” of hepatic porphyria involves the onset of one or more symptoms of hepatic porphyria.

[0202] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered after an acute exacerbation of hepatic porphyria. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered during an acute exacerbation of hepatic porphyria. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively reduces the severity of the exacerbation (e.g., by improving one or more signs or symptoms associated with the exacerbation). In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively shortens the duration of the exacerbation. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively prevents the exacerbation. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered prophylactically to prevent acute exacerbations of hepatic porphyria. In some embodiments, prophylactic administration is performed before, during, or after exposure to or occurrence of a precipitating factor. In some embodiments, the subject is at risk of developing porphyria.

[0203] As used herein, “precipitating factor” refers to an endogenous or exogenous factor that may induce an acute onset of one or more symptoms associated with porphyria. Precipitating factors include fasting (or other forms of reduced or insufficient calorie intake such as rapid-acting diets, long-distance running, 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, antimicrobial agents, and components of alcoholic beverages), endocrine factors (e.g., reproductive hormones (which women may experience exacerbation during the premenstrual period), synthetic estrogens, progesterone, ovulation stimulants, and hormone replacement therapy), and lead. Other common precipitating factors include drugs that induce cytochrome P450 and phenobarbital.

[0204] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered during prodromal symptoms. In some embodiments, 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, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered during a specific phase of the menstrual cycle (e.g., the luteal phase).

[0205] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively prevents seizures (e.g., recurrent seizures associated with prodromal symptoms and / or precipitating factors such as a specific phase of the menstrual cycle, e.g., the luteal phase). In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively reduces the frequency of seizures. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively reduces the severity of seizures (e.g., by improving one or more signs or symptoms associated with a seizure). In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively shortens the duration of a seizure. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively stops seizures.

[0206] In some embodiments, administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively prevents or reduces the frequency or severity of pain (e.g., neuropathic pain). In some embodiments, administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively prevents or reduces the frequency or severity of neuropathy. In some embodiments, the subject has 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.

[0207] The effects of administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof can be established, for example, by comparison with an appropriate control. For example, a reduction in the frequency of acute attacks, and a reduction in the levels of one or more porphyrins or porphyrin precursors, can be determined, for example, by a reduction in frequency in a group of patients with AIP compared to an appropriate control group. The control group (e.g., a group of similar individuals or the same group of individuals in a crossover design) may include, for example, an untreated group, a group already treated with conventional treatment for hepatic porphyria (e.g., conventional treatment for AIP may include glucose, heme chloride, or both); or a group already treated with placebo or a GlyT1 inhibitor (optionally in combination with one or more conventional treatments for hepatic porphyria (e.g., glucose, such as intravenous glucose)).

[0208] As used in this article, subjects “at risk” for 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 biosynthesis pathway, as well as subjects carrying genetic alterations (e.g., mutations) known to be associated with hepatic porphyria.

[0209] In some embodiments, the alteration (e.g., mutation) makes an individual more susceptible to acute exacerbations (e.g., after exposure to precipitating factors such as drugs, diets, or other precipitating factors, 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 velocities.

[0210] In some embodiments, the alteration is a mutation in a gene selected from the following: ALAD, HMBS, UROD, CPOX, and PPOX. In some embodiments, the alteration is an alteration (e.g., a mutation) in a gene encoding an enzyme in the heme biosynthesis pathway. In some embodiments, the subject has a genetic alteration but does not experience an acute attack. In some embodiments, the subject has a mutation associated with AIP, HCP, VP, ADP, PCT, or HEP.

[0211] In some embodiments, hepatic porphyria is AIP. In some such embodiments, the subject has an alteration in PBGD (the gene encoding PBG deaminase), such as at least one mutation. Many PBGD mutations are known in the art. In some embodiments, the subject is heterozygous for the PBGD mutation. In other embodiments, the subject is homozygous for the PBGD mutation. A homozygous subject may carry two identical mutations or two different mutations in the PBGD gene. In some embodiments, hepatic porphyria is HCP. In some embodiments, the subject has an alteration in CPOX (i.e., the gene encoding the enzyme coproporphyrinogen III oxidase), such as at least one mutation. In some embodiments, hepatic porphyria is VP. In some embodiments, the subject has an alteration in PPOX (i.e., the gene encoding protoporphyrinogen oxidase), such as at least one mutation. In some embodiments, hepatic porphyria is ADP (e.g., autosomal recessive ADP). In some embodiments, the subject has an alteration in ALAD (the gene encoding ALA dehydratase), such as at least one mutation. In some embodiments, hepatic porphyria is PCT. In some embodiments, the subject has an alteration in UROD (the gene encoding uroporphyrinogen decarboxylase), such as at least one mutation. In some embodiments, hepatic porphyria is CEP. In some embodiments, the subject has an alteration in UROS (the gene encoding uroporphyrinogen III synthase), such as at least one mutation.

[0212] In some embodiments, the increased porphyrin precursor levels are due to lead poisoning. Lead poisoning inhibits the activity of each of the enzymes involved in heme biosynthesis: ALAD, CPOX, and FECH. Patients with lead poisoning are often misdiagnosed with ADP or other acute porphyria. In some embodiments, the ALAD enzyme activity is decreased in subjects with lead poisoning. In some embodiments, the CPOX enzyme activity is decreased in subjects with lead poisoning. In some embodiments, the FECH enzyme activity is decreased in subjects with lead poisoning. In some embodiments, the lead levels in the blood and / or urine of subjects with lead poisoning are increased. In some embodiments, the ALA levels in subjects with lead poisoning are increased. In some embodiments, the ALA and PBG levels in subjects with lead poisoning are increased. In some embodiments, the ALA levels in subjects with lead poisoning are at least 10 times higher than the reference value. In some embodiments, the ALA levels in subjects with lead poisoning are at least 5 times higher than the reference value. In some embodiments, this disclosure relates to a method of treating lead poisoning in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) 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.

[0213] Porphyrins (e.g., 5-ALA, PBG, uroporphyrin, and coprophyrin) can be found in a variety of biological samples, including skin, urine, feces, plasma, and erythrocytes. In some embodiments, porphyrins can be extracted from biological samples (e.g., plasma) into solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., 400-420 nm light). Porphyrins have a maximum absorption wavelength near 400-420 nm, with their highest absorption peak appearing at 415 nm. The maximum emission of porphyrins is typically around 600 nm and varies slightly depending on the type of porphyrin and the solvent used for analysis. In some embodiments, the diagnosis of hepatic porphyria can be performed using fluorescence analysis. In some embodiments, skin porphyrin levels can be measured by calculating the difference in skin porphyrin levels before and after complete photobleaching using controlled illumination. See, for example, Heerfordt IM.Br J Dermatol.2016;175(6):1284-1289.

[0214] In some embodiments, when irradiated with blue light (e.g., 400-420 nm), the subject's plasma porphyrins fluoresce at a peak of 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm), the subject's plasma porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm), the subject's skin porphyrins fluoresce at a peak of 632 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm), the subject's skin porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm), a sample (e.g., plasma or skin) from the subject containing porphyrin or a porphyrin precursor fluoresces with a peak between 615 nm and 620 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), samples from the subject containing porphyrin or porphyrin precursors (e.g., plasma or skin) fluoresce, with peaks between 624 nm and 627 nm. In some embodiments, a 405 nm laser is used to excite the subject's plasma. In some embodiments, the subject has red fluorescent urine.

[0215] Erythropoietic protoporphyria, X-linked protoporphyria, and congenital protoporphyria

[0216] Erythropoietic porphyria

[0217] Erythropoietic protoporphyria (EPP) is a global epidemic affecting approximately 5,000–10,000 individuals worldwide (Michaels et al., 2010). EPP is considered the most common form of porphyria in children. Erythropoietic protoporphyria is a form of porphyria that varies in severity and can be very painful. It stems from a deficiency of ferrochelatase, resulting in abnormally high levels of protoporphyrin IX in red blood cells, plasma, skin, and liver. Erythropoietic protoporphyria is caused by a hereditary or acquired defect in ferrochelatase activity. X-linked protoporphyria (XLPP) is caused by a hereditary increase in δ-aminolevulinic acid synthase-2 (ALAS2) activity. The enzymes that cause both EPP and XLPP are in the heme biosynthesis pathway. EPP and XLPP are clinically very similar. Congenital erythropoietic porphyria (CEP), also known as Gunther disease, is caused by mutations in the uroporphyrinogen synthase gene, leading to reduced enzyme activity and the accumulation of the upstream metabolite coproporphyrin I. Current treatments for erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) are limited. Therefore, there is a need for novel methods and compositions for the treatment and / or prevention of erythropoietic protoporphyria, X-linked protoporphyria, and congenital erythropoietic porphyria. Methods and uses of glycine transporter inhibitors, such as, but not limited to, GlyT1 inhibitors (e.g., compounds of formula (I) (e.g., any one of compounds 1-60) or pharmaceutically acceptable salts thereof), meet these and other needs.

[0218] This application provides a method for preventing or treating a subject’s impairment related to PPIX accumulation, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0219] Partially, this application relates to methods for treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP), said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this application provides methods for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. These methods are particularly intended for therapeutic and preventative treatment in animals, and more particularly in humans. 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 domesticated animals, etc.), and rodents (e.g., mice and rats). In a particular embodiment, the patient, subject, or individual is a human.

[0220] This application provides a method for preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) or a related syndrome (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. This application further provides a method for preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. For example, this application provides a method for treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0221] This application further provides a method for preventing or treating EPP, XLPP, or CEP in a subject, or a related syndrome thereof (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome), the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. This application further provides a method for preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some of the above embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0222] Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLPP) are erythropoietic cutaneous porphyria characterized by acute non-blistering photosensitivity, sun intolerance, and a significantly reduced quality of life. EPP is caused by a partial deficiency of ferrous chelate synthase (FECH), which catalyzes the final step in the heme biosynthesis pathway. FECH deficiency increases the levels of metal-free erythrocyte PPIX (also referred to herein as “free protoporphyrin IX” and “PPIX”). XLPP is typically caused by a C-terminal deletion in the ALAS2 gene that results in a gain-of-function mutation. These gain-of-function mutations increase the enzymatic activity of ALAS2 and lead to the accumulation of both metal-free PPIX and zinc-bound PPIX. Both EPP and XLPP result in the accumulation of PPIX in erythrocytes and other tissues or bodily fluids (e.g., skin, liver, bile, or feces). PPIX is lipophilic and eliminated via bile, exhibiting hepatotoxicity at high concentrations.

[0223] Patients with EPP or XLPP typically develop photosensitivity in early childhood. They frequently experience symptoms such as burning, itching, painful erythema, and edema in sun-exposed areas. Skin symptoms are sometimes associated with abnormal liver enzyme activity, hepatobiliary damage (such as jaundice and cirrhosis), iron deficiency, and corresponding microcytic anemia.

[0224] The diagnosis of EPP and XLPP can be determined by measuring the levels of total erythrocytes, free protoporphyrin IX, and zinc-protoporphyrin IX in hemolyzed and anticoagulated whole blood. The diagnosis of EPP and / or XLPP can be based on an increase in the level of free protoporphyrin IX in the blood. Patients with XLPP have a significantly higher ratio of zinc-protoporphyrin IX to free protoporphyrin IX (e.g., > 25%) compared to patients with EPP (e.g., ≤ 15%).

[0225] The diagnosis of EPP can also be determined by measuring the level of ferrochelatase activity in a subject. Ferrochelatase is a mitochondrial enzyme that catalyzes the insertion of ferrous iron into PPIX to form heme. Ferrochelatase also catalyzes the insertion of zinc to form zinc protoporphyrin IX (ZPPIX) from any PPIX remaining after heme synthesis is complete. In EPP, free PPIX accumulates in bone marrow reticulocytes because the formation of both heme and ZPPIX is impaired. In some embodiments, this disclosure relates to a method of treating a subject whose ferrochelatase activity level is reduced to between 10% and 35% of the ferrochelatase activity level observed in normal subjects. In some embodiments, this disclosure relates to a method of treating a subject whose ferrochelatase activity level is reduced to less than 50% of the ferrochelatase activity level observed in normal subjects.

[0226] XLPP has a similar phenotype to EPP and can be distinguished based on genetic analysis of ALAS2 or by determining the enzyme activity level of ALAS2. In some embodiments, this disclosure relates to a method for treating a subject with a gain-of-function mutation in ALAS2. In some embodiments, the subject's ALAS2 enzyme activity is increased. Because XLPP does not lack ferrochelate, some of the excess PPIX measured in erythrocytes is ZPPIX, and a low percentage (e.g., 50%-85%) is metal-free. In some embodiments, the subject's zinc-protoporphyrin IX level in erythrocytes is increased. In some embodiments, the method reduces the subject's zinc-protoporphyrin IX level in erythrocytes. In some embodiments, the method reduces the subject's zinc-protoporphyrin IX level in erythrocytes by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0227] In some aspects, this disclosure relates to a method of treating a subject with erythropoietic protoporphyria (EPP) and / or X-linked protoporphyria (XLPP), the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject has increased PPIX levels. In some embodiments, the method relates to a subject having a PPIX level at least 10%, 20%, 30%, 40%, or 50% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a PPIX level at least 10% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a PPIX level at least 20% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a PPIX level at least 30% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a PPIX level at least 40% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a PPIX level at least 50% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's fecal protoporphyrin IX level is increased. In some embodiments, the level of protoporphyrin IX in the subject's skin is increased. In some embodiments, the level of free protoporphyrin IX in the subject's erythrocytes is increased. In some embodiments, the subject's erythrocytes have a protoporphyrin IX level greater than 31 µmol L⁻¹. In some embodiments, the subject's erythrocytes have a protoporphyrin IX level between 31 µmol L⁻¹ and 53 µmol L⁻¹. In some embodiments, the subject's erythrocytes have a protoporphyrin IX level greater than 53 µmol L⁻¹.

[0228] This application further provides a method for inhibiting PPIX synthesis in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure relates to a method for inhibiting PPIX synthesis in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 20%. In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 30%. In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 40%. In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 50%. In some embodiments, this disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 60%. In some embodiments, this disclosure relates to a method for inhibiting at least 70% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of PPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of PPIX synthesis in vivo. This application further provides a method for reducing the rate of PPIX synthesis in vivo, said method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments of the methods and uses disclosed herein, PPIX accumulation is inhibited directly or indirectly. In some such embodiments, PPIX accumulation is inhibited in a dose-dependent manner.

[0229] In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject. In some embodiments, the method involves reducing the level of free protoporphyrin IX in the erythrocytes of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the erythrocytes of a subject to below 53 µmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the erythrocytes of a subject to below 31 µmol L⁻¹. In some embodiments, the method reduces the level of protoporphyrin IX in the erythrocytes of a subject to below 15 µmol L⁻¹. In some embodiments, the method involves reducing the level of protoporphyrin IX in the feces of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the skin of a subject. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 15%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 20%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 25%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 30%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 35%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 40%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 45%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 50%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 55%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 60%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 65%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 70%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 75%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 80%.In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 85%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 90%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 95%. In some embodiments, the method involves reducing the level of free protoporphyrin IX in a subject by at least 100%.

