GLYT-1 inhibitors and their use

Abstract

This application relates to compounds of formula (I) and pharmaceutical compositions / preparations thereof. This application further relates to methods for treating or preventing hematological disorders. In certain embodiments, this application relates to methods for conducting a pharmaceutical business by determining appropriate formulations and dosages of the compounds of this application for treating or preventing any of the diseases or conditions described herein, and by licensing to third parties the right to further develop and market the formulations.

Description

[Technical Field]

[0001] Related applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 538,539, filed on 15 September 2023, and U.S. Provisional Patent Application No. 63 / 658,642, filed on 11 June 2024, which are incorporated herein by reference in their entirety. [Background technology]

[0002] background There are two main types of glycine transporters (GlyT): glycine transporter-1 (GlyT-1) and glycine transporter-2 (GlyT-2). GlyT-1 shows a broad distribution in the brain, red blood cells, and peripheral tissues. In contrast, GlyT-2 is mainly found in the spinal cord and brainstem and is involved in the regulation of glycine. Glyine transporter-1 is the primary source of glycine for heme biosynthesis in red blood cell development. As a result, inhibition of glycine transporter-1 may potentially reduce heme synthesis, leading to new treatments for conditions where excess heme, accumulation of toxic intermediates of heme biosynthesis, or pathological increases in erythropoiesis lead to disease. For example, inhibition of glycine uptake by red blood cells may reduce the accumulation of protoporphyrin IX (PPIX), an intermediate of heme biosynthesis that accumulates and causes disease in myeloid 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 in which excess heme, accumulation of toxic intermediates of heme biosynthesis, or pathological increases in erythropogenesis lead to disease. [Overview of the project] [Means for solving the problem]

[0003] Application Summary This application concerns the compound of formula (I). [ka] or a pharmaceutically acceptable salt thereof [wherein A is an aryl or heteroaryl ring system, wherein the aryl or heteroaryl ring system is optionally substituted one or more times with R 1 ; B is a 4- to 8-membered non-aromatic carbocycle, or a 4- to 8-membered non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the non-aromatic carbocycle or heterocycle is optionally substituted one or more times with R 2 ; R 1 is independently at each occurrence 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, -(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 heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C 1~8 alkyl, -OC 1~8Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl are halogens, CN, -C 1~8 Alkyl, -C 1~8 Alkyl heterocyclyl, -C 1~8 Alkyl heteroaryl, -OC 1~8 The substituents may be substituted 1 to 3 times as needed, with substituents independently selected in each instance from the group consisting of alkyl, aryl, and monocyclic heteroaryl; R 2 These are independently of each other's appearance: 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, -(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 Selected from the group consisting of alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclil, and monocyclic and bicyclic non-aromatic heterocyclil, where -C 1~8 Alkyl, -OC 1~8Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl are halogens, CN, -C 1~8 Alkyl, -C 1~8 Alkyl heterocyclyl, -C 1~8 Alkyl heteroaryl, -OC 1~8 The substituents may be substituted 1 to 3 times as needed, with substituents independently selected in each instance from the group consisting of alkyl, aryl, and monocyclic heteroaryl; R 3 is OH, -C 1~8 Alkyl, -OC 1~8 Alkyl, -O aryl, -O heteroaryl, and -OC 0~8 Alkyl C 3~8 Selected from the group consisting of cycloalkyls, where -C 1~8 Alkyl and -OC 1~8 Alkyls include halogens, haloalkyls (e.g., CH2F, CHF2, CF3), aryls, heterocyclyls, and -C 3~8 It may be substituted 1 to 3 times as needed with substituents independently selected from the group consisting of cycloalkyl groups in each instance; R 4 Is it H; or R 3 and R 4 These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocyclines, where cycloalkyl and heterocyclines are CN, -C 1~8 The substituents may be substituted one or two times as needed with substituents independently selected in each instance from the group consisting of alkyl, aryl, and heterocyclyl, where -C 1~8 Alkyl, aryl, and heterocyclyl groups may be substituted 1 to 3 times as needed with substituents independently selected from the group consisting of halogens in each instance; R 5 H, -OH, -C 1~8 Selected from the group consisting of alkyl and NH2; R 6 is -C 1~8 Selected from the group consisting of alkyl, aryl, and heteroaryl, where -C 1~8 Alkyl, aryl, and heteroaryl compounds contain deuterium, H, or -C.1~8 may be optionally substituted 1 to 3 times with substituents independently selected at each occurrence from the group consisting of alkyl, wherein -C 1~8 alkyl may be optionally substituted with -CONH2, -S(O)2NH2, -S(O)2-C 1~8 alkyl, aryl or heterocyclyl; or R 5 and R 6 together with the atoms to which they are attached form an optionally substituted heterocyclyl; R 7 is deuterium; R a is H or -C 1~8 alkyl; R b is H or -C 1~8 alkyl, wherein -C 1~8 alkyl may be optionally substituted with -CONH2, -S(O)2NH2, -S(O)2-C 1~8 alkyl, aryl or heterocyclyl; or R a and R b together with the nitrogen atom to which they are attached, are substituted with 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, -C(O)OH, -(CH2) k COC 1~8 alkyl, -(CH2) n OC 1~8 alkyl, -NHC(O)OC 1~8 alkyl, -(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, forming non-aromatic heterocyclines which are substituted 1 to 3 times as necessary with substituents independently selected in each instance from the group consisting of aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclines, and monocyclic and bicyclic non-aromatic heterocyclines; R aa is H or -C 1~8 It is alkyl; R bb is -C 1~8 Alkyl, -C 4~8 A cycloalkylmethyl or monocyclic non-aromatic heterocycline, where -C 1~8 Alkyl and -C 4~8 The cycloalkylmethyl may be substituted as needed 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; l is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0004] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, A is selected from phenyl, pyrimidine, pyridine, and thiazole, where phenyl, pyrimidine, pyridine, and thiazole are R 1 It is replaced once or more times as needed.

[0005] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is a halogen.

[0006] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is R 2 It is a five-membered non-aromatic carbon ring that is substituted once or more as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is R 2 It is a six-membered non-aromatic carbon ring that is substituted once or more as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a five-membered non-aromatic heterocycle containing an oxygen atom, where the non-aromatic heterocycle is R2 It is substituted once or more times as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a five-membered non-aromatic heterocycle containing a sulfur atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a five-membered non-aromatic heterocycle containing a nitrogen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a six-membered non-aromatic heterocycle containing a nitrogen atom and an oxygen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a six-membered non-aromatic heterocycle containing one nitrogen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, B is a six-membered non-aromatic heterocycle containing two nitrogen atoms, where the non-aromatic heterocycle is R 2 It is replaced once or more times as needed.

[0007] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 Halogen, =O, -C 1~8 Alkyl, C(O)OC 1~8 Alkyl and -S(O)2-NR a R b It is selected independently of others.

[0008] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 These include halogens, CH2F, CHF2, CF3, aryls, heterocyclyls, and -C 3~8 -OC molecules are substituted 1 to 3 times as needed with substituents independently selected in each instance from the group consisting of cycloalkyl molecules.1~8 It is alkyl. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 -OC is substituted 1 to 3 times as needed with substituents independently selected from halogens in each appearance. 1~8 It is alkyl. In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 is -OCH(CH3)CF3. In certain such embodiments, R 3 It has an (S) configuration. In other such embodiments, R 3 It has an (R) configuration.

[0009] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 4 H is H.

[0010] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 5 H is H.

[0011] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 6 C 1~8 It is alkyl.

[0012] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 6 This is Me.

[0013] This application provides a compound selected from any one of compounds 1 to 60 and a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (1) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (11) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (17) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (52) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (53) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (54) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (55) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (56) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound (57) or a pharmaceutically acceptable salt thereof.

[0014] This application provides a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable additive.

[0015] This application provides a pharmaceutical composition for use as a medicine comprising (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutically acceptable additive.

[0016] This application provides a method for treating a hematological disorder in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

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

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

[0019] This application provides a method for treating one or more complications of hepatic porphyria in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, one or more complications of hepatic porphyria are acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte abnormalities, nausea, vomiting, constipation, diarrhea, dysuria, ileus, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, neuropathy-related pain, muscle paralysis, limb paresis, respiratory depression, respiratory arrest, low The following conditions are selected from the group consisting of natremia, tachycardia, hypertension, increased heart rate, elevated blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive nephropathy, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, nail loss, finger loss, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening liver disease, and end-stage liver disease.

[0020] In certain embodiments of the aforementioned 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), atypical porphyria (VP), hereditary coproporphyria (HCP), or halderoporphyria. In certain embodiments of the aforementioned methods, hepatic porphyria is nonacute hepatic porphyria. In certain such embodiments, nonacute hepatic porphyria is familial or sporadic punctate porphyria (PCT), myelohepatic porphyria (HEP).

[0021] This application provides a method for treating myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital myeloid porphyria (CEP) in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0022] This application provides a method for treating one or more complications of EPP, XLPP, or CEP in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, one or more complications of EPP, XLPP, or CEP are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, nail loss, finger loss, cholestasis, cytolysis, gallstones, cholestatic hepatic failure, cholelithiasis, mild hepatic disease, exacerbation of hepatic disease, end-stage hepatic disease, red teeth, hyperplastic bone marrow, thrombocytopenia, fetal hydrops, and / or intrauterine death.

[0023] This application provides a method for inhibiting protoporphyrin IX (PPIX) synthesis in vivo, comprising administering to a subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0024] This application provides a method for inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject requiring it, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0025] This application provides a method for inhibiting coproporphyrin III synthesis in vivo, comprising administering to a subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0026] This application provides a method for inhibiting zinc-protoporphyrin IX (ZPPIX) synthesis in a subject requiring it, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0027] This application provides a method for inhibiting porphobilinogen (PBG) synthesis in vivo, comprising administering to a subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0028] This application provides a method for inhibiting the synthesis of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) in vivo, comprising administering to a subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0029] This application provides a method for inhibiting hydroxymethylbilan (HMB) synthesis in vivo, comprising administering to a subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

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

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

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

[0033] This application relates to a method for inhibiting the synthesis of porphyrin or porphyrin precursor in vivo, comprising administering to a subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive, wherein the porphyrin or porphyrin precursor is a.5-ALA b.PBG c. Hydroxymethylbilan d.PPIX e.ZPPIX f. Uroporphyrinogen I g. Uroporphyrinogen III h. Heptacarboxyporphyrinogen I i. Heptacarboxyporphyrinogen III j. Hexacarboxyporphyrinogen I k. Hexacarboxyporphyrinogen III l. Pentacarboxyporphyrinogen I m. Pentacarboxyporphyrinogen III n. Coproporphyrinogen I o. Coproporphyrinogen III p. isocoproporphyrin q. porphobilinogen; and r. Protoporphyrinogen IX The present invention provides a method selected from the group consisting of the following.

[0034] In certain embodiments of the described method, the accumulation of one or more heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of 5-ALA, coproporphyrin III, zinc-protoporphyrin IX (ZPPIX), porphobilinogen, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin. In certain such embodiments, the accumulation of one or more heme intermediates is inhibited in a dose-dependent manner.

[0035] In certain embodiments of the aforementioned method, the subject has EPP, XLPP, or CEP. In certain embodiments of the aforementioned method, the subject has hepatic porphyria. In certain embodiments of the aforementioned method, the subject has a mutation in UROS. In certain embodiments of the aforementioned method, the subject has a gene deficiency in the GATA-1 erythrocyte-specific transcription factor. In certain embodiments of the aforementioned method, the subject has a liver disease associated with EPP, XLPP, or CEP.

[0036] In certain embodiments of the methods described above, the method further comprises administering additional active agents and / or supportive therapies. In certain such embodiments, the additional active agents and / or supportive therapies are selected from the group consisting of sun protection, topical sunscreens, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. In certain embodiments, additional active agents and / or supportive therapies are selected from the group consisting of sun avoidance, topical sunscreens, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, heme infusion, adequate calorie support, gibosilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of exacerbating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene into hepatocytes via a viral vector), hemodialysis, pharmacological chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0037] This application provides a method for treating ribosomal dysfunction-related anemia in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0038] This application provides a method for treating one or more complications of ribosomal dysfunction-related anemia in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, the one or more complications of ribosomal dysfunction-related anemia are selected from the group consisting of thrombocytosis, megakaryotypic hyperplasia, infection, bleeding (e.g., from the nose or gums), subcutaneous hemorrhage, splenomegaly, need for more frequent blood 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.

[0039] In certain embodiments of the aforementioned methods for treating ribosomal dysfunction-related anemia or one or more complications of ribosomal dysfunction-related anemia, the ribosomal dysfunction-related anemia is Diamond-Blackfan anemia. In certain such embodiments, the subject is haploinsufficiency with respect to a 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). In other such embodiments, the subject is haploinsufficiency with respect to a 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). 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 group consisting of 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 group consisting of TSR2, GATA1, and EPO.

[0040] In certain embodiments of the aforementioned methods for treating ribosomal dysfunction-related anemia or one or more complications of ribosomal dysfunction-related anemia, the ribosomal dysfunction-related anemia is Schwakman-Diamond syndrome. In certain such embodiments, the subject has one or more mutations in the SBDS gene.

[0041] In certain embodiments of the aforementioned methods for treating ribosomal dysfunction-related anemia or one or more complications of ribosomal dysfunction-related anemia, the ribosomal dysfunction-related anemia is congenital keratosis. In certain such embodiments, the congenital keratosis is x-linked congenital keratosis. In other such embodiments, the subject has one or more mutations in the DKC1 gene.

[0042] In certain embodiments of the aforementioned methods for treating ribosomal dysfunction-related anemia or one or more complications of ribosomal dysfunction-related anemia, the method reduces the risk of bone marrow failure, pulmonary fibrosis, or hepatic fibrosis in the subject.

[0043] In certain embodiments of the aforementioned methods for treating ribosomal dysfunction-related anemia or one or more complications of ribosomal dysfunction-related anemia, the ribosomal dysfunction-related anemia is chondrohair hypoplasia. In certain such embodiments, the subject has one or more mutations in the RMRP gene.

[0044] In certain embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or one or more complications of anemia associated with ribosomal dysfunction, the method reduces intracellular heme levels.

[0045] In certain embodiments of the aforementioned methods for treating anemia associated with ribosomal dysfunction or one or more complications of anemia associated with ribosomal dysfunction, the method increases the number of red blood cells in question.

[0046] In certain embodiments of the foregoing methods for treating anemia associated with ribosomal dysfunction or one or more complications of anemia associated with ribosomal dysfunction, the method further comprises administering an additional active agent and / or supportive therapy. In certain such embodiments, the additional active agent and / or supportive therapy is selected from the group consisting of trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotatercept, ruspatercept, iron chelators, blood transfusions, and platelet transfusions.

[0047] This application provides a method for treating polycythemia in a subject requiring it, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive.

[0048] This application provides a method for treating one or more complications of polycythemia in a subject requiring such treatment, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, the one or more complications of polycythemia are selected from the group consisting of pulmonary embolism, transient ischemic attack, transient visual impairment, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia.

[0049] In certain embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, the polycythemia is primary polycythemia. In certain such embodiments, primary polycythemia is polycythemia vera or pure polycythemia. In other such embodiments, primary polycythemia is primary familial polycythemia.

[0050] In certain embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, the polycythemia is secondary polycythemia. In certain such embodiments, secondary polycythemia is associated with disorders selected from the group consisting of hypoxia, central hypoxic processes, lung disease, right-to-left cardiopulmonary shunt (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, polycythemia in smokers, high-altitude living environments, kidney disease, kidney transplantation, abnormal hemoglobinopathy due to hyperoxygen affinity, decreased levels of erythrocyte 2,3,-DPG, bisphosphoglycerate mutase deficiency, methemoglobinemia, hereditary ATP increase, gene mutations in oxygen-sensing pathways, tumors, drug-induced secondary polycythemia, adrenocortical hypersecretion, and idiopathic polycythemia.

[0051] In certain embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, the polycythemia is relative polycythemia. In certain such embodiments, relative polycythemia is selected from the group consisting of Geisbeck syndrome, pseudocythemia, or stress polycythemia.

[0052] In certain embodiments of the aforementioned methods for treating polycythemia or one or more complications of polycythemia, the polycythemia is Chuvash polycythemia.

[0053] This application provides a method for inhibiting heme synthesis in a subject having polycythemia, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, heme synthesis is inhibited in a dose-dependent manner.

[0054] This application provides a method for inhibiting hemoglobin synthesis in a subject having polycythemia, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, hemoglobin synthesis is inhibited in a dose-dependent manner.

[0055] This application provides a method for inhibiting erythrocyte synthesis in a subject having polycythemia, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, erythrocyte synthesis is inhibited in a dose-dependent manner.

[0056] This application provides a method for reducing the red blood cell count in a subject having polycythemia, comprising administering to the subject (1) a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or (2) (a) a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable additive. In certain embodiments, the red blood cell count is reduced in a dose-dependent manner.

[0057] In certain 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%).

[0058] In certain embodiments of the aforementioned methods, the method further comprises administering additional active agents and / or supportive therapies. In certain such embodiments, the additional active agents and / or supportive therapies are selected from the group consisting of hydroxyurea (e.g., Droxia®, Hydrea®), interferon alpha, interferon alpha-2b (e.g., Intron® A), ruxolitinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiotherapy, hepcidin mimetic (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors. [Brief explanation of the drawing]

[0059] [Figure 1] Figure 1 illustrates the research procedure for evaluating the efficacy of GlyT1 inhibitors in the EPP phototoxicity assay. [Figure 2] Figure 2 shows that compound 11 ("GlyT1 inhibitor") reduces PPIX levels in RBCs in Fechm1Pas / Fechm1Pas homozygous mice, as measured by flow cytometry on days 14 and 18. [Figure 3] Figure 3 shows that treatment with compound 11 ("GlyT1 inhibitor") reduces skin lesions in Fechm1Pas / Fechm1Pas homozygous mice after light exposure. [Figure 4]Figure 4 shows that treatment with compound 11 ("GlyT1 inhibitor") reduces the percentage of area with skin lesions in Fechm1Pas / Fechm1Pas homozygous mice after light exposure. [Figure 5] Figure 5 shows the correlation between skin lesions and PPIX level quantification in Fechm1Pas / Fechm1Pas homozygous mice treated with vehicle or compound 11 ("GlyT1 inhibitor") at day 14. [Modes for carrying out the invention]

[0060] Detailed description of the application The compounds and their pharmaceutical compositions described in this application are useful as inhibitors of GlyT-1 or its variants. While we do not wish to be bound by any particular theory, it is conceivable that the compounds and their pharmaceutical compositions described in this application may inhibit the activity of GlyT-1 or its variants, and thus, through GlyT-1 inhibition, could treat certain diseases and disorders, particularly those caused by iron overload and / or those that regulate heme synthesis. Inhibition of heme synthesis via inhibition of PPIX synthesis may be used to treat numerous hematological disorders, such as myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital myeloid porphyria (CEP). Inhibition of heme synthesis by glycine transporter inhibitors also contributes to iron overload disorders and abnormal hemoglobin disorders, such as polycythemia (e.g., primary polycythemia, polycythemia vera, polycythemia pure, primary familial polycythemia, relative polycythemia, secondary polycythemia, Geisbeck syndrome, pseudocythemia, stress polycythemia, Chuvash polycythemia), and anemia associated with ribosomal dysfunction (e.g., Diamond-Blackfan anemia, Schwakman-Da). It has potential applications in the treatment of Earmond syndrome (chondrohair hypoplasia and congenital keratosis), hepatic porphyria (e.g., acute hepatic porphyria, acute intermittent porphyria, ALA dehydratase porphyria, atypical porphyria, hereditary coproporphyria, halderoporphyria, nonacute hepatic porphyria, familial or sporadic late-onset cutaneous porphyria, myelohepatic porphyria), thalassemia, and other blood-related disorders. Herein, it has been found that the compound of this application and its pharmaceutically acceptable composition are effective as GlyT-1 inhibitors. This application concerns the compound of formula (I). [ka] or a pharmaceutically acceptable salt thereof [in the formula, A is an aryl or heteroaryl ring system, where R 1 It is replaced once or more times as needed; B is a 4-8 member non-aromatic carbon ring, or a 4-8 member non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the non-aromatic carbon ring or heterocycle is R 2 It is replaced once or more times as needed; R 1 These are independently of each other's appearance: 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, -(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 Selected from the group consisting of alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclil, and monocyclic and bicyclic non-aromatic heterocyclil, where -C 1~8 Alkyl, -OC 1~8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl are halogens, CN, -C 1~8 Alkyl, -C 1~8 Alkyl heterocyclyl, -C 1~8Alkyl heteroaryl, -OC 1~8 Substitutions may be made 1 to 3 times as needed, with substituents independently selected in each instance from the group consisting of alkyl, aryl, and monocyclic heteroaryl groups; R 2 These are independently of each other's appearance: 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, -(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 Selected from the group consisting of alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclil, and monocyclic and bicyclic non-aromatic heterocyclil, where -C 1~8 Alkyl, -OC 1~8 Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl are halogens, CN, -C 1~8 Alkyl, -C 1~8 Alkyl heterocyclyl, -C 1~8 Alkyl heteroaryl, -OC 1~8Substitutions may be made 1 to 3 times as needed, with substituents independently selected in each instance from the group consisting of alkyl, aryl, and monocyclic heteroaryl groups; R 3 is OH, -C 1~8 Alkyl, -OC 1~8 Alkyl, -O aryl, -O heteroaryl, and -OC 0~8 Alkyl C 3~8 Selected from the group consisting of cycloalkyls, where -C 1~8 Alkyl and -OC 1~8 Alkyls include halogens, haloalkyls (e.g., CH2F, CHF2, CF3), aryls, heterocyclyls, and -C 3~8 Substitutions may be made 1 to 3 times as needed, with substituents independently selected from the group consisting of cycloalkyl groups in each instance; R 4 Is H; or R 3 and R 4 These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocyclines, where cycloalkyl and heterocyclines are CN, -C 1~8 The substituents may be substituted one or two times as needed with substituents independently selected in each instance from the group consisting of alkyl, aryl, and heterocyclyl, where -C 1~8 Alkyl, aryl, and heterocyclyl groups may be substituted one to three times as needed with substituents independently selected from the group consisting of halogens in each instance; R 5 H, -OH, -C 1~8 Selected from the group consisting of alkyl and NH2; R 6 is -C 1~8 Selected from the group consisting of alkyl, aryl, and heteroaryl, where -C 1~8 Alkyl, aryl, and heteroaryl compounds contain deuterium, H, or -C. 1~8 The substituents can be substituted 1 to 3 times as needed with substituents independently selected from the group consisting of alkyls, where -C 1~8Alkyl compounds include -CONH2, -S(O)2NH2, and -S(O)2-C 1~8 Can be substituted with alkyl, aryl, or heterocyclyl as needed; or R 5 and R 6 They form heterocyclines, which are substituted as needed, along with the atoms to which they bond; R 7 It is deuterium; R a is H or -C 1~8 It is alkyl; R b is H or -C 1~8 It is alkyl, and here, -C 1~8 Alkyl compounds include -CONH2, -S(O)2NH2, and -S(O)2-C 1~8 Can be substituted with alkyl, aryl, or heterocyclyl as needed; or R a and R b These, along with the nitrogen atom to which they bond, are 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, -C(O)OH, -(CH2) k COC 1~8 Alkyl, -(CH2) n OC 1~8 Alkyl, -NHC(O)OC 1~8 Alkyl, -(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, forming non-aromatic heterocyclines which are substituted 1 to 3 times as necessary with substituents independently selected in each instance from the group consisting of aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclines, and monocyclic and bicyclic non-aromatic heterocyclines; R aa is H or -C 1~8 It is alkyl; R bb is -C 1~8 Alkyl, -C 4~8 A cycloalkylmethyl or monocyclic non-aromatic heterocycline, where -C 1~8 Alkyl and -C 4~8 Cycloalkylmethyl can be substituted with NH2, halogen, or CN as needed; 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; l is provided as 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0061] Those skilled in the art will understand that Formula I [ka] However, it will be easily understood that this represents 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 piperidine ring system in formula I through ring A (i.e., the indicated nitrogen of the piperidine ring is directly bonded to one of the atoms of ring A).

