GLYT-1 inhibitors and uses thereof

Abstract

The present application relates to compounds of formula (I) and their pharmaceutical compositions / preparations. This application further relates to methods of treating or preventing hematological disorders.

Description

[0001] GLYT-1 INHIBITORS AND USES THEREOF Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 538,539, filed September 15, 2023, and U.S. Provisional Patent Application No. 63 / 658,642, filed June 11, 2024, which applications are hereby incorporated by reference in their entirety. Background There are two main types of glycine transporters (GlyTs): glycine transporter-1 (GlyT-1) and glycine transporter-2 (GlyT-2). GlyT-1 shows a widespread distribution in the brain, erythrocytes, and peripheral tissues. In contrast, GlyT-2 is found primarily in the spinal cord and brainstem and is involved in the regulation of glycine. Glycine transporter-1 is the primary source of glycine for heme biosynthesis in developing red blood cells. Consequently, inhibition of glycine transporter-1 could potentially reduce heme synthesis leading to new treatments for conditions in which excess heme, the accumulation of toxic intermediates of heme biosynthesis, or pathological increases in erythropoiesis lead to disease. For example, inhibition of red cell glycine uptake could reduce the accumulation of protoporphyrin IX (PPIX), an intermediate in heme biosynthesis that accumulates and causes disease in erythropoietic protoporphyria and X-linked protoporphyria. The present application provides novel compounds that inhibit glycine transporter 1 and are amenable to treating various hematological conditions, particularly conditions in which excess heme, the accumulation of toxic intermediates of heme biosynthesis, or pathological increases in erythropoiesis lead to disease. Summary of Application The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is an aryl or heteroaryl ring system wherein the aryl or heteroaryl ring system is optionally substitued one or more times with R1; B is a 4- to 8-membered non-aromatic carbocycle or a 4- to 8-membered non-aromatic heterocyle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the non-aromatic carbocycle or heterocyle is optionally substituted one or more times with R2; R1is independently for each occurrence selected from the group consisting of OH, halogen, -CF3, - OCF3, -OCH2F, -OCHF2, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, - SC1-8alkyl, -CN, =O, -C(O)H, -(CH2)nNRaRb, -(CH2)nNRaaC(O)Rbb, -C(O)NRaRb, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -NRaRb, -(CH2)mC(O)OC1-8alkyl, -S(O)2-NRaRb, -S(O)2-C1-8alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C1-8alkyl, -OC1-8alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CN, -C1-8alkyl, -C1-8alkylheterocyclyl, -C1-8alkylheteroaryl, -OC1-8alkyl, aryl, and monocyclic heteroaryl; R2is independently for each occurrence selected from the group consisting of OH, halogen, -CF3, - OCF3, -OCH2F, -OCHF2, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, - SC1-8alkyl, -CN, =O, -C(O)H, -(CH2)nNRaRb, -(CH2)nNRaaC(O)Rbb, -C(O)NRaRb, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -NRaRb, -(CH2)mC(O)OC1-8alkyl, -S(O)2-NRaRb, -S(O)2-C1-8alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C1-8alkyl, -OC1-8alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CN, -C1-8alkyl, -C1-8alkylheterocyclyl, -C1-8alkylheteroaryl, -OC1-8alkyl, aryl, and monocyclic heteroaryl; R3is selected from the group consisting of OH, -C1-8alkyl, -OC1-8alkyl, -Oaryl, -Oheteroaryl, and – OC0-8alkylC3-8cycloalkyl, wherein -C1-8alkyl and -OC1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, haloalkyl (e.g., CH2F, CHF2, CF3), aryl, heterocyclyl, and –C3-8cycloalkyl; R4is H; or R3and R4together with the carbon atoms to which they are attached form cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl can be optionally substituted 1 or 2 times with a substituent selected independently at each occurrence from the group consisting of CN, -C1-8alkyl, aryl, and heterocyclyl, wherein -C1-8alkyl, aryl, and heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen; R5is selected from the group consisting of H, -OH, -C1-8alkyl, and NH2; R6is selected from the group consisting of -C1-8alkyl, aryl, and heteroaryl, wherein -C1-8alkyl, aryl, and heteroaryl, can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of deuterium, H or -C1-8alkyl, wherein -C1-8alkyl can be optionally substituted with -CONH2, -S(O)2NH2, -S(O)2-C1-8alkyl, aryl, or heterocyclyl; or R5and R6together with the atoms to which they are attached form optionally substituted heterocyclyl; R7is deuterium; Rais H or -C1-8alkyl; Rbis H or -C1-8alkyl, wherein -C1-8alkyl can be optionally substituted with -CONH2, -S(O)2NH2, -S(O)2-C1-8alkyl, aryl, or heterocyclyl; or Ra and Rbtogether with the nitrogen atom to which they are attached form non-aromatic heterocyclyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of OH, =O, halogen, CF3, -OCF3, -OCH2F, -OCHF2, -C(O)H, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, - SC1-8alkyl, -NRaRb, -CN, -C(O)OC1-8alkyl, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -(CH2)mC(O)OC1-8alkyl, -S(O)2-C1-8alkyl, -S(O)2-aryl, - S(O)2NRaRb, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl; Raais H or -C1-8alkyl; Rbbis -C1-8alkyl, -C4-8cycloalkylmethyl, or monocyclic non-aromatic heterocyclyl, wherein -C1-8alkyl and -C4-8cycloalkylmethyl can be optionally substituted with NH2, halogen, or CN; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, 5, or 6; and l is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, A is selected from phenyl, pyrimidine, pyridine, and thiazole, wherein the phenyl, pyrimidine, pyridine, and thiazole, is optionally substituted one or more times with R1. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is halogen. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 5-membered non-aromatic carbocycle optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 6-membered non-aromatic carbocycle optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 5-membered non-aromatic heterocyle comprising an oxygen atom wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 5-membered non-aromatic heterocyle comprising a sulfur atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 5-membered non-aromatic heterocyle comprising a nitrogen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 6-membered non-aromatic heterocyle comprising a nitrogen atom and an oxygen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 6-membered non-aromatic heterocyle comprising one nitrogen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, B is a 6-membered non-aromatic heterocyle comprising two nitrogen atoms, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is independently selected from halogen, =O, -C1-8alkyl, C(O)OC1-8alkyl, and -S(O)2-NRaRb. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R3is -OC1-8alkyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CH2F, CHF2, CF3, aryl, heterocyclyl, and –C3-8cycloalkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R3is -OC1-8alkyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from halogen. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R3is –OCH(CH3)CF3. In certain such embodiments, R3has (S) configuration. In other such embodiments, R3has (R) configuration. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R4is H. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R5is H. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R6is C1-8alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R6is Me The present application provides a compound selected from any one of compounds 1- 60, and pharmaceutically acceptable salts 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. The present application provides a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient. The present application provides a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient for use as a medicament. The present application provides a method of treating a hematological disorder in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of treating porphyria in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of treating a hepatic porphyria in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method treating one or more complications of a hepatic porphyria in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the one or more complications of hepatic porphyria is selected from the group consisting of: acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte disturbances, nausea, vomiting, constipation, diarrhea, difficulty urinating, ileus, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, pain associated with neuropathy, muscle paralysis, tetraparesis, decreased breathing, respiratory arrest, hyponatremia, tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive renal damage, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, deteriorating liver disease, and terminal phase liver disease. In certain embodiments of the foregoing methods of treating a hepatic porphyria or treating one or more complications of a hepatic porphyria, the hepatic porphyria is an acute hepatic porphyria, acute intermittent porphyria (AIP), ALA dehydratase porphyria (ADP), variegate porphyria (VP), hereditary coproporphyria (HCP), or harderoporphyria. In certain embodiments of the foregoing methods, the hepatic porphyria is non-acute hepatic porphyria. In certain such embodiments, the non-acute hepatic porphyria is familial or sporadic porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP). The present application provides a method of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of treating one or more complications of EPP, XLPP, or CEP in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the one or more complications of EPP, XLPP, or CEP is 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, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, deteriorating liver disease, terminal phase liver disease, erythrodontia, hypercellular bone marrow, thrombocytopenia, hydrops fetalis and / or death in utero. The present application provides a method of inhibiting protoporphyrin IX (PPIX) synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of inhibiting 5-aminolevulinic acid (5- ALA) synthesis in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject The present application provides a method of inhibiting coproporphyrin III synthesis in vivo, comprising administering (1 a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject. The present application provides a method of inhibiting zinc-protoporphyrin IX (ZPPIX) synthesis in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of inhibiting porphobilinogen (PBG) synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of inhibiting 5-aminolevulinic acid (5- ALA) and porphobilinogen (PBG) synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject. The present application provides a method of inhibiting hydroxymethylbilane (HMB) synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject. The present application provides a method of inhibiting uroporphyrin III synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject. The present application provides a method of inhibiting heptacarboxyl-porphyrin synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject. The present application provides a method of inhibiting isocoproporphyrin synthesis in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject. The present application provides a method of inhibiting synthesis of a porphyrin or porphyrin precursor in