[0230] In some aspects, this disclosure relates to a method of treating X-linked protoporphyria (XLPP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject has an increased level of zinc-protoporphyrin IX (ZPPIX). In some embodiments, the method relates to a subject having a ZPPIX level at least 10%, 20%, 30%, 40%, or 50% higher than the ZPPIX level of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a ZPPIX level at least 10% higher than the ZPPIX level of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a ZPPIX level at least 20% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a ZPPIX level at least 30% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a ZPPIX level at least 40% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a ZPPIX level at least 50% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's ZPPIX level in red blood cells is increased.

[0231] In some aspects, this disclosure relates to a method of treating a subject with X-linked protoporphyria (XLPP), the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject has an increased ratio of zinc-protoporphyrin IX (ZPPIX) to free protoporphyrin IX (ZPPIX / PPIX ratio) compared to a subject with EPP. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 15% (e.g., 15%, 20%, 25%, 30%, 35%, 40%, or 45%). In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 20%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 25%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 30%. In some embodiments, the method involves subjects having a ZPPIX / PPIX ratio of at least 35%. In some embodiments, the method involves subjects having a ZPPIX / PPIX ratio of at least 40%. In some embodiments, the method involves subjects having a ZPPIX / PPIX ratio of at least 45%.

[0232] In some aspects, this disclosure relates to a method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 20%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 30%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 40%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 50%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 60%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of ZPPIX in vivo by at least 70%. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of ZPPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of ZPPIX synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of ZPPIX synthesis in vivo.

[0233] In some aspects, this disclosure relates to a method of treating a subject with erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP), the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject has elevated levels of 5-aminolevulinic acid (5-ALA). In some embodiments, the method relates to a subject having a 5-ALA level at least 10%, 20%, 30%, 40%, or 50% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a 5-ALA level at least 10% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a 5-ALA level at least 20% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a 5-ALA level at least 30% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a 5-ALA level at least 40% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a 5-ALA level at least 50% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0234] In some aspects, this disclosure relates to a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 20%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 30%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 40%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 50%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 60%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-ALA in vivo by at least 70%. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of 5-ALA synthesis in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of 5-ALA synthesis in vivo.

[0235] This application further provides the use of one or more compounds selected from formula (I) (e.g., any one of compounds 1-60) or pharmaceutically acceptable salts thereof in the manufacture of formulations for treating subjects with EPP, XLPP, CEP, or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome). In some embodiments, this application provides the use of one or more compounds of formula (I) (e.g., any one of compounds 1-60) or pharmaceutically acceptable salts thereof in the manufacture of formulations for treating subjects with EPP, XLPP, or CEP.

[0236] This application provides for the use of compounds of formula (I) (e.g., any one of compounds 1-60) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceutical compositions for treating subjects with EPP, XLPP, or CEP or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome). In some of the above embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0237] Congenital erythropoietic porphyria (CEP) is a type of erythropoietic cutaneous porphyria characterized by blistering, photosensitivity of the skin. Severe cases of CEP can occur in utero with fetal hydrops, or shortly after birth with severe blistering photosensitivity, hematuria, splenomegaly, hemolysis, and transfusion dependence. Milder cases and later-onset forms typically present with hematuria, severe blistering, and hemolytic anemia.

[0238] Individuals with chronic heme-excessive pulmonary embolism (CEP) are typically homozygous or compound heterozygous for UROS mutations. Some cases of CEP are caused by mutations in the gene encoding the transcriptional regulator GATA1. These mutations lead to reduced activity of uroporphyrinogen III synthase (UROIII-S), the fourth enzyme in the heme biosynthesis pathway. Reduced UROIII-S activity results in the accumulation of hydroxymethylbilisulphran, which spontaneously forms uroporphyrinogen I, which is further metabolized into coproporphyrinogen I. Both uroporphyrinogen I and coproporphyrinogen I accumulate in tissues.

[0239] The diagnosis of CEP can be determined by analyzing the enzymatic activity of uroporphyrinogen III synthase (UROIII-S), by assessing mutations in the UROS gene, by assessing the function of the GATA-1 erythroid-specific transcription factor, by assessing mutations in GATA1, and by determining the subject's uroporphyrin I and coprophyrin I levels. In some embodiments, the subject has a mutation in UROS. In some embodiments, the subject has a gene defect in the GATA-1 erythroid-specific transcription factor. In some embodiments, the method relates to treating the subject, wherein the subject has reduced uroporphyrinogen III synthase activity. In some embodiments, increased uroporphyrin I and / or coprophyrin I levels are measured in the subject's urine or red blood cells. In some embodiments, increased coprophyrin I levels are measured in the subject's stool.

[0240] In some aspects, this disclosure relates to a method of treating a subject with congenital erythropoietic porphyria (CEP), the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject has increased levels of uroporphyrin I and / or coproporphyrin I. In some embodiments, the subject has increased levels of uroporphyrin I and / or coproporphyrin I. In some embodiments, the method relates to a subject having uroporphyrin I levels at least 10%, 20%, 30%, 40%, or 50% higher than those of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a uroporphyrin I level at least 10% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a uroporphyrin I level at least 20% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a uroporphyrin I level at least 30% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a uroporphyrin I level at least 40% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a uroporphyrin I level at least 50% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, this disclosure relates to a method of treating a subject whose coprophyrin I level is at least 10%, 20%, 30%, 40%, or 50% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coprophyrin I level at least 10% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coprophyrin I level at least 20% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a coprophytic I level at least 30% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a coprophytic I level at least 40% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method involves a subject having a coprophytic I level at least 50% higher than that of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0242] In some aspects, this disclosure relates to methods of treating a subject with EPP, XLPP, or CEP, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the dose of said pharmaceutical composition does not cause a significant reduction in heme levels. In some embodiments, the patient's PPIX level is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the patient's PPIX level is reduced by at least 55%. In some embodiments, the patient's PPIX level is reduced by at least 60%. In some embodiments, the patient's PPIX level is reduced by at least 65%. In some embodiments, the patient's PPIX level is reduced by at least 70%. In some embodiments, the patient's PPIX level is reduced by at least 75%. In some embodiments, the patient's PPIX level is reduced by at least 80%. In some embodiments, the patient's PPIX level is reduced by at least 85%. In some embodiments, the patient's PPIX level is reduced by at least 90%. In some embodiments, the patient's PPIX level is reduced by at least 95%. In some implementations, the patient's PPIX level is reduced by at least 100%. In some implementations, the patient's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some implementations, the patient's heme level is reduced by no more than 15%. In some implementations, the patient's heme level is reduced by no more than 20%. In some implementations, the patient's heme level is reduced by no more than 25%. In some implementations, the patient's heme level is reduced by no more than 30%.

[0243] In some embodiments, the accumulation of one or more heme intermediates is inhibited, wherein the one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some embodiments, this disclosure relates to a method for inhibiting PPIX accumulation, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX accumulation, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I accumulation, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the accumulation of coprophyrin I, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the accumulation of 5-ALA, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the accumulation of one or more heme intermediates (e.g., PPIX, ZPPIX, uroporphyrin I, coprophyrin I, and / or 5-ALA) is inhibited in a dose-dependent manner.

[0244] When the liver burden exceeds the tubular excretory capacity, the accumulation of protoporphyrins in EPP, XLPP, and CEP can cause liver injury. Accumulation of PPIX in hepatocytes and bile tubules can lead to cell damage, cholestasis, cell lysis, and further retention of protoporphyrins. Excessive protoporphyrins can exert a cholestatic effect, leading to changes in the hepatobiliary system ranging from mild inflammation to fibrosis and cirrhosis (e.g., cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease). Between 3% and 5% of EPP or XLPP patients develop protoporphyrin-related liver disease, a potentially rapidly progressing and severe liver disease requiring liver transplantation. Approximately 2% of patients will develop severe liver disease.

[0245] In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of liver disease associated with EPP, XLPP, or CEP in a subject, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is cholelithiasis. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is mild liver disease. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is severe liver disease. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is end-stage liver disease.

[0246] Liver function in patients with EPP, XLPP, and CEP can be assessed using a variety of known clinical assays. In some embodiments, liver function tests may be used to determine levels of various biochemical parameters (e.g., elevated aspartate aminotransferase, alkaline phosphatase, or gamma-glutamyl transferase levels). In some embodiments, histopathology of a liver biopsy may be used to assess one or more parameters in the subject (e.g., protoporphyrin deposition, fibrosis, infiltration, portal fibrosis, and periportal fibrosis). In some embodiments, ultrastructural studies of the biopsy specimen may be used to determine the presence of crystalline vacuoles in the subject. As liver function deteriorates, urinary comatose porphyrin excretion increases. In some embodiments, urinary comatose porphyrin excretion may be analyzed to assess liver function in the subject. In some embodiments, ultrasound or magnetic resonance elastography may be used to measure liver stiffness in the subject.

[0247] In some embodiments of the methods and uses disclosed herein, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit PPIX inhibition with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In some embodiments of this application, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit PPIX inhibition with an EC50 of less than 100 nM. In some embodiments of this application, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit PPIX inhibition with an EC50 of less than 50 nM. In some such embodiments, EC50 is measured in a flow cytometry assay.

[0248] In some embodiments of the methods and uses disclosed herein, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit PPIX inhibition with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In some embodiments of this application, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit PPIX inhibition with an EC50 of less than 100 nM. In some embodiments of this application, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit PPIX inhibition with an EC50 of less than 50 nM. In some such embodiments, EC50 is measured in a flow cytometry assay.

[0249] In some embodiments of the methods and uses disclosed herein, cell viability is maintained at at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. In some such embodiments, cell viability is maintained at at least 90%.

[0250] Heme and heme intermediates

[0251] Glycine is one of the key starting substrates for the synthesis of heme and globin. Therefore, a decrease in glycine levels due to GlyT1 inhibition may lead to a decrease in heme synthesis. In some aspects, this disclosure relates to a method of treating a subject with hepatic porphyria, EPP, XLPP, or CEP, said method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, this disclosure relates to a method of treating a subject with hepatic porphyria, EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 15%. In some embodiments, this disclosure relates to a method of treating a subject with hepatic porphyria, EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 20%. In some embodiments, this disclosure relates to methods for treating a subject with hepatic porphyria, EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 25%. In some embodiments, this disclosure relates to methods for treating a subject with hepatic porphyria, EPP, XLPP, or CEP, wherein the subject's heme level is reduced by no more than 30%. In some aspects, this disclosure relates to methods for treating a subject with hepatic porphyria, EPP, XLPP, or CEP, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the dose of said pharmaceutical composition does not cause a significant reduction in heme levels.

[0252] 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, hydroxymethylcholanthane, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isofacoporphyrin, bile pigmentogen; and protoporphyrinogen IX. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in a subject, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject suffers from hepatic porphyria, EPP, XLPP, or CEP. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coproporphyrin III in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of zinc protoporphyrin IX (ZPPIX) in a subject, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject suffers from ALA dehydratase porphyrinosis (ADP). In some embodiments, this disclosure relates to a method for inhibiting the synthesis of bile pigmentogen (PBG) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and bile pigmentogen (PBG) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of hydroxymethylcholestyranne (HMB) in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of uroporphyrin III in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of heptacarboxy-porphyrin in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.In some embodiments, this disclosure relates to a method for inhibiting the synthesis of isoflavone porphyrin in vivo, the method comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the synthesis of one or more heme intermediates (e.g., 5-ALA, coprophyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxy-porphyrin, and isoflavone porphyrin) is inhibited in a dose-dependent manner.

[0253] 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, hydroxymethylcholanthane, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isofacoporphyrin, bile pigmentogen; 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 isofacoporphyrin) is inhibited in a dose-dependent manner.

[0254] In some embodiments, the subject treated according to the methods described herein has elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the subject's porphyrin precursor levels prior to administration of the drug are at least 10%, 20%, 30%, 40%, or 50% higher than those of healthy subjects. In some embodiments, the subject has increased porphyrin precursor levels. In some embodiments, the porphyrin precursor is selected from 5-ALA, HMB, coprophyrin III, ZPPIX, bile pigmentogen, uroporphyrin III, heptacarboxy-porphyrin, and isofacoporphyrin. In some embodiments, the subject's uroporphyrin III levels are increased (e.g., increased uroporphyrin III levels in urine). In some embodiments, the subject's 5-ALA levels are increased (e.g., increased 5-ALA levels in urine or plasma). In some embodiments, the subject's HMB levels are increased. In some embodiments, the subject's coprophyrin III levels are increased (e.g., increased coprophyrin III levels in urine and feces). In some embodiments, the subject's PBG levels are increased (e.g., increased PBG levels in urine). In some embodiments, the ratio of protoporphyrin to coprophyrin in the subject's feces is increased. In some embodiments, the subject's heptacarboxy-porphyrin levels are increased (e.g., increased heptacarboxy-porphyrin levels in urine or feces). In some embodiments, the subject's isoflavone porphyrin levels are increased (e.g., increased isoflavone porphyrin levels in feces). In some embodiments, the subject's ZPPIX levels in erythrocytes are increased.

[0255] The level of porphyrins or porphyrin precursors can be assessed using methods known in the art or methods described herein. In some embodiments, the level of porphyrins or porphyrin precursors (e.g., ALA or PBG) in a subject is assessed based on the absolute level of the porphyrins or porphyrin precursors (e.g., ALA or PBG) in a sample from the subject. In some embodiments, the level of porphyrins or porphyrin precursors (e.g., ALA or PBG) in a subject is assessed based on the relative level of the porphyrins or porphyrin precursors (e.g., ALA or PBG) in a 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 a 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.

[0256] Elevated porphyrin or porphyrin precursor levels (e.g., plasma or urinary levels of ALA and / or PBG) can be determined by showing that the subject's porphyrin or porphyrin precursor levels (e.g., plasma or urinary levels of ALA and / or PBG) are greater than or equal to reference values. A physician with expertise in treating porphyria will be able to determine whether porphyrin or porphyrin precursor levels (e.g., ALA and / or PBG) are elevated, for example, for the purpose of diagnosing hepatic porphyria, EPP, XLPP, or CEP, or for determining whether a subject is at risk of developing hepatic porphyria, EPP, XLPP, or CEP, for example, if the subject may be susceptible to acute exacerbations or porphyria-related symptoms such as chronic pain (e.g., neuropathic pain) and neuropathy (e.g., progressive neuropathy).

[0257] 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 mutations associated with hepatic porphyria, EPP, XLPP, or CEP and / or a group of subjects who do not have symptoms associated with hepatic porphyria, EPP, XLPP, or CEP)).

[0258] In some implementations, the reference value is the pre-disease level in the same individual. In some implementations, the reference value is the level in a reference sample or population. In some implementations, the reference value is the mean or median in a reference sample or population. In some implementations, the reference value is a value two standard deviations above the mean in a reference sample or population. In some implementations, the reference value is a value 2.5, 3, 3.5, 4, 4.5, or 5 standard deviations above the mean in a reference sample or population.