[0062] In a particular embodiment, A is a monocyclic aryl or heteroaryl ring system, where the monocyclic aryl or heteroaryl ring system is fused with ring B, and the monocyclic aryl or heteroaryl ring system is R 1It is substituted once or more times as needed. In certain embodiments, A is selected from phenyl, pyrimidine, pyridine and thiazole, where phenyl, pyrimidine, pyridine and thiazole are R 1 It is replaced once or more times as needed. In a particular embodiment, R 1 is a halogen (e.g., fluoro or chloro) or -C 1~8 It is alkyl. In a particular embodiment, R 1 These are halogens (e.g., fluoro or chloro). In certain embodiments, B is a 5- or 6-membered non-aromatic carbon ring, or a 5- or 6-membered non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the non-aromatic carbon ring or heterocycle is R 2 It is replaced once or more times as needed. In a particular embodiment, B is R 2 It is a five-membered non-aromatic carbon ring that is substituted once or more times as needed. In certain embodiments, B is R 2 It is a six-membered non-aromatic carbon ring that is substituted once or more as needed. In certain embodiments, B is a five-membered non-aromatic heterocycle containing an oxygen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments, B is a five-membered non-aromatic heterocycle containing a nitrogen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments, B is a five-membered non-aromatic heterocycle containing a sulfur atom, where the non-aromatic heterocycle is R 2 The atoms are substituted once or more as needed (for example, sulfur is substituted twice with =O, resulting in the five-membered non-aromatic heterocycle containing a sulfone). In certain embodiments, B is a five-membered non-aromatic heterocycle containing a nitrogen atom and a sulfur atom, where the non-aromatic heterocycle is R 2The atoms are substituted once or more as needed (for example, sulfur is substituted twice with =O, resulting in a 5-membered non-aromatic heterocycle containing a sulfonamide). In certain embodiments, B is a 6-membered non-aromatic heterocycle containing a nitrogen atom, an oxygen atom and a sulfur atom, where the non-aromatic heterocycle is R 2 The atoms are substituted once or more as needed (for example, sulfur is substituted twice with =O, resulting in a 6-membered non-aromatic heterocycle containing a sulfone, an oxygen atom, and a nitrogen atom). In certain embodiments, B is a 6-membered non-aromatic heterocycle containing an oxygen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments, B is a six-membered non-aromatic heterocycle containing nitrogen and oxygen atoms, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments, B is a six-membered non-aromatic heterocycle containing a nitrogen atom, where the non-aromatic heterocycle is R 2 It is substituted once or more times as needed. In certain embodiments, B is a six-membered non-aromatic heterocycle containing two nitrogen atoms, where the non-aromatic heterocycle is R 2 It is replaced once or more times as needed.

[0063] In a particular embodiment, R 2 is =O, -C 1~8 Alkyl (e.g., methyl) and C(O)OC 1~8 It is selected independently of alkyl. In a particular embodiment, [ka] teeth, [ka] [ka] Selected from, where the aryl or heteroaryl ring system of ring A is R 1(For example, halogens such as fluorine or chlorine, or -C such as methyl) 1~8 The alkyl group is substituted once or more as needed, and the 5 or 6-membered non-aromatic carbocyclic or heterocyclic ring of ring B is R 2 (For example, alkyl groups such as methyl, or -(CH2) such as C(O)OtBu) m C(O)OC 1~8 It is further substituted once or more times as needed with alkyl. In certain embodiments, [ka] teeth, [ka] Here, the aryl or heteroaryl ring system of ring A is R 1 (For example, halogens such as fluorine or chlorine, or -C such as methyl) 1~8 The alkyl group is substituted once or more as needed, and the 5 or 6-membered non-aromatic carbocyclic or heterocyclic ring of ring B is R 2 (For example, alkyl groups such as methyl, or -(CH2) such as C(O)OtBu) m C(O)OC 1~8 It is further substituted once or more times as needed with alkyl. In certain embodiments, [ka] teeth, [ka] [ka] [ka] Selected from. In a particular embodiment, [ka] teeth, [ka] That is the case.

[0064] In a particular embodiment, R a and R b These form optionally substituted monocyclic non-aromatic heterocyclines containing 3 to 9 atoms, each having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, along with the nitrogen atom to which they bond. These monocyclic non-aromatic heterocyclines are 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, -CN, -C(O)OC 1~8 Alkyl, -C(O)OH, -(CH2) k COC 1~8 Alkyl, -(CH2) n OC 1~8 Alkyl, -NHC(O)OC 1~8 Alkyl, -(CH2) m C(O)OC 1~8 Alkyl, -S(O)2-C 1~8 The substituents may be substituted 1 to 3 times as needed with substituents independently selected in each instance from the group consisting of alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclil, and monocyclic and bicyclic non-aromatic heterocyclil. In certain embodiments, R a and R b Together with the nitrogen atom to which they are bonded, they form a morpholinyl, oxazolidinyl, thiadinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl, or thiomorpholinyl group, where the morpholinyl, oxazolidinyl, thiadinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl, or thiomorpholinyl group is =O, -C 1~8 Alkyl, OH, and -C(O)OC 1~8It can be substituted 1 to 3 times as needed with substituents independently selected from the group consisting of alkyls in each instance. In a particular embodiment, R a and R b Along with the nitrogen atoms to which they bond, [ka] They form a group, each of which is =O, -C 1~8 Alkyl, OH, and -C(O)OC 1~8 It can be substituted 1 to 3 times as needed with substituents independently selected from the group consisting of alkyls in each instance. In a particular embodiment, R a and R b These, along with the nitrogen atom to which they are bonded, are oxazolidinyl or oxazolidinyl groups: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, form a thiadinyl or thiadinyl group: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, are imidazolidinyl or imidazolidinyl groups: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, form a piperazinyl or piperazinyl group: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, are pyrrolidinyl or pyrrolidinyl groups: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, are thiomorpholinyl or thiomorpholinyl groups: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, are piperidinyl or piperidinyl groups: [ka] Forms R a and R b These, along with the nitrogen atom to which they are bonded, form a morpholinyl or morpholinyl group: [ka] It forms.

[0065] In a particular embodiment, R 3 is OH, -OC 1~8 Alkyl, -O aryl, -O heteroaryl, and -OC 0~8 Alkyl C 3~8 Selected from the group consisting of cycloalkyls, where -C 1~8 Alkyl and -OC 1~8 Alkyls include halogens, haloalkyls (e.g., CH2F, CHF2, CF3), aryls, heterocyclyls, and -C 3~8 It can be substituted 1 to 3 times as needed with substituents independently selected in each instance from the group consisting of cycloalkyl groups. In a particular embodiment, R 3 These include halogens, CF3, aryls, heterocyclines, and -C 3~8 -OC molecules are substituted 1 to 3 times as needed with substituents independently selected in each instance from the group consisting of cycloalkyl molecules. 1~8It is alkyl. In a particular embodiment, R 3 -OC is substituted 1 to 3 times as needed with substituents independently selected from halogens (e.g., fluorine) in each appearance. 1~8 It is alkyl. In a particular embodiment, R 3 This is -OCH(CH3)CF3.

[0066] In a particular embodiment, R 4 H is H.

[0067] In a particular embodiment, R 3 and R 4 These, together with the carbon atoms to which they bond, form a 4- to 8-membered heterocycline, where the 4- to 8-membered heterocycline is -C 1~8 Alkyl, aryl, and heterocyclyl may be substituted once or twice as needed, -C 1~8 Alkyl, aryl, and heterocyclyl can be substituted 1 to 3 times as needed with substituents independently selected in each instance from the group consisting of halogens. In a particular embodiment, R 3 and R 4 These, together with the carbon atoms to which they bond, form tetrahydrofuranyl or dihydrofuranyl, where tetrahydrofuranyl and dihydrofuranyl are -C 1~8 Alkyl can be substituted once or twice as needed, -C 1~8 The alkyl group can be optionally substituted 1 to 3 times with substituents independently selected from the group consisting of halogens in each instance. In a particular embodiment, R 3 and R 4 These, along with the atoms to which they bond, form a 4- to 8-membered heterocycline which may be substituted as needed. In a particular embodiment, R 3 and R 4 These, together with the atoms to which they bind, form tetrahydrothiophene 1,1-dioxide or dihydrothiophene 1,1-dioxide. In a particular embodiment, R 3 and R 4together with the carbon atom to which they are attached, form -C 1~8 tetrahydrofuranyl optionally substituted 1 or 2 times with alkyl, wherein -C 1~8 alkyl may be optionally substituted 1 to 3 times with substituents independently selected at each occurrence from the group consisting of halogen (e.g., Cl or F). Therefore, the compound of formula (I) has the following structure:

Chemical Formula

Chemical Formula

[0068] In certain embodiments, R 5 is H. In certain embodiments, R 5 is selected from the group consisting of H and NH2.

[0069] In certain embodiments, R 6 is C 1~8 alkyl. In certain embodiments, R 6 is Me. In certain embodiments, R 5 and R 6 together with the atom to which they are attached, form tetrahydrothiophene 1,1-dioxide. Therefore, the compound of formula (I) has the following structure:

Chemical Formula

[0070] In certain specific embodiments, R 5 and R 6 and the atoms to which they are attached form dihydrothiophene 1,1-dioxide. Therefore, the compound of formula (I) has the following structure:

Chemical Formula

[0071] In certain specific embodiments, l is 0. In certain specific embodiments, l is 8.

[0072] The present application provides a compound selected from any one of Compounds 1 to 60 and pharmaceutically acceptable salts thereof:

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0073] In certain specific embodiments, the compound is selected from any one of Compounds 1 to 51 and pharmaceutically acceptable salts thereof. In certain specific embodiments, the compound is selected from any one of Compounds 1 to 57 and pharmaceutically acceptable salts thereof. In embodiments of the present application where a compound (for example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for example, any one of Compounds 1 to 60 and a pharmaceutically acceptable salt thereof) is disclosed herein as a specific enantiomer, the present application further contemplates the compound in its racemic form or other enantiomeric forms. For example, for any one of Compounds 1 to 60 presented as the (S) enantiomer, the present application further provides the compound in its racemic form or (R) enantiomeric form, and pharmaceutically acceptable salts thereof. Similarly, for any one of Compounds 1 to 60 presented as the (R) enantiomer, the present application further provides the compound in its racemic form or (S) enantiomeric form, and pharmaceutically acceptable salts thereof.

[0074] In certain embodiments in which alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl or oxime are substituted, they are substituted or unsubstituted alkyls, e.g., perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, 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, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyl Substituted with one or more substituents selected from lylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amide, amidealkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or perfluoroacyl (e.g., C(O)CF3)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl or perfluoroacylalkyl (e.g., acylalkyl including -alkylC(O)CF3)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azide, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate or thioformate), phosphoryl, phosphate, phosphonate or phosphinate.

[0075] If the bond to a substituent is shown intersecting a bond connecting two atoms in the ring, such substituent may bond to any atom on the ring. If substituents are enumerated without indicating the atom to which such substituent bonded to the remainder of the compound of a given formula, such substituent may bond to any atom in such substituent. A combination of substituents, and the positions of substituents and / or variable regions, is acceptable only if such a combination results in a chemically stable compound.

[0076] As used in this application, the term "substituted as necessary" means that the substitution is made as necessary and therefore can be non-substituted for the specified atom or part.

[0077] Compounds of this application containing one or more asymmetrically substituted atoms may be isolated in an optically active form or a racemic form. Methods for preparing the optically active form, such as by resolving the racemic form, by synthesis from optically active starting materials, or by synthesis using optically active reagents, are well known in the art.

[0078] In certain embodiments, the compounds of this application may be racemic. For example, in embodiments of this application in which a compound (e.g., the compound of formula (I) or a pharmaceutically acceptable salt thereof) is disclosed herein as a particular enantiomer, this application further intends to describe the racemic form of the compound. In certain embodiments, the compounds of this application may be enriched with one enantiomer. For example, the compounds of this application may have an ee higher than 30%ee, 40%ee, 50%ee, 60%ee, 70%ee, 80%ee, 90%ee, or even 95%ee or higher.

[0079] In certain embodiments, the therapeutic preparation may be enriched to preferentially provide one enantiomer of the compound (e.g., formula (I) or a pharmaceutically acceptable salt thereof). The enantiomerically enriched mixture may, for example, contain at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent of one enantiomer. In certain embodiments, a compound enriched with one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, in the composition or mixture of compounds, compared to the amount of the other enantiomer. For example, if the composition or mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.

[0080] In certain embodiments, the compounds of the present application may have more than one stereocenter. In certain such embodiments, the compounds of the present application may be enriched with one or more diastereomers. For example, the compounds of the present application may have a de content higher than 30%de, 40%de, 50%de, 60%de, 70%de, 80%de, 90%de, or even higher than 95%de.

[0081] In certain embodiments, the therapeutic preparation may be enriched to preferentially provide one diastereomer of the compound (e.g., the compound of formula (I) or a pharmaceutically acceptable salt thereof). The diastereomerically enriched mixture may, for example, contain at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent of one diastereomer.

[0082] The various compounds in this application may exist in specific geometric or stereoisomeric forms. This application considers all such compounds, including tautomers, cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures, to be encompassed within the scope of this application. All tautomeric forms are encompassed in this application. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in this application unless their stereochemistry or isomeric form is specifically indicated.

[0083] This application further includes compounds labeled with all pharmaceutically acceptable isotopes (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof). A “isotope-labeled” or “radioactively labeled” compound is a compound in which one or more atoms are replaced or substituted by atoms having atomic masses or mass numbers different from those typically found in nature (i.e., naturally occurring). For example, in certain embodiments, in a compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., C 1~6 Alkyl or C 1~6 The hydrogen atom on the alkoxy is replaced by deuterium (e.g., d3-methoxy or 1,1,2,2-d4-3-methylbutyl).

[0084] Compounds labeled with a specific isotope (e.g., those of formula (I) or their pharmaceutically acceptable salts), for example, incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon 14, i.e. 14 C is particularly useful for this purpose due to its ease of implementation and the available means of detection.

[0085] Deuterium, that is, 2 Substitution with heavier isotopes, such as 1H, may offer certain therapeutic benefits derived from greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and is therefore preferable in some situations.

[0086] 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 16N may be useful in positron emission topography (PET) studies to investigate substrate receptor occupancy.

[0087] Isotope-labeled compounds (e.g., those of formula (I) or pharmaceutically acceptable salts thereof) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the appended examples, using appropriate isotope-labeled reagents instead of previously used unlabeling reagents. Suitable isotopes that may be incorporated into the compounds of this application include, but are not limited to, 2 H (deuterium, also written as D), 3 H (tritium, also written as T), 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 is one example.

[0088] In certain embodiments, the application provides a pharmaceutical preparation suitable for use in human patients, comprising any of the compounds shown above (e.g., the compound of formula (I) or any pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable additives. In certain embodiments, the pharmaceutical preparation may be for use in the treatment or prevention of any condition or disease described herein. In certain embodiments, the pharmaceutical preparation has sufficiently low pyrogen activity to be suitable for use in human patients.

[0089] In certain embodiments, the compounds disclosed herein (e.g., the compound according to formula (I) or a pharmaceutically acceptable salt thereof) demonstrate reduced cerebral permeability (e.g., compared to compounds known to cross the blood-brain barrier, such as metoprolol). In certain embodiments, the compounds disclosed herein (e.g., the compound according to formula (I) or a pharmaceutically acceptable salt thereof) are unable to cross the blood-brain barrier (i.e., the compound is restricted to the periphery). In certain embodiments, the compounds disclosed herein (e.g., the compound according to formula (I) or a pharmaceutically acceptable salt thereof) are substrates for human efflux transporter P-glycoprotein (P-gp). In certain embodiments, the compounds disclosed herein (e.g., the compound according to formula (I) or a pharmaceutically acceptable salt thereof) have efflux ratios higher than approximately 1.75, 1.8, 1.9, 2.0, 5.0, 10, 15, 20, 25, 30, 35, or 40, where,

number

[0090] Any compound of the above structure may be used in the manufacture of a pharmaceutical product for the treatment of any disease or condition disclosed herein.

[0091] Use of compounds The compounds of this application may be administered orally, parenterally, buccally, vaginally, rectally, by inhalation, gas injection, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, subarachnoidally, intraventricularly, and intraarticularly by injection.

[0092] The dosage depends on the route of administration, the severity of the disease, the patient's age and weight, and other factors typically considered by the attending physician when determining the most appropriate individual regimen and dosage level for a particular patient. The amount of compound administered varies for the patient being treated, ranging from approximately 100 ng / kg body weight to 100 mg / kg body weight per day. For example, the dosage can be readily determined by those skilled in the art from the present disclosure and knowledge in the art. Here, those skilled in the art can readily determine the amounts of the compound, and, if necessary, additives, vehicles and / or carriers, in the composition to be administered in the method of this application. In certain embodiments, this application relates to a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof for use as a pharmaceutically acceptable agent, for example, for the treatment of any of the disorders disclosed herein.

[0093] In certain embodiments, the compounds and compositions described herein are generally useful for inhibiting GlyT-1 or its variants. The activity of the compounds used herein as inhibitors of GlyT-1 or its variants may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of GlyT-1 or its variants. Alternative in vitro assays quantify the ability of inhibitors to bind to GlyT-1 or its variants. Detailed conditions for assaying the compounds used herein as inhibitors of GlyT-1 or its variants are shown in the following examples.

[0094] In certain embodiments, this application relates to a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0095] This application provides a method for preventing or treating a disorder in a subject associated with a disease-causing condition resulting from an excess of heme, accumulation of toxic intermediates of heme biosynthesis, or pathological increase in erythropogenesis, comprising administering one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more glycine transporter inhibitor prodrugs or pharmaceutically acceptable salts thereof, to the subject. In certain embodiments, the disorder is a porphyria (e.g., myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital myeloid porphyria (CEP)), a hepatic porphyria (e.g., acute hepatic porphyria, acute intermittent porphyria, ALA dehydratase porphyria, atypical porphyria, hereditary coproporphyria, halderoporphyria, nonacute hepatic porphyria, familial or sporadic late-onset cutaneous porphyria, bone marrow hepatic porphyria) These include porphyria, anemia associated with ribosomal disorders (e.g., Diamond-Blackfan anemia, Schwakman-Diamond syndrome, chondrohair hypoplasia, and congenital keratosis), polycythemia (e.g., primary polycythemia, polycythemia vera, polycythemia pure, primary familial polycythemia, relative polycythemia, secondary polycythemia, Geisbeck syndrome, pseudocythemia, stress polycythemia, Chuvasi polycythemia), thalassemia, or other blood-related disorders. In certain embodiments, the glycine transporter inhibitor is a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. For example, this application provides a method for preventing or treating a disorder associated with the accumulation of PPIX in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject.

[0096] In the treatment of any of the disorders disclosed herein, different compounds of this application may be administered (e.g., in combination) with one or more other compounds of this application (e.g., any one of the compounds of formula (I) (e.g., any one of compounds 1 to 60) or any pharmaceutically acceptable salt thereof). In addition, any one or more of the compounds of formula (I) (e.g., any one of compounds 1 to 60) or any pharmaceutically acceptable salt thereof may be administered in combination with other conventional therapeutic agents in the treatment of any one or more disease conditions referred to herein.

[0097] In certain embodiments, the compounds of this application may be used alone or administered in combination with another type of therapeutic agent. As used herein, the term “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 (for example, two compounds being effective simultaneously in the patient, which may include a synergistic effect of the two compounds). For example, different therapeutic compounds may be administered simultaneously, sequentially, or by separate dosing of the individual components of the treatment, either in the same formulation or in separate formulations. In certain embodiments, different therapeutic compounds may be administered to each other within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic compounds.

[0098] In certain embodiments, co-administration of the compounds of this application with one or more additional therapeutic agents provides improved efficacy compared to each individual administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or one or more additional therapeutic agents. In certain such embodiments, the co-administration provides an additive effect, where the additive effect refers to the sum of the effects of each individual administration of the compounds of this application and one or more additional therapeutic agents.