vivo, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to a subject, wherein the porphyrin or porphyrin precursor is selected from the group consisting of: a. 5-ALA b. PBG c. Hydroxymethylbilane 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. In certain embodiments of the foregoing methods, accumulation of one or more heme intermediates is inhibited, and wherein 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 the one or more heme intermediates is inhibited in a dose dependent manner. In certain embodiments of the foregoing methods, the subject has EPP, XLPP, or CEP. In certain embodiments of the foregoing methods, the subject has hepatic porphyria. In certain embodiments of the foregoing methods, the subject has a mutation in UROS. In certain embodiments of the foregoing methods, the subject has a gene defect in GATA-1 erythroid-specific transcription factor. In certain embodiments of the foregoing methods, wherein the subject has liver disease associated with EPP, XLPP, or CEP. In certain embodiments of the foregoing methods, the method further comprises administering to the subject 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: avoiding sunlight, 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, the additional active agent and / or supportive therapy is selected from the group consisting of: avoiding sunlight, topical sunscreens, skin protection, UVB phototherapy, Afamelanotide (Scenesse®), bortezomib, heme infusions, sufficient caloric support, Givosiran, RNAi mediated silencing of various enzymes (e.g., ALA synthase), avoiding precipitating factors, 4-aminoquinolines, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of PBGD gene in liver cells by viral vectors), hemodialysis, pharmacologic chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. The present application provides a method of treating anemia associated with a ribosomal disorder in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of treating of one or more complications of anemia associated with a ribosomal disorder in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the one or more complications of anemia associated with a ribosomal disorder is selected from the group consisting of: thrombocytosis, megakaryotypic hyperplasia, infections, bleeding (e.g., from the nose or gums), bruising, splenomegaly, the need for more frequent blood transfusions, the need for increased glucocorticoid use, the need for allogenic hematopoietic stem cell transplantation, the need for autologous gene therapy, marrow failure, leukemia, and acute myelogenous leukemia. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the anemia associated with a ribosomal disorder is Diamond-Blackfan anemia. In certain such embodiments, the subject is haploinsufficient for 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 haploinsufficient for 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. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the anemia associated with a ribosomal disorder is Shwachman-Diamond syndrome. In certain such embodiments, the subject has one or more mutations in the SBDS gene. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the anemia associated with a ribosomal disorder is dyskeratosis congenita. In certain such embodiments, the dyskeratosis congenita is x-linked dyskeratosis congenita. In other such embodiments, the subject has one or more mutations in the DKC1 gene. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the method decreases the risk of bone marrow failure, pulmonary fibrosis, or liver fibrosis in the subject. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the anemia associated with a ribosomal disorder is cartilage hair hypoplasia. In certain such embodiments, the subject has one or more mutations in the RMRP gene. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the method reduces intracellular heme levels. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the method increases the subject’s red blood cell count. In certain embodiments of the foregoing methods of treating anemia associated with a ribosomal disorder or treating of one or more complications of anemia associated with a ribosomal disorder, the method further comprises administering to the subject 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, luspatercept, iron chelators, blood transfusion, platelet transfusion, The present application provides a method of treating polycythemia in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. The present application provides a method of treating one or more complications of polycythemia in a subject in need thereof, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the one or more complications of polycythemia is selected from the group consisting of: pulmonary embolisms, transient ischemic attacks, transient visual defects, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia. In certain embodiments of the foregoing methods of treating polycythemia or treating one or more complications of polycythemia, the polycythemia is primary polycythemia. In certain such embodiments, the primary polycythemia is polycythemia vera or pure erythrocytosis. In other such embodiments, the primary polycythemia is primary familial polycythemia. In certain embodiments of the foregoing methods of treating polycythemia or treating one or more complications of polycythemia, the polycythemia is secondary polycythemia. In certain such embodiments, the secondary polycythemia is associated with a disorder selected from the group consisting of hypoxia, central hypoxic process, lung disease, right-to-left cardiopulmonary vascular shunts (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, smoker’s erythrocytosis, high-altitude habitat, renal disease, kidney transplant, hemoglobinopathy with high-oxygen-affinity, decreased levels of erythrocyte 2,3,- DPG, bisphosphoglycerate mutase deficiency, methemoglobinemia, hereditary ATP increase, oxygen sensing pathway gene mutations, tumor, drug-induced secondary polycythemia, adrenal cortical hypersecretion, and idiopathic polycythemia. In certain embodiments of the foregoing methods of treating polycythemia or treating one or more complications of polycythemia, the polycythemia is relative polycythemia. In certain such embodiments, the relative polycythemia is selected from the group consisting of Gaisbock’s syndrome, spurious polycythemia, or stress erythrocytosis. In certain embodiments of the foregoing methods of treating polycythemia or treating one or more complications of polycythemia, the polycythemia is Chuvash polycythemia. The present application provides a method of inhibiting heme synthesis in a subject with polycythemia, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the heme synthesis is inhibited in a dose dependent manner. The present application provides a method of inhibiting hemoglobin synthesis in a subject with polycythemia, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the hemoglobin synthesis is inhibited in a dose dependent manner. The present application provides a method of inhibiting red blood cell synthesis in a subject with polycythemia, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, red blood cell synthesis is inhibited in a dose dependent manner. The present application provides a method of decreasing the red blood cell count in a subject with polycythemia, comprising administering (1) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or (2) a pharmaceutical composition comprising (a) a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient to the subject. In certain embodiments, the red blood cell count is decreased in a dose dependent manner. In certain embodiments of the foregoing methods, the method decreases 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%). In certain embodiments of the foregoing methods, the method further comprises administering to the subject 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: Hydroxyruea (e.g., Droxia®, Hydrea®), Interferon alpha, Interferon alpha-2b (e.g., Intron® A), Ruxolitinib (e.g., Jakafi®), Busulfan (e.g., Busulfex®, Myleran®), radiation treatment, hepcidin mimetics (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors. Brief Description of the Drawings FIGURE 1 illustrates the study procedure to evaluate the efficacy of a GlyT1 inhibitor in EPP phototoxicity assay. FIGURE 2 shows compound 11 (“GlyT1 inhibitor”) reduces PPIX levels in RBCs in Fechm1Pas / Fechm1Pashomozygous mice as measured by flow cytometry on Day 14 and Day 18. FIGURE 3 shows compound 11 (“GlyT1 inhibitor”) treatment reduces skin lesions in Fechm1Pas / Fechm1Pashomozygous mice after light exposure. FIGURE 4 shows compound 11 (“GlyT1 inhibitor”) treatment reduces the percentage of area with skin lesions in Fechm1Pas / Fechm1Pashomozygous mice after light exposure. FIGURE 5 shows a correlation between the quantification of skin lesions and PPIX levels in Fechm1Pas / Fechm1Pashomozygous mice at day 14 treated with vehicle or compound 11 (“GlyT1 inhibitor”). Detailed Description of the Application Compounds of the present application, and pharmaceutical compositions thereof, are useful as inhibitors of GlyT-1, or a mutant thereof. Without wishing to be bound by any particular theory, it is believed that compounds of the present application, and pharmaceutical compositions thereof, may inhibit the activity GlyT-1, or a mutant thereof, and thus treat certain diseases, disorders, via GlyT-1 inhibition, such as various hematological disorders, particularly those caused by iron overload and / or regulate heme synthesis. Inhibition of heme synthesis via inhibition of PPIX synthesis could be used to treat numerous hematological disorders such as erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP). Inhibition of heme synthesis with glycine transporter inhibitors also has the potential in treatment of iron overload disorder and hemoglobinopathies such as polycythemia (e.g., primary polycythemia, polycythemia vera, pure erythrocytosis, primary familial polycythemia, relative polycythemia, secondary polycythemia, Gaisbock’s syndrome, spurious polycythemia, stress erythrocytosis, Chuvash polycythemia), anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Cartilage-hair hypoplasia, and dyskeratosis congenita), hepatic porphyria (e.g., acute hepatic porphyria, acute intermittent porphyria, ALA dehydratase porphyria, variegate porphyria, hereditary coproporphyria, harderoporphyria, non-acute hepatic porphyria, familial or sporadic porphyria cutanea tarda, hepatoerythropoietic porphyria), thalassemia, and other blood related disorders. It has now been found that compounds of the present application, and pharmaceutically acceptable compositions thereof, are effective as GlyT-1inhibitors. The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is an aryl or heteroaryl ring system wherein the aryl or heteroaryl ring system is optionally substitued one or more times with R1; B is a 4- to 8-membered non-aromatic carbocycle or a 4- to 8-membered non-aromatic heterocyle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the non-aromatic carbocycle or heterocyle is optionally substituted one or more times with R2; R1is independently for each occurrence selected from the group consisting of OH, halogen, - CF3, -OCF3, -OCH2F, -OCHF2, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, -SC1-8alkyl, -CN, =O, -C(O)H, -(CH2)nNRaRb, -(CH2)nNRaaC(O)Rbb, -C(O)NRaRb, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -NRaRb, - (CH2)mC(O)OC1-8alkyl, -S(O)2-NRaRb, -S(O)2-C1-8alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C1-8alkyl, -OC1-8alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CN, -C1-8alkyl, -C1-8alkylheterocyclyl, -C1-8alkylheteroaryl, -OC1-8alkyl, aryl, and