[0259] In some embodiments, the subject's plasma or urine levels of ALA or PBG are higher than reference values. In some embodiments, the subject has elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG), with the subject's ALA and / or PBG levels being at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than reference values. In some embodiments, the subject's porphyrin or porphyrin precursor (e.g., ALA and / or PBG) levels are at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the reference values.

[0260] In some implementations, the reference value is the upper limit of the reference range. As used herein, "upper limit of the reference range" refers to the upper limit of the 95% confidence interval for 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 genetic mutations associated with porphyria and / or do not have hepatic porphyria, EPP, XLPP, or CEP). Therefore, the lower limit of the reference range refers to the lower limit of the same 95% confidence interval.

[0261] In some embodiments, the subject has elevated levels (e.g., plasma or urine levels) of porphyrin or porphyrin precursors that are 2, 3, 4, or 5 times greater than or equal to a reference value (e.g., the upper limit of the reference value). In some embodiments, the subject's urine level of porphyrin or porphyrin precursors is greater than 4 times the upper limit of the reference value.

[0262] In some implementations, the subject's urinary PBG level is greater than or equal to 1.4 mmol / mol creatinine. In some implementations, the subject's urinary PBG level is greater than or equal to 4.8 mmol / mol creatinine. In some implementations, the subject's urinary PBG level is greater than or equal to about 3, 4, 5, 6, 7, or 8 mmol / mol creatinine.

[0263] In some implementations, the reference value for plasma PBG is 0.12 μmol / L. In some implementations, the subject's plasma 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 implementations, the subject's plasma PBG level is greater than or equal to 0.48 μmol / L.

[0264] In some implementations, the reference value for urinary PBG is 1.2 mmol / mol creatinine. In some implementations, the reference value for urinary PBG is 1.4 mmol / mol creatinine. In some implementations, the subject's urinary PBG level is 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 implementations, the subject's urinary PBG level is greater than or equal to 4.8 mmol / mol creatinine.

[0265] In some implementations, the reference value for plasma ALA is 0.12 μmol / L. In some implementations, 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 implementations, the subject's plasma ALA level is greater than or equal to 0.48 μmol / L.

[0266] In some implementations, the reference value for urinary ALA is 3.1 mmol / mol creatinine. In some implementations, the reference value for urinary ALA is 6.3 mmol / mol creatinine. In some implementations, the subject's urinary 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.

[0267] In some implementations, the reference value for urinary porphyrin is less than 4.5 µmol / mol creatinine. In some implementations, the subject's urinary porphyrin 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.

[0268] In some implementations, the reference value for urinary coprophyte is less than 20.7 µmol / mol creatinine. In some implementations, the subject's urinary coprophyte level 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.

[0269] In some embodiments, the reference value for plasma porphyrin is 10 nmol / L. In some embodiments, the subject's plasma porphyrin level is greater than or equal to 10 nmol / L. In some embodiments, the subject's plasma porphyrin level is greater than or equal to 8, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nmol / L. In some embodiments, the subject's plasma porphyrin level is greater than or equal to 40 nmol / L.

[0270] In some embodiments, the reference value for urinary porphyrin is 25 μmol / mol creatinine. In some embodiments, the reference value for urinary porphyrin is less than 28.4 μmol / mol creatinine. In some embodiments, the subject's urinary porphyrin level is greater than or equal to 25 μmol / mol creatinine. In some embodiments, the subject's urinary porphyrin level is greater than or equal to 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 μmol / mol creatinine.

[0271] In some implementations, the subject's porphyrin or porphyrin precursor levels (e.g., plasma or urine levels) are higher than those in 99% of healthy individuals.

[0272] In some implementations, the subject's ALA or PBG levels (e.g., plasma or urine levels) are levels that are two standard deviations higher than the average level in healthy individual samples.

[0273] In some embodiments, the subject's urinary ALA level is 1.6 times or more the average level of normal subjects (e.g., subjects not carrying mutations associated with porphyria). In some embodiments, the subject's plasma ALA level is 2 or 3 times the average level of normal subjects. In some embodiments, the subject's urinary PBG level is four times or more the average level of normal subjects. In some embodiments, the subject's plasma PBG level is four times or more the average level of normal subjects.

[0274] In some embodiments, administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof results in a reduction in the level of one or more porphyrins or porphyrin precursors as described herein (e.g., ALA and / or PBG). The reduction can be measured relative to any suitable 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 pre-treatment levels (e.g., immediately prior to treatment). The reduction in the level of porphyrin precursors, porphyrins, or porphyrin metabolites can be measured using any method known in the art.

[0275] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof effectively reduces the levels of ALA and / or PBG in a subject. The levels 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 the level of another protein or compound, such as creatinine). In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample.

[0276] In some embodiments, the method reduces the subject's 5-ALA level. In some embodiments, the method reduces the subject's 5-ALA 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 HMB level. In some embodiments, the method reduces the subject's HMB 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 coprophytin III level. In some embodiments, the method reduces the subject's coprophyrin 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 subject's urinary porphyrin 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 protoporphyrin to coprophyrin ratio. In some embodiments, the method reduces the subject's protoporphyrin to coprophyrin ratio 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 heptacarboxy-porphyrin level.In some embodiments, the method reduces the subject's heptacarboxy-porphyrin levels by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's isoflavone porphyrin levels. In some embodiments, the method reduces the subject's isoflavone porphyrin levels by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's ZPPIX levels. In some embodiments, 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%). In some embodiments, the method reduces the subject's porphyrin or porphyrin precursor (e.g., ALA or PBG) levels to normal levels. In some embodiments, normal levels are reference values ​​for porphyrin or porphyrin precursors as described herein (e.g., urinary ALA levels < 6.3 mmol / mol creatine and urinary PBG levels < 1.4 mmol / mol creatine).

[0277] In some aspects, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I and / or coprophyrin I in vivo, said methods comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I in vivo by at least 20%. In some embodiments, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I in vivo by at least 30%. In some embodiments, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I in vivo by at least 40%. In some embodiments, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I in vivo by at least 50%. In some embodiments, this disclosure relates to methods for inhibiting the synthesis of uroporphyrin I in vivo by at least 60%. In some embodiments, this disclosure relates to a method for inhibiting at least 70% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 80% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 90% of the synthesis of uroporphyrin I in vivo. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of the synthesis of uroporphyrin I in vivo.

[0278] In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 20%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 30%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 40%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 50%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 60%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 70%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 80%. In some embodiments, this disclosure relates to a method for inhibiting the synthesis of coprophyrin I in vivo by at least 90%. In some embodiments, this disclosure relates to a method for inhibiting at least 100% of coproporphyrin I synthesis in vivo.

[0279] Porphyrins (e.g., PPIX, ZPPIX, uroporphyrin I, and coprophyrin I) can be found in a variety of biological samples, including skin, urine, feces, plasma, and erythrocytes. In some embodiments, porphyrins can be extracted from biological samples into solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., 400-420 nm light). Porphyrins have a maximum absorption wavelength near 400-420 nm, with their highest absorption peak appearing at 415 nm. The maximum emission of porphyrins is typically around 600 nm and varies slightly depending on the type of porphyrin and the solvent used for analysis. In some embodiments, the diagnosis of hepatic porphyria, EPP, XLPP, and CEP can be performed using fluorescence analysis. In some embodiments, skin porphyrin levels (e.g., PPIX levels) can be measured by calculating the difference before and after complete photobleaching of PPIX using controlled illumination. See, for example, Heerfordt IM.Br J Dermatol.2016;175(6):1284-1289.

[0280] In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's plasma porphyrins fluoresce at a peak of 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's plasma porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's skin porphyrins fluoresce at a peak of 632 nm. In some embodiments, when irradiated with blue light (e.g., 400-420 nm light), the subject's skin porphyrins fluoresce at a peak between 626 nm and 634 nm. In some embodiments, the subject's skin protoporphyrin IX level is greater than 0.2 FluoDerm units (FDU). In some embodiments, the subject's skin protoporphyrin IX level is greater than 1.0 FDU. In some embodiments, the protoporphyrin IX level in the subject's skin is between 1.0 FDU and 2.5 FDU. In some embodiments, the protoporphyrin IX level in the subject's skin is greater than 2.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 0.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 1.0 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 1.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 2.0 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 2.5 FDU. In some embodiments, the subject has red fluorescent urine. In some embodiments, using plasma porphyrin fluorescence analysis, the subject has a peak between 615 nm and 620 nm.

[0281] In some aspects, the methods provided herein include administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the subject's PPIX level is reduced while the patient's heme level is substantially maintained. In some embodiments, the patient's PPIX level is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the patient's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient's PPIX level is reduced by at least 85% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 80% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 75% and the patient's heme level is reduced by no more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 70% and the patient's heme level is reduced by no more than 15%. In some implementations, the patient's PPIX level is reduced by at least 65% and the patient's heme level is reduced by no more than 15%. In some implementations, the patient's PPIX level is reduced by at least 60% and the patient's heme level is reduced by no more than 15%. In some implementations, the patient's PPIX level is reduced by at least 55% and the patient's heme level is reduced by no more than 15%. In some implementations, the patient's PPIX level is reduced by at least 50% and the patient's heme level is reduced by no more than 15%.

[0282] In some aspects, this disclosure relates to methods for treating a subject with hepatic porphyria, EPP, XLPP, or CEP, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein the dose of said pharmaceutical composition does not cause a significant decrease in heme levels. In some embodiments, the patient's PPIX level is reduced by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the patient's PPIX level is reduced by at least 55%. In some embodiments, the patient's PPIX level is reduced by at least 60%. In some embodiments, the patient's PPIX level is reduced by at least 65%. In some embodiments, the patient's PPIX level is reduced by at least 70%. In some embodiments, the patient's PPIX level is reduced by at least 75%. In some embodiments, the patient's PPIX level is reduced by at least 80%. In some embodiments, the patient's PPIX level is reduced by at least 85%. In some embodiments, the patient's PPIX level is reduced by at least 90%. In some implementations, the patient's PPIX level is reduced by at least 95%. In some implementations, the patient's PPIX level is reduced by at least 100%. In some implementations, the patient's heme level is reduced by no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some implementations, the patient's heme level is reduced by no more than 15%. In some implementations, the patient's heme level is reduced by no more than 20%. In some implementations, the patient's heme level is reduced by no more than 25%. In some implementations, the patient's heme level is reduced by no more than 30%.

[0283] In some embodiments, the accumulation of one or more heme intermediates is inhibited, wherein the one or more heme intermediates are selected from PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some embodiments, this disclosure relates to a method for inhibiting PPIX accumulation, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX accumulation, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I accumulation, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the accumulation of coprophyrin I, the method comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method for inhibiting the accumulation of 5-ALA, the method comprising administering to a subject a pharmaceutical composition comprising v. In some embodiments, the accumulation of one or more heme intermediates (e.g., PPIX, ZPPIX, uroporphyrin I, coprophyrin I, and / or 5-ALA) is inhibited in a dose-dependent manner.

[0284] Complications of porphyria

[0285] In some aspects, this disclosure relates to methods for preventing or treating one or more complications of hepatic porphyria, EPP, XLPP, or CEP in a subject, or for reducing their rate of progression and / or severity, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more complications of hepatic porphyria are selected from: acute photosensitivity, skin photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte disturbances, nausea, vomiting, constipation, diarrhea, dysuria, intestinal obstruction, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, seizures, neuropathic pain, muscle paralysis, quadriplegia, weakened respiration, respiratory arrest, hyponatremia, and cardiac arrest. Tachycardia, hypertension, tachycardia, elevated 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 keratosis, bullae, lesions, scars, deformities, nail loss, finger / toe defects, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease. In some implementations, one or more of the aforementioned complications are indirectly improved. In some implementations, one or more complications of EPP, XLPP, or CEP are selected from: acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scarring, deformities, nail loss, finger / toe defects, cholelithiasis, cholestasis, cell lysis, gallstones, cholestatic liver failure, red teeth syndrome, myelocytosis, thrombocytopenia, fetal hydrops, and / or intrauterine death. In some embodiments, this disclosure considers a method for treating one or more complications of EPP, XLPP, or CEP (e.g., acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scarring, malformations, nail loss, finger / toe defects, cholelithiasis, cholestasis, cell lysis, gallstones, cholestatic liver failure, red teeth syndrome, myelocytosis, thrombocytopenia, fetal hydrops, and / or intrauterine death), said method comprising administering to said subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, said one or more complications are indirectly improved.In some embodiments, this disclosure contemplates methods for preventing one or more complications of hepatic porphyria, EPP, XLPP, or CEP, said methods comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure contemplates methods for reducing the rate of progression of one or more complications of hepatic porphyria, EPP, XLPP, or CEP, said methods comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure contemplates methods for reducing the severity of one or more complications of hepatic porphyria, EPP, XLPP, or CEP, said methods comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0286] The treatments described herein can be used to improve one or more symptoms associated with hepatic porphyria or reduce the risk of developing porphyria-related conditions such as neuropathy (e.g., progressive neuropathy) or hepatocellular carcinoma. Symptoms associated with hepatic porphyria may include abdominal pain or cramps, headache, effects caused by neurological abnormalities, and photosensitivity, causing skin rashes, blisters, and scarring (photodermatitis). In some implementations, hepatic porphyria is AIP. Symptoms of AIP 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, progressive neuropathy, headache, neuropsychiatric symptoms (e.g., confusion, anxiety, agitation, hallucinations, hysteria, delirium, emotional blunting, depression, panic disorder, psychosis, insomnia, somnolence, coma), autonomic nervous system involvement (leading to, for example, cardiovascular symptoms (e.g., tachycardia, hypertension, and / or arrhythmias) and other symptoms such as increased circulating catecholamine levels, sweating, restlessness, and / or tremors), dehydration, and electrolyte abnormalities.

[0287] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered together with (e.g., before, after, or in parallel with) another treatment that can relieve one or more of the above-mentioned symptoms. For example, abdominal pain may be treated, for example, with a narcotic analgesic; epilepsy may be treated, for example, with an anti-seizure drug; nausea / vomiting may be treated, for example, with a phenothiazine; and tachycardia / hypertension may be treated, for example, with a beta-blocker.

[0288] Optionally, the methods disclosed herein for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in subjects may further include administering to the patient one or more supportive therapies or additional active agents for the treatment of EPP, XLPP, or CEP. For example, the patient may also be administered one or more supportive therapies or active agents selected from: sun avoidance, topical sunscreens, skin protection, UVB phototherapy, afanotide (Scenesse®), bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. In some embodiments, the methods described herein may further include administering afanotide (Scenesse®) to the patient.