[0099] Such combination products use the compound of this application within the dosage range described herein, as well as one or more other pharmaceutically active compounds within the approved dosage range and / or dosages described in the reference publications.

[0100] Porphyria Porphyria is a family of hereditary or acquired disorders resulting from deficiencies in the activity of specific enzymes in the heme biosynthesis pathway, also referred to herein as the porphyrin pathway. Porphyrins are the main precursors of heme. Examples of porphyrins and porphyrin precursors include 5-aminolevulinic acid (ALA), porphopilinogen (PBG), hydroxymethylbilan (HMB), uroporphyrinogen I or III, coproporphyrinogen I or III, protoporphrinogen IX, and protoporphyrin IX. Heme is an essential component of hemoglobin, myoglobin, catalase, peroxidase, and cytochromes, the latter including respiratory and P450 hepatic cytochromes. Heme is synthesized in almost all human cells. Approximately 85% of heme is produced in erythrocytes, primarily for hemoglobin. Most of the remaining heme is produced in the liver, and 80% of it is used for cytochrome synthesis. Deficiencies in certain enzymes of the porphyrin pathway lead to insufficient heme production and, at high concentrations, the accumulation of porphyrin precursors and / or porphyrins, which can also be toxic to the function of cells or organs.

[0101] Porphyria can be classified according to the primary site of overproduction and accumulation of porphyrins or their precursors. In hepatic porphyria, porphyrins and porphyrin precursors are preferentially overproduced in the liver, while in myeloid porphyria, porphyrins are overproduced in bone red blood cells. Acute or hepatic porphyria results in nervous system dysfunction and neurological signs that can affect both the central and peripheral nervous systems, such as pain (e.g., abdominal pain and / or chronic neuropathic pain), vomiting, neuropathy (e.g., acute neuropathy, progressive neuropathy), muscle weakness, epileptic seizures, mental disorders (e.g., hallucinations, depression, anxiety, delusions), cardiac arrhythmias, tachycardia, constipation, and diarrhea. Cutaneous or myeloid porphyria primarily affects the skin, causing symptoms such as painful photosensitivity, herpes, 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 (e.g., fingers, toes). Most porphyrias are caused by mutations encoding enzymes in the heme biosynthesis pathway. However, not all porphyrias are hereditary. For example, patients with liver disease may develop porphyria as a result of liver dysfunction. Patients with PCT may suffer from a deficiency of uroporphyrinogen decarboxylase (URO-D) activity, resulting from the formation of the ORO-D enzyme with lower than normal enzyme activity.

[0102] Acute hepatic porphyria Porphyria encompasses eight hereditary metabolic disorders of heme biosynthesis, in which various enzymes in the complex heme biosynthesis pathway are disrupted. Porphyria are broadly classified, based on their clinical presentation, as acute versus nonacute, or hepatic versus myeloid porphyria. Acute hepatic porphyrias include acute intermittent porphyria (AIP), atypical porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinic acid dehydratase deficiency porphyria (ADP), which often result in severe abdominal, psychiatric, neurological, or cardiovascular symptoms. Each acute hepatic porphyria arises from a genetic defect resulting in a deficiency of one of the enzymes in the heme synthesis pathway in the liver. AIP, HCP, and VP are autosomal dominant porphyrias, while ADP is an autosomal recessive porphyria. In rare cases, AIP, HCP, and VP occur as homozygous dominant forms. Late-onset cutaneous porphyria (PCT) is a nonacute hepatic porphyria in which patients often present with herpes, vesicles, milia, and hirsutism on the cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as myelohepatic porphyria (HEP). The clinical and laboratory characteristics of these porphyrias are described in Table 1 below. [Table 1]

[0103] NV: Visceral nerve symptoms; C: Skin symptoms; A: Anemia; LD: Liver injury; 1 Clinical characteristics that vary at the time of manifestation; ALA: 5-aminolevulinic acid; Copro: coproporphyrin; PBG: porphobilinogen; Uro: uroporphyrin; Hepta: heptacarboxyl-porphyrin; Proto: protoporphyrin; Isocopro: isocoproporphyrin; Acute intermittent porphyria (AIP), also known as porphobilinogen (PBG) deaminase deficiency or hydroxymethylbilan synthase (HMBS) deficiency, is the most common type of acute hepatic porphyria. Other types of acute hepatic porphyria include hereditary coproporphyria (HCP), atypical porphyria (VP), and ALA dehydratase deficiency porphyria (ADP). Nonacute hepatic porphyria include porphyria cutaneous (PCT), a disorder in which patients often present with herpes, vesicles, milia, and hirsutism on the cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as myelohepatic porphyria (HEP). The clinical and laboratory characteristics of these porphyrias are described in Table 1.

[0104] AIP has been found to have a high prevalence of approximately 1 in 10,000 in certain populations (e.g., northern Sweden). The prevalence of the variant in the general European population, excluding the United States and the United Kingdom, is estimated to be approximately 1 in 10,000 to 1 in 20,000. Clinical disease itself appears in only about 10–15% of individuals with a variant known to be associated with AIP. However, the penetrance is as high as 40% in individuals with a particular variant (e.g., the W198X variant). AIP is typically latent before puberty. Symptoms are more common in women than in males. The prevalence of the disease is likely underestimated, possibly due to its incomplete penetrance and long latency period. In the United States, it is estimated that there are approximately 2,000 patients who have experienced at least one seizure. In France, Sweden, the United Kingdom, and Poland, it is estimated that there are approximately 150 cases of active relapse, these patients being primarily young women with a median age of 30 years.

[0105] AIP affects, for example, the visceral nervous system, peripheral nervous system, autonomic nervous system, and central nervous system. The symptoms of AIP are variable and include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (dysuria, urinary retention / incontinence, or dark urine), neurological symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting cranial nerves and / or resulting in weakness in the arms or legs), epileptic seizures, neuropathic pain (e.g., pain associated with progressive neuropathy, e.g., chronic neuropathic pain), neuropsychiatric symptoms (e.g., mental confusion, anxiety, restlessness, hallucinations, hysteria, delirium, emotional blunting, depression, phobias, psychosis, insomnia, somnolence, coma), autonomic nervous system issues (e.g., cardiovascular symptoms such as tachycardia, hypertension and / or arrhythmias), and, for example, Symptoms include increased circulating catecholamine levels, sweating, restlessness and / or tremors, dehydration, and electrolyte imbalances. The most common symptoms are abdominal pain and tachycardia. In addition, patients frequently have chronic neuropathic pain and develop progressive neuropathy. Patients with recurrent seizures often have prodromal symptoms. Persistent paralysis may occur after a severe seizure. Recovery from a severe seizure that is not treated promptly may take weeks or months. Acute seizures can be fatal, for example, due to paralysis of the respiratory muscles or circulatory failure from electrolyte imbalance. Before hemin treatment became available, up to 20% of patients with AIP died from the disease.

[0106] Individuals carrying the gene for AIP have an increased risk of hepatocellular carcinoma. In individuals with recurrent attacks, the risk of hepatocellular carcinoma is particularly significant, and after age 50, the risk is nearly 100 times higher than in the general population.

[0107] Acute porphyria attacks can be triggered by endogenous or exogenous factors. Mechanisms by which such factors induce attacks include, for example, increased demand for hepatic P450 enzymes and / or induction of ALAS1 activity in the liver. Increased demand for hepatic P450 enzymes leads to a decrease in hepatic free heme, thereby inducing hepatic ALAS1 synthesis.

[0108] Aggravating factors include hunger (or other forms of reduced or insufficient calorie intake resulting from crash diets, long-distance running, etc.), metabolic stress (e.g., infections, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), smoking, lipid-soluble exogenous chemicals (e.g., chemicals present in tobacco smoke, certain prescription drugs, organic solvents, biocides, and components in alcoholic beverages), and endocrine factors (e.g., reproductive hormones (women may experience worsening during the premenstrual period), synthetic estrogens, progesterone, ovulation stimulation, and hormone replacement therapy).

[0109] For example, more than 1,000 drugs, including alcohol, barbiturates, carbamazepine, carisoprodol, clonazepam (high dose), danazol, diclofenac and possibly other NSAIDs, ergot, estrogen, eschlorbinol, glutetimide, griseofulvin, mephenytoin, meprobamate (also mebutamate and tibutamate), metiprilone, metoclopramide, phenytoin, primidone, progesterone and synthetic progestins, pyrazinamide, pyrazolone (aminopyrine and antipyrine), rifampin, succinimide (ethosuximide and metosuximide), sulfonamide antibiotics, and valproic acid, are contraindicated in acute hepatic porphyria (e.g., AIP, HCP, ADP, and VP).

[0110] Objective signs of AIP include discoloration of the urine during acute attacks (urine may appear red or reddish-brown), as well as increased concentrations of PBG and ALA in the urine during acute attacks. Molecular genetic testing has identified mutations in the PBG deaminase (also known as HMBS) gene in more than 98% of affected individuals.

[0111] Differential diagnosis of porphyria may involve determining the type of porphyria by measuring individual levels of porphyrin or porphyrin precursors (e.g., ALA, PBG) in urine, feces, and / or plasma during seizures (e.g., by chromatography and fluorescence). A diagnosis of AIP can be confirmed by establishing that erythrocyte PBG deaminase activity is 50% or lower than normal levels. DNA testing for mutations may be performed in the patient and members of at-risk families. A diagnosis of AIP is typically confirmed by DNA testing to identify a specific causative gene mutation (e.g., HMBS mutation).

[0112] Treatment of acute seizures typically requires hospitalization to control and manage acute symptoms, including, for example, abdominal pain, epileptic seizures, dehydration / hyponatremia, nausea / vomiting, tachycardia / hypertension, and urinary retention / ileus. For example, abdominal pain may be treated with, for example, narcotic analgesics; epileptic seizures may be treated with seizure prophylaxis and possibly pharmacotherapy (although many anti-epileptic drug therapies are contraindicated); nausea / vomiting may be treated with, for example, phenothiazines; and tachycardia / hypertension may be treated with, for example, beta-blockers. Treatment may include withdrawal from dangerous drug therapies, monitoring of respiratory function, as well as muscle strength and neurological status. Mild seizures (e.g., seizures without paresis or hyponatremia) may be treated with at least 300 g of intravenous 10% glucose per day, but intensified, hemin is immediately provided. Severe seizures should be treated as early as possible with intravenous hemin (3-4 mg / kg daily for 4-14 days) and with IV glucose while waiting for IV hemin to take effect. Typically, seizures are treated with IV hemin for 4 days and IV glucose while waiting for IV hemin administration.

[0113] Hemin (Panhematin® or Hemin for Injection, formerly known as Hematin) is the only heme product approved for use in the United States and was the first drug approved under the Orphan Medicine Act. Panhematin® is a hemin derived from treated red blood cells (PRBCs) and is a protoporphyrin IX containing trivalent iron ions (heme B) and chloride ligands. Heme acts to restrict hepatic and / or myelochemical synthesis of porphyrins. The exact mechanism by which hemin produces symptomatic improvement in patients with acute episodes of hepatic porphyria is not fully understood, however, its action may be due to (feedback) inhibition of δ-aminolevulinic acid (ALA) synthase, an enzyme that limits the rate of porphyrin / heme biosynthesis pathways. Inhibition of ALA synthase should result in reduced production of ALA and PBG, as well as porphyrins and porphyrin intermediates.

[0114] Disadvantages of hemin include its delayed effect on clinical symptoms and its inability to prevent seizure recurrence. Adverse reactions associated with hemin administration may include thrombophlebitis, anticoagulation, thrombocytopenia, renal arrest, or iron overload, which are particularly likely in patients requiring multiple courses of hemin treatment for recurrent seizures. To prevent phlebitis, an indwelling intravenous catheter is required for access in patients with recurrent seizures. Rarely reported side effects include fever, throbbing pain, malaise, hemolysis, anaphylaxis, and circulatory collapse.

[0115] Heme is difficult to prepare in a stable form for intravenous administration. It is insoluble at neutral pH, but can be prepared as heme hydroxide at pH 8 or above. Panhematin® is a lyophilized hemin preparation. When lyophilized hemin is solubilized for intravenous administration, degradation products form rapidly, and these degradation products cause transient anticoagulant effects and phlebitis at the injection site. Hemealbumin and heme alginate (Normosang, the European version of hemin) are more stable and potentially less likely to cause thrombophlebitis. However, heme alginate is not approved for use in the United States. Panhemin® can be stabilized for injection by solubilizing it in 30% human albumin rather than sterile water; however, albumin adds an effect of expanding intravascular volume, increasing the cost of the procedure as well as the risk of pathogens, since it is isolated from human blood.

[0116] Successful treatment of acute seizures does not prevent or delay recurrence. There is doubt as to whether hemin itself can induce recurrent seizures due to the induction of heme oxygenase. Nevertheless, in some regions (particularly France), young women with multiple recurrent seizures are being treated with hemin weekly with the goal of achieving prevention.

[0117] Current therapies for acute neurological seizures include intravenous administration of hemin (Panhematin®, Lundbeck or Normosang®, Orphan Europe), which provides exogenous heme for negative feedback inhibition of ALAS1, thereby reducing the production of ALA and PBG. Hemin is used for treatment between acute seizures and for the prevention of seizures, particularly in women with acute porphyria who experience frequent seizures due to hormonal changes during their menstrual cycle. Patients generally respond well, but the effect is slow, typically taking 2-4 days or longer for urinary ALA and PBG concentrations to return to normal levels. Because intravenous hemin is rapidly metabolized, 3-4 infusions are usually required to effectively treat or prevent acute seizures. In addition, repeated infusions can cause iron overload and phlebitis, which can impair peripheral venous access.

[0118] Givlaari®, a small molecular weight interfering ribonucleic acid (siRNA) against aminolevulinic acid synthase 1, is also used to treat patients with acute hepatic porphyria by targeting and degrading ALAS1 mRNA in hepatocytes using RNA interference. Concerning risks associated with the use of Givlaari include anaphylactic reactions, hepatotoxicity, and nephrotoxicity. For example, 15% of patients in Givlaari clinical trials showed transaminase (ALT) elevations three times the upper limit of normal. In addition, 15% of patients receiving Givlaari have renal-related adverse reactions, including elevated serum creatinine levels and decreased estimated glomerular filtration rate. One final treatment is orthotopic liver transplantation. While orthotopic liver transplantation is curative, this procedure has a considerable morbidity and mortality rate, and the availability of liver donors is limited. Therefore, there is a need for new methods and compositions to treat and / or prevent hepatic porphyria. Methods and uses of glycine transporter inhibitors, such as compounds of formula (I) (e.g., any one of compounds 1 to 60) or pharmaceutically acceptable salts thereof, satisfy these needs and other requirements.

[0119] Limited experience with liver transplantation suggests that, when successful, it is an effective treatment for AIP. There have been approximately 12 transplants in Europe in human patients with curative or varying effects. 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 transplantation"), the recipient may develop AIP. While orthotopic liver transplantation is curative, this procedure has a considerable morbidity and mortality rate, and the availability of liver donors is limited.

[0120] Among the long-term clinical effects of acute porphyria is, for example, chronic neuropathic pain that may arise from progressive neuropathy due to the neurotoxic effects of elevated porphyrin precursors (e.g., ALA and / or PBG). Patients may experience neuropathic pain before or during acute attacks. Elderly patients may experience an increase in neuropathic pain with age, and various narcotics are typically prescribed for this purpose. Electromyographic abnormalities and decreased conduction time have been observed in patients with acute hepatic porphyria. In patients with acute porphyria (e.g., ADP, AIP, HCP, or VP), levels of porphyrin precursors (ALA and PBG) are often elevated between attacks in both asymptomatic and symptomatic patients. Therefore, reducing porphyrin precursors and resuming normal heme biosynthesis by reducing ALAS1 expression and / or activity levels is expected to prevent and / or minimize the development of chronic and progressive neuropathy. Treatments, such as chronic treatments (e.g., periodic treatment with iRNAs as described herein, e.g., treatments with drug regimens as described herein, e.g., weekly or bi-weekly treatments), can sustainably reduce ALAS1 expression in patients with acute porphyria who have elevated levels of porphyrin precursors, porphyrins, porphyrin products, or their metabolites. Such treatments may be provided as needed to prevent or reduce the frequency or severity of individual patients' symptoms (e.g., pain and / or neuropathy) and / or to reduce levels of porphyrin precursors, porphyrins, porphyrin products, or metabolites.

[0121] There is a need to identify novel therapeutic agents that may be used to treat porphyria. As discussed above, existing treatments such as hemin, gibosilan, and liver transplantation have numerous drawbacks. For example, the effect of hemin on clinical symptoms is delayed, it is expensive, and it can have side effects (e.g., thrombophlebitis, anticoagulation, thrombocytopenia, iron overload, renal arrest).

[0122] In certain embodiments, the present application provides the use of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment of hepatic porphyria in a subject requiring such treatment. In some embodiments, the present disclosure provides a method for preventing or treating hepatic porphyria in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. For example, the present application provides a method for preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject.

[0123] If necessary, methods disclosed herein for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria (e.g., AIP, HCP, VP, HARPO, ADP, PCT, and HEP) in a subject may further include administering to the patient one or more supportive therapies or additional active agents for treating the porphyria (e.g., AIP, HCP, VP, HARPO, ADP, PCT, and HEP). For example, patients may also be administered one or more supportive therapies or active agents selected from the group consisting of sun protection, topical sunscreens, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, heme infusion, adequate calorie support, gibosilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of exacerbating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene into hepatocytes via a viral vector), hemodialysis, pharmacological chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0124] In some embodiments, subjects are administered concomitant treatments, such as a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, as well as one or more additional treatments known to be effective against AIP, HCP, VP, HARPO, ADP, PCT, and HEP (e.g., heme products such as glucose and / or hemin as described herein) or related symptoms.

[0125] In one embodiment, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with glucose or dextrose. For example, 10-20% dextrose in saline may be delivered intravenously. Typically, if glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. A compound selected from a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may also be administered intravenously as part of the same infusion used to administer glucose or dextrose, or as a separate infusion administered before, simultaneously with, or after the administration of glucose or dextrose. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 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 one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with parenteral complete nutrition. The compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may be administered before, concurrently with, or after the administration of parenteral complete nutrition.

[0126] In certain embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional treatments, such as hepatic porphyria or another treatment known to be effective in treating the symptoms of hepatic porphyria. In one embodiment, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product (e.g., hemin, heme alginate, or hemalbumin). In further embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product and glucose, a heme product and dextrose, or a heme product and parenteral complete nutrition. The additional treatments may be administered before, after, or concurrently with the administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. A compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, and additional therapeutic agents can be administered, for example, intravenously in combination in the same composition, or the additional therapeutic agents can be administered as part of separate compositions or by other methods described herein. In some embodiments, the subject has been previously treated with a heme product (e.g., hemin, heme alginate, or hemalbumin) as described herein.

[0127] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in combination with one or more additional treatments (e.g., glucose, dextrose), reduces the frequency of acute seizures (e.g., by preventing acute seizures from occurring again, or by reducing the number of seizures that occur in a particular period, e.g., fewer seizures per year). In some such embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered according to a regular dosing regimen, e.g., bid, daily, weekly, bi-weekly or monthly.

[0128] In some embodiments, the subjects have or are at risk of developing hepatic porphyria (e.g., AIP, HCP, VP, ADP, PCT, HARPO, and HEP). In some embodiments, hepatic porphyria is acute hepatic porphyria (e.g., AIP, HCP, VP, and ADP). In some embodiments, hepatic porphyria is nonacute hepatic porphyria (e.g., PCT and HEP). In some embodiments, hepatic porphyria is dual hepatic porphyria, e.g., at least two types of hepatic porphyria. In some embodiments, dual hepatic porphyria includes two or more types of hepatic porphyria selected from the group consisting of AIP, HCP, VP, ADP, HARPO, PCT, and HEP.

[0129] In some embodiments, hepatic porphyria is caused by heterozygous mutations resulting in reduced enzyme activity. In some embodiments, hepatic porphyria is caused by homozygous mutations resulting in reduced enzyme activity. In some embodiments, hepatic porphyria is an autosomal recessive disorder (e.g., ADP). In some embodiments, the subject has the genetic modification (e.g., mutation) described herein but is otherwise asymptomatic.

[0130] Mutations associated with hepatic porphyria include mutations in genes encoding specific enzymes in the heme biosynthesis pathway (porphyrin pathway) or in genes that alter the expression of genes in the heme biosynthesis pathway (e.g., ALAD, HMBS, UROD, UROS, CPOX, and PPOX). In many embodiments, the subject has one or more mutations in enzymes of the porphyrin pathway (e.g., ALA-dehydratase, PBG deaminase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase).

[0131] In some embodiments, hepatic porphyria is acute hepatic porphyria. In some embodiments, hepatic porphyria is nonacute 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 variant porphyria (VP). In some embodiments, hepatic porphyria is hereditary coproporphyria (HCP). In some embodiments, hepatic porphyria is halderoporphyria (HARPO). In some embodiments, hepatic porphyria is patulous cutaneous porphyria (PCT). In some embodiments, PCT is familial or sporadic PCT. In some embodiments, hepatic porphyria is myelohepatic porphyria (HEP). In some embodiments, patients with acute hepatic porphyria (e.g., AIP), or those with mutations associated with acute hepatic porphyria (e.g., AIP) but who are asymptomatic, have elevated ALA and / or PBG levels compared to healthy individuals. In such cases, ALA and / or PBG levels may be elevated even if the patient does not have seizures or has never experienced seizures. 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.

[0132] In some embodiments, the subject has an acute attack of hepatic porphyria. In some embodiments, the subject has a non-acute attack of hepatic porphyria. In some embodiments, the subject has not previously experienced an acute attack of hepatic porphyria. In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject has nerve damage. In some embodiments, the subject has EMG changes and / or changes in nerve conduction velocity. In some embodiments, the subject is asymptomatic. In some embodiments, the subject is at risk of developing hepatic porphyria (e.g., has a gene mutation associated with hepatic porphyria) and is asymptomatic. In some embodiments, the subject had previously had an acute attack of hepatic porphyria but is asymptomatic at the time of treatment.