monocyclic heteroaryl; R2is independently for each occurrence selected from the group consisting of OH, halogen, - CF3, -OCF3, -OCH2F, -OCHF2, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, -SC1-8alkyl, -CN, =O, -C(O)H, -(CH2)nNRaRb, -(CH2)nNRaaC(O)Rbb, -C(O)NRaRb, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -NRaRb, - (CH2)mC(O)OC1-8alkyl, -S(O)2-NRaRb, -S(O)2-C1-8alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C1-8alkyl, -OC1-8alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CN, -C1-8alkyl, -C1-8alkylheterocyclyl, -C1-8alkylheteroaryl, -OC1-8alkyl, aryl, and monocyclic heteroaryl; R3is selected from the group consisting of OH, -C1-8alkyl, -OC1-8alkyl, -Oaryl, -Oheteroaryl, and – OC0-8alkylC3-8cycloalkyl, wherein -C1-8alkyl and -OC1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, haloalkyl (e.g., CH2F, CHF2, CF3), aryl, heterocyclyl, and –C3-8cycloalkyl; R4is H; or R3and R4together with the carbon atoms to which they are attached form cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl can be optionally substituted 1 or 2 times with a substituent selected independently at each occurrence from the group consisting of CN, -C1-8alkyl, aryl, and heterocyclyl, wherein -C1-8alkyl, aryl, and heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen; R5is selected from the group consisting of H, -OH, -C1-8alkyl, and NH2; R6is selected from the group consisting of -C1-8alkyl, aryl, and heteroaryl, wherein -C1-8alkyl, aryl, and heteroaryl, can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of deuterium, H or - C1-8alkyl, wherein -C1-8alkyl can be optionally substituted with -CONH2, -S(O)2NH2, - S(O)2-C1-8alkyl, aryl, or heterocyclyl; or R5and R6together with the atoms to which they are attached form optionally substituted heterocyclyl; R7is deuterium; Rais H or -C1-8alkyl; Rbis H or -C1-8alkyl, wherein -C1-8alkyl can be optionally substituted with -CONH2, - S(O)2NH2, -S(O)2-C1-8alkyl, aryl, or heterocyclyl; or Raand Rbtogether with the nitrogen atom to which they are attached form non-aromatic heterocyclyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of OH, =O, halogen, CF3, - OCF3, -OCH2F, -OCHF2, -C(O)H, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, - OC1-8alkyl, -SC1-8alkyl, -NRaRb, -CN, -C(O)OC1-8alkyl, -C(O)OH, -(CH2)kCOC1-8alkyl, - (CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -(CH2)mC(O)OC1-8alkyl, -S(O)2-C1-8alkyl, - S(O)2-aryl, -S(O)2NRaRb, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl; Raais H or -C1-8alkyl; Rbbis -C1-8alkyl, -C4-8cycloalkylmethyl, or monocyclic non-aromatic heterocyclyl, wherein - C1-8alkyl and -C4-8cycloalkylmethyl can be optionally substituted with NH2, halogen, or CN; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, 5, or 6; and l is 0, 1, 2, 3, 4, 5, 6, 7, or 8. It will be readily understood by those skilled in the art that of formula I represents a ring system in which rings A and B are fused. It will be further understood by those skilled in the art that the foregoing ring system is bound to the adjacent piperizine ring system in Formula I through the A ring (i.e., the indicated nitrogen of the piperizine ring is bound directly to one of the atoms of the A ring). In certain embodiments, A is a monocyclic aryl or heteroaryl ring system wherein the monocyclic aryl or heteroaryl ring system is fused to ring B, and wherein the monocyclic aryl or heteroaryl ring system is optionally substitued one or more times with R1. In certain embodiments, A is selected from phenyl, pyrimidine, pyridine, and thiazole, wherein the phenyl, pyrimidine, pyridine, and thiazole, is optionally substituted one or more times with R1. In certain embodiments, R1is halogen (e.g., fluoro or chloro) or -C1-8alkyl. In certain embodiments, R1is halogen (e.g., fluoro or chloro). In certain embodiments, B is a 5- or 6-membered non-aromatic carbocycle or a 5- or 6- membered non-aromatic heterocyle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the non-aromatic carbocycle or heterocyle is optionally substituted one or more times with R2. In certain embodiments, B is a 5-membered non-aromatic carbocycle optionally substituted one or more times with R2. In certain embodiments, B is a 6-membered non-aromatic carbocycle optionally substituted one or more times with R2. In certain embodiments, B is a 5-membered non-aromatic heterocyle comprising an oxygen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments, B is a 5-membered non-aromatic heterocyle comprising a nitrogen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments, B is a 5-membered non-aromatic heterocyle comprising a sulfur atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2(e.g., the sulfur is substituted two times with =O such that the 5-membered non-aromatic heterocyle comprises a sulfone). In certain embodiments, B is a 5-membered non-aromatic heterocyle comprising a nitrogen atom and a sulfur atom, wherein the non- aromatic heterocyle is optionally substituted one or more times with R2(e.g., the sulfur is substituted two times with =O such that the 5-membered non-aromatic heterocyle comprises a sulfonamide). In certain embodiments, B is a 6-membered non-aromatic heterocyle comprising a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2(e.g., the sulfur is substituted two times with =O such that the 6-membered non-aromatic heterocyle comprises a sulfone, an oxygen atom, and a nitrogen atom). In certain embodiments, B is a 6-membered non-aromatic heterocyle comprising an oxygen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments, B is a 6-membered non-aromatic heterocyle comprising a nitrogen atom and an oxygen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments, B is a 6-membered non-aromatic heterocyle comprising a nitrogen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments, B is a 6-membered non-aromatic heterocyle comprising two nitrogen atoms, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2. In certain embodiments, R2is independently selected from =O, -C1-8alkyl (e.g., methyl), and C(O)OC1-8alkyl. In certain embodiments, is selected from: wherein the aryl or heteroaryl ring system of ring A is optionally substitued one or more times with R1(e.g., halogen, such as fluorine or chlorine, or -C1-8alkyl, such as methyl), and the 5- or 6 -membered non-aromatic carbocycle or heterocyle of ring B is optionally further substituted one or more times with R2(e.g., alkyl, such as methyl, or -(CH2)mC(O)OC1-8alkyl, such as C(O)OtBu). In certain embodiments, wherein the aryl or heteroaryl ring system of ring A is optionally substitued one or more times with R1(e.g., halogen, such as fluorine or chlorine, or -C1-8alkyl, such as methyl), and the 5- or 6 -membered non-aromatic carbocycle or heterocyle of ring B is optionally further substituted one or more times with R2(e.g., alkyl, such as methyl, or -(CH2)mC(O)OC1-8alkyl, such as C(O)OtBu). In certain embodiments, is selected from: , , , , , and In certain embodiments, In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form an optionally substituted monocyclic non-aromatic heterocyclyl containing 3-9 atoms having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. This monocyclic non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of OH, =O, halogen, CF3, -OCF3, -OCH2F, -OCHF2, -C(O)H, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, -SC1-8alkyl, -CN, -C(O)OC1-8alkyl, -C(O)OH, –(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -(CH2)mC(O)OC1-8alkyl, –S(O)2-C1-8alkyl, - S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl. In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form morpholinyl, oxazolidinyl, thiazinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl, or thiomorpholinyl group, wherein morpholinyl, oxazolidinyl, thiazinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl, or thiomorpholinyl group can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of =O, -C1-8alkyl, OH, and -C(O)OC1-8alkyl. In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form , or group, each of which can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of =O, -C1-8alkyl, OH, and -C(O)OC1-8alkyl. In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form oxazolidinyl or oxazolidinyl group: . In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form thiazinyl or thiazinyl group: In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form imidazolidinyl or an imidazolidinyl group: In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form piperazinyl or a piperazinyl group: In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form pyrrolidinyl or a pyrrolidinyl group: In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form thiomorpholinyl or a thiomorpholinyl group: . In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form piperidinyl or a piperidinyl group: . In certain embodiments, Raand Rbtogether with the nitrogen atom to which they are attached form morpholinyl or a morpholinyl group: In certain embodiments, R3is selected from the group consisting of OH, -OC1-8alkyl, - Oaryl, -Oheteroaryl, and – OC0-8alkylC3-8cycloalkyl, wherein -C1-8alkyl and -OC1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, haloalkyl (e.g., CH2F, CHF2, CF3), aryl, heterocyclyl, and –C3-8cycloalkyl. In certain embodiments, R3is -OC1-8alkyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CF3, aryl, heterocyclyl, and –C3-8cycloalkyl. In certain embodiments, R3is -OC1-8alkyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from halogen (e.g., fluorine). In certain embodiments, R3is –OCH(CH3)CF3. In certain embodiments, R4is H. In certain embodiments, R3and R4together with the carbon atoms to which they are attached form a 4-8 membered heterocyclyl, wherein 4-8 membered heterocyclyl can be optionally substituted 1 or 2 times with -C1-8alkyl, aryl, and heterocyclyl, wherein -C1-8alkyl, aryl, and heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen. In certain embodiments, R3and R4together with the carbon atoms to which they are attached form tetrahydrofuranyl or dihydrofuranyl, wherein tetrahydrofuranyl and dihydrofuranyl can be optionally substituted 1 or 2 times with -C1-8alkyl, wherein -C1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen. In certain embodiments, R3and R4together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl. In certain embodiments, R3and R4together with the atoms to which they are attached form tetrahydrothiophene 1,1-dioxide or dihydrothiophene 1,1-dioxide. In certain embodiments, R3and R4together with the carbon atoms to which they are attached form tetrahydrofuranyl optionally substituted 1 or 2 times with -C1-8alkyl, wherein - C1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen (e.g., Cl or F). Thus, the compound of Formula (I) has the following structure: . In certain embodiments, R3and R4together with the carbon atoms to which they are attached form dihydrofuranyl optionally substituted 1 or 2 times with -C1-8alkyl, wherein -C1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen (e.g., Cl or F). Thus, the compound of Formula (I) has the following structure:

[0002] In certain embodiments, R5is H. In certain embodiments, R5is selected from the group consisting of H and NH2. In certain embodiments, R6is C1-8alkyl. In certain embodiments, R6is Me. In certain embodiments, R5and R6together with the atoms to which they are attached form tetrahydrothiophene 1,1-dioxide. Thus, the compound of Formula (I) has the following structure: . In certain embodiments, R5and R6with the atoms to which they are attached form dihydrothiophene 1,1-dioxide. Thus, the compound of Formula (I) has the following structure: . In certain embodiments, l is 0. In certain embodiments, l is 8. The present application provides a compound selected from any one of compounds 1- 60, and pharmaceutically acceptable salts thereof:

[0003]

[0004] In certain embodiments, the compound is selected from any one of compounds 1-51, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is selected from any one of compounds 1-57, and pharmaceutically acceptable salts thereof. In embodiments of the application wherein a compound (e.g., a compound of formula (I), or pharmaceutically acceptable salts thereof, such as any one of compounds 1-60, and pharmaceutically acceptable salts thereof) is disclosed herein as a particular enantiomer, the application further contemplates the compound in its racemic or other enantiomeric form. For example, for any one of compounds 1-60 shown as the (S) enantiomer, the present application further provides the compound in its racemic or (R) enantiomeric form, and pharmaceutically acceptable salts thereof. Similarly, for any one of compounds 1-60 shown as the (R) enantiomer, the present application further provides the compound in its racemic or (S) enantiomeric form, and pharmaceutically acceptable salts thereof. In certain embodiments wherein alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, or oxime are substituted, they are substituted, valency permitting, with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(O)CF3)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(O)CF3)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. As used in this application, the term "optionally substituted" means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. Compounds of the present application containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents. In certain embodiments, compounds of the application may be racemic. For example, in embodiments of the application wherein a compound (e.g., a compound of formula (I), or pharmaceutically acceptable salts thereof) is disclosed herein as a particular enantiomer, the application further contemplates the compound in its racemic form. In certain embodiments, compounds of the application may be enriched in one enantiomer. For example, a compound of the application may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer. In certain embodiments, compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent. A variety of compounds in the present application may exist in particular geometric or stereoisomeric forms. The present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated. The present application further includes all pharmaceutically acceptable isotopically labelled compounds (e.g., compounds of formula (I), or pharmaceutically acceptable salts thereof). An "isotopically" or "radio-labelled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in certain embodiments, in compounds (e.g., compounds of formula (I), or pharmaceutically acceptable salts thereof), hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a C1-6alkyl or a C1-6alkoxy are replaced with deuterium, such as d3-methoxy or 1,1,2,2-d4-3-methylbutyl). Certain isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof), in the application, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon 14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O, and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labelled compounds (e.g., 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 analogous to those described in the accompanying examples using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),11C,13C,14C,13N,15N,15O,17O,18O,18F,35S,36Cl ,82B r,75Br,76B r,77Br,123I,124I,125I, and131I. In certain embodiments, the present application provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of formula (I), or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient. In certain embodiments, a compound as disclosed herein (e.g., a compound according to formula (I), or a pharmaceutically acceptable salt thereof) demonstrates reduced brain pentration (e.g., as compared to compounds known to cross the blood brain barrier, such as metoprolol). In certain embodiments, a compound as disclosed herein (e.g., a compound according to formula (I), or a pharmaceutically acceptable salt thereof) is not capable of crossing the blood brain barrier (i.e., the compound is peripherally restricted). In certain embodiments, a compound as disclosed herein (e.g., a compound according to formula (I), or a pharmaceutically acceptable salt thereof) is a substrate for the human efflux transporter P- glycoprotein (P-gp). In certain embodiments, a compound as disclosed herein (e.g., a compound according to formula (I), or a pharmaceutically acceptable salt thereof) has an efflux ratio greater than about 1.75, 1.8, 1.9, 2.0, 5.0, 10, 15, 20, 25, 30, 35, or 40, wherein and where Papp (A-B)indicates the apparent permeability coefficient in basolateral to apical direction, and Papp (A-B)indicates the apparent permeability coefficient in apical to basolateral direction. In certain such embodiments, the efflux ratio is determined in the absence of a P-gp inhibitor. In other such embodiments, at least a 50%, 60%, 70%, 80%, 90%, or 95% reduction of the efflux ratio is demonstrated when measured in the presence of a known P-gp inhibitor. Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Uses of the compounds Compounds of the present application may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. The quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng / kg of body weight to 100 mg / kg of body weight per day. For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. This, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and / or carrier in compositions and to be administered in methods of the application. In certain embodiments, the application relates to a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, for use as a medicament, e.g., for treatment of any of the disorders disclosed herein. In certain embodiments, compounds and compositions described herein are generally useful for the inhibition of GlyT-1, or a mutant thereof. The activity of a compound utilized in this disclosure as an inhibitor of GlyT-1, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of GlyT-1, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to GlyT-1, or a mutant thereof. Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of GlyT-1, or a mutant thereof, are set forth in the Examples below. In certain embodiments, the application relates to a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, for use as a medicament. The present application provides methods of preventing or treating disorders associated with conditions in which excess heme, the accumulation of toxic intermediates of heme biosynthesis, or pathological increases in erythropoiesis lead to disease in a subject, the method comprising administering to the subject one or more glycine transporter inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of the one or more glycine transporter inhibitor or its pharmaceutically acceptable salt. In certain aspects, the disorder is a porphyria (e.g., as erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP)), a hepatic porphyria (e.g., acute hepatic porphyria, acute intermittent porphyria, ALA dehydratase porphyria, variegate porphyria, hereditary coproporphyria, harderoporphyria, non-acute hepatic porphyria, familial or sporadic porphyria cutanea tarda, hepatoerythropoietic porphyria), anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Cartilage-hair hypoplasia, and dyskeratosis congenita), polycythemia (e.g., primary polycythemia, polycythemia vera, pure erythrocytosis, primary familial polycythemia, relative polycythemia, secondary polycythemia, Gaisbock’s syndrome, spurious polycythemia, stress erythrocytosis, Chuvash polycythemia), thalassemia, or other blood related disorder. In certain embodiments, the glycine transporter inhibitor is a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. For example, the present application provides a method of preventing or treating disorders associated with accumulation of PPIX in a subject, comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In the treatment of any of the disorders disclosed herein, different compounds of the application may be (e.g., conjointly) administered with one or more other compounds of the application (e.g., a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof). Moreover, any one or more of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein. In certain embodiments, compounds of the present application may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds. In certain embodiments, conjoint administration of compounds of the present application with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the present application and the one or more additional therapeutic agent(s). Such combination products employ the compounds of this present application within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and / or the dosage described in the publication reference. Porphyrias Porphyrias are a family of inherited or acquired disorders resulting from the deficient activity of specific enzymes in the heme biosynthetic pathway, also referred to herein as the porphyrin pathway. Porphyrins are the main precursors of heme. Porphyrins and porphyrin precursors include 5-aminolevulinic acid (ALA), porphopilinogen (PBG), hydroxymethylbilane (HMB), uroporphyrinogen I or III, coproporphyrinogen I or III, protoporphrinogen IX, and protoporphyrin IX. Heme is an essential part of hemoglobin, myoglobin, catalases, peroxidases, and cytochromes, the latter including the respiratory and P450 liver cytochromes. Heme is synthesized in most or all human cells. About 85% of heme is made in erythroid cells, primarily for hemoglobin. Most of the remaining heme is made in the liver, 80% of which is used for the synthesis of cytochromes. Deficiency of specific enzymes in the porphyrin pathway leads to insufficient heme production and also to an accumulation of porphyrin precursors and / or porphyrins, which can be toxic to cell or organ function in high concentrations. Porphyrias may be classified by the primary site of the overproduction and accumulation of porphyrins or their precursors. In hepatic porphyrias, porphyrins and porphyrin precursors are overproduced predominantly in the liver, whereas in erythropoietic porphyrias, porphyrins are overproduced in the erythroid cells in the bone. The acute or hepatic porphyrias lead to dysfunction of the nervous system and neurologic manifestations that can affect both the central and peripheral nervous system, resulting in symptoms such as, for example, pain (e.g., abdominal pain and / or chronic neuropathic pain), vomiting, neuropathy (e.g., acute neuropathy progressive neuropathy), muscle weakness, seizures, mental disturbances (e.g., hallucinations, depression anxiety, paranoia), cardiac arrhythmias, tachycardia, constipation, and diarrhea. The cutaneous or erythropoietic porphyrias primarily affect the skin, causing symptoms such as photosensitivity that can be painful, blisters, necrosis, itching, swelling, and increased hair growth on areas such as the forehead. Subsequent infection of skin lesions can lead to bone and tissue loss, as well as scarring, disfigurement, and loss of digits (e.g., fingers, toes). Most porphyrias are caused by mutations that encode enzymes in the heme biosynthetic pathway. However, not all porphyrias are