[0289] Porphyrin photosensitization in certain hepatic porphyriae (e.g., VP, HCP, PCT, and HEP), EPP, XLPP, and CEP produces two distinct clinical syndromes: (1) acute photosensitivity under sunlight with erythema and edema, and (2) a syndrome in which subepidermal bullae appear in sun-exposed areas of the skin. In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of EPP, XLPP, or CEP in a subject, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, wherein said method increases the subject’s painless light exposure. In some embodiments, said method increases the subject’s painless light exposure by at least 10%, 20%, 30%, 40%, or 50% compared to painless light exposure prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, said method reduces the subject’s photosensitivity. In some embodiments, the method reduces the photosensitivity of the subject by at least 10%, 20%, 30%, 40%, or 50% compared to the photosensitivity prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a history of phototoxicity from EPP. In some embodiments, the subject is an adult, child, infant, or pregnant woman.

[0290] EC50 and application

[0291] In some embodiments of the methods and uses disclosed herein, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit inhibition of porphyrin precursors (e.g., 5-ALA or PBG) with EC50 values ​​less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In some embodiments of this application, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit inhibition of porphyrin precursors (e.g., 5-ALA or PBG) with EC50 values ​​less than 100 nM. In some embodiments of this application, compounds of formula (I) (e.g., any of compounds 1-60) or pharmaceutically acceptable salts thereof exhibit inhibition of porphyrin precursors (e.g., 5-ALA or PBG) with EC50 values ​​less than 50 nM. In some embodiments, EC50 is measured in a flow cytometry assay. In some implementations, EC50 is measured in an LC-MS / MS assay.

[0292] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered to prevent recurrent episodes (e.g., cyclical episodes associated with a precipitating factor) or to reduce their severity or frequency. In some embodiments, the precipitating factor is the menstrual cycle. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered repeatedly (e.g., at regular intervals) to prevent recurrent episodes (e.g., cyclical episodes associated with a precipitating factor (e.g., the menstrual cycle, such as a specific phase of the menstrual cycle, such as the luteal phase)) or to reduce their severity or frequency. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof 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 hormone levels associated with a specific phase of the menstrual cycle). In some implementations, on one or more specific days of the menstrual cycle, such as 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), a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered during the luteal phase (e.g., one or more days between day 14 and day 28 of the menstrual cycle, or a later day in subjects with menstrual cycles longer than 28 days)). In some embodiments, ovulation of the subject is assessed (e.g., using a blood or urine test to detect ovulation-related hormones (e.g., LH), and a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered at predetermined intervals after ovulation. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered immediately after ovulation. In some implementations, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof 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 may optionally be repeated in one or more iterations.The number of iterations can depend on the desired effect, such as the achievement of a therapeutic or preventative effect, such as reducing or preventing one or more symptoms associated with hepatic porphyria, EPP, XLPP, or CEP, to reduce the frequency of attacks associated with hepatic porphyria, EPP, XLPP, or CEP.

[0293] In some embodiments, an initial dose of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered, and ALA or PBG levels are tested, for example, 1-48 hours (e.g., 2, 4, 8, 12, or 24 hours) after administration of the initial dose. In some embodiments, if ALA and / or PBG levels decrease (e.g., a predetermined reduction, such as normalization) and / or if symptoms associated with hepatic porphyria, EPP, XLPP, or CEP (e.g., pain) improve (e.g., the patient becomes asymptomatic), no further dose is administered, but if ALA and / or PBG levels do not decrease (e.g., the predetermined reduction has not been achieved, such as normalization), a further dose of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a further dose is administered 12, 24, 36, 48, 60, or 72 hours after the initial dose. In some implementations, if the initial dose does not effectively reduce ALA and / or PBG levels, the dose is modified, for example, by increasing it, to achieve the desired reduction in ALA or PBG levels (e.g., a predetermined reduction, such as normalization).

[0294] In some implementations, the predetermined reduction is a reduction of at least 10%, 20%, 30%, 40%, or 50%. In some implementations, the predetermined reduction is a reduction that effectively prevents or improves symptoms (e.g., pain, prodromal symptoms, or recurrent attacks).

[0295] In some implementations, the predetermined reduction is a reduction of at least one, two, three or more standard deviations, wherein the standard deviations are determined based on values ​​from a reference sample (e.g., a reference sample as described herein).

[0296] In some embodiments, the predetermined reduction is to reduce the level of porphyrin or porphyrin precursor to a level less than or equal to a reference value (e.g., a reference value as described herein).

[0297] As used herein, “normalization” (or “normal” or “normalized level”) of ALA or PBG levels means that the level of ALA or PBG or both (e.g., urine and / or plasma levels) is within the expected range for healthy individuals, asymptomatic individuals (e.g., individuals who do not experience pain and / or do not have neuropathy), or individuals who do not have mutations associated with porphyria. For example, in some embodiments, the normalization level is within two standard deviations of the normal mean. In some embodiments, the normalization level is within normal reference limits, such as within a 95% confidence interval of an appropriate control sample (e.g., a sample from a healthy individual or an individual who does not carry a gene 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 levels increase above the reference value, a further dose of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered.

[0298] Administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may, for example, reduce the level of porphyrin or porphyrin precursor in a patient's cells, tissues, blood, urine, or other compartments 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. During an acute episode of AIP, administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may also reduce the level of porphyrin or porphyrin precursor.

[0299] Combination therapy

[0300] Optionally, the methods disclosed herein for preventing or treating one or more complications of porphyria (e.g., hepatic porphyria, EPP, XLPP, or CEP) in subjects, or for reducing its rate of progression and / or severity, may further include administering to the patient one or more supportive therapies or additional active agents for the treatment of porphyria (e.g., hepatic porphyria, EPP, XLPP, or CEP). For example, patients may also be given one or more supportive therapies or active agents selected from the following: avoidance of sunlight, topical sunscreen, skin protection, UVB phototherapy, afanotide (Scenesse®), bortezomib, heme infusion, adequate caloric support, gevorcilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of precipitating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venipuncture, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes via viral vector), hemodialysis, pharmacological companion therapy, proteasome inhibitors, chemical companions, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0301] In some implementations, the subject is given a combination therapy, such as a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, with one or more other treatments known to be effective against hepatic porphyria, EPP, XLPP or CEP or their associated symptoms (e.g., glucose and / or heme products such as heme chloride as described herein).

[0302] In one embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with glucose or dextrose. For example, 10%-20% dextrose in physiological saline may be administered intravenously. Typically, when glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. A compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof may also be administered intravenously as part of the same infusion for the administration of glucose or dextrose, or as a separate infusion administered before, concurrently with, or after the administration of glucose or dextrose. In some embodiments, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered via a different route of administration (e.g., subcutaneously). In yet another embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with total parenteral nutrition. A compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be administered before, concurrently with, or after total parenteral nutrition.

[0303] In some embodiments, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other treatments (e.g., another known effective treatment for porphyria or porphyria symptoms). In one embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product (e.g., heme chloride, heme arginine salt, or heme albumin). In another embodiment, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product and glucose, a heme product and dextran, or a heme product and total parenteral nutrition. One or more other treatments may be administered before, after, or concurrently with the administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof. A compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be administered in combination with an additional therapeutic agent in the same composition (e.g., intravenously), or the additional therapeutic agent may be administered as 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., heme chloride, heme arginine salt, or heme albumin).

[0304] In some embodiments, administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof, or administration of a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof, in combination with one or more other treatments (e.g., glucose, dextrose), may reduce the frequency of acute attacks (e.g., by preventing acute attacks from occurring again, or by reducing the number of attacks occurring within a certain period of time, e.g., fewer attacks per year). In some such embodiments, a compound of formula (I) (e.g., any of compounds 1-60) or a pharmaceutically acceptable salt thereof is administered according to a regular dosing regimen, such as twice daily, once daily, once weekly, once every two weeks, or once monthly.

[0305] Anemia associated with ribosome dysfunction

[0306] Mutations in the ribosomal protein (RP) gene or other transcription factors (e.g., GATA1) can lead to the loss of erythrocyte progenitor cells and cause anemia associated with ribosomal dysfunction. One example of anemia associated with ribosomal dysfunction is Diamond-Blackfan anemia (DBA), a rare blood disorder almost entirely related to haploinadequacy of the RP gene. DBA affects approximately seven per million live births and is typically diagnosed within the first year of life. Classical diagnostic criteria include: (1) macrocytic normochromic anemia; (2) reticulopenia; (3) bone marrow erythroid dysplasia; and (4) early onset of anemia (90% of cases occur before the age of one).

[0307] In patients with DBA (Dysplastic Erythroid Abnormalities), the erythrocyte precursors do not mature sufficiently, leading to congenital erythroid dysplasia and developmental defects. Affected individuals may have physical abnormalities such as craniofacial deformities, thumb or upper limb abnormalities, cleft palate, and defects in the genitals, urinary tract, eyes, and heart. In some cases, low birth weight and short stature are observed. Patients with DBA also have a moderate risk of developing leukemia and other malignancies.

[0308] Current treatment options for DBA include corticosteroids, blood transfusions, and bone marrow transplantation. Approximately 80% of DBA patients respond to an initial course of corticosteroids. However, in many patients, the efficacy of corticosteroids diminishes over time. These patients, along with the 20% who initially do not respond to this therapy, require long-term blood transfusions and iron chelation therapy. Long-term blood transfusions are known to cause iron overload in various organs, including the liver, heart, and endocrine system. Other therapies such as interleukin-3, high-dose corticosteroids, cyclosporine, anti-thymocyte globulin, immunoglobulins, and metoclopramide have unproven benefits and / or have shown to benefit only a relatively small number of people. Pharmacological doses of erythropoietin (EPO) are also ineffective. Bone marrow transplantation is the only treatment for the hematological manifestations of DBA-related anemia, but due to high morbidity and mortality, it is usually considered only for corticosteroid-resistant patients. Typically, transplantation from siblings with the same human leukocyte antigen (HLA) is considered only. For many patients, the lack of a suitable donor precludes bone marrow transplantation as a treatment option.

[0309] Therefore, there is a high unmet need for effective therapies for treating anemia associated with ribosomal dysfunction. Therefore, the purpose of this application is to provide methods for treating, preventing, or reducing the rate of progression and / or severity of anemia associated with ribosomal dysfunction. These needs include, but are not limited to, methods and uses of glycine transporter inhibitors such as, but not limited to, compounds of formula (I) (e.g., any one of compounds 1-60) or their pharmaceutically acceptable salts, as well as others.

[0310] In some aspects, this application provides the use of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating ribosomal dysfunction-related anemia in a subject of need. This application provides a method for preventing or treating ribosomal dysfunction-related anemia in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof.

[0311] Partially, this application relates to a method of treating a subject with ribosomal dysfunction-related anemia, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to a method of preventing, treating, or reducing the rate of progression and / or severity of ribosomal dysfunction-related anemia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the ribosomal dysfunction is Diamond-Blackfan anemia. In some embodiments, the ribosomal dysfunction is Schwarzmann-Diamond syndrome. In some embodiments, the ribosomal dysfunction is X-linked congenital keratosis. In some embodiments, the ribosomal dysfunction is chondrodysplasia. In certain embodiments, the patient, subject, or individual is a person.

[0312] This application provides methods for preventing or treating ribosomal dysfunction-related anemia in a subject, or for reducing its rate of progression and / or severity, said methods comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some of the embodiments described above, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0313] This application further provides the use of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof in the manufacture of a formulation for the treatment of anemia associated with ribosome dysfunction (e.g., Diamond-Blackfan anemia).

[0314] Diamond Blackfan anemia

[0315] Diamond-Black Fan anemia (DBA) is a congenital erythroid dysplasia that typically develops during the neonatal period. DBA is characterized by a low red blood cell count (anemia) and a reduction in erythroid progenitor cells in the bone marrow. In patients with DBA, the levels of other blood components, such as platelets and white blood cells, are normal. This contrasts with Schwarzmann-Diamond syndrome, in which bone marrow defects primarily result in a low neutrophil count (neutropenia).

[0316] Ribosomal protein mutations are associated with the pathophysiology of DBA. In approximately 25% of DBA patients, the first gene mutation has been identified as RPS19 (ribosomal protein S19) (Gustavsson et al., Nat Genet. 1997 Aug; 16(4): 368-71; Draptchinskaia et al., Nat Genet. Feb. 1999; 21(2): 169-75). Sequencing of patient samples has identified mutations in the large (60S) or small (40S) subunit ribosomal protein in more than 50% of patients (Vlachos et al., BrJ Haematol. Sep. 2008; 142(6): 859-876). The identified genes include, but are not limited to, RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28, and RPS29, as well as three other non-RP genes, TSR2, GATA1, and EPO (Da Costa L et al. F1000 Res. 2018;7). All patients identified to date are heterozygous for these mutations and consistently maintain wild-type copies of the affected RP genes. However, approximately 30% of individuals with DBA do not have detectable RP mutations. Some phenotypic / genotypic correlations are known to be associated with congenital abnormalities. Ibid.

[0317] DBA exists in many subtypes, each caused by different mutations in various genes. For example, Diamond Blackfan anemia-1 (DBA1, OMIM #105650) is caused by a heterozygous mutation in the RPS19 gene on chromosome l9ql3. Other forms of DBA include DBA2 (OMIM #606129), caused by mutations on chromosome 8p23-p22; DBA3 (OMIM #610629), caused by mutations in the RPS24 gene on l0q22; DBA4 (OMIM #612527), caused by mutations in the RPS17 gene on 15q; DBA5 (OMIM #612528), caused by mutations in the RPL35A gene on 3q29; DBA6 (OMIM #612561), caused by mutations in the RPL5 gene on lp22; DBA7 (OMIM #612562), caused by mutations in the RPL11 gene on lp36; DBA8 (OMIM #612563), caused by mutations in the RPS7 gene on 2p25; DBA9 (OMIM #613308), caused by mutations in the RPS10 gene on 6p; DBA10 (OMIM #610629), caused by mutations in the RPS24 gene on 10q2 ... DBA11 (OMIM #613309), caused by a mutation in the RPL26 gene on chromosome 12q; DBA12 (OMIM #615550), caused by a mutation in the RPL15 gene on chromosome 3p24; DBA13 (OMIM #615909), caused by a mutation in the RPS29 gene on chromosome 14q; DBA14 (OMIM #300946), caused by a mutation in the SR2 gene on Xpl 1; DBA15 (OMIM #606164), caused by a mutation in the RPS28 gene on chromosome 19p 13; DBA16 (OMIM #617408), caused by a mutation in the RPL27 gene on chromosome 17q21; and DBA17 (OMIM #617409), caused by a mutation in the RPS27 gene on chromosome 1q21.

[0318] Mutations in ribosomal proteins impair their function, leading to ribosomal dysfunction and increased stress. Impaired ribosomal biogenesis is associated with p53 induction and cell cycle arrest. Knockdown of ribosomal proteins results in an increase in free ribosomal proteins. Some ribosomal proteins (including RPL11, RPL5, and RPL13) bind to MDM2 and block MDM2-mediated p53 ubiquitination and degradation (Lindstrom et al., Cell Cycle 6:4, 434-437, February 15, 2007; Fumagalli et al., Nat Cell Biol. April 2009; ll(4):50l-8). Other ribosomal proteins may activate p53 through different mechanisms. For example, RPL26 has been found to enhance the translation rate of p53 mRNA by binding to its 5' untranslated region (Tagaki et al., Cell. October 7, 2005; l23(l):49-63). The negative impact of DBA on ribosomal protein function leads to reduced globin synthesis, which is essential for hemoglobin production. Heme synthesis appears unaffected. This imbalance between heme synthesis and globin results in the accumulation of free heme in DBA-affected erythroid cells (Rio S et al. Blood. 2019;133(12):1358-1370). Heme is cytotoxic by increasing the production of reactive oxygen species, lipid peroxidation, and apoptosis. Consequently, excessive heme levels due to the heme / globin imbalance have detrimental effects on erythropoiesis.