[0133] In some embodiments, subjects are at risk of developing hepatic porphyria and are treated prophylactically to prevent the development of hepatic porphyria. In some embodiments, subjects have elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, prophylactic treatment is initiated during adolescence. In some embodiments, treatment reduces levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG) (e.g., plasma or urinary levels). In some embodiments, treatment prevents the development of elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, treatment prevents the development of symptoms associated with hepatic porphyria (e.g., pain or nerve damage) or reduces their frequency or severity.

[0134] This application further provides the use of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in the manufacture of a formulation for the treatment of hepatic porphyria in a subject.

[0135] In some embodiments, the subject treated by the described method suffers from pain, for example, chronic pain. In some embodiments, the method is effective in treating pain (for example, by reducing the severity of pain or by curing pain). In some embodiments, the method is effective in reducing or preventing nerve damage.

[0136] In some embodiments, the subjects treated by the methods described herein (a) have elevated levels of ALA and / or PBG, and (b) suffer from pain (e.g., chronic pain). In some embodiments, the methods are effective in reducing elevated levels of ALA and / or PBG, and / or treating pain (e.g., by reducing the severity of pain or by curing pain).

[0137] In some embodiments, the subject is experiencing one or more acute episodes of one or more symptoms of hepatic porphyria. In other embodiments, the subject is experiencing one or more symptoms of hepatic porphyria chronically (e.g., pain, e.g., neuropathic pain, and / or neuropathy, e.g., progressive neuropathy). In some embodiments, the subject treated by the method described herein has recently experienced prodromal symptoms or is currently experiencing prodromal symptoms.

[0138] When used herein, “prodromal symptoms” include any symptoms experienced by an individual subject immediately prior to the onset of an acute attack. Typical 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.

[0139] An acute “attack” of hepatic porphyria typically involves the onset of one or more symptoms of hepatic porphyria in patients with mutations associated with hepatic porphyria (e.g., mutations in genes encoding enzymes in the porphyrin pathway).

[0140] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered after an acute attack of hepatic porphyria. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered during an acute attack of hepatic porphyria. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in reducing the severity of an attack (e.g., by restoring one or more signs or symptoms associated with the attack). In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in shortening the duration of an attack. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in stopping an attack. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered prophylactically to prevent an acute attack of hepatic porphyria. In some embodiments, the prophylactic administration is before, during, or after exposure to or the onset of an exacerbating factor. In some embodiments, the subject is at risk of developing porphyria.

[0141] As used herein, “exacerbating factors” refer to endogenous or exogenous factors that can induce acute exacerbations of one or more symptoms associated with porphyria. Exacerbating factors include hunger (or other forms of reduced or insufficient calorie intake, such as those resulting from crush diets or long-distance running), metabolic stress (e.g., infections, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), smoking, lipid-soluble exogenous chemicals (e.g., chemicals present in tobacco smoke, certain prescription drugs, organic solvents, biocides, and components in alcoholic beverages), endocrine factors (e.g., reproductive hormones (women may experience exacerbations during the premenstrual period), synthetic estrogens, progesterone, ovulation stimulation, and hormone replacement therapy), and lead. Other common exacerbating factors include cytochrome P450-inducing drugs and phenobarbital.

[0142] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 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 to 60) or a pharmaceutically acceptable salt thereof is administered during a specific stage of the menstrual cycle, for example, during the luteal phase.

[0143] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in preventing seizures (e.g., prodromal symptoms and / or exacerbating factors, e.g., recurrent seizures associated with a specific stage 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 to 60) or a pharmaceutically acceptable salt thereof is effective in reducing the frequency of seizures. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in reducing the severity of seizures (e.g., by restoring one or more signs or symptoms associated with seizures). In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in shortening the duration of seizures. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in stopping a seizure.

[0144] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in preventing pain, e.g., neuropathic pain, or reducing its frequency or severity. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in preventing neuropathy, or reducing its frequency or severity. In some embodiments, the subject has or is at risk of developing hepatic porphyria and suffers from pain (e.g., neuropathic pain, e.g., 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.

[0145] The effects of administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof can be established, for example, by comparison with a suitable 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 established as a reduction in frequency compared to a suitable control group, for example, in a group of patients with AIP. 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 population, a population treated with conventional treatments for hepatic porphyria (e.g., conventional treatments for AIP may include glucose, hemin, or both); and, as necessary, a population treated with placebo or a GlyT1 inhibitor in combination with one or more conventional treatments for hepatic porphyria (e.g., glucose, e.g., IV glucose).

[0146] Subjects “at risk” of developing hepatic porphyria, as used herein, include subjects with a family history of hepatic porphyria and / or a history of one or more recurrent or chronic symptoms of hepatic porphyria, and / or subjects with genetic modifications (e.g., mutations) in genes encoding enzymes of the heme biosynthesis pathway, and subjects with genetic modifications known to be associated with hepatic porphyria, e.g., mutations.

[0147] In some embodiments, the modification, e.g., the mutation, makes an individual susceptible to acute attacks (e.g., exacerbating factors, e.g., drugs, diet, or other exacerbating factors, e.g., exposure to exacerbating factors disclosed herein). In some embodiments, the modification, e.g., the mutation, is related to elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the modification, e.g., the mutation, is related to chronic pain (e.g., chronic neuropathic pain) and / or neuropathy (e.g., progressive neuropathy). In some embodiments, the modification, e.g., the mutation, is related to changes in EMG and / or nerve conduction velocity.

[0148] In some embodiments, the alteration is a mutation in a gene selected from the group consisting of ALAD, HMBS, UROD, CPOX, and PPOX. In some embodiments, the alteration is a change, 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 suffer from acute attacks. In some embodiments, the subject has a mutation related to AIP, HCP, VP, ADP, PCT, or HEP.

[0149] In some embodiments, hepatic porphyria is AIP. In some such embodiments, the subject has a modification in PBGD (the gene encoding PBG deaminase), e.g., 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 have two identical mutations or two different mutations in the PBGD gene. In some embodiments, hepatic porphyria is HCP. In some embodiments, the subject has a modification in CPOX (i.e., the gene encoding the enzyme coproporphyrinogen III oxidase), e.g., at least one mutation. In some embodiments, hepatic porphyria is VP. In some embodiments, the subject has a modification in PPOX (i.e., the gene encoding protoporphyrinogen oxidase), e.g., at least one mutation. In some embodiments, hepatic porphyria is ADP (e.g., autosomal recessive ADP). In some embodiments, the subject has a modification in ALAD (the gene encoding ALA dehydratase), for example, at least one mutation. In some embodiments, hepatic porphyria is PCT. In some embodiments, the subject has a modification in UROD (the gene encoding urodecarboxylase), for example, at least one mutation. In some embodiments, hepatic porphyria is CEP. In some embodiments, the subject has a modification in UROS (the gene encoding uroporphyrinogen III synthase), for example, at least one mutation.

[0150] In some embodiments, elevated levels of porphyrin precursors are attributed to lead poisoning. Lead poisoning inhibits the activity of ALAD, CPOX, and FECH, enzymes involved in heme biosynthesis. Patients with lead poisoning are frequently misdiagnosed with ADP or other acute porphyria. In some embodiments, subjects with lead poisoning have reduced enzymatic activity of ALAD. In some embodiments, subjects with lead poisoning have reduced enzymatic activity of CPOX. In some embodiments, subjects with lead poisoning have reduced enzymatic activity of FECH. In some embodiments, subjects with lead poisoning have elevated levels of lead in their blood and / or urine. In some embodiments, subjects with lead poisoning have elevated levels of ALA. In some embodiments, subjects with lead poisoning have elevated levels of both ALA and PBG. In some embodiments, subjects with lead poisoning have ALA levels increased at least 10-fold relative to a reference value. In some embodiments, subjects with lead poisoning have ALA levels increased at least 5-fold relative to a reference value. In some embodiments, the present disclosure relates to a method for treating lead poisoning in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject is further administered a chelating agent. In some embodiments, the chelating agent is 2,3-dimercaptosuccinic acid. In some embodiments, the chelating agent is disodium calcium ethylenediaminetetraacetate.

[0151] Porphyrins (e.g., 5-ALA, PBG, uroporphyrin, and coproporphyrin) can be found in a variety of biological samples, including skin, urine, feces, plasma, and red blood cells. In some embodiments, porphyrins may be extracted from biological samples (e.g., plasma) into a solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., light between 400 and 420 nm). Porphyrins have a maximum absorption wavelength around 400–420 nm, with their highest absorption peak occurring at 415 nm. The maximum emission of porphyrins is typically around 600 nm, varying slightly depending on the type of porphyrin and the solvent used for the analysis. In some embodiments, the diagnosis of hepatic porphyria may be made using fluorescence analysis. In some embodiments, skin porphyrin levels can be measured by calculating the difference before and after complete photobleaching of skin porphyrins using controlled illumination. For example, see Heerfordt IM. Br J Dermatol. 2016;175(6):1284-1289.

[0152] In some embodiments, the target plasma porphyrin fluoresces at a peak of 634 nm when irradiated with blue light (e.g., light in the 400-420 nm range). In some embodiments, the target plasma porphyrin fluoresces at a peak of 626 nm to 634 nm when irradiated with blue light (e.g., light in the 400-420 nm range). In some embodiments, the target skin porphyrin fluoresces at a peak of 632 nm when irradiated with blue light (e.g., light in the 400-420 nm range). In some embodiments, the target skin porphyrin fluoresces at a peak of 626 nm to 634 nm when irradiated with blue light (e.g., light in the 400-420 nm range). In some embodiments, a sample from a subject containing porphyrin or a porphyrin precursor (e.g., plasma or skin) fluoresces at a peak of 615 nm to 620 nm when irradiated with blue light (e.g., light in the 400-420 nm range). In some embodiments, a sample from a subject containing porphyrin or a porphyrin precursor (e.g., plasma or skin) fluoresces with a peak at 624 nm to 627 nm when irradiated with blue light (e.g., 400 to 420 nm light). In some embodiments, the plasma of the subject is excited using a 405 nm laser. In some embodiments, the subject has red fluorescent urine. Myeloid protoporphyria, X-linked protoporphyria, and congenital myeloid porphyria

[0153] Myeloid protoporphyria (EPP) is widespread globally, affecting approximately 5,000 to 10,000 individuals worldwide (Michaels et al. 2010). EPP is considered the most common form of porphyria in children. Myeloid protoporphyria is a form of porphyria that varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, resulting in abnormally high levels of protoporphyrin IX in red blood cells, plasma, skin, and liver. Myeloid protoporphyria is caused by a hereditary or acquired deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is caused by a hereditary increase in the activity of delta-aminolevulinic acid synthase-2 (ALAS2). The enzymes that cause both EPP and XLPP are located in the heme biosynthesis pathway. EPP and XLPP are clinically nearly identical. Congenital erythropoiesis-induced porphyria (CEP), also known as Günther's disease, is caused by mutations in the gene for uroporphyrinogen synthase, resulting in reduced activity of this enzyme and accumulation of its upstream metabolite, coproporphyrin I. Current treatments for myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoiesis-induced porphyria (CEP) are limited. Therefore, there is a need for new methods and compositions to treat and / or prevent myeloid protoporphyria, X-linked protoporphyria, and congenital erythropoiesis-induced porphyria. Methods and uses of glycine transporter inhibitors, such as GlyT1 inhibitors (e.g., any one of compounds of formula (I) (e.g., any one of compounds 1-60) or pharmaceutically acceptable salts thereof), satisfy these needs and others.

[0154] This application provides a method for preventing or treating a disorder associated with the accumulation of PPIX in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject.

[0155] In part, this application relates to methods for treating myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoiesis-induced porphyria (CEP) in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In certain embodiments, the disclosure provides methods for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. These methods are intended, in particular, for therapeutic and prophylactic treatment in animals, more specifically, in humans. The terms “subject,” “individual,” or “patient” are interchangeable throughout this specification and refer to either human or non-human animals. These terms include mammals, e.g., humans, non-human primates, laboratory animals, domesticated animals (including cattle, pigs, camels, etc.), companion animals (e.g., dogs, cats, other domesticated animals, etc.), and rodents (e.g., mice and rats). In certain embodiments, the patient, subject, or individual is human.

[0156] This application provides a method for preventing or treating myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoiesis-porphyria (CEP), or related syndromes thereto (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. This application further provides a method for preventing or treating EPP, XLPP, or CEP in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject.

[0157] This application further provides a method for preventing or treating EPP, XLPP, or CEP, or related syndromes thereof (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. This application further provides a method for preventing or treating EPP, XLPP, or CEP in a subject, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. In certain embodiments of the foregoing, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0158] Myeloid protoporphyria (EPP) and X-linked protoporphyria (XLPP) are erythrocytic cutaneous porphyrias characterized by acute non-bullous photosensitivity, phototolerance, and a marked reduction in quality of life. EPP is caused by a partial deficiency in ferrochelatase (FECH), which catalyzes the final step in the heme biosynthesis pathway. FECH deficiency increases the levels of metal-free erythrocyte PPIX (also referred herein as "free protoporphyrin IX" and "PPIX"). XLPP is typically caused by a C-terminal deletion in the ALAS2 gene resulting in gain-of-function mutations. These gain-of-function mutations increase the enzymatic activity of ALAS2, leading to the accumulation of both metal-free and zinc-bound PPIX. Both EPP and XLPP result in the accumulation of PPIX in erythrocytes and other tissues or bodily fluids (e.g., skin, liver, bile, or feces). PPIX, being lipid-soluble and excreted via bile, is hepatotoxic at high concentrations.

[0159] Patients with EPP or XLPP typically develop photosensitivity during early childhood. Patients frequently exhibit symptoms of burns, itching, pain, erythema, and edema in areas exposed to sunlight. Skin symptoms may be associated with abnormal liver enzyme activity, hepatobiliary damage (e.g., jaundice and cirrhosis), iron deficiency, and corresponding microcytic anemia.

[0160] Diagnosis of EPP and XLPP can be determined by measuring the levels of total red blood cells, free protoporphyrin IX, and zinc protoporphyrin IX in hemolyzed, anticoagulated whole blood. Diagnosis of EPP and / or XLPP can be made based on elevated levels of free protoporphyrin IX in the blood. Patients with XLPP have a significantly higher percentage of zinc protoporphyrin IX relative to free protoporphyrin IX (e.g., >25%) compared to patients with EPP (e.g., ≤15%).

[0161] Diagnosis of EPP can also be determined by measuring the level of ferrochelatase activity in the subject. Ferrokelatase is a mitochondrial enzyme that catalyzes the insertion of ferrous iron into PPIX to form heme. Ferrokelatase also catalyzes the insertion of zinc to form zinc protoporphyrin IX (ZPPIX) from any PPIX, which remains after the completion of heme synthesis. In EPP, both heme and ZPPIX formation are impaired, so free PPIX accumulates in bone marrow reticulocytes. In some embodiments, this disclosure relates to a method for treating subjects in which the ferrochelatase activity level is reduced to 10–35% of the ferrochelatase activity level observed in normal subjects. In some embodiments, this disclosure relates to a method for treating subjects in which the ferrochelatase activity level is reduced to less than 50% of the ferrochelatase activity level observed in normal subjects.

[0162] XLPP has a phenotype similar to EPP and can be identified based on a genetic analysis of ALAS2 or by determining the enzyme activity level of ALAS2. In some embodiments, this disclosure relates to a method for treating subjects having a gain-of-function mutation in ALAS2. In some embodiments, the ALAS2 enzyme activity of the subject is increased. Since ferrochelatase is not deficient in XLPP, some of the excess PPIX measured in erythrocytes is ZPPIX, and a lower percentage (e.g., 50-85%) is metal-free. In some embodiments, the subject has increased zinc protoporphyrin IX levels in erythrocytes. In some embodiments, the method reduces zinc protoporphyrin IX levels in the erythrocytes of the subject. In some embodiments, the method reduces the zinc protoporphyrin IX level in the target red blood cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0163] In certain embodiments, the Disclosure relates to a method for treating myeloid protoporphyria (EPP) and / or X-linked protoporphyria (XLPP) in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the subject has an increased PPIX level. In some embodiments, the method relates to a subject having a PPIX level at least 10%, 20%, 30%, 40%, or 50% higher than the PPIX level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 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 the PPIX level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a PPIX level at least 20% higher than the PPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a PPIX level at least 30% higher than the PPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a PPIX level at least 40% higher than the PPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a PPIX level at least 50% higher than the PPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an increased protoporphyrin IX level in the feces. In some embodiments, the subject has increased protoporphyrin IX levels in the skin. In some embodiments, the subject has increased free protoporphyrin IX levels in red blood cells.In some embodiments, the subject has protoporphyrin IX levels in red blood cells higher than 31 μmol L-1. In some embodiments, the subject has protoporphyrin IX levels in red blood cells between 31 μmol L-1 and 53 μmol L-1. In some embodiments, the subject has protoporphyrin IX levels in red blood cells higher than 53 μmol L-1.

[0164] This application further provides a method for inhibiting PPIX synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In certain embodiments, the disclosure relates to a method for inhibiting PPIX synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 20%. In some embodiments, the disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 30%. In some embodiments, the disclosure relates to a method for inhibiting PPIX synthesis in vivo by at least 40%. In some embodiments, the Disclosure relates to a method for inhibiting PPIX synthesis by at least 50% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting PPIX synthesis by at least 60% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting PPIX synthesis by at least 70% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting PPIX synthesis by at least 80% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting PPIX synthesis by at least 90% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting PPIX synthesis by at least 100% in vivo. The Application further provides a method for reducing the rate of PPIX synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In certain embodiments of the methods and uses disclosed herein, PPIX accumulation is inhibited directly or indirectly. In certain such embodiments, PPIX accumulation is inhibited in a dose-dependent manner.

[0165] In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in the red blood cells of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the red blood cells of a subject to less than 53 μmol L-1. In some embodiments, the method reduces the level of protoporphyrin IX in the red blood cells of a subject to less than 31 μmol L-1. In some embodiments, the method reduces the level of protoporphyrin IX in the red blood cells of a subject to less than 15 μmol L-1. In some embodiments, the method relates to reducing the level of protoporphyrin IX in the feces of a subject. In some embodiments, the method reduces the level of protoporphyrin IX in the skin of a subject. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 15%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 20%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 25%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 30%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 35%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 40%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 45%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 50%.In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 55%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 60%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 65%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 70%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 75%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 80%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 85%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 90%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 95%. In some embodiments, the method relates to a method for reducing the level of free protoporphyrin IX in a subject by at least 100%.

[0166] In certain embodiments, the Disclosure relates to a method for treating X-linked protoporphyria (XLPP) in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the subject has elevated zinc-protoporphyrin IX (ZPPIX) levels. 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 in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 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 in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a ZPPIX level at least 20% higher than the ZPPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a ZPPIX level at least 30% higher than the ZPPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a ZPPIX level at least 40% higher than the ZPPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a ZPPIX level at least 50% higher than the ZPPIX level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an increased ZPPIX level in red blood cells.

[0167] In certain embodiments, the Disclosure relates to a method for treating X-linked protoporphyria (XLPP) in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 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 having EPP. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 15% (e.g., 15%, 20%, 25%, 30%, 35%, 40%, or 45%). In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 20%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 25%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 30%. In some embodiments, the method relates to a subject having a ZPPIX / PPIX ratio of at least 35%. In some embodiments, the method relates to an object having a ZPPIX / PPIX ratio of at least 40%. In some embodiments, the method relates to an object having a ZPPIX / PPIX ratio of at least 45%.

[0168] In certain embodiments, the Disclosure relates to a method for inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the Disclosure relates to a method for inhibiting ZPPIX synthesis by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%) in vivo. In some embodiments, the Disclosure relates to a method for inhibiting ZPPIX synthesis by at least 20% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting ZPPIX synthesis by at least 30% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting ZPPIX synthesis by at least 40% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting ZPPIX synthesis by at least 50% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting ZPPIX synthesis by at least 60% in vivo. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX synthesis by at least 70% in vivo. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX synthesis by at least 80% in vivo. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX synthesis by at least 90% in vivo. In some embodiments, this disclosure relates to a method for inhibiting ZPPIX synthesis by at least 100% in vivo.

[0169] In certain embodiments, the Disclosure relates to a method for treating myeloid protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoiesis-induced porphyria (CEP) in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the subject has an increased level of 5-aminolevulinic acid (5-ALA). In some embodiments, the method relates to a subject having a 5-ALA level that is at least 10%, 20%, 30%, 40%, or 50% higher than the 5-ALA level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a 5-ALA level that is at least 10% higher than the 5-ALA level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a 5-ALA level at least 20% higher than the 5-ALA level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a 5-ALA level at least 30% higher than the 5-ALA level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a 5-ALA level at least 40% higher than the 5-ALA level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a 5-ALA level at least 50% higher than the 5-ALA level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.

[0170] In certain embodiments, the Disclosure relates to a method for inhibiting 5-aminolevulinic acid (5-ALA) synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the Disclosure relates to a method for inhibiting 5-ALA synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the Disclosure relates to a method for inhibiting 5-ALA synthesis in vivo by at least 20%. In some embodiments, the Disclosure relates to a method for inhibiting 5-ALA synthesis in vivo by at least 30%. In some embodiments, the Disclosure relates to a method for inhibiting 5-ALA synthesis in vivo by at least 40%. In some embodiments, the Disclosure relates to a method for inhibiting 5-ALA synthesis in vivo by at least 50%. In some embodiments, the disclosure relates to a method for inhibiting 5-ALA synthesis by at least 60% in vivo. In some embodiments, the disclosure relates to a method for inhibiting 5-ALA synthesis by at least 70% in vivo. In some embodiments, the disclosure relates to a method for inhibiting 5-ALA synthesis by at least 80% in vivo. In some embodiments, the disclosure relates to a method for inhibiting 5-ALA synthesis by at least 90% in vivo. In some embodiments, the disclosure relates to a method for inhibiting 5-ALA synthesis by at least 100% in vivo.