genetic. For example, patients with liver disease may develop porphyria as a result of liver dysfunction. Patients with PCT can acquire the deficient activity of uroporphyrinogen decarboxylase (URO-D), due to the formation of a ORO-D enzyme with lower than normal enzymatic activity. Acute Hepatic Porphyrias Porphyrias comprise eight inherited metabolic disorders of heme biosynthesis in which various enzymes in the complex heme biosynthetic pathway are disrupted. Porphyrias are broadly classified as acute vs non-acute or hepatic vs erythropoietic porphyrias, based on their clinical presentation. Acute hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinic acid dehydratase deficient porphyria (ADP), and often lead to serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Each acute hepatic porphyria results from a genetic defect leading to deficiency in one of the enzymes of the heme synthesis pathway in the liver. AIP, HCP, and VP are autosomal dominant porphyrias and ADP is autosomal recessive porphyria. In rare cases, AIP, HCP, and VP occur as homozygous dominant forms. Porphyria cutanea tarda (PCT) is a non-acute hepatic porphyria in which patients often present with blisters, bullae, milia, and hypertrichosis on cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as hepatoerythropoietic porphyria (HEP). The clinical and laboratory features of these porphyrias are described in Table 1 below. Table 1: Symptoms and Diagnostic Strategy in Hepatic Porphyrias and Lead Poisoning Acute intermittent porphyria (AIP) (also be referred to as porphobilinogen (PBG) deaminase deficiency, or hydroxymethylbilane synthase (HMBS) deficiency), is the most common type of acute hepatic porphyria. Other types of acute hepatic porphyrias include hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA deyhdratase deficiency porphyria (ADP). Non-acute hepatic porphyrias include porphyria cutanea tarda (PCT), a disease in which patients often present with blisters, bullae, milia, and hypertrichosis on cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as hepatoerythropoietic porphyria (HEP). The clinical and laboratory features of these porphyrias are described in Table 1. AIP has been found to have a prevalence as high as 1 in 10,000 in certain populations (e.g., in Northern Sweden). The prevalence of mutations in the general population in United States and Europe, excluding the U.K., is estimated to be about 1 in 10,000 to 1 in 20,000. Clinical disease manifests itself in only approximately 10-15% of individuals who carry mutations that are known to be associated with AIP. However, the penetrance is as high as 40% in individuals with certain mutations (e.g., the W198X mutation). AIP is typically latent prior to puberty. Symptoms are more common in females than in males. The prevalence of the disease is probably underestimated due to its incomplete penetrance and long periods of latency. In the United States, it is estimated that there are about 2000 patients who have suffered at least one attack. It is estimated that there are about 150 active recurrent cases in France, Sweden, the U.K., and Poland; these patients are predominantly young women, with a median age of 30. AIP affects, for example, the visceral, peripheral, autonomic, and central nervous systems. Symptoms of AIP are variable and include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (dysuria, urinary retention / incontinence, or dark urine), neurologic symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting the cranial nerves and / or leading to weakness in the arms or legs), seizures, neuropathic pain (e.g., pain associated with progressive neuropathy, e.g., chronic neuropathic pain), neuropsychiatric symptoms (e.g., mental confusion, anxiety, agitation, hallucination, hysteria, delirium, apathy, depression, phobias, psychosis, insomnia, somnolence, coma), autonomic nervous system involvement (resulting e.g., in cardiovascular symptoms such as tachycardia, hypertension, and / or arrhythmias, as well as other symptoms, such as, e.g., increased circulating catecholamine levels, sweating, restlessness, and / or tremor), dehydration, and electrolyte abnormalities. The most common symptoms are abdominal pain and tachycardia. In addition, patients frequently have chronic neuropathic pain and develop a progressive neuropathy. Patients with recurring attacks often have a prodrome. Permanent paralysis may occur after a severe attack. Recovery from severe attacks that are not promptly treated may take weeks or months. An acute attack may be fatal, for example, due to paralysis of respiratory muscles or cardiovascular failure from electrolyte imbalance. Prior to the availability of Hemin treatments, up to 20% of patients with AIP died from the disease. In individuals who carry genes for AIP, the risk of hepatocellular cancer is increased. In those with recurrent attacks, the risk of hepatocellular cancer is particularly grave: after the age of 50, the risk is nearly 100-fold greater than in the general population. Attacks of acute porphyria may be precipitated by endogenous or exogenous factors. The mechanisms by which such factors induce attacks may include, for example, increased demand for hepatic P450 enzymes and / or induction of ALAS1 activity in the liver. Increased demand for hepatic P450 enzymes results in decreased hepatic free heme, thereby inducing the synthesis of hepatic ALAS1. Precipitating factors include fasting (or other forms of reduced or inadequate caloric intake, due to crash diets, long-distance athletics, etc.), metabolic stresses (e.g., infections, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), cigarette smoking, lipid-soluble foreign chemicals (including, e.g., chemicals present in tobacco smoke, certain prescription drugs, organic solvents, biocides, components in alcoholic beverages), endocrine factors (e.g., reproductive hormones (women may experience exacerbations during the premenstrual period), synthetic estrogens, progesterones, ovulation stimulants, and hormone replacement therapy). Over 1000 drugs are contraindicated in the acute hepatic porphyrias (e.g., AIP, HCP, ADP, and VP) including, for example, alcohol, barbiturates, Carbamazepine, Carisoprodol, Clonazepam (high doses), Danazol, Diclofenac and possibly other NSAIDS, Ergots, estrogens, Ethyclorvynol, Glutethimide, Griseofulvin, Mephenytoin, Meprobamate (also mebutamate and tybutamate), Methyprylon, Metodopramide, Phenytoin, Primidone, progesterone and synthetic progestins, Pyrazinamide, Pyrazolones (aminopyrine and antipyrine), Rifampin, Succinimides (ethosuximide and methsuximide), sulfonamide antibiotics, and Valproic acid. Objective signs of AIP include discoloration of the urine during an acute attack (the urine may appear red or red-brown), and increased concentrations of PBG and ALA in urine during an acute attack. Molecular genetic testing identifies mutations in the PBG deaminase (also known as HMBS) gene in more than 98% of affected individuals. The differential diagnosis of porphyrias may involve determining the type of porphyria by measuring individual levels of porphyrins or porphyrin precursors (e.g., ALA, PBG) in the urine, feces, and / or plasma (e.g., by chromatography and fluorometry) during an attack. The diagnosis of AIP can be confirmed by establishing that erythrocyte PBG deaminase activity is at 50% or less of the normal level. DNA testing for mutations may be carried out in patients and at-risk family members. The diagnosis of AIP is typically confirmed by DNA testing to identify a specific causative gene mutation (e.g., an HMBS mutation). Treatment of acute attacks typically requires hospitalization to control and treat acute symptoms, including, e.g., abdominal pain, seizures, dehydration / hyponatremia, nausea / vomiting, tachycardia / hypertension, urinary retention / ileus. For example, abdominal pain may be treated, e.g., with narcotic analgesics, seizures may be treated with seizure precautions and possibly medications (although many anti-seizure medications are contraindicated), nausea / vomiting may be treated, e.g., with phenothiazines, and tachycardia / hypertension may be treated, e.g., with beta blockers. Treatment may include withdrawal of unsafe medications, monitoring of respiratory function, as well as muscle strength and neurological status. Mild attacks (e.g., those with no paresis or hyponatremia) may be treated with at least 300 g intravenous 10% glucose per day, although increasingly hemin is provided immediately. Severe attacks should be treated as soon as possible with intravenous hemin (3-4 mg / kg daily for 4-14 days) and with IV glucose while waiting for the IV hemin to take effect. Typically, attacks are treated with IV hemin for 4 days and with IV glucose while waiting for administration of the IV hemin. Hemin (Panhematin® or hemin for injection, previously known as hematin) is the only heme product approved for use in the United States and was the first drug approved under the Orphan Drug Act. Panhematin ® is hemin derived from processed red blood cells (PRBCs), and is Protoporphyrin IX containing a ferric iron ion (Heme B) with a chloride ligand. Heme acts to limit the hepatic and / or marrow synthesis of porphyrin. The exact mechanism by which hemin produces symptomatic improvement in patients with acute episodes of the hepatic porphyrias has not been elucidated; however, its action is likely due to the (feedback) inhibition of δ-aminolevulinic acid (ALA) synthase, the enzyme which limits the rate of the porphyrin / heme biosynthetic pathway. Inhibition of ALA synthase should result in reduced production of ALA and PBG as well as porphyrins and porphyrin intermediates.

[0005] Drawbacks of hemin include its delayed impact on clinical symptoms and its failure to prevent the recurrence of attacks. Adverse reactions associated with hemin administration may include thrombophlebitis, anticoagulation, thrombocytopenia, renal shut down, or iron overload, which is particularly likely in patients requiring multiple courses of hemin treatment for recurrent attacks. To prevent phlebitis, an indwelling venous catheter is needed for access in patients with recurrent attacks. Uncommonly reported side effects include fever, aching, malaise, hemolysis, anaphalaxis, and circulatory collapse.

[0006] Heme is difficult to prepare in a stable form for intravenous administration. It is insoluble at neutral pH but can be prepared as heme hydroxide at pH 8 or higher. Panhematin® is a lyophilized hemin preparation. When lyophilized hemin is solubilized for intravenous administration, degradation products form rapidly; these degradation products are responsible for a transient anticoagulant effect and for phlebitis at the site of infusion. Heme albumin and heme arginate (Normosang, the European version of hemin) are more stable and may potentially cause less thrombophlebitis. However, heme arginate is not approved for use in the United States. Panhemin® may be stabilized by solubilizing it for infusion in 30% human albumin rather than in sterile water; however, albumin adds intravascular volumeexpanding effects and increases the cost of treatment as well as risk of pathogens since it is isolated from human blood.

[0007] The successful treatment of an acute attack does not prevent or delay recurrence.

[0008] There is a question of whether hemin itself can trigger recurring attacks due to induction of heme oxygenase. Nonetheless, in some areas (especially France), young women with multiply recurrent attacks are being treated with weekly hemin with the goal of achieving prophylaxis.