[0319] Typically, DBA is diagnosed through blood counts and bone marrow biopsy. The diagnosis is based on anemia, low reticulocyte (immature red blood cell) counts, and a reduction in erythroid precursors in the bone marrow. Supporting features for a DBA diagnosis include the presence of congenital abnormalities, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells. Most patients are diagnosed within the first two years of life. However, some mildly affected individuals only receive attention after more severely affected family members are identified. Genetic testing is commonly used to identify mutations in ribosomal protein genes and other non-ribosomal protein genes. Mutations in the RPS19 gene can be identified in approximately 20-25% of DBA patients using genetic testing. Approximately 10-25% of DBA cases have a family history, and most pedigrees show an autosomal dominant inheritance pattern.

[0320] In some aspects, this disclosure relates to methods for treating ribosomal dysfunction-related anemia in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of ribosomal dysfunction-related anemia in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the ribosomal dysfunction-related anemia is Diamond Blackfan anemia (DBA). In some embodiments, DBA is caused by a haploinadequacy of a ribosomal protein selected from the following: 40S ribosomal protein S14 (RPS14), 40S ribosomal protein S19 (RPS19), 40S ribosomal protein S24 (RPS24), 40S ribosomal protein S17 (RPS17), 60S ribosomal protein L35a (RPL35a), 60S ribosomal protein L5 (RPL5), 60S ribosomal protein L11 (RPL11), and 40S ribosomal protein S7 (RPS7). In some embodiments, DBA is caused by a haploinadequacy of a ribosomal protein selected from the following: 40S ribosomal protein S10 (RPS10), 40S ribosomal protein S26 (RPS26), 60S ribosomal protein L15 (RPL15), 60S ribosomal protein L17 (RPL17), 60S ribosomal protein L19 (RPL19), 60S ribosomal protein L26 (RPL26), 60S ribosomal protein L27 (RPL27), 60S ribosomal protein L31 (RPL31), 40S ribosomal protein S15a (RPS15a), 40S ribosomal protein S20 (RPS20), 40S ribosomal protein S27 (RPS27), 40S ribosomal protein S28 (RPS28), and 40S ribosomal protein S29 (RPS29). In some implementations, the patient has one or more mutations in the ribosomal protein gene.

[0321] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be used in a method of treating anemia associated with ribosomal dysfunction, wherein the subject has a mutation in ribosomal protein 19 (RPS19). The phenotypic indications of DBA patients particularly affect hematopoietic stem cell defects in erythroid progenitor cell populations. The RPS19 protein is involved in ribosome production. Disease characteristics may be related to the nature of the RPS19 mutation. The disease is characterized by dominant inheritance and is therefore due to partial loss of RPS19 protein function.

[0322] In alternative embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be used in a method of treating anemia associated with ribosomal dysfunction, wherein the subject has a mutation in a ribosomal protein derived from at least one of, but not limited to, the following: RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28, and RPS29. For example, mutations or variants in RPS19 lead to DBA1, those in RPS24 to DBA3, those in RPS17 to DBA4, those in RPS34A to DBA5, those in RPLS to DBA6, those in RPL11 to DBA7, and those in RPS7 to DBA8. In some implementations, subjects with ribosomal disorders have mutations in non-ribosomal proteins selected from TSR2, GATA1, and EPO.

[0323] In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of ribosomal dysfunction-related anemia in a subject, said methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, said one or more complications of ribosomal dysfunction-related anemia are selected from: thrombocytosis, megakaryocyte proliferation, infection, bleeding (e.g., from the nose or gums), contusion, splenomegaly, need for more frequent transfusions, need for increased glucocorticoid use, need for allogeneic hematopoietic stem cell transplantation, need for autologous gene therapy, bone marrow failure, leukemia, and acute myeloid leukemia.

[0324] In some aspects, this disclosure relates to a method of treating a subject with splenomegaly associated with ribosomal dysfunction-related anemia, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an increased spleen size (e.g., splenomegaly). In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof reduces splenomegaly in a subject suffering from ribosomal dysfunction-related anemia (e.g., Diamond-Blackfan anemia). In some embodiments, the method reduces the spleen size of the subject. In some embodiments, the method reduces the spleen size of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the spleen size of the subject by at least 15%. In some embodiments, the method reduces the spleen size of the subject by at least 20%. In some embodiments, the method reduces the spleen size of the subject by at least 25%. In some embodiments, the method reduces the spleen size of the subject by at least 30%. In some embodiments, the method reduces the spleen size of the subject by at least 35%. In some embodiments, the method reduces the spleen size of the subject by at least 40%. In some embodiments, the method reduces the spleen size of the subject by at least 45%. In some embodiments, the method reduces the spleen size of the subject by at least 50%. In some embodiments, the method reduces the spleen size of the subject by at least 55%. In some embodiments, the method reduces the spleen size of the subject by at least 60%. In some embodiments, the method reduces the spleen size of the subject by at least 65%. In some embodiments, the method reduces the spleen size of the subject by at least 70%. In some embodiments, the method reduces the spleen size of the subject by at least 75%. In some embodiments, the method reduces the spleen size of the subject by at least 80%. In some embodiments, the method reduces the spleen size of the subject by at least 85%. In some embodiments, the method reduces the spleen size of the subject by at least 90%. In some embodiments, the method reduces the spleen size of the subject by at least 95%. In some embodiments, the method reduces the spleen size of the subject by at least 100%.

[0325] In some implementations, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be used to treat a subject with a ribosomal disorder (such as DBA) in which the subject has symptoms of macrocytic anemia and / or craniofacial abnormalities.

[0326] Schwarzman-Diamond syndrome

[0327] Schwachman-Diamond syndrome (SDS), or Schwachman-Bodian-Diamond syndrome, is a rare genetic disorder that affects many parts of the body, particularly the pancreas, bone marrow, and skeletal system. Schwachman-Diamond syndrome is inherited in an autosomal recessive pattern. Most cases of SDS are caused by mutations in the SBDS gene, located at cytogenetic location 7ql 1 on the long arm of chromosome 7. The protein encoded by SBDS is thought to play a role in RNA processing and ribosome biogenesis, but the exact mechanisms by which SBDS mutations lead to the main signs and symptoms of Schwachman-Diamond syndrome remain unclear. Typical symptoms of Schwachman-Diamond syndrome include pancreatic exocrine insufficiency, hypotonia, low blood neutrophil count (neutropenia), anemia, and skeletal dysplasia affecting the bones of the ribs and / or arms and / or legs (metaphyseal dysplasia).

[0328] Schwarzman-Diamond syndrome can be diagnosed based on clinical findings including pancreatic dysfunction and characteristic hematological abnormalities (e.g., neutropenia and thrombocytopenia). Genetic testing can be used to confirm the diagnosis. Mutations in the SBDS gene are known to cause approximately 90% of Schwarzman-Diamond syndrome cases. The remaining 10% of cases have unknown genetic causes, therefore genetic testing is not an option for these cases.

[0329] Schwarzman-Diamond syndrome is incurable. Treatment typically includes oral pancreatic enzyme replacement therapy, vitamin supplementation, blood and / or platelet transfusions, administration of granulocyte colony-stimulating factor (G-CSF), and / or hematopoietic stem cell transplantation. The lack of neutrophils in patients with Schwarzman-Diamond syndrome leads to neutropenia, making them more susceptible to infections such as pneumonia. Patients with Schwarzman-Diamond syndrome also have a higher than average chance of developing aplastic anemia and leukemia, such as acute myeloid leukemia.

[0330] In some aspects, this disclosure relates to methods for treating Schwarzman-Diamond syndrome in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of Schwarzman-Diamond syndrome in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has one or more mutations in the SBDS gene. In some embodiments, the method reduces the subject's need for hematopoietic stem cell transplantation. In some embodiments, the method reduces the subject's neutropenia. In some embodiments, the method reduces the subject's thrombocytopenia. In some embodiments, the method reduces the subject's risk of developing leukemia. In some embodiments, the method reduces the subject's risk of developing infection. In some embodiments, the method reduces the subject's risk of developing pneumonia. In some implementations, the subject has low neutrophil levels.

[0331] Congenital keratosis

[0332] Congenital dyskeratosis (also known as Zinsser-Engman-Cole syndrome) is a rare inherited form of bone marrow failure commonly associated with oral leukoplakia, nail dystrophy, and reticular pigmentation. It is most commonly inherited in an X-linked recessive manner. Therefore, males are three times more likely to be affected than females. Symptoms vary widely and may include atrophic, wrinkled skin, eye disease, and bone marrow failure. Individuals with congenital dyskeratosis have an increased risk of developing leukemia and other cancers (e.g., cancers of the head, neck, anus, or genitals) as well as fibrosis (e.g., pulmonary fibrosis and liver fibrosis).

[0333] Most patients have a mutation in the dyskerin gene (DKC1), which is directly involved in stabilizing an enzyme called telomerase, responsible for catalyzing the reaction that maintains telomere length. Without a protein like dyskerin, telomeres gradually shorten, leading to cell apoptosis or senescence. In congenital dyskeratosis, mutations have also been found in other genes, including TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, and RTEL1.

[0334] Treatment options for patients with congenital dyskeratosis are limited. In patients with congenital dyskeratosis, the only long-term treatment option for bone failure is hematopoietic stem cell transplantation. However, long-term outcomes remain poor, with an estimated 10-year survival rate of 23%. Short-term treatment options include anabolic steroids (e.g., oxymethylenetetramine), granulocyte-macrophage colony-stimulating factor (AMPF), and erythropoietin.

[0335] In some aspects, this disclosure relates to methods for treating congenital dyskeratosis in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of congenital dyskeratosis in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has congenital dyskeratosis. In some embodiments, the congenital dyskeratosis is x-linked congenital dyskeratosis. In some embodiments, the subject has one or more mutations in the DKC1 gene. In some embodiments, the subject has one or more mutations in a gene selected from: TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, PARN, CTC1, and RTEL1. In some embodiments, the method reduces the risk of bone marrow failure in the subject. In some embodiments, the method reduces the risk of pulmonary fibrosis in the subject. In some embodiments, the method reduces the risk of liver fibrosis in the subject.

[0336] Cartilage-hair dysplasia

[0337] Achondroplasia (also known as McCusick's type metaphyseal dysplasia) is a skeletal growth disorder characterized by short stature (dwarfism) accompanied by other skeletal abnormalities; thin and sparse hair; hypermobility of joints; anemia; increased risk of malignancy; gastrointestinal dysfunction; impaired spermatogenesis; and immune system dysfunction that often leads to recurrent infections. Patients with achondroplasia have a mutation in the RMRP gene (OMIM number 157660), typically a 70A→G conversion mutation. The RMRP gene encodes the non-translated RNA component of a ribonuclease (RNase MRP) that processes mitochondrial RNA.

[0338] The diagnosis of achondroplasia is primarily based on clinical findings, characteristic imaging findings, and, in some cases, evidence of immune dysfunction, macrocytic anemia, and / or gastrointestinal problems. Molecular genetic testing can be used to identify pathogenic variants of RMRP in patients.

[0339] Treatment for patients typically involves repeated blood transfusions and surgery to fuse unstable vertebrae or treat progressive kyphosis that impairs lung function. Corrective osteotomy may also be necessary to treat progressive varus deformity associated with knee ligament laxity. For immunocompromised patients, frequent treatment of underlying infections is required. Prophylactic antibiotic therapy and / or immunoglobulin replacement therapy are frequently needed. Recurrent severe infections and / or the presence of severe combined immunodeficiency (SCID) and / or severely suppressed erythropoiesis may require bone marrow transplantation.

[0340] In some aspects, this disclosure relates to methods for treating chondrodysplasia in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of chondrodysplasia in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has one or more mutations in the RMRP gene. In some embodiments, the methods reduce the subject's need for bone marrow transplantation.

[0341] Erythropoiesis defect

[0342] Erythropy generally refers to the process by which red blood cells (erythrocytes) are produced from hematopoietic stem cells (HSCs), and includes the formation of erythroid progenitor cells. Erythropy is a carefully sequenced series of events. It initially occurs in fetal hepatocytes, and in children and adults, the bone marrow takes over the process. Although a variety of cytokines and growth factors are specifically responsible for the proliferation of red blood cells, the major regulator is erythropoietin (EPO). Red blood cell development is initially regulated by stem cell factor (SCF), which enables hematopoietic stem cells to develop into erythroid progenitor cells. Subsequently, EPO continues to stimulate the development and terminal differentiation of these progenitor cells. In the fetus, EPO is produced by monocytes and macrophages found in the liver. After birth, EPO is produced in the kidneys; however, Epo messenger RNA (mRNA) and EPO protein have also been found in the brain and red blood cells (RBCs), indicating paracrine and autocrine functions.

[0343] Erythropoiesis gradually increases as increased EPO gene expression leads to higher levels of circulating EPO. EPO gene expression is known to be influenced by various factors, including hypoxemia, transition metals (Co2+, Ni2+, Mn2+), and iron chelators. However, the primary effect is hypoxia, including decreased oxygen tension, erythrocyte loss, and increased hemoglobin oxygen affinity. For example, in severe hypoxia, EPO production can increase by up to 1000-fold.

[0344] Erythropoiesis requires the proper biosynthesis of heme, and as erythroblasts mature, their demand for heme and iron increases dramatically. Erythroid cells synthesize large amounts of heme and hemoglobin, while simultaneously absorbing significant amounts of iron into the cell. An imbalance between globulin chain and heme synthesis is known to occur in erythroid cells of patients with Diamond-Black Fan anemia. This imbalance leads to the accumulation of excess free heme and increased production of reactive oxygen species.

[0345] It has been shown that blocking erythroid differentiation and proliferation in Diamond-Black Fan anemia affects immature progenitor cells or erythroid burst-forming units (BFU-e), leading to impaired hematopoiesis. Circulating EPO levels are increased in patients with Diamond-Black Fan anemia, indicating bone marrow unresponsiveness to anemia-associated EPO stimulation. An increased tendency for erythroid progenitor apoptosis has also been reported during in vitro EPO deprivation and RPS19 deficiency.

[0346] Glycine is one of the key starting substrates for heme synthesis. Therefore, decreased glycine levels due to GlyT1 inhibition may lead to reduced heme synthesis. In some aspects, this disclosure relates to a method for inhibiting heme synthesis in a subject suffering from anemia associated with ribosome dysfunction, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, heme synthesis is inhibited in a dose-dependent manner.