[0171] This application further provides the use of one or more compounds of formula (I) (e.g., any one of compounds 1 to 60) or pharmaceutically acceptable salts thereof in the manufacture of formulations for the treatment of EPP, XLPP, CEP, or related syndromes (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject. In some embodiments, this application provides the use of one or more compounds of formula (I) (e.g., any one of compounds 1 to 60) or pharmaceutically acceptable salts thereof in the manufacture of formulations for the treatment of EPP, XLPP, or CEP in a subject.

[0172] This application provides the use of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment of EPP, XLPP, or CEP, or related syndromes thereof (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject. In certain embodiments described above, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0173] Congenital erythropoiesis-induced porphyria (CEP) is a cutaneous porphyria characterized by bullous photosensitivity. Severe cases of CEP may present with fetal hydrops in utero or, immediately after birth, with severe bullous photosensitivity, erythruria, splenomegaly, hemolysis, and transfusion dependence. Milder cases and later onset typically present with erythruria, severe vesicular formation, and hemolytic anemia.

[0174] Individuals with CEP are often homozygous or heterozygous for the UROS mutation. Some cases of CEP are due to mutations in the gene encoding the transcription factor GATA1. These mutations result in reduced enzymatic activity of uroporphyrinogen III synthase (UROIII-S), the fourth enzyme in the heme biosynthesis pathway. The reduced activity of UROIII-S leads to the accumulation of hydroxymethylbilane, which spontaneously forms uroporphyrinogen I, which is further metabolized to coproporphyrinogen I. Uroporphyrinogen I and coproporphyrinogen I accumulate in tissues.

[0175] The diagnosis of CEP can be determined by analyzing the enzymatic activity of uroporphyrinogen III synthase (UROIII-S), evaluating mutations in the UROS gene, evaluating the function of the GATA-1 erythrocyte-specific transcription factor, evaluating mutations in GATA1, and determining the levels of uroporphyrin I and coproporphyrin I in the subject. In some embodiments, the subject has a mutation in UROS. In some embodiments, the subject has a gene deletion in the GATA-1 erythrocyte-specific transcription factor. In some embodiments, the method relates to a method for treating a subject, wherein the subject has reduced activity of uroporphyrinogen III synthase. In some embodiments, elevated levels of uroporphyrin I and / or coproporphyrin I are measured in the urine or erythrocytes of the subject. In some embodiments, elevated levels of coproporphyrin I are measured in the feces of the subject.

[0176] In certain embodiments, the Disclosure relates to a method for treating congenital erythropoiesis-porphyria (CEP) in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the subject has elevated uroporphyrin I and / or coproporphyrin I levels. In some embodiments, the subject has elevated uroporphyrin I and / or coproporphyrin I levels. In some embodiments, the method relates to a subject having a uroporphyrin I level that is at least 10%, 20%, 30%, 40%, or 50% higher than the uroporphyrin I level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a uroporphyrin I level at least 10% higher than the uroporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a uroporphyrin I level at least 20% higher than the uroporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a uroporphyrin I level at least 30% higher than the uroporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a uroporphyrin I level at least 40% higher than the uroporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a uroporphyrin I level at least 50% higher than the uroporphyrin I level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the disclosure relates to a method for treating a subject having a coproporphyrin I level that is at least 10%, 20%, 30%, 40%, or 50% higher than the coproporphyrin I level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coproporphyrin I level at least 10% higher than the coproporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coproporphyrin I level at least 20% higher than the coproporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coproporphyrin I level at least 30% higher than the coproporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coproporphyrin I level at least 40% higher than the coproporphyrin I level in a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to a subject having a coproporphyrin I level at least 50% higher than the coproporphyrin I level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.

[0178] In certain embodiments, the Disclosure relates to a method for treating EPP, XLPP, or CEP in a subject, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject, wherein the administration of the pharmaceutical composition does not cause a substantial 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 decreases by at least 90%. In some embodiments, the patient's PPIX level decreases by at least 95%. In some embodiments, the patient's PPIX level decreases by at least 100%. In some embodiments, the patient's heme level does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's heme level does not decrease by more than 20%. In some embodiments, the patient's heme level does not decrease by more than 25%. In some embodiments, the patient's heme level does not decrease by more than 30%.

[0179] In some embodiments, the accumulation of one or more successive heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I and / or 5-ALA. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of PPIX, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of ZPPIX, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of uroporphyrin I, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of coproporphyrin I, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of 5-ALA, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the accumulation of one or more heme intermediates (e.g., PPIX, ZPPIX, uroporphyrin I, coproporphyrin I and / or 5-ALA) is inhibited in a dose-dependent manner.

[0180] Protoporphyrin accumulation in EPP, XLPP, and CEP can cause liver damage when hepatic load exceeds the capacity of bile canal clearing. Accumulation of PPIX in hepatocytes and bile canals can lead to cell damage, cholestasis, cytolysis, and further retention of protoporphyrin. Excess protoporphyrin can exhibit cholestatic effects, resulting in hepatobiliary changes that can range from mild inflammation to fibrosis and cirrhosis (e.g., cholelithiasis, mild hepatic disease, exacerbation of hepatic disease, and end-stage hepatic disease). Three to five percent of patients with EPP or XLPP develop protoporphyric liver injury, a rapidly progressing, severe liver disease that may require a liver transplant. Approximately two percent of patients develop severe liver disease.

[0181] In certain embodiments, the Disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of EPP, XLPP, or CEP-related liver disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the EPP, XLPP, or CEP-related liver disease is gallstones. In some embodiments, the EPP, XLPP, or CEP-related liver disease is mild liver disease. In some embodiments, the EPP, XLPP, or CEP-related liver disease is exacerbation of liver disease. In some embodiments, the EPP, XLPP, or CEP-related liver disease is end-stage liver disease.

[0182] Liver function in patients with EPP, XLPP, and CEP can be assessed using a variety of known clinical assays. In some embodiments, liver function tests can be used to determine the levels of various biochemical parameters (e.g., elevated aspartate transaminase levels, alkaline phosphatase, or γ-glutamyltransferase levels). In some embodiments, histopathology of liver biopsies 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, suprastrumatic studies of biopsy specimens may be used to determine the presence of vacuolar-containing crystals in the subject. Deterioration of liver function increases urinary coproporphyrin excretion. In some embodiments, urinary coproporphyrin excretion may be analyzed to assess liver function in the subject. In some embodiments, liver stiffness in the subject may be measured using ultrasound or magnetic resonance modulus measurement.

[0183] In certain embodiments of the methods and uses disclosed herein, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates PPIX inhibition at EC50 less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of this application, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates PPIX inhibition at EC50 less than 100 nM. In certain embodiments of this application, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates PPIX inhibition at EC50 less than 50 nM. In certain such embodiments, EC50 is measured in a flow cytometry assay.

[0184] In certain embodiments of the methods and uses disclosed herein, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates PPIX inhibition at an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of this application, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates PPIX inhibition at an EC50 of less than 100 nM. In certain embodiments of this application, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates PPIX inhibition at an EC50 of less than 50 nM. In certain such embodiments, EC50 is measured in a flow cytometry assay.

[0185] In certain embodiments of the methods and uses disclosed herein, cell viability of at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95% is maintained. In certain such embodiments, cell viability of at least 90% is maintained.

[0186] Heme and heme intermediates Glycine is one of the important first substrates for heme and globin synthesis. Therefore, a decrease in glycine levels due to GlyT1 inhibition can result in a decrease in heme synthesis. In certain embodiments, the disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 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, the disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the subject's heme level is reduced by no more than 15%. In some embodiments, the disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the subject's heme level is reduced by no more than 20%. In some embodiments, the disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the heme level of the subject is reduced by no more than 25%. In some embodiments, the disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the heme level of the subject is reduced by no more than 30%. In certain particular embodiments, the disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the dosage of the pharmaceutical composition does not cause a substantial reduction in the heme level.

[0187] In some embodiments, the synthesis of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, and one or more heme intermediates are selected from the group consisting of 5-ALA, PBG, hydroxymethylbilane, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isocoproporphyrin, porphobilinogen; and protoporphyrinogen IX. In some embodiments, the disclosure relates to a method for inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has hepatic porphyria, EPP, XLPP, or CEP. In some embodiments, the disclosure relates to a method for inhibiting coproporphyrin III synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the disclosure relates to a method for inhibiting zinc-protoporphyrin IX (ZPPIX) synthesis in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has ALA dehydratase porphyria (ADP). In some embodiments, the disclosure relates to a method for inhibiting porphobilinogen (PBG) synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the target. In some embodiments, the disclosure relates to a method for inhibiting 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the target.In some embodiments, the disclosure relates to a method for inhibiting hydroxymethylbilan (HMB) synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the disclosure relates to a method for inhibiting uroporphyrin III synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the disclosure relates to a method for inhibiting heptacarboxyl-porphyrin synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the disclosure relates to a method for inhibiting isocoproporphyrin synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the synthesis of one or more heme intermediates (e.g., 5-ALA, coproporphyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin) is inhibited in a dose-dependent manner.

[0188] In some embodiments, the accumulation of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, and one or more heme intermediates are selected from the group consisting of 5-ALA, PBG, hydroxymethylbilane, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isocoproporphyrin, porphobilinogen; and protoporphyrinogen IX. In some embodiments, the accumulation of one or more heme intermediates (e.g., 5-ALA, coproporphyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin) is inhibited in a dose-dependent manner.

[0189] In some embodiments, the subject treated by the method described herein has elevated levels of porphyrin or porphyrin precursors, e.g., ALA and / or PBG. In some embodiments, the subject has porphyrin precursor levels at least 10%, 20%, 30%, 40%, or 50% higher than those in a healthy subject prior to administration of v. In some embodiments, the subject has elevated levels of porphyrin precursors. In some embodiments, the porphyrin precursor is selected from the group consisting of 5-ALA, HMB, coproporphyrin III, ZPPIX, porphobilinogen, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin. In some embodiments, the subject has elevated levels of uroporphyrin III (e.g., elevated levels of uroporphyrin III in urine). In some embodiments, the subject has elevated levels of 5-ALA (e.g., elevated levels of 5-ALA in urine or plasma). In some embodiments, the subject has elevated levels of HMB. In some embodiments, the subject has increased levels of coproporphyrin III (e.g., increased levels of coproporphyrin III in urine and feces). In some embodiments, the subject has increased levels of PBG (e.g., increased levels of PBG in urine). In some embodiments, the subject has an increased ratio of protoporphyrin to coproporphyrin in feces. In some embodiments, the subject has increased heptacarboxyl-porphyrin levels (e.g., increased heptacarboxyl-porphyrin levels in urine or feces). In some embodiments, the subject has increased isocoproporphyrin levels (e.g., increased isocoproporphyrin levels in feces). In some embodiments, the subject has increased ZPPIX levels in red blood cells.

[0190] The level of porphyrin or porphyrin precursor can be evaluated using methods known in the art or methods described herein. In some embodiments, the level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in a subject is evaluated based on the absolute level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in a sample from the subject. In some embodiments, the level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in a subject is evaluated based on the relative level of porphyrin or porphyrin precursor (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., 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.

[0191] Elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG) can be established by indicating that a subject has levels of porphyrins or porphyrin precursors (e.g., plasma or urinary levels of ALA and / or PBG) that are higher than or equal to a reference value. A physician with expertise in the treatment of porphyria may be able to determine whether levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG) are elevated, for example, for the purpose of diagnosing hepatic porphyria, EPP, XLPP, or CEP, or to determine whether a subject is at risk of developing hepatic porphyria, EPP, XLPP, or CEP, for example, whether the subject may be predisposed to acute attacks or conditions associated with porphyria, such as chronic pain (e.g., neuropathic pain) and neuropathy (e.g., progressive neuropathy).

[0192] As used herein, “reference value” means a value from a subject who is not in a disease state, or from a normal or healthy subject, or from a reference sample or population, for example, a group of normal or healthy subjects (e.g., a group of subjects who do not have 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).

[0193] In some embodiments, the reference value is the pre-symptomatic level in the same individual. In some embodiments, the reference value is the level in a reference sample or population. In some embodiments, the reference value is the mean or median in a reference sample or population. In some embodiments, the reference value is two standard deviations above the mean in a reference sample or population. In some embodiments, the reference value is 2.5, 3, 3.5, 4, 4.5, or 5 standard deviations above the mean in a reference sample or population.

[0194] In some embodiments, the subject has plasma or urine levels of ALA or PBG higher than the reference value. In some embodiments, the subject has elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG), the subject has levels of ALA and / or PBG that are at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than the reference value. In some embodiments, the subject has levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG) that are at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the reference value.

[0195] In some embodiments, the reference value is the upper reference limit. As used herein, “upper reference limit” refers to the level that is 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, e.g., individuals without genetic mutations associated with porphyria, and / or individuals without hepatic porphyria, EPP, XLPP, or CEP. Accordingly, the lower reference limit refers to the level that is the lower limit of the same 95% confidence interval.

[0196] In some embodiments, the subject has elevated levels of porphyrin or porphyrin precursors (e.g., plasma levels or urine levels) that are higher or equal to 2, 3, 4, or 5 times a reference value (e.g., upper reference limit). In some embodiments, the subject has urine levels of porphyrin or porphyrin precursors that are higher than 4 times the upper reference limit.

[0197] In some embodiments, the subject has a urinary PBG level higher than or equal to 1.4 mmol / mol creatinine. In some embodiments, the subject has a urinary PBG level higher than or equal to 4.8 mmol / mol creatinine. In certain embodiments, the subject has a urinary PBG level higher than or equal to about 3, 4, 5, 6, 7, or 8 mmol / mol creatinine.

[0198] In some embodiments, the reference value for plasma PBG is 0.12 μmol / L. In some embodiments, the subject has plasma PBG levels higher than or equal to 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject has plasma PBG levels higher than or equal to 0.48 μmol / L.

[0199] In some embodiments, the reference value for urinary PBG is 1.2 mmol / mol creatinine. In some embodiments, the reference value for urinary PBG is 1.4 mmol / mol creatinine. In some embodiments, the subject has a urinary PBG level that is higher than, or equal to, 1.0 mmol / mol creatinine, 1.2 mmol / mol creatinine, 2.4 mmol / mol creatinine, 3.6 mmol / mol creatinine, 4.8 mmol / mol creatinine, or 6.0 mmol / mol creatinine. In some embodiments, the subject has a urinary PBG level that is higher than, or equal to, 4.8 mmol / mol creatinine.

[0200] In some embodiments, the reference value for plasma ALA is 0.12 μmol / L. In some embodiments, the subject has plasma ALA levels higher than or equal to 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject has plasma ALA levels higher than or equal to 0.48 μmol / L.

[0201] In some embodiments, the reference value for urinary ALA is 3.1 mmol / mol creatinine. In some embodiments, the reference value for urinary ALA is 6.3 mmol / mol creatinine. In some embodiments, the subject has a urinary ALA level that is higher 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.

[0202] In some embodiments, the reference value for urinary uroporphyrin is creatinine less than 4.5 μmol / mol. In some embodiments, the subjects have urinary uroporphyrin levels that are higher 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.

[0203] In some embodiments, the reference value for urinary coproporphyrin is creatinine less than 20.7 μmol / mol. In some embodiments, subjects have urinary coproporphyrin levels higher 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.

[0204] In some embodiments, the reference value for plasma porphyrin is 10 nmol / L. In some embodiments, the subject has plasma porphyrin levels higher than or equal to 10 nmol / L. In some embodiments, the subject has plasma porphyrin levels higher than or equal to 8, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nmol / L. In some embodiments, the subject has plasma porphyrin levels higher than or equal to 40 nmol / L.

[0205] 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 has a urinary porphyrin level that is higher than, or equal to, 25 μmol / mol creatinine. In some embodiments, the subject has a urinary porphyrin level that is higher than, or equal to, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 μmol / mol creatinine.

[0206] In some embodiments, the subject has levels of porphyrin or porphyrin precursors (e.g., plasma levels or urine levels) that are higher than the levels found in 99% of healthy individuals in samples from other individuals.

[0207] In some embodiments, the subject has ALA or PBG levels (e.g., plasma levels or urine levels) that are more than two standard deviations above the mean level in a sample from a healthy individual.

[0208] In some embodiments, subjects have urinary ALA levels 1.6 times or higher than the average level in normal subjects (e.g., subjects without porphyria-related mutations). In some embodiments, subjects have plasma ALA levels 2 or 3 times the average level in normal subjects. In some embodiments, subjects have urinary PBG levels 4 times or higher than the average level in normal subjects. In some embodiments, subjects have plasma PBG levels 4 times or higher than the average level in normal subjects.

[0209] In certain embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof results in a decrease in the level of one or more porphyrins or porphyrin precursors (e.g., ALA and / or PBG) as described herein. The decrease may be measured against any suitable control or reference value. For example, a decrease in the level of one or more porphyrins or porphyrin precursors, e.g., a decrease of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or higher compared to the level before treatment (e.g., immediately before treatment), may be established in individual subjects. The decrease in the levels of porphyrin precursors, porphyrins, or porphyrin metabolites may be measured using any method known in the art.

[0210] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is effective in reducing 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 (e.g., relative to the level of another protein or compound, e.g., creatinine). In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample.

[0211] In some embodiments, the method reduces the 5-ALA level in the subject. In some embodiments, the method reduces the 5-ALA level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the HMB level in the subject. In some embodiments, the method reduces the HMB level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the coproporphyrin III level in the subject. In some embodiments, the method reduces coproporphyrin III levels 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 PBG levels in the subject. In some embodiments, the method reduces PBG levels 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 uroporphyrin III levels in the subject. In some embodiments, the method reduces the uroporphyrin III level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in the subject.In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the heptacarboxyl-porphyrin level in the subject. In some embodiments, the method reduces the heptacarboxyl-porphyrin level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces isocoproporphyrin levels in the subject. In some embodiments, the method reduces isocoproporphyrin levels 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 ZPPIX levels in the subject. In some embodiments, the method reduces ZPPIX levels 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 porphyrin or porphyrin precursor (e.g., ALA or PBG) levels in the subject to normal levels. In some embodiments, normal levels are reference values ​​for porphyrin or porphyrin precursor described herein (e.g., urinary ALA levels of <6.3 mmol / mol creatinine and urinary PBG levels of <1.4 mmol / mol creatine).

[0212] In certain embodiments, the Disclosure relates to a method for inhibiting uroporphyrin I and / or coproporphyrin I synthesis in vivo, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a target. In some embodiments, the Disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%) in vivo. In some embodiments, the Disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 20% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 30% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 40% in vivo. In some embodiments, the Disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 50% in vivo. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 60% in vivo. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 70% in vivo. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 80% in vivo. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 90% in vivo. In some embodiments, this disclosure relates to a method for inhibiting uroporphyrin I synthesis by at least 100% in vivo.

[0213] In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%) in vivo. In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 20% in vivo. In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 30% in vivo. In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 40% in vivo. In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 50% in vivo. In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 60% in vivo. In some embodiments, the disclosure provides a method for inhibiting coproporphyrin I synthesis by at least 70% in vivo. In some embodiments, this disclosure relates to a method for inhibiting coproporphyrin I synthesis by at least 80% in vivo. In some embodiments, this disclosure relates to a method for inhibiting coproporphyrin I synthesis by at least 90% in vivo. In some embodiments, this disclosure relates to a method for inhibiting coproporphyrin I synthesis by at least 100% in vivo.

[0214] Porphyrins (e.g., PPIX, ZPPIX, uroporphyrin I, and coproporphyrin I) can be found in a variety of biological samples, including skin, urine, feces, plasma, and red blood cells. In some embodiments, porphyrins may be extracted from the biological sample into solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., light between 400 and 420 nm). Porphyrins have a maximum absorption wavelength around 400–420 nm, with their highest absorption peak occurring at 415 nm. The maximum emission of porphyrins is typically around 600 nm, varying slightly depending on the type of porphyrin and the solvent used for the analysis. In some embodiments, the diagnosis of hepatic porphyria, EPP, XLPP, and CEP may be made 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. For example, see Heerfordt IM. Br J Dermatol. 2016;175(6):1284-1289.

[0215] In some embodiments, the target plasma porphyrin fluoresces at a peak of 634 nm when irradiated with blue light (e.g., 400-420 nm light). In some embodiments, the target plasma porphyrin fluoresces at a peak of 626-634 nm when irradiated with blue light (e.g., 400-420 nm light). In some embodiments, the target skin porphyrin fluoresces at a peak of 632 nm when irradiated with blue light (e.g., 400-420 nm light). In some embodiments, the target skin porphyrin fluoresces at a peak of 626-634 nm when irradiated with blue light (e.g., 400-420 nm light). In some embodiments, the subject has a skin protoporphyrin IX level higher than 0.2 FluoDerm units (FDU). In some embodiments, the subject has a skin protoporphyrin IX level higher than 1.0 FDU. In some embodiments, the subject has a protoporphyrin IX level in the skin of 1.0 FDU to 2.5 FDU. In some embodiments, the subject has a protoporphyrin IX level in the skin of higher than 2.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 0.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 1.0 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 1.5 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 2.0 FDU. In some embodiments, the method reduces the protoporphyrin IX level in the subject's skin to less than 2.5 FDU. In some embodiments, the subject has red fluorescent urine. In some embodiments, the subject has a peak at 615 nm to 620 nm using plasma porphyrin fluorescence analysis.

[0216] In certain embodiments, the methods provided herein involve administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject, such that the subject's PPIX level is reduced while substantially maintaining the patient's heme level. 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 not reduced by 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 not reduced by more than 15%. In some embodiments, the patient's PPIX level is reduced by at least 80% and the patient's heme level is not reduced by more than 15%. In some embodiments, the patient's PPIX level decreases by at least 75%, and the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's PPIX level decreases by at least 70%, and the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's PPIX level decreases by at least 65%, and the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's PPIX level decreases by at least 60%, and the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's PPIX level decreases by at least 55%, and the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's PPIX level decreases by at least 50%, and the patient's heme level does not decrease by more than 15%.