[0009] The current therapy for acute neurological attacks includes the intravenous administration of hemin (Panhematin®, Lundbeck or Normosang ®, Orphan Europe), which provides exogenous heme for the negative feedback inhibition of ALAS1, and thereby, decreases production of ALA and PBG. Hemin is used for the treatment during an acute attack and for prevention of attacks, particularly in women having an acute porphyria who experience frequent attacks due to hormonal changes during their menstrual cycles. While patients generally respond well, its effect is slow, typically taking two to four days or longer for urinary ALA and PBG concentrations to trend towards normal levels. As the intravenous hemin is rapidly metabolized, three to four infusions are usually necessary to effectively treat or prevent an acute attack. In addition, repeated infusions may cause iron overload and phlebitis, which may compromise peripheral venous access. Givosiran (Givlaari ®), an aminolevulinate synthase 1-directed small interfering ribonucleic acid (siRNA) is also used to treat patients with acute hepatic porphyrias by targeting and degrading ALAS1 mRNA in hepatocytes using RNA interference. The concerned risks associated with the use of givosiran include anaphylactic reactions, liver toxicity, and renal toxicity. For example, 15% patients in givosiran clinical trials showed transaminase (ALT) elevations 3 times the upper limit of normal. Additionally, 15% of patients receiving givosiran have renal-related adverse reactions including elevated serum creatinine levels and decreased estimated glomerular filtration rate. One final treatment is orthotrophic liver transplantation. While orthotrophic liver transplantation is curative, this procedure has significant morbidity and mortality and the availability of liver donors is limited. Accordingly, there is a need for new methods and compositions for treating and / or preventing hepatic porphyrias. The methods and use of glycine transporter inhibitors, such as, but not limited to, a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, fulfill these needs as well as others. Limited experience with liver transplantation suggests that if 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 the liver of a patient with AP is transplanted into another patient ("domino transplant"), the patient receiving the transplant may develop AIP. While orthotrophic liver transplantation is curative, this procedure has significant morbidity and mortality, and the availability of liver donors is limited. Among the long-term clinical effects of acute porphyrias is chronic neuropathic pain that may result from a progressive neuropathy due to neurotoxic effects, e.g., of elevated porphyrin precursors (e.g., ALA and / or PBG). Patients may suffer from neuropathic pain prior to or during an acute attack. Older patients may experience increased neuropathic pain with age for which various narcotic drugs are typically prescribed. Electromyogram abnormalities and decreased conduction times have been documented in patients with acute hepatic porphyrias. In patients with acute porphyria (e.g., ADP, AIP, HCP, or VP), levels of porphyrin precursors (ALA & PBG) are often elevated in asymptomatic patients and in symptomatic patients between attacks. Thus, reduction of the porphyrin precursors and resumption of normal heme biosynthesis by reducing the level of ALAS1 expression and / or activity is expected to prevent and / or minimize development of chronic and progressive neuropathy. Treatment, e.g., chronic treatment (e.g., periodic treatment with iRNA as described herein, e.g., treatment according to a dosing regimen as described herein, e.g., weekly or biweekly treatment) can continuously reduce the ALAS1 expression in acute porphyria patients who have elevated levels of porphyrin precursors, porphyrins, porphyrin products or their metabolites. Such treatment may be provided as needed to prevent or reduce the frequency or severity of an individual patient's symptoms (e.g., pain and / or neuropathy) and / or to reduce a level of a porphyrin precursor, porphyrin, porphyrin product or metabolite. The need exists for identifying novel therapeutics that can be used for the treatment of porphyrias. As discussed above, existing treatments such as hemin, givosiran, and liver transplant have numerous drawbacks. For example, the impact of hemin on clinical symptoms is delayed, it is expensive, and it may have side effects (e.g., thrombophlebitis, anticoagulation, thrombocytopenia, iron overload, renal shutdown). In certain aspects, the present application provides the use of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment of a hepatic porphyria in a subject in need thereof. In some embodiments, the disclosure provides methods of preventing or treating a hepatic porphyria in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. For example, the present application provides a method of preventing, treating, or reducing the progression rate and / or severity of a hepatic porphyria in a subject, comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. Optionally, methods disclosed herein for preventing, treating, or reducing the progression rate and / or severity of one or more complications of a hepatic porphyria (e.g., AIP, HCP, VP, HARPO, ADP, PCT, and HEP) in a subject, may further comprise administering to the patient one or more supportive therapies or additional active agents for treating porphyria (e.g., AIP, HCP, VP, HARPO, ADP, PCT, and HEP). For example, the patient also may be administered one or more supportive therapies or active agents selected from the group consisting of: avoiding sunlight, topical sunscreens, skin protection, UVB phototherapy, Afamelanotide (Scenesse®), bortezomib, heme infusions, sufficient caloric support, Givosiran, RNAi mediated silencing of various enzymes (e.g., ALA synthase), avoiding precipitating factors, 4-aminoquinolines, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of PBGD gene in liver cells by viral vectors), hemodialysis, pharmacologic chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. In some embodiments, the subject is administered a combination treatment, e.g., a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, and one or more additional treatments known to be effective against AIP, HCP, VP, HARPO, ADP, PCT, and HEP (e.g., glucose and / or a heme product such as hemin, as described herein) or its associated symptoms. In one embodiment, a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered in combination with glucose or dextrose. For example, 10-20% dextrose in normal saline may be provided intravenously. Typically, when glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. The compound selected from a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may also be administered intravenously, as part of the same infusion that is used to administer the glucose or dextrose, or as a separate infusion that is administered before, concurrently, or after the administration of the glucose or dextrose. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered via a different route of administration (e.g., subcutaneously). In yet another embodiment, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered in combination with total parenteral nutrition. The compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may be administered before, concurrent with, or after the administration of total parenteral nutrition. In certain embodiments, a compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional treatments, e.g., another treatment known to be effective in treating a hepatic porphyria or symptoms of a hepatic porphyria. In one embodiment, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered in combination with a heme product (e.g., hemin, heme arginate, or heme albumin). In a further embodiment, the compound of formula (I) (e.g., any one of compounds 1-60), 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 total parenteral nutrition. The additional treatment(s) may be administered before, after, or concurrent with the administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. The compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent can be administered in combination in the same composition, e.g., intravenously, or the additional therapeutic agent can be administered as part of a separate composition or by another method described herein. In some embodiments, the subject has previously been treated with a heme product (e.g., hemin, heme arginate, or heme albumin), as described herein. In some embodiments, administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in combination one or more additional treatments (e.g., glucose, dextrose), decreases the frequency of acute attacks (e.g., by preventing acute attacks so that they no longer occur, or by reducing the number of attacks that occur in a certain time period, e.g., fewer attacks occur per year). In some such embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered according to a regular dosing regimen, e.g., b.i.d., daily, weekly, biweekly, or monthly. In some embodiments, the subject has or is at risk for developing a hepatic porphyria (e.g., AIP, HCP, VP, ADP, PCT, HARPO, and HEP). In some embodiments, the hepatic porphyria is an acute hepatic porphyria (e.g., AIP, HCP, VP, and ADP). In some embodiments, the hepatic porphyria is a non-acute hepatic porphyria (e.g., PCT and HEP). In some embodiments, the hepatic porphyria is a dual hepatic porphyria, e.g., at least two hepatic porphyrias. In some embodiments, the dual hepatic porphyria comprises two or more hepatic porphyrias selected from the group consisting of AIP, HCP, VP, ADP, HARPO, PCT, and HEP. In some embodiments, the hepatic porphyria is a caused by a heterozygous mutation resulting in reduced enzymatic activity. In some embodiments, the hepatic porphyria is a caused by a homozygous mutation resulting in reduced enzymatic activity. In some embodiments, the hepatic porphyria is an autosomal recessive diseases (e.g., ADP). In some embodiments, the subject carries a genetic alteration (e.g., a mutation) as described herein but is otherwise asymptomatic. A mutation associated with a hepatic porphyria includes mutations in a gene encoding certain enzymes in the heme biosynthetic pathway (porphyrin pathway) or a gene which alters the expression of a gene in the heme biosynthetic pathway (e.g., ALAD, HMBS, UROD, UROS, CPOX, and PPOX). In many embodiments, the subject carries one or more mutations in an enzyme of the porphyrin pathway (e.g., ALA-dehydratase, PBG deaminase, uroporphyrinogen III synthase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase). In some embodiments, the hepatic porphyria is acute hepatic porphyria. In some embodiments, the hepatic porphyria is non-acute hepatic porphyria. In some embodiments, the hepatic porphyria is acute intermittent porphyria (AIP). In some embodiments, the hepatic porphyria is ALA dehydratase porphyria (ADP). In some embodiments, the hepatic porphyria is variegate porphyria (VP). In some embodiments, the hepatic porphyria is hereditary coproporphyria (HCP). In some embodiments, the hepatic porphyria is harderoporphyria (HARPO). In some embodiments, the hepatic porphyria is porphyria cutanea tarda (PCT). In some embodiments, the PCT is familial or sporadic PCT. In some embodiments, the hepatic porphyria is hepatoerythropoietic porphyria (HEP). In some embodiments, patients with an acute hepatic porphyria (e.g., AIP), or patients who carry mutations associated with an acute hepatic porphyria (e.g., AIP) but who are asymptomatic, have elevated ALA and / or PBG levels compared with healthy individuals. In such cases, the level of ALA and / or PBG can be elevated even when the patient is not having, or has never had, an attack. In some such cases, the patient is otherwise completely asymptomatic. In some such cases, the patient suffers from pain, e.g., neuropathic pain, which can be chronic pain (e.g., chronic neuropathic pain). In some cases, the patient has a neuropathy. In some cases, the patient has a progressive neuropathy. 