[0347] In some embodiments, subjects with ribosome dysfunction-related anemia (e.g., Diamond-Black Fan anemia) have elevated heme levels. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 10% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 20% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 30% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 40% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 50% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 60% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 70% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 80% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 90% higher than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a heme level at least 100% higher than that of a healthy subject.

[0348] In some embodiments, the method reduces the subject's heme 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 heme level by at least 15%. In some embodiments, the method reduces the subject's heme level by at least 20%. In some embodiments, the method reduces the subject's heme level by at least 25%. In some embodiments, the method reduces the subject's heme level by at least 30%. In some embodiments, the method reduces the subject's heme level by at least 35%. In some embodiments, the method reduces the subject's heme level by at least 40%. In some embodiments, the method reduces the subject's heme level by at least 45%. In some embodiments, the method reduces the subject's heme level by at least 50%. In some embodiments, the method reduces the subject's heme level by at least 55%. In some embodiments, the method reduces the subject's heme level by at least 60%. In some embodiments, the method reduces the subject's heme level by at least 65%. In some embodiments, the method reduces the subject's heme level by at least 70%. In some embodiments, the method reduces the subject's heme level by at least 75%. In some embodiments, the method reduces the subject's heme level by at least 80%. In some embodiments, the method reduces the subject's heme level by at least 85%. In some embodiments, the method reduces the subject's heme level by at least 90%. In some embodiments, the method reduces the subject's heme level by at least 95%. In some embodiments, the method reduces the subject's heme level by at least 100%.

[0349] In some embodiments, the method reduces the subject's heme synthesis 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 heme synthesis by at least 15%. In some embodiments, the method reduces the subject's heme synthesis by at least 20%. In some embodiments, the method reduces the subject's heme synthesis by at least 25%. In some embodiments, the method reduces the subject's heme synthesis by at least 30%. In some embodiments, the method reduces the subject's heme synthesis by at least 35%. In some embodiments, the method reduces the subject's heme synthesis by at least 40%. In some embodiments, the method reduces the subject's heme synthesis by at least 45%. In some embodiments, the method reduces the subject's heme synthesis by at least 50%. In some embodiments, the method reduces the subject's heme synthesis by at least 55%. In some embodiments, the method reduces the subject's heme synthesis by at least 60%. In some embodiments, the method reduces the subject's heme synthesis by at least 65%. In some embodiments, the method reduces the subject's heme synthesis by at least 70%. In some embodiments, the method reduces the subject's heme synthesis by at least 75%. In some embodiments, the method reduces the subject's heme synthesis by at least 80%. In some embodiments, the method reduces the subject's heme synthesis by at least 85%. In some embodiments, the method reduces the subject's heme synthesis by at least 90%. In some embodiments, the method reduces the subject's heme synthesis by at least 95%. In some embodiments, the method reduces the subject's heme synthesis by at least 100%. In some embodiments, the method reduces intracellular heme levels. In some embodiments, the method reduces intracellular heme levels in erythroid precursor cells.

[0350] In some embodiments, the method reduces the risk of heme toxicity in the subject. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 15%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 20%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 25%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 30%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 35%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 40%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 45%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 50%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 55%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 60%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 65%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 70%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 75%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 80%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 85%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 90%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 95%. In some embodiments, the method reduces the risk of heme toxicity in the subject by at least 100%.

[0351] In some embodiments, the subject has hepatic iron overload. In some embodiments, the method reduces the risk of hepatic iron overload. In some embodiments, the method reduces the level of iron in the liver. In some embodiments, the method reduces the level of iron in the liver by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of iron in the liver by at least 15%. In some embodiments, the method reduces the level of iron in the liver by at least 20%. In some embodiments, the method reduces the level of iron in the liver by at least 25%. In some embodiments, the method reduces the level of iron in the liver by at least 30%. In some embodiments, the method reduces the level of iron in the liver by at least 35%. In some embodiments, the method reduces the level of iron in the liver by at least 40%. In some embodiments, the method reduces the level of iron in the liver by at least 45%. In some embodiments, the method reduces the level of iron in the liver by at least 50%. In some embodiments, the method reduces the iron level in the liver by at least 55%. In some embodiments, the method reduces the iron level in the liver by at least 60%. In some embodiments, the method reduces the iron level in the liver by at least 65%. In some embodiments, the method reduces the iron level in the liver by at least 70%. In some embodiments, the method reduces the iron level in the liver by at least 75%. In some embodiments, the method reduces the iron level in the liver by at least 80%. In some embodiments, the method reduces the iron level in the liver by at least 85%. In some embodiments, the method reduces the iron level in the liver by at least 90%. In some embodiments, the method reduces the iron level in the liver by at least 95%. In some embodiments, the method reduces the iron level in the liver by at least 100%.

[0352] In some embodiments, the subject has cardiac iron overload. In some embodiments, the method reduces the risk of cardiac iron overload. In some embodiments, the method reduces the level of iron in the heart. In some embodiments, the method reduces the level of iron in the heart by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the level of iron in the heart by at least 15%. In some embodiments, the method reduces the level of iron in the heart by at least 20%. In some embodiments, the method reduces the level of iron in the heart by at least 25%. In some embodiments, the method reduces the level of iron in the heart by at least 30%. In some embodiments, the method reduces the level of iron in the heart by at least 35%. In some embodiments, the method reduces the level of iron in the heart by at least 40%. In some embodiments, the method reduces the level of iron in the heart by at least 45%. In some embodiments, the method reduces the level of iron in the heart by at least 50%. In some embodiments, the method reduces the level of iron in the heart by at least 55%. In some embodiments, the method reduces the level of iron in the heart by at least 60%. In some embodiments, the method reduces the level of iron in the heart by at least 65%. In some embodiments, the method reduces the level of iron in the heart by at least 70%. In some embodiments, the method reduces the level of iron in the heart by at least 75%. In some embodiments, the method reduces the level of iron in the heart by at least 80%. In some embodiments, the method reduces the level of iron in the heart by at least 85%. In some embodiments, the method reduces the level of iron in the heart by at least 90%. In some embodiments, the method reduces the level of iron in the heart by at least 95%. In some embodiments, the method reduces the level of iron in the heart by at least 100%.

[0353] In some embodiments, the subject has reduced erythroid precursor survival compared to a healthy subject. In some embodiments, the subject has reduced differentiation of erythroid precursors into mature erythrocytes compared to a healthy subject. In some embodiments, the subject has impaired hematopoiesis. In some embodiments, the method increases the erythroid precursor survival of the subject. In some embodiments, the method increases the erythroid precursor survival of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the erythroid precursor survival of the subject by at least 15%. In some embodiments, the method increases the erythroid precursor survival of the subject by at least 20%. In some embodiments, the method increases the erythroid precursor survival of the subject by at least 25%. In some embodiments, the method increases the erythroid precursor survival of the subject by at least 30%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 35%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 40%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 45%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 50%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 55%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 60%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 65%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 70%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 75%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 80%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 85%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 90%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 95%. In some embodiments, the method increases the survival of erythroid precursors in the subject by at least 100%.

[0354] In some embodiments, the method increases the differentiation of the subject's erythroid precursors into mature erythrocytes. In some embodiments, the method increases the differentiation of the subject's erythroid precursors into mature erythrocytes by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 15%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 20%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 25%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 30%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 35%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 40%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 45%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 50%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 55%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 60%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 65%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 70%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 75%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 80%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 85%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 90%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 95%. In some embodiments, the method increases the differentiation of erythroid precursors into mature erythrocytes by at least 100%. In some embodiments, the subject has elevated erythrocyte adenosine deaminase activity. In some embodiments, the subject has normal bone marrow cellularity and lacks erythrocyte precursors. In some embodiments, the subject has normal neutrophil and / or platelet counts.

[0355] In some embodiments, the anemia is due to failure of erythropoiesis. In some embodiments, the method reduces the anemia in the subject. In some embodiments, the method reduces the anemia in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the anemia in the subject by at least 15%. In some embodiments, the method reduces the anemia in the subject by at least 20%. In some embodiments, the method reduces the anemia in the subject by at least 25%. In some embodiments, the method reduces the anemia in the subject by at least 30%. In some embodiments, the method reduces the anemia in the subject by at least 35%. In some embodiments, the method reduces the anemia in the subject by at least 40%. In some embodiments, the method reduces the anemia in the subject by at least 45%. In some embodiments, the method reduces the anemia in the subject by at least 50%. In some embodiments, the method reduces the subject's anemia by at least 55%. In some embodiments, the method reduces the subject's anemia by at least 60%. In some embodiments, the method reduces the subject's anemia by at least 65%. In some embodiments, the method reduces the subject's anemia by at least 70%. In some embodiments, the method reduces the subject's anemia by at least 75%. In some embodiments, the method reduces the subject's anemia by at least 80%. In some embodiments, the method reduces the subject's anemia by at least 85%. In some embodiments, the method reduces the subject's anemia by at least 90%. In some embodiments, the method reduces the subject's anemia by at least 95%. In some embodiments, the method reduces the subject's anemia by at least 100%. In some embodiments, the subject suffers from macrocytic anemia. In some embodiments, the method reduces the subject's anemia by reducing free heme toxicity.

[0356] In some embodiments, the method increases the total number of red blood cells. In some embodiments, the method decreases the mean corpuscular volume (MCV). In some embodiments, the method decreases erythrocyte adenosine deaminase. In some embodiments, the method decreases erythrocyte adenosine deaminase in subjects with DBA. In some embodiments, the method decreases the fetal hemoglobin content in red blood cells.

[0357] Red blood cell count and hematocrit

[0358] Certain embodiments of this application relate to a method of administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject has a low red blood cell count (e.g., less than about 4.5 million red blood cells / μl of blood for men and less than about 4.1 million red blood cells / μl of blood for women, typically in a clinically or statistically significant amount) or a low hematocrit (e.g., greater than about 38% for men or greater than about 35% for women, typically in a clinically or statistically significant amount). In some embodiments, the subject's hematocrit level is less than 38%. In some embodiments, the subject's hematocrit level is less than 35%.

[0359] In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 10% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 20% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 30% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 40% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 50% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 60% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 70% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 80% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject's hematocrit level is at least 90% lower than that of a healthy subject.

[0360] In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 10% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 20% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 30% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 40% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 50% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 60% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 70% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 80% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a red blood cell count at least 90% lower than that of a healthy subject. In some embodiments, the subject's red blood cell count is less than 4.5 x 10⁻⁶. 12 / L. In some embodiments, the subject's red blood cell count is less than 4.1 x 10⁹ / L. 12 / L.

[0361] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof increases erythrocyte synthesis (also known as erythropoiesis) and can be used to treat conditions associated with erythropoiesis. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may regulate erythrocyte synthesis by reducing heme formation. In some embodiments, this disclosure relates to a method of increasing erythrocyte synthesis in a subject suffering from anemia associated with ribosome dysfunction, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, erythrocyte synthesis is increased in a dose-dependent manner. In some embodiments, erythrocyte count is increased in a dose-dependent manner. In some embodiments, by way of non-limiting example only, if desired, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be administered directly to the subject to increase erythrocyte count. Red blood cell count can also be reflected by a person's hematocrit (i.e., filled cell volume (PCV) or red blood cell fraction (EVF)), which is the proportion or percentage of blood volume occupied by red blood cells. Typically, a normal hematocrit is about 49% in men and about 48% in women. A lower hematocrit value indicates a lower number of red blood cells.

[0362] In some embodiments, administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof to such a subject increases their red blood cell count or hematocrit. Methods for increasing the red blood cells of a subject, including subjects having a lower than normal red blood cell count or hematocrit or at risk of developing such a condition, are also included, the methods comprising administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof to the subject, thereby increasing the subject's red blood cell count or hematocrit.

[0363] In some embodiments, the method increases the red blood cell count of the subject. In some embodiments, the method increases the red blood cell count of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the red blood cell count of the subject by at least 15%. In some embodiments, the method increases the red blood cell count of the subject by at least 20%. In some embodiments, the method increases the red blood cell count of the subject by at least 25%. In some embodiments, the method increases the red blood cell count of the subject by at least 30%. In some embodiments, the method increases the red blood cell count of the subject by at least 35%. In some embodiments, the method increases the red blood cell count of the subject by at least 40%. In some embodiments, the method increases the red blood cell count of the subject by at least 45%. In some embodiments, the method increases the red blood cell count of the subject by at least 50%. In some embodiments, the method increases the subject's red blood cell count by at least 55%. In some embodiments, the method increases the subject's red blood cell count by at least 60%. In some embodiments, the method increases the subject's red blood cell count by at least 65%. In some embodiments, the method increases the subject's red blood cell count by at least 70%. In some embodiments, the method increases the subject's red blood cell count by at least 75%. In some embodiments, the method increases the subject's red blood cell count by at least 80%. In some embodiments, the method increases the subject's red blood cell count by at least 85%. In some embodiments, the method increases the subject's red blood cell count by at least 90%. In some embodiments, the method increases the subject's red blood cell count by at least 95%. In some embodiments, the method increases the subject's red blood cell count by at least 100%. In some embodiments, the method increases the subject's red blood cell count to a normal level. In some embodiments, the method increases the subject's red blood cell count to 4.5-5.9 x 10⁻⁶. 12 Between / L. In some embodiments, the method increases the subject's red blood cell count to 4.1-5.1 x 10⁹ / L. 12 Between / L.

[0364] In some embodiments, the method increases the hematocrit level of the subject. In some embodiments, the method increases the hematocrit level of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the hematocrit level of the subject by at least 15%. In some embodiments, the method increases the hematocrit level of the subject by at least 20%. In some embodiments, the method increases the hematocrit level of the subject by at least 25%. In some embodiments, the method increases the hematocrit level of the subject by at least 30%. In some embodiments, the method increases the hematocrit level of the subject by at least 35%. In some embodiments, the method increases the hematocrit level of the subject by at least 40%. In some embodiments, the method increases the hematocrit level of the subject by at least 45%. In some embodiments, the method increases the subject's hematocrit level by at least 50%. In some embodiments, the method increases the subject's hematocrit level by at least 55%. In some embodiments, the method increases the subject's hematocrit level by at least 60%. In some embodiments, the method increases the subject's hematocrit level by at least 65%. In some embodiments, the method increases the subject's hematocrit level by at least 70%. In some embodiments, the method increases the subject's hematocrit level by at least 75%. In some embodiments, the method increases the subject's hematocrit level by at least 80%. In some embodiments, the method increases the subject's hematocrit level by at least 85%. In some embodiments, the method increases the subject's hematocrit level by at least 90%. In some embodiments, the method increases the subject's hematocrit level by at least 95%. In some embodiments, the method increases the subject's hematocrit level by at least 100%. In some embodiments, the method increases the subject's hematocrit level by at least 38%. In some implementations, the method increases the subject's hematocrit level by at least 35%.

[0365] Reticulocyte count and hemoglobin

[0366] In some embodiments, this application relates to a method of administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject has reduced reticulocytes (e.g., less than 1%, typically in a clinically or statistically significant amount) or reduced hemoglobin levels (e.g., less than about 13.2 g / dL for men, or less than about 11.6 g / dL for women, typically in a clinically or statistically significant amount).