[0217] In certain embodiments, the Disclosure relates to a method for treating hepatic porphyria, EPP, XLPP, or CEP in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the dosage of the pharmaceutical composition does not cause a substantial reduction in heme levels. In some embodiments, the patient's PPIX levels are 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 levels are reduced by at least 55%. In some embodiments, the patient's PPIX levels are reduced by at least 60%. In some embodiments, the patient's PPIX levels are reduced by at least 65%. In some embodiments, the patient's PPIX levels are reduced by at least 70%. In some embodiments, the patient's PPIX levels are reduced by at least 75%. In some embodiments, the patient's PPIX levels are reduced by at least 80%. In some embodiments, the patient's PPIX level decreases by at least 85%. In some embodiments, the patient's PPIX level decreases by at least 90%. In some embodiments, the patient's PPIX level decreases by at least 95%. In some embodiments, the patient's PPIX level decreases by at least 100%. In some embodiments, the patient's heme level does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient's heme level does not decrease by more than 15%. In some embodiments, the patient's heme level does not decrease by more than 20%. In some embodiments, the patient's heme level does not decrease by more than 25%. In some embodiments, the patient's heme level does not decrease by more than 30%.

[0218] In some embodiments, the accumulation of one or more of the following heme intermediates is inhibited, and one or more of the heme intermediates are selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I and / or 5-ALA. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of PPIX, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of ZPPIX, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of uroporphyrin I, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of coproporphyrin I, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the disclosure relates to a method for inhibiting the accumulation of 5-ALA, comprising administering a pharmaceutical composition comprising v to a subject. In some embodiments, the accumulation of one or more heme intermediates (e.g., PPIX, ZPPIX, uroporphyrin I, coproporphyrin I and / or 5-ALA) is inhibited in a dose-dependent manner. Complications of porphyria

[0219] In certain embodiments, the Disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria, EPP, XLPP, or CEP in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more complications of hepatic porphyria include acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte abnormalities, nausea, vomiting, constipation, diarrhea, dysuria, ileus, paresthesia, insomnia, restlessness, restlessness, anxiety, confusion, hallucinations, psychosis, convulsions, neuropathy-related pain, muscle paralysis, limb paresis, respiratory depression, respiratory arrest, and hyponatremia. The group is selected from thoremia, tachycardia, hypertension, increased heart rate, elevated blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive nephropathy, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformity, nail loss, finger loss, cholestasis, cytolysis, gallstones, cholestatic hepatic failure, cholelithiasis, mild hepatic disease, worsening hepatic disease, and end-stage hepatic disease. In some embodiments, one or more complications are indirectly improved. In some embodiments, one or more complications of EPP, XLPP, or CEP are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, nail loss, finger loss, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic hepatic failure, red teeth, hyperplastic bone marrow, thrombocytopenia, fetal hydrops, and / or intrauterine death.In some embodiments, the Disclosure intends to describe a method for treating one or more complications of EPP, XLPP, or CEP (e.g., acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, nail loss, finger loss, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic hepatic failure, red teeth, hyperplastic bone marrow, thrombocytopenia, fetal hydrops, and / or intrauterine death), comprising administering a pharmaceutical composition containing a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the target. In some embodiments, one or more complications are indirectly ameliorated. In some embodiments, the Disclosure intends a method for preventing one or more complications of hepatic porphyria, EPP, XLPP, or CEP, comprising administering a pharmaceutical composition containing a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the Disclosure intends a method for reducing the rate of progression of one or more complications of hepatic porphyria, EPP, XLPP, or CEP, comprising administering a pharmaceutical composition containing a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the Disclosure intends a method for reducing the severity of one or more complications of hepatic porphyria, EPP, XLPP, or CEP, comprising administering a pharmaceutical composition containing a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject.

[0220] The treatment methods provided herein may work to alleviate one or more symptoms associated with hepatic porphyria or to reduce the risk of developing porphyria-related conditions (e.g., neuropathy (e.g., progressive neuropathy), hepatocellular carcinoma). Symptoms associated with hepatic porphyria may include abdominal pain or muscle spasms, headaches, effects caused by abnormalities in the nervous system, and photosensitivity that causes rashes, blistering, and skin scarring (ultraviolet dermatitis). In certain embodiments, hepatic porphyria is AIP. Symptoms of AIP include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (dysuria, urinary retention / incontinence, or dark urine), neurological symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting cranial nerves and / or resulting in weakness in the arms or legs), epileptic seizures, neuropathic pain, progressive neuropathy, headache, neuropsychiatric symptoms (e.g., confusion, anxiety, restlessness, hallucinations, hysteria, delirium, emotional blunting, depression, phobias, psychosis, insomnia, somnolence, coma), autonomic nervous system issues (e.g., cardiovascular symptoms such as tachycardia, hypertension and / or arrhythmias, as well as other symptoms such as elevated circulating catecholamine levels, sweating, restlessness and / or tremors), dehydration, and electrolyte imbalances.

[0221] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in conjunction with (e.g., before, after, or concurrently with) another treatment that may alleviate one or more of the above symptoms. For example, abdominal pain may be treated with, for example, narcotic analgesics; epileptic seizures may be treated with, for example, anticonvulsant pharmacotherapy; nausea / vomiting may be treated with, for example, phenothiazines; and tachycardia / hypertension may be treated with, for example, beta-blockers.

[0222] If necessary, the methods disclosed herein for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of EPP, XLPP, or CEP in a subject may further include administering to the patient one or more supportive therapies or additional active agents for treating EPP, XLPP, or CEP. For example, the patient may also be administered one or more supportive therapies or active agents selected from the group consisting of sun avoidance, topical sunscreens, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. In some embodiments, the methods described herein may further include administering to the patient afamelanotide (Scenesse®).

[0223] Porphyrin photosensitivity in certain hepatic porphyrias (e.g., VP, HCP, PCT, and HEP), EPP, XLPP, and CEP results in two distinct clinical syndromes: (1) acute photosensitivity to sun exposure with erythema and edema, and (2) a syndrome in which subepidermal blisters develop in areas of the skin exposed to sunlight. In certain embodiments, the Disclosure relates to a method for preventing, treating, or reducing the rate and / or severity of progression of EPP, XLPP, or CEP in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, wherein the method increases analgesic photoexposure in the subject. In some embodiments, the method increases analgesic photoexposure in the subject by at least 10%, 20%, 30%, 40%, or 50% compared to analgesic photoexposure before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the method reduces photosensitivity in a subject. In some embodiments, the method reduces photosensitivity in a subject by at least 10%, 20%, 30%, 40%, or 50% compared to pre-administration photosensitivity to a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a history of phototoxic reactions from EPP. In some embodiments, the subject is an adult, child, infant, or pregnant woman. EC50 and administration

[0224] In certain embodiments of the methods and uses disclosed herein, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates inhibition of porphyrin precursors (e.g., 5-ALA or PBG) at EC50 less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the methods and uses disclosed herein, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates inhibition of porphyrin precursors (e.g., 5-ALA or PBG) at an EC50 of less than 100 nM. In certain embodiments of the methods and uses disclosed herein, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof demonstrates inhibition of porphyrin precursors (e.g., 5-ALA or PBG) at an EC50 of less than 50 nM. In certain embodiments, EC50 is measured in a flow cytometry assay. In certain embodiments, EC50 is measured in an LC-MS / MS assay.

[0225] In certain embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered to prevent or reduce the severity or frequency of recurrent seizures, e.g., periodic seizures associated with an exacerbating factor. In some embodiments, the exacerbating factor is the menstrual cycle. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered repeatedly, e.g., at regular intervals, to prevent or reduce the severity or frequency of recurrent seizures, e.g., periodic seizures, associated with an exacerbating factor, e.g., the menstrual cycle, e.g., a particular stage of the menstrual cycle, e.g., the luteal phase. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered during a particular stage of the menstrual cycle or based on the hormone levels of the patient being treated (e.g., based on hormone levels associated with a particular stage of the menstrual cycle). In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered on one or more specific days of the menstrual cycle, e.g., days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 (or later for subjects with longer menstrual cycles). In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered during the luteal phase, e.g., on one or more days between days 14 and 28 of the menstrual cycle (or later for subjects with longer menstrual cycles). In some embodiments, ovulation of the subject is evaluated (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 to 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 to 60) or a pharmaceutically acceptable salt thereof is administered immediately after ovulation.In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 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 be repeated for one or more repetitions, as needed. The number of repetitions may depend on achieving the desired effect, e.g., achieving a therapeutic or preventive effect, e.g., reducing or preventing one or more symptoms associated with hepatic porphyria, EPP, XLPP, or CEP, or reducing the frequency of seizures associated with hepatic porphyria, EPP, XLPP, or CEP.

[0226] In some embodiments, an initial dose of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered, and the levels of ALA or PBG are tested, for example, 1 to 48 hours after administration of the initial dose, e.g., 2, 4, 8, 12, or 24 hours later. In some embodiments, if the levels of ALA and / or PBG decrease (e.g., a predetermined reduction, e.g., normalization is achieved) and / or if the symptoms associated with hepatic porphyria, EPP, XLPP, or CEP (e.g., pain) improve (e.g., the patient is asymptomatic), no further dose is administered; however, if the levels of ALA and / or PBG do not decrease (e.g., a predetermined reduction is not achieved, e.g., normalization is not achieved), a further dose of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered. In some embodiments, the further dose is administered 12, 24, 36, 48, 60, or 72 hours after the initial dose. In some embodiments, if the initial dose is not effective in reducing ALA and / or PBG levels, further doses are modified, for example, increased, to achieve a desired reduction in ALA or PBG levels (e.g., a predetermined reduction, e.g., normalization).

[0227] In some embodiments, a predetermined reduction is a reduction of at least 10%, 20%, 30%, 40%, or 50%. In some embodiments, a predetermined reduction is a reduction that is effective in preventing or relieving symptoms, such as pain, prodromal symptoms, or recurrent attacks.

[0228] In some embodiments, a predetermined reduction is a reduction of at least 1, 2, 3, or more standard deviations, the standard deviation being determined based on values ​​from a reference sample, e.g., a reference sample described herein.

[0229] In some embodiments, a predetermined reduction is a reduction that brings the level of porphyrin or porphyrin precursor to a level below a reference value (e.g., a reference value described herein), or to a level below or equal to such a level.

[0230] As used herein, “normalization” (or “normal” or “normalized” levels) of ALA or PBG levels refer to levels of ALA or PBG, or both (e.g., urinary and / or plasma levels), that are within the expected range for a healthy individual, an asymptomatic individual (e.g., an individual that has not experienced pain and / or has no neuropathy) or an individual that does not have a porphyria-related mutation. For example, in some embodiments, the normalized level is within two standard deviations of the normal mean. In some embodiments, the normalized level is within the normal reference limit, e.g., within the 95% confidence interval for a suitable control sample, e.g., a sample from a healthy individual or an individual that does not have a porphyria-related gene mutation. In some embodiments, the ALA and / or PBG levels in question (e.g., urinary and / or plasma ALA and / or PBG levels) are periodically monitored, and further doses of the compound of formula (I) (e.g., any one of compounds 1-60) or a pharmaceutically acceptable salt thereof are administered if the level increases above a reference value.

[0231] Administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may reduce porphyrin or porphyrin precursor levels 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. Administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may also reduce porphyrin or porphyrin precursor levels during acute attacks of AIP.

[0232] Combination therapy If necessary, methods disclosed herein for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of porphyria (e.g., hepatic porphyria, EPP, XLPP, or CEP) in a subject may further include administering to the patient one or more supportive therapies or additional active agents for treating porphyria (e.g., hepatic porphyria, EPP, XLPP, or CEP). For example, patients may also be administered one or more supportive therapies or active agents selected from the group consisting of sun protection, topical sunscreens, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, heme infusion, adequate calorie support, gibosilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of exacerbating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene into hepatocytes via a viral vector), hemodialysis, pharmacological chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

[0233] In some embodiments, subjects are administered concomitant treatments, such as a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, and one or more additional treatments known to be effective against hepatic porphyria, EPP, XLPP, or CEP (e.g., heme products such as glucose and / or hemin as described herein) or related symptoms.

[0234] In one embodiment, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with glucose or dextrose. For example, 10-20% dextrose in saline may be delivered intravenously. Typically, if glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. A compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may also be administered intravenously as part of the same infusion used to administer glucose or dextrose, or as a separate infusion administered before, simultaneously with, or after the administration of glucose or dextrose. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 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 one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with parenteral total nutrition. A compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may be administered before, concurrently with, or after the administration of parenteral total nutrition.

[0235] In certain embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional treatments, such as another treatment known to be effective in treating porphyria or symptoms of porphyria. In one embodiment, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product (e.g., hemin, heme alginate, or hemalbumin). In further embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered in combination with a heme product and glucose, a heme product and dextrose, or a heme product and parenteral complete nutrition. The additional treatments may be administered before, after, or concurrently with the administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. A compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, and additional therapeutic agents can be administered, for example, intravenously in combination in the same composition, or the additional therapeutic agents can be administered as part of separate compositions or by other methods described herein. In some embodiments, the subject has been previously treated with a heme product (e.g., hemin, heme alginate, or hemalbumin) as described herein.

[0236] In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof, or administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in combination with one or more additional treatments (e.g., glucose, dextrose), reduces the frequency of acute attacks (e.g., by preventing acute attacks so that they no longer occur, or by reducing the number of attacks occurring in a particular period, e.g., fewer attacks per year). In some such embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is administered according to a regular dosing regimen, e.g., bid, daily, weekly, bi-weekly, or monthly.

[0237] Anemia associated with ribosomal dysfunction Mutations in ribosomal protein (RP) genes or other transcription factors (e.g., GATA1) can lead to the loss of erythrocyte progenitor cells (progenitor cells) and cause ribosomal dysfunction-related anemia. One example of ribosomal dysfunction-related anemia is Diamond-Blackfan anemia (DBA), a rare blood disorder almost exclusively associated with RP gene haploinsufficiency. DBA occurs in approximately 7 per million births and is usually diagnosed during the first year of life. Traditional diagnostic criteria include (1) macrocytic normochromic anemia; (2) reticulocytopenia; (3) myeloerythroblast hypoplasia; and (4) premature anemia (present in 90% of cases before 1 year of age).

[0238] In patients with DBA, erythrocyte precursors do not mature properly, resulting in congenital erythrodysplasia and developmental disorders. Affected individuals may have physical abnormalities, such as craniofacial malformations, abnormalities of the thumb or upper limbs, cleft palate, and defects of 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.

[0239] 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, the effectiveness of corticosteroids can diminish over time in many patients. These patients, and the 20% who do not initially respond to such therapy, must maintain chronic blood transfusions with iron chelation. Chronic 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, immunoglobulin, and metoclopramide have not demonstrated a proven benefit and / or appear to benefit only a relatively small number of people. Pharmacological doses of erythropoietin (EPO) are also ineffective. Bone marrow transplantation is a monotherapy for the hematological manifestations of DBA-associated anemia, but is usually considered only in corticosteroid-resistant individuals due to its considerable morbidity and mortality rates. Typically, only transplants from siblings with identical human leukocyte antigens (HLA) were considered. For many patients, the lack of suitable donors ruled out bone marrow transplantation as a treatment option.

[0240] Therefore, there is an unmet need for effective therapies to treat anemia associated with ribosomal dysfunction. Accordingly, the object 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. Methods and uses of glycine transporter inhibitors, such as compounds of formula (I) (e.g., any one of compounds 1 to 60) or pharmaceutically acceptable salts thereof, satisfy these needs and others.

[0241] In certain embodiments, the present application provides the use of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment of ribosomal dysfunction-related anemia in a subject requiring such treatment. The present application also provides a method for preventing or treating ribosomal dysfunction-related anemia in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject.

[0242] In part, the present application relates to a method for treating ribosomal disorder-related anemia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of ribosomal disorder-related anemia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the ribosomal disorder is Diamond-Blackfan anemia. In some embodiments, the ribosomal disorder is Schwakman-Diamond syndrome. In some embodiments, the ribosomal disorder is X-linked congenital keratosis. In some embodiments, the ribosomal disorder is chondrohair hypoplasia. In certain embodiments, the patient, subject, or individual is human.

[0243] This application provides a method for preventing, treating, or reducing the rate of progression and / or severity of ribosomal dysfunction-related anemia in a subject, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. In certain embodiments of the foregoing, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0244] This application further provides the use of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in the manufacture of a formulation for the treatment of ribosomal dysfunction-related anemia (e.g., Diamond-Blackfan anemia) in a subject. Diamond-Blackfan anemia

[0245] Diamond-Blackfan anemia (DBA) is a congenital erythropoiesis that typically develops during the neonatal period. DBA is characterized by a low red blood cell count (anemia) accompanied by a decrease in red blood cell precursors (progenitors) in the bone marrow. In patients with DBA, levels of other blood components such as platelets and white blood cells are normal. This is in contrast to Schwakman-Diamond syndrome, which primarily results in a low neutrophil count (neutropenia) due to bone marrow defects.

[0246] Ribosomal protein mutations are involved in the pathophysiology of DBA. The first gene mutated in approximately 25% of DBA patients was identified as RPS19 (ribosomal protein S19) (Gustavsson et al, Nat Genet. 1997 Aug;16(4):368-7l; Draptchinskaia et al, Nat Genet. 1999 Feb;21(2):169-75). Sequencing of patient samples has identified mutations in either the large (60s) or small (40s) subunit of ribosomal protein in over 50% of patients (Vlachos et al, Br J Haematol. 2008 Sep; 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. F1000Res. 2018;7). All patients identified to date are heterozygous for these mutations and consistently maintain a wild-type copy of the affected RP gene. However, approximately 30% of people with DBA did not have any detectable RP mutations. Some phenotypic / genotype correlations associated with congenital abnormalities are publicly known. (Ibid.)

[0247] There are numerous subtypes of DBA, each of which is caused by different mutations in various genes. For example, Diamond-Blackfan anemia-l (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 in 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.l; DBA7 (OMIM #612562) caused by mutations in the RPL11 gene on lp36; DBA8 (OMIM #612563) caused by mutations in the RPS7 gene on 2p25; and DBA9 (OMIM #612563) caused by mutations in the RPS10 gene on 6p. DBA10 (OMIM #613309) caused by a mutation in the RPS26 gene on chromosome lq2l; DBA11 (OMIM #614900) caused by a mutation in the RPL26 gene on chromosome 17r13; 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 l4q; DBA14 (OMIM #300946) caused by a mutation in the / 'SR 2 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) caused by a mutation in the RPS27 gene on chromosome lq2l (#617409) is one example.

[0248] Mutations in ribosomal proteins affect ribosomal protein function, leading to ribosomal dysfunction and increased stress. Impaired ribosomal biogenesis is associated with p53 induction and cell cycle arrest. Ribosomal protein knockdown 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, 15 February 2007; Fumagalli et al, Nat Cell Biol. 2009 Apr; ll(4):50l-8). Other ribosomal proteins may activate p53 through different mechanisms. For example, RPL26 has been found to increase the translation rate of p53 mRNA by binding to its 5' untranslated region (Tagaki et al., Cell. 2005 Oct 7; l23(l):49-63). The negative effects of DBA on ribosomal protein function result in a decrease in globin synthesis, which is necessary for hemoglobin production. Heme synthesis does not appear to be impaired. The imbalance between heme synthesis and globin leads to the accumulation of free heme in DBA erythrocytes (Rio S, et al. Blood. 2019;133(12):1358-1370). Heme is toxic to cells by increasing the production of reactive oxygen species, lipid peroxidation, and apoptosis. As a result, the excessive heme levels resulting from the heme / globin imbalance have a detrimental effect on erythroipoiesis.

[0249] Typically, the diagnosis of DBA is made by blood cell count and bone marrow biopsy. The diagnosis of DBA is based on anemia, low reticulocyte (immature red blood cell) count, and reduced red blood cell 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 two years of birth. However, some mildly affected individuals are only noticed after more severely affected family members have been identified. Genetic testing is frequently used to identify mutations in ribosomal protein genes and some other non-ribosomal protein genes. Approximately 20–25% of DBA patients can be identified using genetic testing for mutations in the RPS19 gene. Approximately 10–25% of DBA cases have a family history of the disease, and most families suggest an autosomal dominant inheritance pattern.

[0250] In certain embodiments, the Disclosure relates to a method for treating ribosomal dysfunction-related anemia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In certain embodiments, the Disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of ribosomal dysfunction-related anemia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 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 haploinsufficiency with a 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). In some embodiments, DBA is caused by haploinsufficiency with a 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). In some embodiments, the patient has one or more mutations in the ribosomal protein gene.

[0251] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof can be used in a method for treating anemia associated with ribosomal dysfunction, where the subject has a mutation in ribosomal protein 19 (RPS19). The phenotype of DBA patients shows a defect in hematopoietic stem cells that specifically affects the progenitor population. The RPS19 protein is involved in ribosome production. The features of the disease may be related to the characteristics of the RPS19 mutation. The disease is characterized by dominant inheritance and therefore occurs due to a partial loss of RPS19 protein function.

[0252] In an alternative embodiment, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may be used in a method for treating anemia associated with ribosomal dysfunction, wherein the subject has a mutation in a ribosomal protein from, but is 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. For example, a mutation or variant in RPS19 causes DBA1, a mutation or variant in RPS24 causes DBA3, a mutation or variant in RPS17 causes DBA4, a mutation or variant in RPS34A causes DBA5, a mutation or variant in RPLS causes DBA6, a mutation or variant in RPL11 causes DBA7, and a mutation or variant in RPS7 causes DBA8. In some embodiments, subjects with ribosomal dysfunction have mutations in non-ribosomal proteins selected from the group consisting of TSR2, GATA1, and EPO.

[0253] In certain embodiments, the Disclosure relates to a method 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, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more complications of ribosomal dysfunction-related anemia are selected from the group consisting of thrombocytosis, megakaryocyte hyperplasia, infection, bleeding (e.g., from the nose or gums), subcutaneous hemorrhage, splenomegaly, need for more frequent blood 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.