[0367] In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level that is at least 10% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level that is at least 20% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level that is at least 30% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level at least 40% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level at least 50% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level at least 60% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level at least 70% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level at least 80% lower than that of a healthy subject. In some embodiments, prior to administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, the subject has a hemoglobin level at least 90% lower than that of a healthy subject. In some embodiments, the subject's hemoglobin level is below 13 g / dL. In some embodiments, the subject's hemoglobin level is below 11 g / dL. In some embodiments, the subject has elevated fetal hemoglobin levels.

[0368] In some embodiments, the subject has a low reticulocyte count, also known as reticulopenia. In some embodiments, the subject's reticulocyte count is less than 1%. In some embodiments, the subject's reticulocyte count is less than 0.9%. In some embodiments, the subject's reticulocyte count is less than 0.8%. In some embodiments, the subject's reticulocyte count is less than 0.7%. In some embodiments, the subject's reticulocyte count is less than 0.6%. In some embodiments, the subject's reticulocyte count is less than 0.5%. In some embodiments, the subject's reticulocyte count is less than 0.4%. In some embodiments, the subject's reticulocyte count is less than 0.3%. In some embodiments, the subject's reticulocyte count is less than 0.2%. In some embodiments, the subject's reticulocyte count is less than 0.1%.

[0369] In some embodiments, administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof to such a subject increases their reticulocyte or hemoglobin levels. Methods for increasing the reticulocyte count of a subject, and methods for increasing the hemoglobin level of a subject, including subjects having below-normal reticulocyte or hemoglobin levels or at risk of developing such a condition, are also included, the methods comprising administering a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof to the subject, thereby reducing the subject's reticulocyte or hemoglobin levels.

[0370] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof increases hemoglobin synthesis in a subject suffering from anemia associated with ribosomal dysfunction and can be used to treat conditions associated with erythropoiesis. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof can regulate hemoglobin synthesis by reducing heme formation. In some embodiments, this disclosure relates to a method of increasing hemoglobin synthesis in a subject suffering from anemia associated with ribosomal dysfunction, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof. In some embodiments, hemoglobin synthesis is increased in a dose-dependent manner.

[0371] In some embodiments, the method increases the subject's hemoglobin level. In some embodiments, the method increases the subject's hemoglobin level by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the subject's hemoglobin level by at least 15%. In some embodiments, the method increases the subject's hemoglobin level by at least 20%. In some embodiments, the method increases the subject's hemoglobin level by at least 25%. In some embodiments, the method increases the subject's hemoglobin level by at least 30%. In some embodiments, the method increases the subject's hemoglobin level by at least 35%. In some embodiments, the method increases the subject's hemoglobin level by at least 40%. In some embodiments, the method increases the subject's hemoglobin level by at least 45%. In some embodiments, the method increases the subject's hemoglobin level by at least 50%. In some embodiments, the method increases the subject's hemoglobin level by at least 55%. In some embodiments, the method increases the subject's hemoglobin level by at least 60%. In some embodiments, the method increases the subject's hemoglobin level by at least 65%. In some embodiments, the method increases the subject's hemoglobin level by at least 70%. In some embodiments, the method increases the subject's hemoglobin level by at least 75%. In some embodiments, the method increases the subject's hemoglobin level by at least 80%. In some embodiments, the method increases the subject's hemoglobin level by at least 85%. In some embodiments, the method increases the subject's hemoglobin level by at least 90%. In some embodiments, the method increases the subject's hemoglobin level by at least 95%. In some embodiments, the method increases the subject's hemoglobin level by at least 100%. In some embodiments, the method increases the subject's hemoglobin level to at least 13 g / dL. In some implementations, the method increases the subject's hemoglobin level to at least 11 g / dL.

[0372] In some embodiments, the method increases the reticulocyte count of the subject. In some embodiments, the method increases the reticulocyte count of the subject by 1% to 2%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.5%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.6%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.7%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.8%. In some embodiments, the method increases the reticulocyte count of the subject by at least 0.9%. In some embodiments, the method increases the reticulocyte count of the subject by at least 1%. In some embodiments, the method increases the reticulocyte count of the subject by at least 1.5%. In some embodiments, the method increases the reticulocyte count of the subject by at least 2%. In some embodiments, the method increases the reticulocyte count of the subject by 0.5%. In some implementations, the method increases the reticulocyte count of the subject by 1%.

[0373] Combination therapy

[0374] Some embodiments may include combination therapy for treating anemia associated with ribosomal dysfunction, said combination therapy comprising administration of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents or modes of treatment. Examples of combination therapy include, but are not limited to, one or more additional active agents and / or supportive therapies selected from: trifluoperazine, HDAC inhibitors, glucocorticoids, sotexip, rotezip, iron chelators, blood transfusions, platelet transfusions, allogeneic hematopoietic stem cell transplantation, autologous gene therapy, lenalidomide (REVLIMID®), and antibiotics. In some embodiments, the method further includes administration of another therapeutic agent to treat ribosomal protein deficiency, said other therapeutic agent being selected from: corticosteroids and bone marrow transplantation, and other treatments known to those skilled in the art. For example, corticosteroids may be used to treat anemia associated with ribosomal dysfunction (such as DBA). Blood transfusions may also be used to treat anemia associated with ribosomal dysfunction (such as DBA). Remission periods may occur, during which blood transfusions and steroid treatment are not required. Bone marrow transplantation (BMT) can treat the hematological aspects of DBA. However, adverse events may occur in transfusion patients. In some embodiments, the method reduces the subject's need for corticosteroid treatment. In some embodiments, the method reduces the required dose of corticosteroid treatment for the subject. In some embodiments, the corticosteroid is a glucocorticoid steroid.

[0375] As described above, common treatments for anemia associated with ribosomal dysfunction include the use of regularly scheduled blood transfusions. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof may be used to treat a subject requiring a blood transfusion who has anemia associated with ribosomal dysfunction (e.g., Diamond-Blackfan anemia). In some embodiments, the method reduces the subject's need for a blood transfusion. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the subject's need for a blood transfusion by at least 15%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 20%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 25%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 30%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 35%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 40%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 45%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 50%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 55%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 60%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 65%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 70%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 75%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 80%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 85%. In some embodiments, the method reduces the subject's need for a blood transfusion by at least 90%. In some embodiments, the method reduces the subject's need for blood transfusion by at least 95%. In some embodiments, the method reduces the subject's need for blood transfusion by at least 100%. In some embodiments, the method eliminates the subject's need for blood transfusion.

[0376] Quality of life and lifespan

[0377] In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of anemia associated with ribosomal dysfunction (e.g., treating or preventing one or more complications of anemia associated with ribosomal dysfunction, or reducing the rate of progression and / or severity of progression), said methods comprising administering to a patient in need an effective amount of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, said method improving the patient's quality of life by at least 1% (e.g., 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%). In some embodiments, said methods involve improving the patient's quality of life. In some embodiments, said methods involve improving the patient's quality of life by at least 1%. In some embodiments, said methods involve improving the patient's quality of life by at least 2%. In some embodiments, said methods involve improving the patient's quality of life by at least 3%. In some embodiments, the method involves improving the patient's quality of life by at least 4%. In some embodiments, the method involves improving the patient's quality of life by at least 5%. In some embodiments, the method involves improving the patient's quality of life by at least 10%. In some embodiments, the method involves improving the patient's quality of life by at least 15%. In some embodiments, the method involves improving the patient's quality of life by at least 20%. In some embodiments, the method involves improving the patient's quality of life by at least 25%. In some embodiments, the method involves improving the patient's quality of life by at least 30%. In some embodiments, the method involves improving the patient's quality of life by at least 35%. In some embodiments, the method involves improving the patient's quality of life by at least 40%. In some embodiments, the method involves improving the patient's quality of life by at least 45%. In some embodiments, the method involves improving the patient's quality of life by at least 50%. In some embodiments, the method involves improving the patient's quality of life by at least 55%. In some embodiments, the method involves improving the patient's quality of life by at least 60%. In some embodiments, the method involves improving the patient's quality of life by at least 65%. In some embodiments, the method involves improving the patient's quality of life by at least 70%. In some embodiments, the method involves improving the patient's quality of life by at least 75%. In some embodiments, the method involves improving the patient's quality of life by at least 80%. In some embodiments, the method involves improving the patient's quality of life by at least 85%. In some embodiments, the method involves improving the patient's quality of life by at least 90%.In some embodiments, the method involves improving the patient's quality of life by at least 95%. In some embodiments, the method involves improving the patient's quality of life by at least 100%. In some embodiments, the patient has a low quality of life.

[0378] In some embodiments, the Cancer Treatment Functional Assessment - Anemia (FACT-An) is used to measure the patient's quality of life. In some embodiments, the Cancer Treatment Functional Assessment - Fatigue (FACT-Fatigue) is used to measure the patient's quality of life. In some embodiments, the Treatment Functional Assessment for Chronic Diseases (FACIT) is used to measure the patient's quality of life. In some embodiments, the Treatment Functional Assessment for Chronic Diseases - Fatigue (FACIT-Fatigue) is used to measure the patient's quality of life. In some embodiments, the Treatment Functional Assessment for Chronic Diseases - Anemia (FACIT-Anemia) is used to measure the patient's quality of life. In some embodiments, the SF-36 Universal PRO tool is used to measure the patient's quality of life. In some embodiments, the SF-6D Universal PRO tool is used to measure the patient's quality of life. In some embodiments, the Linear Analog Scale Assessment (LASA) is used to measure the patient's quality of life.

[0379] In some aspects, this disclosure relates to methods for preventing, treating, or reducing the rate of progression and / or severity of ribosomal dysfunction-related anemia (e.g., treating or preventing one or more complications of ribosomal dysfunction-related anemia or reducing its rate of progression and / or severity), said methods comprising administering to a patient in need an effective amount of a compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof, said method increasing the patient's survival by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, said methods increase the patient's survival. In some embodiments, said methods increase the patient's survival by at least 15%. In some embodiments, said methods increase the patient's survival by at least 20%. In some embodiments, said methods increase the patient's survival by at least 25%. In some embodiments, the method increases the patient's survival by at least 30%. In some embodiments, the method increases the patient's survival by at least 35%. In some embodiments, the method increases the patient's survival by at least 40%. In some embodiments, the method increases the patient's survival by at least 45%. In some embodiments, the method increases the patient's survival by at least 50%. In some embodiments, the method increases the patient's survival by at least 55%. In some embodiments, the method increases the patient's survival by at least 60%. In some embodiments, the method increases the patient's survival by at least 65%. In some embodiments, the method increases the patient's survival by at least 70%. In some embodiments, the method increases the patient's survival by at least 75%. In some embodiments, the method increases the patient's survival by at least 80%. In some embodiments, the method increases the patient's survival by at least 85%. In some embodiments, the method increases the patient's survival by at least 90%. In some embodiments, the method increases the patient's survival by at least 95%. In some embodiments, the method increases the patient's survival by at least 100%.

[0380] In some embodiments, the method increases the patient's sur...

Claims

1. A compound of formula (I) (I), or a pharmaceutically acceptable salt thereof, wherein: A is an aryl or heteroaryl ring system, wherein the aryl or heteroaryl ring system is optionally composed of R 1 Replace one or more times; B is a 4- to 8-membered non-aromatic carbon ring or a 4- to 8-membered non-aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic carbon ring or heterocycle is optionally surrounded by R. 2 Replace one or more times; R 1 Each occurrence is independently selected from OH, halogen, -CF3, -OCF3, -OCH2F, -OCHF2, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -CN, =O, -C(O)H, -(CH2) n NR a R b -(CH2) n NR aa C(O)R bb -C(O)NR a R b -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl, -NR a R b -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-NR a R b -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic, wherein -C 1-8 Alkyl, -OC 1-8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups may optionally be selected independently, each time they appear, from halogens, CN, and -C. 1-8 Alkyl, -C 1-8 alkyl heterocyclic group, -C 1-8 Alkyl heteroaryl, -OC 1-8 Alkyl, aryl, and monocyclic heteroaryl substituents are substituted 1 to 3 times; R 2 Each occurrence is independently selected from OH, halogen, -CF3, -OCF3, -OCH2F, -OCHF2, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -CN, =O, -C(O)H, -(CH2) n NR a R b -(CH2) n NR aa C(O)R bb -C(O)NR a R b -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl, -NR a R b -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-NR a R b -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic, wherein -C 1-8 Alkyl, -OC 1-8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups may optionally be selected independently, each time they appear, from halogens, CN, and -C. 1-8 Alkyl, -C 1-8 alkyl heterocyclic group, -C 1-8 Alkyl heteroaryl, -OC 1-8 Alkyl, aryl, and monocyclic heteroaryl substituents are substituted 1 to 3 times; R 3 Selected from OH, -C 1-8 Alkyl, -OC 1-8 Alkyl, -O aryl, -O heteroaryl and -OC 0-8 Alkyl C 3-8 cycloalkyl, wherein -C 1-8 Alkyl and -OC 1-8 Alkyl groups can optionally be selected independently, each time they appear, from halogens, haloalkyl groups (e.g., CH2F, CHF2, CF3), aryl groups, heterocyclic groups, and -C groups. 3-8 The cycloalkyl substituents are substituted 1 to 3 times; R 4 It is H; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form cycloalkyl or heterocyclic groups, wherein the cycloalkyl and heterocyclic groups can optionally be independently selected from CN, -C in each occurrence. 1-8 Alkyl, aryl, and heterocyclic substituents are substituted once or twice, wherein -C 1-8 Alkyl, aryl, and heterocyclic groups can optionally be substituted 1 to 3 times with substituents selected independently of halogens each time they appear; R 5 Selected from H, -OH, -C 1-8 Alkyl groups and NH2; R 6 Selected from -C 1-8 Alkyl, aryl, and heteroaryl, wherein -C 1-8 Alkyl, aryl, and heteroaryl groups can optionally be independently selected from deuterium, H, or -C each time they appear. 1-8 The alkyl group is substituted 1 to 3 times, wherein -C 1-8 Alkyl groups can optionally be converted by -CONH2, -S(O)2NH2, or -S(O)2-C 1-8 Alkyl, aryl, or heterocyclic substitution; or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted heterocyclic groups; R 7 It is deuterium; R a Is it H or -C 1-8 alkyl; R b Is it H or -C 1-8 Alkyl, wherein -C 1-8 Alkyl groups can optionally be converted by -CONH2, -S(O)2NH2, or -S(O)2-C 1-8 Alkyl, aryl, or heterocyclic substitution; or R a and R b Together with the nitrogen atoms to which they are attached, they form non-aromatic heterocyclic groups, which are optionally selected independently each time they appear from OH, =O, halogens, CF3, -OCF3, -OCH2F, -OCHF2, -C(O)H, -C 1-8 Alkyl, -C 3-8 cycloalkyl, -C 4-16 cycloalkylalkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NR a R b -CN, -C(O)OC 1-8 Alkyl group, -C(O)OH, -(CH2) k COC 1-8 Alkyl group, -(CH2) n OC 1-8 Alkyl, -NHC(O)OC 1-8 Alkyl group, -(CH2) m C(O)OC 1-8 Alkyl, -S(O)2-C 1-8 Alkyl, -S(O)2-aryl, -S(O)2NR a R b Substituents of aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclic, and monocyclic and bicyclic non-aromatic heterocyclic groups are substituted 1 to 3 times; R aa Is it H or -C 1-8 alkyl; R bb It is -C 1-8 Alkyl, -C 4-8 Cycloalkylmethyl or monocyclic nonaromatic heterocyclic group, wherein -C 1-8 Alkyl and -C 4-8 Cycloalkylmethyl groups can be optionally substituted with NH2, halogens, or CN; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, 5, or 6; and l can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, pyrimidine, pyridine, and thiazole, wherein the phenyl, pyrimidine, pyridine, and thiazole are optionally replaced by R. 1 Replace once or multiple times.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 It is halogen.

4. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein B is optionally converted to R. 2 It replaces one or more 5-membered non-aromatic carbon rings.

5. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein B is optionally converted by R. 2 It replaces one or more 6-membered non-aromatic carbon rings.

6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic heterocycle containing an oxygen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replace once or multiple times.

7. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic heterocycle containing a sulfur atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replace once or multiple times.

8. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic heterocycle containing a nitrogen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replace once or multiple times.

9. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic heterocycle comprising a nitrogen atom and an oxygen atom, wherein the non-aromatic heterocycle is optionally composed of R 2 Replace once or multiple times.

10. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic heterocycle containing a nitrogen atom, wherein the non-aromatic heterocycle is optionally replaced by R. 2 Replace once or multiple times.

11. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic heterocycle comprising two nitrogen atoms, wherein the non-aromatic heterocycle is optionally surrounded by R. 2 Replace once or multiple times.

12. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 Independently selected from halogens, =O, -C 1-8 Alkyl, C(O)OC 1-8 Alkyl groups and -S(O)2-NR a R b .

13. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 It is optionally selected independently each time it appears from halogens, CH2F, CHF2, CF3, aryl, heterocyclic and -C. 3-8 The cycloalkyl substituents are substituted 1 to 3 times with -OC 1-8 alkyl.

14. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 3 -OC is optionally substituted 1 to 3 times by substituents selected independently from halogens each time it appears. 1-8 alkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 3 It is -OCH(CH3)CF3.

16. The compound according to claim 15, wherein R 3 It has an (S) configuration.

17. The compound according to claim 15, wherein R 3 It has an (R) configuration.

18. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 4 It is H.

19. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is H.

20. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is C 1-8 alkyl.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 6 It's me.

22. A compound selected from compounds 1-60 and their pharmaceutically acceptable salts.

23. The compound according to claim 22, wherein the compound is compound 1. (1), or its pharmaceutically acceptable salt.

24. The compound of claim 22, wherein the compound is compound 11. (11), or its pharmaceutically acceptable salt.

25. The compound according to claim 22, wherein the compound is compound 17. (17), or a pharmaceutically acceptable salt thereof.

26. The compound of claim 22, wherein the compound is compound 52. (52), or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 22, wherein the compound is compound 53. (53), or its pharmaceutically acceptable salt.

28. The compound of claim 22, wherein the compound is compound 54. (54), or its pharmaceutically acceptable salt.

29. The compound according to claim 22, wherein the compound is compound 55. (55), or a pharmaceutically acceptable salt thereof.

30. The compound of claim 22, wherein the compound is compound 56. (56), or its pharmaceutically acceptable salt.

31. The compound according to claim 22, wherein the compound is compound 57. (57), or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising (a) a compound according to any of the preceding claims; and (b) a pharmaceutically acceptable excipient.

33. The compound according to any one of claims 1-31 or the pharmaceutical composition according to claim 32, for use as a medicine.

34. A method of treating a blood disorder in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

35. A method of treating porphyria in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

36. A method of treating hepatic porphyria in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

37. A method of treating one or more complications of hepatic porphyria in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

38. The method of claim 37, wherein one or more complications of hepatic porphyria are selected from: acute photosensitivity, skin photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte disturbances, nausea, vomiting, constipation, diarrhea, dysuria, intestinal obstruction, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, seizures, neuropathic pain, muscle paralysis, quadriplegia, decreased respiration, respiratory arrest, and hyponatremia. Hematuria, tachycardia, hypertension, tachycardia, elevated 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 keratosis, bullae, lesions, scars, deformities, nail loss, finger / toe defects, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease.

39. The method according to any one of claims 36-38, wherein the hepatic porphyria is acute hepatic porphyria, acute intermittent porphyria (AIP), ALA dehydratase porphyria (ADP), mixed porphyria (VP), hereditary coprophyria (HCP), or Had porphyria.

40. The method according to any one of claims 36-38, wherein the hepatic porphyria is non-acute hepatic porphyria.

41. The method of claim 40, wherein the non-acute hepatic porphyria is familial or sporadic porphyria cutanea (PCT) or hepatic erythropoietic porphyria (HEP).

42. A method of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic protoporphyria (CEP) in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

43. A method of treating one or more complications of EPP, XLPP, or CEP in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

44. The method according to claim 43, wherein one or more complications of the EPP, XLPP, or CEP are selected from: acute photosensitivity, skin photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, bullae, lesions, scarring, deformities, nail loss, finger / toe defects, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, end-stage liver disease, red teeth syndrome, myelocytosis, thrombocytopenia, fetal hydrops, and / or intrauterine death.

45. A method for inhibiting the synthesis of protoporphyrin IX (PPIX) in vivo, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

46. ​​A method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

47. A method for inhibiting the synthesis of coprophyrin III in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

48. A method for inhibiting the synthesis of zinc-protoporphyrin IX (ZPPIX) in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

49. A method for inhibiting the synthesis of bilirubinogen (PBG) in vivo, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

50. A method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and bile pigmentogen (PBG) in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

51. A method for inhibiting the synthesis of hydroxymethylbilirubin (HMB) in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

52. A method for inhibiting the synthesis of uroporphyrin III in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

53. A method for inhibiting the synthesis of heptacarboxy-porphyrin in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

54. A method for inhibiting the synthesis of isoflavones in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

55. A method for inhibiting the synthesis of porphyrin or a porphyrin precursor in vivo, the method comprising administering to a subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32, wherein the porphyrin or porphyrin precursor is selected from: s.5-ALA t.PBG u. hydroxymethylbilirubin v.PPIX w.ZPPIX x. Uroporphyrinogen I y. Uroporphyrinogen III z. Heptacarboxyporphyrinogen I aa. Heptacarboxyporphyrinogen III bb. Hexacarboxyporphyrinogen I cc. hexacarboxyporphyrinogen III dd. Pentacarboxyporphyrinogen I ee. Pentacarboxyporphyrinogen III ff. coprophyrinogen I gg. coprophyrinogen III hh. Isoproporphyrin ii. Bile pigmentogen; and jj.protoporphyrin IX.

56. The method according to any one of claims 34-55, 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), bile pigmentogen, uroporphyrin III, heptacarboxy-porphyrin, and isoflavone.

57. The method of claim 56, wherein the accumulation of said one or more heme intermediates is inhibited in a dose-dependent manner.

58. The method according to any one of claims 44-55, wherein the subject suffers from EPP, XLPP, or CEP.

59. The method according to any one of claims 44-55, wherein the subject suffers from hepatic porphyria.

60. The method according to any one of claims 35-41 and 59, wherein the subject has a mutation in UROS.

61. The method according to any one of claims 42-44 and 58, wherein the subject has a genetic defect in the GATA-1 erythroid-specific transcription factor.

62. The method according to any one of claims 42-44, 58 and 61, wherein the subject suffers from liver disease associated with EPP, XLPP or CEP.

63. The method according to any one of claims 35-62, wherein the method comprises further administering additional active agents and / or supportive therapies to the subject.

64. The method of claim 63, wherein the additional active agent and / or supportive therapy is selected from: sun protection, topical sunscreens, skin protection, UVB phototherapy, Scenesene®, bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

65. The method of claim 63, wherein the additional active agent and / or supportive therapy is selected from: sun protection, topical sunscreens, skin protection, UVB phototherapy, Scenesene® (afanotide), bortezomib, heme infusion, adequate caloric support, gevorcilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of precipitating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venipuncture, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene in hepatocytes via a viral vector), hemodialysis, pharmacological companion therapy, proteasome inhibitors, chemical companions, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

66. A method of treating anemia associated with ribosome dysfunction in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

67. A method for treating one or more complications of anemia associated with ribosome dysfunction in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

68. The method according to any one of claims 66-67, wherein the anemia associated with ribosome dysfunction is Diamond-Blackfan anemia.

69. The method of claim 68, wherein the subject's ribosomal protein selected from the group consisting of: 40S ribosomal protein S14 (RPS14), 40S ribosomal protein S19 (RPS19), 40S ribosomal protein S24 (RPS24), 40S ribosomal protein S17 (RPS17), 60S ribosomal protein L35a (RPL35a), 60S ribosomal protein L5 (RPL5), 60S ribosomal protein L11 (RPL11), and 40S ribosomal protein S7 (RPS7).

70. The method of claim 68, wherein the subject's ribosomal protein selected from the group consisting of: 40S ribosomal protein S10 (RPS10), 40S ribosomal protein S26 (RPS26), 60S ribosomal protein L15 (RPL15), 60S ribosomal protein L17 (RPL17), 60S ribosomal protein L19 (RPL19), 60S ribosomal protein L26 (RPL26), 60S ribosomal protein L27 (RPL27), 60S ribosomal protein L31 (RPL31), 40S ribosomal protein S15a (RPS15a), 40S ribosomal protein S20 (RPS20), 40S ribosomal protein S27 (RPS27), 40S ribosomal protein S28 (RPS28), and 40S ribosomal protein S29 (RPS29).

71. The method of claim 68, wherein the subject has one or more mutations in the ribosomal protein gene.

72. The method of claim 68, wherein the subject has one or more mutations in a ribosomal protein gene selected from the following: RPL5, RPL9, RPL11, RPL15, RPL17, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35a, RPS7, RPS10, RPS14, RPS15a, RPS15, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27a, RPS27, RPS28, and RPS29.

73. The method of claim 68, wherein the subject has one or more mutations in one of the following non-ribosomal protein genes selected from: TSR2, GATA1, and EPO.

74. The method of claim 66 or claim 67, wherein the anemia associated with ribosome dysfunction is Schwarzman-Diamond syndrome.

75. The method of claim 74, wherein the subject has one or more mutations in the SBDS gene.

76. The method of claim 66 or claim 67, wherein the anemia associated with ribosome dysfunction is congenital dyskeratosis.

77. The method of claim 76, wherein the congenital dyskeratosis is X-linked congenital dyskeratosis.

78. The method of claim 76 or 77, wherein the subject has one or more mutations in the DKC1 gene.

79. The method according to any one of claims 66-78, wherein the method reduces the risk of bone marrow failure, pulmonary fibrosis, or liver fibrosis in the subject.

80. The method of claim 66 or claim 67, wherein the anemia associated with ribosome dysfunction is chondrodysplasia.

81. The method of claim 80, wherein the subject has one or more mutations in the RMRP gene.

82. The method of claim 67, wherein one or more complications of the anemia associated with ribosome dysfunction are selected from: thrombocytosis, megakaryocyte proliferation, infection, bleeding (e.g., from the nose or gums), contusion, splenomegaly, need for more frequent transfusions, need for increased glucocorticoid use, need for allogeneic hematopoietic stem cell transplantation, need for autologous gene therapy, bone marrow failure, leukemia, and acute myeloid leukemia.

83. The method according to any one of claims 66-82, wherein the method reduces intracellular heme levels.

84. The method according to any one of claims 66-82, wherein the method increases the red blood cell count of the subject.

85. The method according to any one of claims 66-84, wherein the method comprises further administering additional active agents and / or supportive therapies to the subject.

86. The method of claim 85, wherein the additional active agent and / or supportive therapy is selected from: trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotexip, rotezip, iron chelators, blood transfusion, platelet transfusion.

87. A method of treating polycythemia in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

88. A method of treating one or more complications of polycythemia in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

89. The method according to claim 87 or 88, wherein the polycythemia is essential polycythemia.

90. The method of claim 89, wherein the primary polycythemia is polycythemia vera or polycythemia pureis.

91. The method of claim 89, wherein the essential polycythemia is essential familial polycythemia.

92. The method according to claim 87 or 88, wherein the polycythemia is secondary polycythemia.

93. The method of claim 92, wherein the secondary polycythemia is associated with a disorder selected from the following: hypoxia, central hypoxia, lung disease, right-to-left cardiopulmonary shunt (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, erythrocytosis in smokers, high-altitude living, kidney disease, kidney transplantation, hemoglobinopathies with hyperoxygen affinity, decreased erythrocyte 2,3,-DPG levels, bisphosphoglycerate mutase deficiency, methemoglobinemia, hereditary ATP increase, gene mutations in oxygen sensing pathways, tumors, drug-induced secondary polycythemia, adrenocortical hypersecretion, and idiopathic polycythemia.

94. The method according to claim 87 or 88, wherein the polycythemia is relative polycythemia.

95. The method of claim 94, wherein the relative polycythemia is selected from Gasbock syndrome, pseudopolycythemia, or stress-induced polycythemia.

96. The method according to claim 87 or 88, wherein the polycythemia is Chuvash polycythemia.

97. The method of claim 88, wherein one or more complications of the polycythemia are selected from: pulmonary embolism, transient ischemic attack, transient visual loss, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia.

98. A method for inhibiting heme synthesis in a subject suffering from polycythemia, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

99. The method of claim 98, wherein heme synthesis is inhibited in a dose-dependent manner.

100. A method for inhibiting hemoglobin synthesis in a subject suffering from polycythemia, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

101. The method of claim 100, wherein hemoglobin synthesis is inhibited in a dose-dependent manner.

102. A method for inhibiting erythrocyte synthesis in a subject suffering from polycythemia, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

103. The method of claim 102, wherein erythrocyte synthesis is inhibited in a dose-dependent manner.

104. A method for reducing the red blood cell count in a subject suffering from polycythemia, the method comprising administering to the subject a compound according to any one of claims 1-31 or a pharmaceutical composition according to claim 32.

105. The method of claim 104, wherein the red blood cell count is reduced in a dose-dependent manner.

106. The method according to any one of claims 87-105, wherein the method reduces the incidence of iron deficiency by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

107. The method according to any one of claims 87-106, the method comprising further administering additional active agents and / or supportive therapies to the subject.

108. The method of claim 107, wherein the additional active agent and / or supportive therapy is selected from: hydroxyurea (e.g., Droxia®, Hydrea®), interferon α, interferon α-2b (e.g., Intron® A), ruxotinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiotherapy, hepcidin mimics (e.g., PTG-300), membrane serine protease-2 inhibitors, iron transporter inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors.

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