[0254] In certain embodiments, the Disclosure relates to a method for treating splenomegaly associated with ribosomal dysfunction-related anemia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an increased spleen size (e.g., splenomegaly). In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof reduces splenomegaly in a subject having 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 size of the spleen by at least 15%. In some embodiments, the method reduces the size of the spleen by at least 20%. In some embodiments, the method reduces the size of the spleen by at least 25%. In some embodiments, the method reduces the size of the spleen by at least 30%. In some embodiments, the method reduces the size of the spleen by at least 35%. In some embodiments, the method reduces the size of the spleen by at least 40%. In some embodiments, the method reduces the size of the spleen by at least 45%. In some embodiments, the method reduces the size of the spleen by at least 50%. In some embodiments, the method reduces the size of the spleen by at least 55%. In some embodiments, the method reduces the size of the spleen by at least 60%. In some embodiments, the method reduces the size of the spleen by at least 65%. In some embodiments, the method reduces the size of the spleen by at least 70%. In some embodiments, the method reduces the size of the spleen by at least 75%. In some embodiments, the method reduces the size of the spleen by at least 80%. In some embodiments, the method reduces the size of the spleen in question by at least 85%. In some embodiments, the method reduces the size of the spleen in question by at least 90%.In some embodiments, the method reduces the size of the spleen in question by at least 95%. In some embodiments, the method reduces the size of the spleen in question by at least 100%.

[0255] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may be used to treat a subject having ribosomal disorders such as DBA, where the subject has symptoms of macrocytic anemia and / or craniofacial malformations.

[0256] Schwakman-Diamond Syndrome Schwakman-Diamond syndrome (SDS), or Schwakman-Bodian-Diamond syndrome, is a rare genetic disorder that affects many parts of the body, particularly the pancreas, bone marrow, and skeletal system. Schwakman-Diamond syndrome is inherited in an autosomal recessive pattern. Most cases of SDS are caused by mutations in the SBDS gene, located on the long arm of chromosome 7 at cytogenetic position 7ql1. While the protein encoded by SBDS is thought to play a role in RNA processing and ribosomal biogenesis, the exact mechanism by which SBDS mutations lead to the main signs and symptoms of Schwakman-Diamond syndrome remains unclear. Typical symptoms of Schwakman-Diamond syndrome include exocrine pancreatic insufficiency, hypotonia, low blood neutrophil count (neutropenia), anemia, and abnormal bone development affecting the bones of the rib cage and / or arms and / or limbs (metaphyseal hypoplasia).

[0257] A diagnosis of Schwakman-Diamond syndrome can be made based on clinical findings, including pancreatic dysfunction and characteristic hematological abnormalities (e.g., neutropenia and thrombocytopenia). Genetic testing may be used to confirm the diagnosis. It is known that SBDS gene mutations cause approximately 90% of cases of Schwakman-Diamond syndrome. The remaining 10% of cases have unknown genetic causes, and therefore, genetic testing is not an option for these cases.

[0258] There is no cure for Schwakman-Diamond syndrome. Treatment typically includes oral pancreatic enzyme replacement, vitamin replacement, blood and / or platelet transfusions, administration of granulocyte colony-stimulating factor (G-CSF), and / or hematopoietic stem cell transplantation. Neutrophil deficiency in individuals with Schwakman-Diamond syndrome can lead to neutropenia, which makes patients more vulnerable to infections such as pneumonia. Patients with Schwakman-Diamond syndrome also have a higher-than-average chance of developing aplastic anemia and leukemia (e.g., acute myeloid leukemia).

[0259] In certain embodiments, the disclosure relates to a method for treating Schwakman-Diamond syndrome in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In certain embodiments, the disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of Schwakman-Diamond syndrome in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 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 need for hematopoietic stem cell transplantation in the subject. In some embodiments, the method reduces neutropenia in the subject. In some embodiments, the method reduces thrombocytopenia in the subject. In some embodiments, the method reduces the risk of the subject developing leukemia. In some embodiments, the method reduces the risk of the subject developing infection. In some embodiments, the method reduces the risk of the subject developing pneumonia. In some embodiments, the subject has low neutrophil levels.

[0260] Congenital dyskeratosis Congenital keratosis, also known as Zinser-Engmann-Coll syndrome, is a rare inheritance of bone marrow failure, classically associated with oral leukoplakia, onychomycosis, and reticular hyperpigmentation. The inheritance is most commonly x-linked recessive; therefore, males are three times more likely to be affected than females. Symptoms vary widely and may include atrophic, wrinkled skin, eye disorders, and bone marrow failure. Individuals with congenital keratosis 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 hepatic fibrosis).

[0261] The majority of patients have mutations in the dickelin gene (DKC1), a protein directly involved in stabilizing an enzyme called telomerase, which catalyzes the reaction that maintains telomere length. Without proteins like dickelin, telomeres gradually shorten, causing cells to undergo apoptosis or senescence. Other genes, including TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, and RTEL1, have been shown to be mutated in congenital keratosis.

[0262] Treatment options for patients with congenital keratosis are limited. The only long-term treatment option for bone failure in patients with congenital keratosis is hematopoietic stem cell transplantation. However, long-term outcomes remain insufficient, with an estimated 10-year survival rate of 23%. Short-term treatment options include anabolic steroids (e.g., oxymetholone), granulocyte-macrophage colony-stimulating factor, and erythropoietin.

[0263] In certain embodiments, the disclosure relates to a method for treating a congenital keratosis in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In certain embodiments, the disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of a congenital keratosis in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a congenital keratosis. In some embodiments, the congenital keratosis is x-linked congenital keratosis. In some embodiments, the subject has one or more mutations in the DKC1 gene. In some embodiments, the subjects have one or more mutations in genes selected from the group consisting of 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 subjects. In some embodiments, the method reduces the risk of pulmonary fibrosis in the subjects. In some embodiments, the method reduces the risk of hepatic fibrosis in the subjects.

[0264] cartilage hypoplasia Chondrohair hypoplasia, also known as McKusig's metaphyseal chondrodysplasia, is a disorder of bone growth characterized by short stature (dwarfism) with other skeletal abnormalities; thin, sparse hair; joint hypermobility; anemia; increased risk of malignant tumors; gastrointestinal disorders; impaired spermatogenesis; and abnormal immune system function, often resulting in recurrent infections. Most patients with chondrohair hypoplasia have a mutation in the RMRP gene (OMIM no. 157660), commonly presenting as a transient 70A→G mutation. The RMRP gene encodes the non-coding RNA component of RNase MRP, a mitochondrial RNA processing ribonuclease.

[0265] The diagnosis of chondrohair hypoplasia is primarily based on clinical findings, characteristic radiographic findings, and, in some cases, evidence of immunodeficiency, macrocytic anemia, and / or gastrointestinal problems. Molecular genetic testing can be used in patients to identify pathogenic variants according to RMRP.

[0266] Patient treatment often includes repeated blood transfusions and surgical fixation of unstable vertebrae or surgery to treat progressive kyphoscoliosis that impairs lung function. Corrective osteotomy may also be required to treat progressive varus deformity associated with knee ligament laxity. Patients with immunodeficiency require frequent treatment of the underlying infection. Prophylactic antibiotic therapy and / or immunoglobulin replacement therapy are often necessary. The presence of recurrent severe infections and / or severe combined immunodeficiency (SCID) and / or severely suppressed erythropoiesis may be justifiable reasons for bone marrow transplantation.

[0267] In certain embodiments, the disclosure relates to a method for treating chondrohair hypoplasia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In certain embodiments, the disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of chondrohair hypoplasia in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 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 method reduces the need for bone marrow transplantation in the subject.

[0268] Defect in red blood cell production Erythropoiesis generally refers to the process by which red blood cells are produced from hematopoietic stem cells (HSCs), including the formation of progenitor cells. Erythropoiesis is a carefully ordered sequence of events. It first occurs in fetal hepatocytes, and the process is continued in the bone marrow in children and adults. Several cytokines and growth factors are dedicated to red blood cell proliferation, but the main regulator is erythropoietin (EPO). Red blood cell development is initially regulated by stem cell factors (SCFs), which involve hematopoietic stem cells in developing into red blood cell progenitors. Subsequently, EPO continues to stimulate development and completes the differentiation of these progenitors. 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 are also found in the brain and red blood cells (RBCs), suggesting the presence of paracrine and autocrine functions.

[0269] Increased erythropoiesis, as a result of increased EPO gene expression, leads to higher levels of circulating EPO. EPO gene expression is known to be affected by several factors, including hypoxemia, transition metals (CO2+, Ni2+, Mn2+), and iron chelators. However, the primary influence is hypoxia, which includes factors such as decreased oxygen partial pressure, erythrocyte loss, and increased hemoglobin oxygen affinity. For example, EPO production can increase to approximately 1000-fold in severe hypoxia.

[0270] Erythrocyte formation requires proper heme biosynthesis, and as erythroblasts mature, their requirements for heme and iron increase dramatically. Erythrocytes synthesize large amounts of heme and hemoglobin while simultaneously absorbing a large amount of iron into the cell. An imbalance between globin chain and heme synthesis is known to occur in the erythrocytes of patients with Diamond-Blackfan anemia. This imbalance leads to the accumulation of excess free heme and increased production of reactive oxygen species.

[0271] Blocking erythrocyte differentiation and proliferation in Diamond-Blackfan anemia has been shown to affect immature progenitor cells or erythroblast burst-forming units (BFU-e), leading to impaired hematopoiesis. Circulating EPO levels are elevated in Diamond-Blackfan anemia patients, indicating bone marrow unresponsiveness to anemia-related EPO stimulation. Increased progenitor tendencies toward apoptosis during in vitro EPO loss and in RPS19 deficiency have also been reported.

[0272] Glycine is one of the important initial substrates for heme synthesis. Therefore, a decrease in glycine levels resulting from GlyT1 inhibition can lead to a decrease in heme synthesis. In certain embodiments, the disclosure relates to a method for inhibiting heme synthesis in a subject having anemia associated with ribosomal dysfunction, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, heme synthesis is inhibited in a dose-dependent manner.

[0273] In some embodiments, subjects having anemia associated with ribosomal dysfunction (e.g., Diamond-Blackfan anemia) have elevated heme levels. In some embodiments, subjects have heme levels at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than those in healthy subjects prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, subjects have heme levels at least 10% higher than those in healthy subjects prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, subjects have heme levels at least 20% higher than those in healthy subjects prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 30% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 40% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 50% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 60% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 70% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.In some embodiments, the subject has a heme level at least 80% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 90% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a heme level at least 100% higher than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the method reduces the heme level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the heme level in the subject by at least 15%. In some embodiments, the method reduces the heme level in the subject by at least 20%. In some embodiments, the method reduces the heme level in the subject by at least 25%. In some embodiments, the method reduces the heme level in the subject by at least 30%. In some embodiments, the method reduces the heme level in the subject by at least 35%. In some embodiments, the method reduces the heme level in the subject by at least 40%. In some embodiments, the method reduces the heme level in the subject by at least 45%. In some embodiments, the method reduces the heme level in the subject by at least 50%. In some embodiments, the method reduces the heme level in the target by at least 55%. In some embodiments, the method reduces the heme level in the target by at least 60%. In some embodiments, the method reduces the heme level in the target by at least 65%. In some embodiments, the method reduces the heme level in the target by at least 70%. In some embodiments, the method reduces the heme level in the target by at least 75%. In some embodiments, the method reduces the heme level in the target by at least 80%. In some embodiments, the method reduces the heme level in the target by at least 85%. In some embodiments, the method reduces the heme level in the target by at least 90%. In some embodiments, the method reduces the heme level in the target by at least 95%. In some embodiments, the method reduces the heme level in the target by at least 100%.

[0275] In some embodiments, the method reduces heme synthesis 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 heme synthesis in the subject by at least 15%. In some embodiments, the method reduces heme synthesis in the subject by at least 20%. In some embodiments, the method reduces heme synthesis in the subject by at least 25%. In some embodiments, the method reduces heme synthesis in the subject by at least 30%. In some embodiments, the method reduces heme synthesis in the subject by at least 35%. In some embodiments, the method reduces heme synthesis in the subject by at least 40%. In some embodiments, the method reduces heme synthesis in the subject by at least 45%. In some embodiments, the method reduces heme synthesis in the subject by at least 50%. In some embodiments, the method reduces heme synthesis in the target by at least 55%. In some embodiments, the method reduces heme synthesis in the target by at least 60%. In some embodiments, the method reduces heme synthesis in the target by at least 65%. In some embodiments, the method reduces heme synthesis in the target by at least 70%. In some embodiments, the method reduces heme synthesis in the target by at least 75%. In some embodiments, the method reduces heme synthesis in the target by at least 80%. In some embodiments, the method reduces heme synthesis in the target by at least 85%. In some embodiments, the method reduces heme synthesis in the target by at least 90%. In some embodiments, the method reduces heme synthesis in the target by at least 95%. In some embodiments, the method reduces heme synthesis in the target by at least 100%. In some embodiments, the method reduces intracellular heme levels. In some embodiments, the method reduces intracellular heme levels in erythrocyte precursors.

[0276] 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%.

[0277] 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 iron level in the liver by at least 45%. In some embodiments, the method reduces the iron level 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%.

[0278] 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%.

[0279] In some embodiments, the subjects have reduced precursor survival compared to healthy subjects. In some embodiments, the subjects have reduced differentiation of precursors into mature red blood cells compared to healthy subjects. In some embodiments, the subjects have impaired hematopoiesis. In some embodiments, the method increases the precursor survival of the subjects. In some embodiments, the method increases the precursor survival of the subjects 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 precursor survival of the subjects by at least 15%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 20%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 25%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 30%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 35%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 40%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 45%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 50%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 55%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 60%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 65%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 70%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 75%.In some embodiments, the method increases the survival of the target red blood cell precursor by at least 80%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 85%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 90%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 95%. In some embodiments, the method increases the survival of the target red blood cell precursor by at least 100%.

[0280] In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes 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 increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 15%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 20%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 25%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 30%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 35%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 40%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 45%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 50%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 55%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 60%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 65%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 70%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 75%.In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 80%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 85%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 90%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 95%. In some embodiments, the method increases the differentiation of erythrocyte precursors into mature erythrocytes in the subject by at least 100%. In some embodiments, the subject has elevated erythrocyte adenosine deaminase activity. In some embodiments, the subject has normal myelocyte solidity with a deficiency of erythrocyte precursors. In some embodiments, the subject has a normal neutrophil and / or platelet count.

[0281] In some embodiments, anemia is caused by a failure in red blood cell production. In some embodiments, the method reduces anemia in a subject. In some embodiments, the method reduces anemia in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces anemia in a subject by at least 15%. In some embodiments, the method reduces anemia in a subject by at least 20%. In some embodiments, the method reduces anemia in a subject by at least 25%. In some embodiments, the method reduces anemia in a subject by at least 30%. In some embodiments, the method reduces anemia in a subject by at least 35%. In some embodiments, the method reduces anemia in a subject by at least 40%. In some embodiments, the method reduces anemia in a subject by at least 45%. In some embodiments, the method reduces anemia in the subject by at least 50%. In some embodiments, the method reduces anemia in the subject by at least 55%. In some embodiments, the method reduces anemia in the subject by at least 60%. In some embodiments, the method reduces anemia in the subject by at least 65%. In some embodiments, the method reduces anemia in the subject by at least 70%. In some embodiments, the method reduces anemia in the subject by at least 75%. In some embodiments, the method reduces anemia in the subject by at least 80%. In some embodiments, the method reduces anemia in the subject by at least 85%. In some embodiments, the method reduces anemia in the subject by at least 90%. In some embodiments, the method reduces anemia in the subject by at least 95%. In some embodiments, the method reduces anemia in the subject by at least 100%. In some embodiments, the subject has macrocytic anemia. In some embodiments, the method reduces anemia in the subject by reducing free heme toxicity.

[0282] In some embodiments, the method increases the red blood cell count. In some embodiments, the method decreases the mean corpuscular volume of red blood cells. In some embodiments, the method decreases red blood cell adenosine deaminase. In some embodiments, the method decreases red blood cell adenosine deaminase in subjects having DBA. In some embodiments, the method decreases the fetal hemoglobin count in red blood cells.

[0283] Red blood cell count and hematocrit Certain embodiments of this application relate to a method for administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has a low red blood cell count (e.g., less than about 4.5 million red blood cells per μl of blood for males and less than about 4.1 million red blood cells per μl of blood for females, often a clinically or statistically significant amount) or a low hematocrit (e.g., higher than about 38% for males or higher than about 35% for females, often a clinically or statistically significant amount). In some embodiments, the subject has a hematocrit level of less than 38%. In some embodiments, the subject has a hematocrit level of less than 35%.

[0284] In some embodiments, the hematocrit level of the subject is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than the hematocrit level of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 10% lower than the hematocrit level of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 20% lower than the hematocrit level of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 30% lower than the hematocrit level of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 40% lower than the hematocrit level of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 50% lower than the hematocrit level of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 60% lower than the hematocrit level of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 70% lower than the hematocrit level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.In some embodiments, the hematocrit level of the subject is at least 80% lower than the hematocrit level of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the hematocrit level of the subject is at least 90% lower than the hematocrit level of a healthy subject before administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the subject has a red blood cell count that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 10% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 20% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count at least 30% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count at least 40% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count at least 50% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count at least 60% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count at least 70% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count at least 80% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.In some embodiments, the subject has an erythrocyte count at least 90% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an erythrocyte count of 4.5 × 10⁻⁶. 12 Having a red blood cell count of less than / L. In some embodiments, the subject is 4.1 × 10 12 The red blood cell count is less than / L.

[0286] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof increases erythrocyte synthesis (also known as erythropoiesis) and can therefore be used to treat conditions associated with a decrease in red blood cells. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof can modulate erythrocyte synthesis by reducing heme formation. In some embodiments, the present disclosure relates to a method for increasing erythrocyte synthesis in a subject having anemia associated with ribosomal dysfunction, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, erythrocyte synthesis increases in a dose-dependent manner. In some embodiments, the red blood cell count increases in a dose-dependent manner. In some embodiments, for the sake of non-limiting examples, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may be administered directly to a subject, if desired, to increase the red blood cell count. The red blood cell count may also be reflected in a person's hematocrit (i.e., pack cell volume (PCV) or erythrocyte volume ratio (EVF)), which is the percentage of blood volume occupied by red blood cells. A normal hematocrit is typically about 49% for men and about 48% for women. A lower hematocrit value indicates a lower number of red blood cells.

[0287] In certain embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to such subjects increases their red blood cell count or hematocrit. Also included are methods for increasing red blood cells in subjects, including subjects who have a lower-than-normal red blood cell count or hematocrit, or who are at risk of developing such a condition, and methods for increasing hematocrit in subjects, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subjects, thereby increasing the red blood cell count or hematocrit in the subjects.

[0288] In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 15%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 20%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 25%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 30%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 35%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 40%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 45%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 50%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 55%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 60%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 65%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 70%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 75%.In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 80%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 85%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 90%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 95%. In some embodiments, the method increases the number of target red blood cells. In some embodiments, the method increases the number of target red blood cells by at least 100%. In some embodiments, the method increases the number of target red blood cells to a normal level. In some embodiments, the method increases the number of target red blood cells to 4.5-5.9 × 10⁻¹⁰. 12 Increase the number of red blood cells between / L. In some embodiments, the method involves increasing the number of red blood cells in question to 4.1-5.1 × 10⁻⁶. 12 Increase it during / L.

[0289] 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 target by at least 45%. In some embodiments, the method increases the hematocrit level of the target by at least 50%. In some embodiments, the method increases the hematocrit level of the target by at least 55%. In some embodiments, the method increases the hematocrit level of the target by at least 60%. In some embodiments, the method increases the hematocrit level of the target by at least 65%. In some embodiments, the method increases the hematocrit level of the target by at least 70%. In some embodiments, the method increases the hematocrit level of the target by at least 75%. In some embodiments, the method increases the hematocrit level of the target by at least 80%. In some embodiments, the method increases the hematocrit level of the target by at least 85%. In some embodiments, the method increases the hematocrit level of the target by at least 90%. In some embodiments, the method increases the hematocrit level of the target by at least 95%. In some embodiments, the method increases the hematocrit level of the target by at least 100%. In some embodiments, the method increases the hematocrit level of the subject to at least 38%.In some embodiments, the method increases the hematocrit level of the subject to at least 35%.

[0290] Reticulocyte count and hemoglobin In certain embodiments, the present application relates to a method for administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has reduced reticulocyte count (e.g., less than 1%, often a clinically or statistically significant amount) or reduced hemoglobin levels (e.g., less than about 13.2 g / dL for males or less than about 11.6 g / dL for females, often a clinically or statistically significant amount).

[0291] In some embodiments, the subject has a hemoglobin level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than the hemoglobin level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level that is at least 10% lower than the hemoglobin level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level that is at least 20% lower than the hemoglobin level in a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level at least 30% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level at least 40% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level at least 50% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level at least 60% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level at least 70% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof.In some embodiments, the subject has a hemoglobin level at least 80% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level at least 90% lower than that of a healthy subject prior to administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a hemoglobin level of less than 13 g / dL. In some embodiments, the subject has a hemoglobin level of less than 11 g / dL. In some embodiments, the subject has an elevated fetal hemoglobin level.

[0292] In some embodiments, the subject has a low reticulocyte count, also known as reticulopenia. In some embodiments, the subject has a reticulocyte count of less than 1%. In some embodiments, the subject has a reticulocyte count of less than 0.9%. In some embodiments, the subject has a reticulocyte count of less than 0.8%. In some embodiments, the subject has a reticulocyte count of less than 0.7%. In some embodiments, the subject has a reticulocyte count of less than 0.6%. In some embodiments, the subjects have a reticulocyte count of less than 0.5%. In some embodiments, the subjects have a reticulocyte count of less than 0.4%. In some embodiments, the subjects have a reticulocyte count of less than 0.3%. In some embodiments, the subjects have a reticulocyte count of less than 0.2%. In some embodiments, the subjects have a reticulocyte count of less than 0.1%.

[0293] In certain embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to such subjects increases their reticulocyte or hemoglobin levels. Also included are methods for increasing reticulocytes in subjects, including subjects having lower-than-normal reticulocyte or hemoglobin levels, or subjects at risk of developing such conditions, and methods for increasing hemoglobin levels in subjects, comprising administering a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to subjects, thereby reducing the reticulocyte or hemoglobin levels in the subjects.

[0294] In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof increases hemoglobin synthesis in subjects having ribosomal dysfunction-related anemia and may therefore be used to treat conditions associated with a decrease in red blood cells. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof may modulate hemoglobin synthesis by reducing heme formation. In some embodiments, the present disclosure relates to a method for increasing hemoglobin synthesis in subjects having ribosomal dysfunction-related anemia, comprising administering a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, hemoglobin synthesis is increased in a dose-dependent manner.

[0295] In some embodiments, the method increases the hemoglobin level of the target. In some embodiments, the method increases the hemoglobin level of the target 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 hemoglobin level of the target by at least 15%. In some embodiments, the method increases the hemoglobin level of the target by at least 20%. In some embodiments, the method increases the hemoglobin level of the target by at least 25%. In some embodiments, the method increases the hemoglobin level of the target by at least 30%. In some embodiments, the method increases the hemoglobin level of the target by at least 35%. In some embodiments, the method increases the hemoglobin level of the target by at least 40%. In some embodiments, the method increases the hemoglobin level of the target by at least 45%. In some embodiments, the method increases the target hemoglobin level by at least 50%. In some embodiments, the method increases the target hemoglobin level by at least 55%. In some embodiments, the method increases the target hemoglobin level by at least 60%. In some embodiments, the method increases the target hemoglobin level by at least 65%. In some embodiments, the method increases the target hemoglobin level by at least 70%. In some embodiments, the method increases the target hemoglobin level by at least 75%. In some embodiments, the method increases the target hemoglobin level by at least 80%. In some embodiments, the method increases the target hemoglobin level by at least 85%. In some embodiments, the method increases the target hemoglobin level by at least 90%. In some embodiments, the method increases the target hemoglobin level by at least 95%. In some embodiments, the method increases the target hemoglobin level by at least 100%. In some embodiments, the method increases the target hemoglobin level to at least 13 g / dL. In some embodiments, the method increases the target hemoglobin level to at least 11 g / dL.

[0296] In some embodiments, the method increases the number of reticulocytes in the target. In some embodiments, the method increases the number of reticulocytes in the target between 1% and 2%. In some embodiments, the method increases the number of reticulocytes in the target to at least 0.5%. In some embodiments, the method increases the number of reticulocytes in the target to at least 0.6%. In some embodiments, the method increases the number of reticulocytes in the target to at least 0.7%. In some embodiments, the method increases the number of reticulocytes in the target to at least 0.8%. In some embodiments, the method increases the number of reticulocytes in the target to at least 0.9%. In some embodiments, the method increases the number of reticulocytes in the target to at least 1%. In some embodiments, the method increases the number of reticulocytes in the target to at least 1.5%. In some embodiments, the method increases the number of reticulocytes in the target to at least 2%. In some embodiments, the method increases the number of reticulocytes in the target by 0.5%. In some embodiments, the method increases the number of reticulocytes in the target by 1%. Combination therapy

[0297] Certain embodiments may include combination therapies for treating ribosomal dysfunction-related anemia, comprising the administration of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents or treatment modalities. Examples of combination therapies include, but are not limited to, trifluoperazine, HDAC inhibitors, glucocorticoids, sotatercept, ruspatercept, iron chelators, blood transfusions, platelet transfusions, allogeneic hematopoietic stem cell transplantation, autologous gene therapy, lenalidomide (REVLIMID®), and antibiotics, one or more additional active agents and / or supportive therapies. In some embodiments, the method further comprises the administration of another therapeutic agent for treating ribosomal protein defects, selected from the group consisting of corticosteroids and bone marrow transplantation, as well as other treatments known to those skilled in the art. For example, corticosteroids can be used to treat ribosomal dysfunction-related anemia such as DBA. Blood transfusions can also be used to treat severe anemia associated with ribosomal disorders such as DBA. Periods of remission may occur, during which blood transfusions and steroid treatment are not required. Bone marrow transplantation (BMT) can treat hematological aspects of DBA. However, adverse events may occur in transfusion patients. In some embodiments, the method reduces the need for corticosteroid treatment in the subject. In some embodiments, the method reduces the dose of corticosteroid treatment required in the subject. In some embodiments, the corticosteroid is a glucocorticoid steroid.

[0298] As described above, common therapies for treating ribosomal dysfunction-related anemia include the use of regularly scheduled blood transfusions. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof is useful for treating subjects having ribosomal dysfunction-related anemia (e.g., Diamond-Blackfan anemia) requiring blood transfusions. In some embodiments, the method reduces the subject's need for transfusions. In some embodiments, the method reduces the subject's need for transfusions 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 transfusions by at least 15%. In some embodiments, the method reduces the subject's need for transfusions by at least 20%. In some embodiments, the method reduces the need for the target blood transfusion by at least 25%. In some embodiments, the method reduces the need for the target blood transfusion by at least 30%. In some embodiments, the method reduces the need for the target blood transfusion by at least 35%. In some embodiments, the method reduces the need for the target blood transfusion by at least 40%. In some embodiments, the method reduces the need for the target blood transfusion by at least 45%. In some embodiments, the method reduces the need for the target blood transfusion by at least 50%. In some embodiments, the method reduces the need for the target blood transfusion by at least 55%. In some embodiments, the method reduces the need for the target blood transfusion by at least 60%. In some embodiments, the method reduces the need for the target blood transfusion by at least 65%. In some embodiments, the method reduces the need for the target blood transfusion by at least 70%. In some embodiments, the method reduces the need for the target blood transfusion by at least 75%. In some embodiments, the method reduces the need for the target blood transfusion by at least 80%. In some embodiments, the method reduces the need for the target blood transfusion by at least 85%. In some embodiments, the method reduces the need for the target blood transfusion by at least 90%. In some embodiments, the method reduces the need for the target blood transfusion by at least 95%.In some embodiments, the method reduces the need for the blood transfusion in question by at least 100%. In some embodiments, the method eliminates the need for the blood transfusion in question.

[0299] Quality of life and survival In certain embodiments, the Disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of ribosomal dysfunction-related anemia (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of ribosomal dysfunction-related anemia), comprising administering an effective amount of a compound of formula (I) (e.g., any one of compounds 1 to 60) or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the method increases 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, the method relates to increasing the patient's quality of life. In some embodiments, the method relates to increasing the patient's quality of life by at least 1%. In some embodiments, the method relates to increasing the patient's quality of life by at least 2%. In some embodiments, the method relates to increasing the patient's quality of life by at least 3%. In some embodiments, the method relates to increasing the patient's quality of life by at least 4%. In some embodiments, the method relates to increasing the patient's quality of life by at least 5%. In some embodiments, the method relates to increasing the patient's quality of life by at least 10%. In some embodiments, the method relates to increasing the patient's quality of life by at least 15%. In some embodiments, the method relates to increasing the patient's quality of life by at least 20%. In some embodiments, the method relates to increasing the patient's quality of life by at least 25%. In some embodiments, the method relates to increasing the patient's quality of life by at least 30%. In some embodiments, the method relates to increasing the patient's quality of life by at least 35%. In some embodiments, the method relates to increasing the patient's quality of life by at least 40%.In some embodiments, the method relates to increasing the patient's quality of life by at least 45%. In some embodiments, the method relates to increasing the patient's quality of life by at least 50%. In some embodiments, the method relates to increasing the patient's quality of life by at least 55%. In some embodiments, the method relates to increasing the patient's quality of life by at least 60%. In some embodiments, the method relates to increasing the patient's quality of life by at least 65%. In some embodiments, the method relates to increasing the patient's quality of life by at least 70%. In some embodiments, the method relates to increasing the patient's quality of life by at least 75%. In some embodiments, the method relates to increasing the patient's quality of life by at least 80%. In some embodiments,...

Claims

1. Compound of formula (I) 【Transformation 62】 or a pharmaceutically acceptable salt thereof [in the formula, A is an aryl or heteroaryl ring system, where the aryl or heteroaryl ring system is R １ It is replaced once or more times as needed; B is a 4-8 member non-aromatic carbon ring, or a 4-8 member non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the non-aromatic carbon ring or heterocycle is R ２ It is replaced once or more times as needed; R １ is, independently for each occurrence, selected from OH, halogen, -CF ３ , -OCF ３ , -OCH ２ F, -OCHF ２ , -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, -(CH ２ ) ｎ NR ａ R ｂ , -(CH ２ ) ｎ NR ａａ C(O)R ｂｂ , -C(O)NR ａ R ｂ , -C(O)OH, -(CH ２ ) ｋ COC １～８ alkyl, -(CH ２ ) ｎ OC １～８ alkyl, -NHC(O)OC １～８ alkyl, -NR ａ R ｂ , -(CH ２ ) 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 heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C １～８ alkyl, -OC １～８ alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl are substituted with halogen, CN, -C １～８ alkyl, -C １～８ alkylheterocyclyl, -C １～８ Alkyl heteroaryl, -OC １～８ Substitutions may be made one to three times as needed, with substituents independently selected in each instance from the group consisting of alkyl, aryl, and monocyclic heteroaryl groups; R ２ For each of their appearances, OH, halogen, and -CF are independent. ３ , -OCF ３ , -OCH ２ F, -OCHF ２ , -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, -(CH ２ ) ｎ NR ａ R ｂ ,-(CH ２ ) ｎ NR ａａ C(O)R ｂｂ , -C(O)NR ａ R ｂ , -C(O)OH, -(CH ２ ) ｋ COC １～８ Alkyl, -(CH ２ ) ｎ OC １～８ Alkyl, -NHC(O)OC １～８ Alkyl, -NR ａ R ｂ ,-(CH ２ ) ｍ C(O)OC １～８ Alkyl, -S(O) ２ -NR ａ R ｂ , -S(O) ２ -C １～８ Alkyl, -S(O) ２ - Selected from the group consisting of aryls, aryls, monocyclic and bicyclic heteroaryls, monocyclic and bicyclic heterocyclines, and monocyclic and bicyclic non-aromatic heterocyclines, where -C １～８ Alkyl, -OC １～８ Alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl are halogens, CN, -C １～８ Alkyl, -C １～８ Alkyl heterocyclyl, -C １～８ alkylheteroaryl, -OC １～８ which may be optionally substituted 1 to 3 times with a substituent independently selected at each occurrence from the group consisting of alkyl, aryl and monocyclic heteroaryl; R ３ is selected from OH, -C １～８ alkyl, -OC １～８ alkyl, -Oaryl, -Oheteroaryl, and -OC ０～８ alkylC ３～８ cycloalkyl, wherein -C １～８ alkyl and -OC １～８ alkyl may be optionally substituted 1 to 3 times with a substituent independently selected at each occurrence from the group consisting of halogen, haloalkyl (for example, CH ２ F, CHF ２ , CF ３ ), aryl, heterocyclyl, and -C ３～８ cycloalkyl; R ４ is H; or R ３ and R ４ These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocyclines, where cycloalkyl and heterocyclines are CN, -C １～８ The substituents may be substituted one or two times as needed with substituents independently selected in each instance from the group consisting of alkyl, aryl, and heterocyclyl, where -C １～８ Alkyl, aryl, and heterocyclyl groups may be substituted one to three times as needed with substituents independently selected from the group consisting of halogens in each instance; R ５ H, -OH, -C １～８ Alkyl and NH ２ Selected from the group consisting of; R ６ is, -C １～８ Selected from the group consisting of alkyl, aryl, and heteroaryl, where -C １～８ Alkyl, aryl, and heteroaryl compounds contain deuterium, H, or -C. １～８ It may be substituted one to three times as needed with substituents independently selected from the group consisting of alkyl groups, where -C １～８ Alkyl is -CONH ２ , -S(O) ２ NH ２ , -S(O) ２ -C １～８ They may be substituted with alkyl, aryl or heterocyclyl as needed; or R ５ and R ６ They form heterocyclines, which are substituted as needed, along with the atoms to which they bond; R ７ It is deuterium; R ａ is H or -C １～８ It is alkyl; R ｂ is H or -C １～８ It is alkyl, and here, -C １～８ Alkyl is -CONH ２ , -S(O) ２ NH ２ , -S(O) ２ -C １～８ They may be substituted with alkyl, aryl or heterocyclyl as needed; or R ａ and R ｂ These, along with the nitrogen atom to which they bond, are OH, =O, halogen, CF ３ , -OCF ３ , -OCH ２ F, -OCHF ２ , -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, -C(O)OH, -(CH ２ ) ｋ COC １～８ Alkyl, -(CH ２ ) ｎ OC １～８ Alkyl, -NHC(O)OC １～８ Alkyl, -(CH ２ ) ｍ C(O)OC １～８ Alkyl, -S(O) ２ -C １～８ Alkyl, -S(O) ２ -Ayl, -S(O) ２ NR ａ R ｂ , forming non-aromatic heterocyclines which are substituted one to three times as necessary with substituents independently selected in each instance from the group consisting of aryls, monocyclic and bicyclic heteroaryls, monocyclic and bicyclic heterocyclines, and monocyclic and bicyclic non-aromatic heterocyclines; R ａａ is H or -C １～８ It is alkyl; R ｂｂ is, -C １～８ Alkyl, -C ４～８ It is a cycloalkylmethyl or monocyclic non-aromatic heterocycline, where -C １～８ Alkyl and -C ４～８ Cycloalkylmethyl is NH ２ , which may be substituted with halogen or CN as needed; 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; l is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. A is selected from phenyl, pyrimidine, pyridine, and thiazole, where the phenyl, pyrimidine, pyridine, and thiazole are R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

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

4. B is R ２ A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, which is a five-membered non-aromatic carbon ring that is substituted once or more times as required.

5. B is R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a six-membered non-aromatic carbon ring that is substituted once or more times as required.

6. B is a five-membered non-aromatic heterocycle containing an oxygen atom, where R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

7. B is a five-membered non-aromatic heterocycle containing a sulfur atom, where R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

8. B is a five-membered non-aromatic heterocycle containing a nitrogen atom, where R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

9. B is a six-membered non-aromatic heterocycle containing a nitrogen atom and an oxygen atom, where the non-aromatic heterocycle is R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

10. B is a six-membered non-aromatic heterocycle containing one nitrogen atom, where R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

11. B is a six-membered non-aromatic heterocycle containing two nitrogen atoms, where the non-aromatic heterocycle is R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted once or more times as needed.

12. R ２ However, halogen, =O, -C １～８ Alkyl, C(O)OC １～８ Alkyl and -S(O) ２ -NR ａ R ｂ A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, independently selected from the above.

13. R ３ However, halogen, CH ２ F, CHF ２ CF ３ aryl, heterocyclyl and -C ３～８ -OC molecules are substituted one to three times as needed with substituents independently selected from the group consisting of cycloalkyl groups in each instance. １～８ A compound according to any of the preceding claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

14. R ３ However, the halogen is substituted one to three times as needed with substituents independently selected in each appearance of the halogen -OC １～８ A compound according to any one of claims 1 to 12, which is alkyl, or a pharmaceutically acceptable salt thereof.

15. R ３ However, -OCH(CH ３ ) CF ３ The compound according to claim 14, or a pharmaceutically acceptable salt thereof.

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

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

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

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

20. R ６ However, C １～８ A compound according to any of the preceding claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

21. R ６ The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein Me is present.

22. A compound selected from one of compounds 1 to 60 and its pharmaceutically acceptable salts.

23. The aforementioned compound is compound 1 【Transformation 63】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

24. The aforementioned compound is compound 11 【Chemistry 64】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

25. The aforementioned compound is compound 17 【Transformation 65】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

26. The aforementioned compound is compound 52 Chem. 66 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

27. The aforementioned compound is compound 53 【Transformation 67】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

28. The aforementioned compound is compound 54 【Transformation 68】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound is compound 55 【Transformation 69】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

30. The aforementioned compound is compound 56 【Transformation 70】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

31. The aforementioned compound is compound 57 【Chemistry 71】 The compound according to claim 22, 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 additive.

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

34. A method for treating a hematological disorder in a subject requiring such treatment, comprising administering to the subject a compound according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32.

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

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

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

38. One or more complications of the aforementioned hepatic porphyria include acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte abnormalities, nausea, vomiting, constipation, diarrhea, dysuria, ileus, paresthesia, insomnia, restlessness, restlessness, anxiety, confusion, hallucinations, psychosis, convulsions, neuropathy-related pain, muscle paralysis, limb paresis, respiratory depression, respiratory arrest, hyponatremia, tachycardia, The method according to claim 37, selected from the group consisting of hypertension, increased heart rate, 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 keratoderma, blisters, lesions, scarring, deformity, nail loss, finger loss, cholestasis, cell lysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening of liver disease, and end-stage liver disease.

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

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

41. The method according to claim 40, wherein the nonacute hepatic porphyria is familial or sporadic cutaneous porphyria (PCT) or myelohepatic porphyria (HEP).

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

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

44. The method according to claim 43, wherein one or more complications of EPP, XLPP, or CEP are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformities, nail loss, finger loss, cholestasis, cytolysis, gallstones, cholestatic hepatic failure, cholelithiasis, mild hepatic disease, exacerbation of hepatic disease, end-stage hepatic disease, red teeth, hyperplastic bone marrow, thrombocytopenia, fetal hydrops and / or intrauterine death.

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

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

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

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

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

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

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

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

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

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

55. A method for inhibiting the synthesis of porphyrin or porphyrin precursor in vivo, comprising administering to a target compound according to any one of claims 1 to 31 or the pharmaceutical composition according to claim 32, wherein the porphyrin or porphyrin precursor is s. 5-ALA t. PBG u. Hydroxymethylbilan 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. Coproporphyrinogen I gg. Coproporphyrinogen III hh. Isocoproporphyrin ii. Porphobilinogen; and jj. Protoporphyrinogen IX A method selected from the group consisting of the following.

56. The method according to any one of claims 34 to 55, wherein the accumulation of one or more heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of 5-ALA, coproporphyrin III, zinc-protoporphyrin IX (ZPPIX), porphobilinogen, uroporphyrin III, heptacarboxyporphyrin, and isocoproporphyrin.

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

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

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

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

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

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

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

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

65. The method according to claim 63, wherein the additional active agents and / or supportive therapies are selected from the group consisting of sun avoidance, topical sunscreens, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, heme infusion, adequate calorie support, giboshilan, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of exacerbating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, venotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene into hepatocytes by a viral vector), hemodialysis, pharmacological chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

66. A method for treating anemia associated with ribosomal dysfunction in a subject requiring such treatment, comprising administering to the subject a compound according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32.

67. A method for treating one or more complications of ribosomal dysfunction-related anemia in a subject requiring such treatment, comprising administering to the subject a compound according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32.

68. The method according to any one of claims 66 to 67, wherein the ribosomal disorder-related anemia is Diamond-Blackfan anemia.

69. The method according to claim 68, wherein the subject is haploinsufficient with respect to a 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 according to claim 68, wherein the subject is haploinsufficient with respect to a 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 according to claim 68, wherein the subject has one or more mutations in a ribosomal protein gene.

72. The method according to claim 68, wherein the subject has one or more mutations in a ribosomal protein gene selected from the group consisting of 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 according to claim 68, wherein the subject has one or more mutations in a non-ribosomal protein gene selected from the group consisting of TSR2, GATA1, and EPO.

74. The method according to claim 66 or claim 67, wherein the ribosomal disorder-related anemia is Schwakman-Diamond syndrome.

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

76. The method according to claim 66 or claim 67, wherein the anemia associated with the ribosomal disorder is a congenital keratinization disorder.

77. The method according to claim 76, wherein the congenital keratosis is x-linked congenital keratosis.

78. The method according to 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 to 78, wherein the method reduces the risk of bone marrow failure, pulmonary fibrosis, or hepatic fibrosis in the subject.

80. The method according to claim 66 or claim 67, wherein the ribosomal disorder-related anemia is chondrohair hypoplasia.

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

82. The method according to claim 67, wherein one or more complications of the ribosomal dysfunction-related anemia are selected from the group consisting of thrombocytosis, megakaryocyte hyperplasia, infection, bleeding (e.g., from the nose or gums), subcutaneous hemorrhage, splenomegaly, need for more frequent blood 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 to 82, wherein the method reduces intracellular heme levels.

84. The method according to any one of claims 66 to 82, wherein the method increases the number of red blood cells in the subject.

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

86. The method according to claim 85, wherein the additional active agent and / or supportive therapy is selected from the group consisting of trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotatercept, ruspatercept, iron chelators, blood transfusions, and platelet transfusions.

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

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

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

90. The method according to claim 89, wherein the primary polycythemia is polycythemia vera or polycythemia pure.

91. The method according to claim 89, wherein the primary polycythemia is primary familial polycythemia.

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

93. The method according to claim 92, wherein the secondary polycythemia is related to a disorder selected from the group consisting of hypoxia, central hypoxic processes, lung disease, right-to-left cardiopulmonary shunt (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, polycythemia in smokers, high-altitude living environments, kidney disease, kidney transplantation, hyperoxygen-affinity hemoglobinopathy, decreased levels of erythrocyte 2,3,-DPG, bisphosphoglycerate mutase deficiency, methemoglobinemia, hereditary ATP elevation, 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 erythrocytosis is relative erythrocytosis.

95. The method according to claim 94, wherein the relative polycythemia is selected from the group consisting of Geisbeck syndrome, pseudocytosis, or stress polycythemia.

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

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

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

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

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

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

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

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

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

105. The method according to claim 104, wherein the number of red blood cells is reduced in a dose-dependent manner.

106. The method according to any one of claims 87 to 105, wherein the method reduces the incidence of iron deficiency by at least 10% (for example, 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 to 106, further comprising administering additional active agents and / or supportive therapies to the subject.

108. The method according to claim 107, wherein the additional active agent and / or supportive therapy is selected from the group consisting of hydroxyurea (e.g., Droxia®, Hydrea®), interferon alpha, interferon alpha-2b (e.g., Intron® A), ruxolitinib (e.g., Jakafi®), busulfan (e.g., Busulfex®, Myleran®), radiotherapy, hepcidin mimetic (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors.

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