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 never 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 for developing a hepatic porphyria (e.g., carries a gene mutation associated with a hepatic porphyria) and is asymptomatic. In some embodiments, the subject has previously had an acute attack of hepatic porphyria but is asymptomatic at the time of treatment. In some embodiments, the subject is at risk for developing a hepatic porphyria and is treated prophylactically to prevent the development of a hepatic porphyria. In some embodiments the subject has an elevated level of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, the prophylactic treatment begins at puberty. In some embodiments the treatment lowers the level (e.g., the plasma level or the urine level) of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, the treatment prevents the development of an elevated level of a porphyrin or a porphyrin precursor, (e.g., ALA and / or PBG). In some embodiments, the treatment prevents the development of, or decreases the frequency or severity of, a symptom associated with a hepatic porphyria (e.g., pain or nerve damage). The present application further provides use of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a formulation for the treatment of a hepatic porphyria in a subject. In some embodiments, the subject to be treated according to the methods described suffers from pain, e.g., chronic pain. In some embodiments, the method is effective to treat the pain (e.g., by reducing the severity of the pain or curing the pain). In some embodiments, the method is effective to decrease or prevent nerve damage. In some embodiments, the subject to be treated according to the methods described herein (a) has an elevated level of ALA and / or PBG and (b) suffers from pain (e.g., chronic pain). In some embodiments, the method is effective to decrease an elevated level of ALA and / or PBG and / or to treat the pain (e.g., by reducing the severity of the pain or curing the pain). In some embodiments, the subject is a subject who has suffered one or more acute attacks of one or more hepatic porphyric symptoms. In other embodiments, the subject is a subject who has suffered chronically from one or more symptoms of hepatic porphyria (e.g., pain, e.g., neuropathic pain and or neuropathy, e.g., progressive neuropathy). In some embodiments, the subject to be treated according to the methods described herein has recently experienced or is currently experiencing a prodrome. A “prodrome,” as used herein, includes any symptom that the individual subject has previously experienced immediately prior to developing an acute attack. Typical symptoms of a prodrome include, e.g., abdominal pain, nausea, headaches, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the subject experiences pain (e.g., abdominal pain and / or a headache) during the prodrome. In some embodiments, the subject experiences nausea during the prodrome. In some embodiments, the subject experiences psychological symptoms (e.g., anxiety) during the prodrome. In some embodiments, the subject becomes restless and / or suffers from insomnia during the prodrome. An acute “attack” of hepatic porphyria involves the onset of one or more symptoms of hepatic porphyria, typically in a patient who carries a mutation associated with hepatic porphyria (e.g., a mutation in a gene that encodes an enzyme in the porphyrin pathway). In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, is administered after an acute attack of a hepatic porphyria. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered during an acute attack of a hepatic porphyria. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to lessen the severity of the attack (e.g., by ameliorating 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 1-60), or a pharmaceutically acceptable salt thereof, is effective to shorten the duration of an attack. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to stop an attack. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), 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 occurrence of a precipitating factor. In some embodiments, the subject is at risk of developing porphyria. A “precipitating factor” as used herein, refers to an endogenous or exogenous factor that may induce an acute attack of one or more symptoms associated with porphyria. Precipitating factors include fasting (or other forms of reduced or inadequate caloric intake, due to crash diets, long-distance athletics, etc.), metabolic stresses (e.g., infections, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), cigarette smoking, lipid-soluble foreign chemicals (including, e.g., chemicals present in tobacco smoke, certain prescription drugs, organic solvents, biocides, components in alcoholic beverages), endocrine factors (e.g., reproductive hormones (women may experience exacerbations during the premenstrual period), synthetic estrogens, progesterones, ovulation stimulants, and hormone replacement therapy), and lead. Other common precipitating factors include cytochrome P450 inducing drugs and phenobarbitol. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, is administered during a prodrome. In some embodiments, the prodrome is characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered during a particular phase of the menstrual cycle, e.g., during the luteal phase. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to prevent attacks (e.g., recurrent attacks that are associated with a prodrome and / or with a precipitating factor, e.g., with a particular phase of the menstrual cycle, e.g., the luteal phase). In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, is effective to reduce the frequency of attacks. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to lessen the severity of the attack (e.g., by ameliorating 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 1-60), or a pharmaceutically acceptable salt thereof, is effective to shorten the duration of an attack. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to stop an attack. In some embodiments administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to prevent or decrease the frequency or severity of pain, e.g., neuropathic pain. In some embodiments administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to prevent or decrease the frequency or severity of neuropathy. In some embodiments, the subject has or is at risk for developing a 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 an elevated level of ALA and / or PBG and suffers from chronic pain. Effects of administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, can be established, for example, by comparison with an appropriate control. For example, a decrease in the frequency of acute attacks, as well as a decrease in the level of one or more porphyrins or porphyrin precursors, may be established, for example, in a group of patients with AIP, as a decreased frequency compared with an appropriate control group. A 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 that has been treated with a conventional treatment for hepatic porphyria (e.g., a conventional treatment for AIP may include glucose, hemin, or both); a population that has been treated with placebo, or a GlyT1 inhibitor, optionally in combination with one or more conventional treatments for hepatic porphyria (e.g., glucose, e.g., IV glucose). A subject “at risk” of developing hepatic porphyria, as used herein, includes a subject with a family history of hepatic porphyria and / or a history of one or more recurring or chronic hepatic porphyria symptoms, and / or a subject who carries a genetic alteration (e.g., a mutation) in a gene encoding an enzyme of the heme biosynthetic pathway, and a subject who carries a genetic alteration, e.g., a mutation known to be associated with hepatic porphyria. In some embodiments, the alteration, e.g., the mutation, makes an individual susceptible to an acute attack (e.g., upon exposure to a precipitating factor, e.g., a drug, dieting or other precipitating factor, e.g., a precipitating factor as disclosed herein). In some embodiments, the alteration, e.g., the mutation, is associated with elevated levels of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG). In some embodiments, the alteration, e.g., the mutation, is associated with chronic pain (e.g., chronic neuropathic pain) and / or neuropathy (e.g., progressive neuropathy). In some embodiments, the alteration, e.g., the mutation, is associated with changes in EMG and / or nerve conduction velocities. 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 an alteration, e.g., a mutation, in a gene that encodes an enzyme in the heme biosynthetic 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 associated with AIP, HCP, VP, ADP, PCT, or HEP. In some embodiments, the hepatic porphyria is AIP. In some such embodiments, the subject has an alteration, e.g., at least one mutation, in PBGD (gene encoding PBG deaminase). Many PBGD mutations are known in the art. In some embodiments, the subject is heterozygous for a PBGD mutation. In other embodiments, the subject is homozygous for a PBGD mutation. A homozygous subject may carry two identical mutations or two different mutations in the PBGD gene. In some embodiments, the hepatic porphyria is HCP. In some embodiments, the subject has an alteration, e.g., at least one mutation, in CPOX (i.e, gene that encodes the enzyme coproporphyrinogen III oxidase). In some embodiments, the hepatic porphyria is VP. In some embodiments, the subject has an alteration, e.g., at least one mutation, in PPOX (i.e., gene that encodes protoporphrinogen oxidase). In some embodiments, the hepatic porphyria is ADP (e.g., autosomal recessive ADP). In some embodiments, the subject has an alteration, e.g., at least one mutation, in ALAD (gene that encodes ALA dehydratase). In some embodiments, the hepatic porphyria is PCT. In some embodiments, the subject has an alteration, e.g., at least one mutation, in UROD (gene that encodes uro-decarboxylase). In some embodiments, the hepatic porphyria is CEP. In some embodiments, the subject has an alteration, e.g., at least one mutation, in UROS (gene that encodes uroporphyrinogen III synthase). In some embodiments, the increased levels of porphyrin precursors are due to lead poisoning. Lead poisoning inhibits the activity of each of ALAD, CPOX, and FECH, enzymes which are involved in heme biosynthesis. Patients with lead poisoning are frequently misdiagnosed with ADP or other acute porphyrias. In some embodiments, a subject with lead poisoning has decreased enzymatic activity of ALAD. In some embodiments, a subject with lead poisoning has decreased enzymatic activity of CPOX. In some embodiments, a subject with lead poisoning has decreased enzymatic activity of FECH. In some embodiments, a subject with lead poisoning has increased levels of lead in the blood and / or urine. In some embodiments, a subject with lead poisoning has increased levels of ALA. In some embodiments, a subject with lead poisoning has increased levels of ALA and PBG. In some embodiments, a subject with lead poisoning has ALA levels which are increased by at least 10 fold over a reference value. In some embodiments, a subject with lead poisoning has ALA levels which are increased by at least 5 fold over a reference value. In some embodiments, the disclosure relates to methods of treating lead poisoning in a subject, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the 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 calcium disodium ethylenediamine-tetraacetate. Porphyrins (e.g., 5-ALA, PBG, uroporphyrin, and coproporphyrin) can be found in various biological samples including the skin, urine, stool, plasma, and erythrocytes. In some embodiments, the porphyrins may be extracted from the biological sample (e.g., plasma) into a solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct inspection using long wavelength ultraviolet light (e.g., 400-420 nm light). Porphyrins have the greatest absorption wavelengths near 400-420 nm, with their highest absorption peak occurring at 415 nm. The emission maxima of porphyrins is typically around 600 nm and varies slightly based on the type of porphyrins and the solvent used for analysis. In some embodiments, diagnosis of a 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 the skin porphyrin using controlled illumination. See, e.g., Heerfordt IM. Br J Dermatol.2016;175(6):1284-1289. In some embodiments, the subject’s plasma porphyrin fluoresces at a peak of 634 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s plasma porphyrin fluoresces at a peak between 626 nm and 634 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s skin porphyrin fluoresces at a peak of 632 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s skin porphyrin fluoresces at a peak between 626 nm and 634 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, a sample from the subject (e.g., plasma or skin) containing a porphyrin or porphyrin precursor fluoresces at a peak between 615 nm and 620 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, a sample from the subject (e.g., plasma or skin) containing a porphyrin or porphyrin precursor fluoresces at a peak between 624 nm and 627 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s plasma is excited using a 405 nm laser. In some embodiments, the subject has red fluorescent urine. Erythropoietic Protoporphyria, X-linked Protoporphyria, and Congenital Erythropoietic Porphyria Erythropoietic protoporphyria (EPP) is prevalent globally and affects about 5,000- 10,000 individuals worldwide (Michaels et al.2010). EPP is considered the most common form of porphyria in children. Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin IX in red blood cells (erythrocytes), plasma, skin, and liver. Erythropoietic protoporphyria is due to an inherited or acquired deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity of delta-aminolevulinic acid synthase-2 (ALAS2). Enzymes that cause both EPP and XLPP are in the heme biosynthetic pathway. EPP and XLPP are nearly identical clinically. Congenital erythropoietic porphyria (CEP), also known as Gunther disease, caused by mutations in the gene for uroporphyrinogen synthase resulting in reduced activity of this enzyme and accumulation of the upstream metabolite coproporphyrin I. Current treatments for erythropoietic protoporphyria (EPP), X- linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) are limited. Thus, there is a need for new methods and compositions for treating and / or preventing erythropoietic protoporphyria, X-linked protoporphyria, and congenital erythropoietic porphyria. The methods and use of glycine transporter inhibitors, such as, but not limited to, GlyT1 inhibitors (e.g., a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof) fulfill these needs as well as others. The present application provides methods of preventing or treating disorders associated with accumulation of PPIX in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In part, the present application relates to methods of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present application provides methods of preventing, treating, or reducing the progression rate and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. These methods are particularly aimed at therapeutic and prophylactic treatments of animals, and more particularly, humans. The terms "subject," an "individual," or a "patient" are interchangeable throughout the specification and refer to either a human or a non-human animal. These terms include mammals, such as humans, non-human primates, laboratory animals, livestock animals (including bovines, porcines, camels, etc.), companion animals (e.g., canines, felines, other domesticated animals, etc.) and rodents (e.g., mice and rats). In particular embodiments, the patient, subject or individual is a human. The present application provides methods of preventing or treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP), or related syndrome (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) thereof in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. The present application further provides methods of preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. For example, the present application provides methods of treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. The present application further provides methods of preventing or treating EPP, XLPP, or CEP, or related syndrome thereof (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. The present application further provides methods of preventing or treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain embodiments of the foregoing, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLPP) are erythropoietic cutaneous porphyrias characterized by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced 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 levels of metal-free erythrocyte PPIX (also referred to herein as “free-protoporphyrin IX” and “PPIX”). XLPP is typically caused by C-terminal deletions in the ALAS2 gene which result in a gain-of-function mutation. These gain-of- function mutations increase the enzymatic activity of ALAS2 and cause an accumulation of both metal-free and zinc-bound PPIX. Both EPP and XLPP result in an accumulation of PPIX in erythrocytes and other tissues or biological fluids (e.g., skin, liver, bile, or stool). PPIX, which is lipophilic and eliminated via bile, is hepatotoxic at high concentrations. Patients with EPP or XLPP usually develop photosensitivity during early childhood. Patients frequently present with symptoms of burning, itching, pain erythema, and edema on sun-exposed areas. Cutaneous symptoms are sometimes associated with abnormal liver enzyme activities, hepatobiliary injury, such as jaundice and liver cirrhosis, iron deficiency, and corresponding microcytic anemia. The diagnosis of EPP and XLPP can be determined by measuring the levels of total erythrocyte, free-protoporphyrin IX, and zinc-protoporphyrin IX in hemolyzed anticoagulated whole blood. A diagnosis of EPP and / or XLPP can be made based on increased levels of free-protoporphyrin IX in blood. Patients with XLPP have a significantly higher proportion of zinc-protoporphyrin IX to free-protoporphyrin IX (e.g., >25%) as compared to those with EPP (e.g., ≤15%). The diagnosis of EPP can also be determined by measuring the level of ferrocheletase activity in a subject. Ferrocheletase is a mitochondrial enzyme that catalyzes the insertion of ferrous iron into PPIX to form heme. Ferrocheletase also catalyzes the insertion of zinc, to form zinc protoporphyrin IX (ZPPIX) from any PPIX that remains after completion of heme synthesis. In EPP, free PPIX accumulates in bone marrow reticulocytes, since formation of both heme and ZPPIX is impaired. In some embodiments, the disclosure relates to methods of a treating a subject whose ferrochelatase activity level is reduced to between 10 to 35% of the ferrocheletase activity level observed in normal subjects. In some embodiments, the disclosure relates to methods of a treating a subject whose ferrochelatase activity level is reduced to less than 50% of the ferrocheletase activity level observed in normal subjects. XLPP has a similar phenotype to EPP, and can be differentiated based on genetic analysis of ALAS2 or by determining the enzymatic activity level of ALAS2. In some embodiments, the disclosure relates to methods of a treating a subject having a gain-of- function mutation in ALAS2. In some embodiments, the subject’s ALAS2 enzyme activity is increased. Since ferrocheletase 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 decreases zinc-protoporphyrin IX levels in the subject’s erythrocytes. In some embodiments, method decreases zinc-protoporphyrin IX levels in the subject’s erythrocytes by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In certain aspects, the disclosure relates to methods of treating erythropoietic protoporphyria (EPP) and / or X-linked protoporphyria (XLPP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has increased PPIX levels. In some embodiments, the method relates to subjects having PPIX levels that are at least 10%, 20%, 30%, 40%, or 50% more than PPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having PPIX levels that are at least 10% more than PPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having PPIX levels that are at least 20% more than PPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having PPIX levels that are at least 30% more than PPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having PPIX levels that are at least 40% more than PPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having PPIX levels that are at least 50% more than PPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has increased protoporphyrin IX levels in the stool. 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 erythrocytes. In some embodiments, the subject has greater than 31 µmol L-1 protoporphyrin IX levels in the erythrocytes. In some embodiments, the subject has between 31 µmol L-1 and 53 µmol L-1 protoporphyrin IX levels in the erythrocytes. In some embodiments, the subject has greater than 53 µmol L-1 protoporphyrin IX levels in the erythrocytes. The present application further provides methods of inhibiting PPIX synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of inhibiting PPIX synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of 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 methods of inhibiting PPIX synthesis in vivo by at least 20%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 30%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 40%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 50%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 60%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 70%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 80%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 90%. In some embodiments, the disclosure relates to methods of inhibiting PPIX synthesis in vivo by at least 100%. The present application further provides methods of decreasing the rate of PPIX synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain embodiments of the methods and uses as disclosed herein inhibit PPIX accumulation directly or indirectly. In certain such embodiments, PPIX accumulation is inhibited in a dose dependent manner.

[0010] In some embodiments, the method relates to methods of decreasing free- protoporphyrin IX levels in the subject. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject’s erythrocytes. In some embodiments, the method decreases protoporphyrin IX levels in the erythrocytes of the subject to levels less than 53 μmol L-l. In some embodiments, the method decreases protoporphyrin IX levels in the erythrocytes of the subject to levels less than 31 μmol L- 1. In some embodiments, the method decreases protoporphyrin IX levels in the erythrocytes of the subject to levels less than 15 μmol L-l. In some embodiments, the method relates to decreasing protoporphyrin IX levels in the stool of the subject. In some embodiments, the method decreases protoporphyrin IX levels in the skin of the subject. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX 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 relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 15%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 20%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 25%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 30%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 35%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 40%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 45%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 50%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 55%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 60%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 65%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 70%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 75%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 80%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 85%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 90%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 95%. In some embodiments, the method relates to methods of decreasing free-protoporphyrin IX levels in the subject by at least 100%. In certain aspects, the disclosure relates to methods of treating X-linked protoporphyria (XLPP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has increased zinc-protoporphyrin IX (ZPPIX) levels. In some embodiments, the method relates to subjects having ZPPIX levels that are at least 10%, 20%, 30%, 40%, or 50% more than ZPPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having ZPPIX levels that are at least 10% more than ZPPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having ZPPIX levels that are at least 20% more than ZPPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having ZPPIX levels that are at least 30% more than ZPPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having ZPPIX levels that are at least 40% more than ZPPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having ZPPIX levels that are at least 50% more than ZPPIX levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has increased ZPPIX levels in erythrocytes. In certain aspects, the disclosure relates to methods of treating X-linked protoporphyria (XLPP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has increased proportion of zinc-protoporphyrin IX (ZPPIX) to free-protoporphyrin IX (ZPPIX / PPIX ratio) as compared to those with EPP. In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 15% (e.g., 15%, 20%, 25%, 30%, 35%, 40%, or 45%). In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 20%. In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 25%. In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 30%. In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 35%. In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 40%. In some embodiments, the method relates to subjects having a ZPPIX / PPIX ratio that is at least 45%. In certain aspects, the disclosure relates to methods of inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 20%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 30%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 40%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 50%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 60%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 70%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 80%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 90%. In some embodiments, the disclosure relates to methods of inhibiting ZPPIX synthesis in vivo by at least 100%. In certain aspects, the disclosure relates to methods of treating erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLPP), or congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has increased 5-aminolevulinic acid (5-ALA) levels. In some embodiments, the method relates to subjects having 5-ALA levels that are at least 10%, 20%, 30%, 40%, or 50% more than 5- ALA levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having 5-ALA levels that are at least 10% more than 5-ALA levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having 5-ALA levels that are at least 20% more than 5-ALA levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having 5-ALA levels that are at least 30% more than 5-ALA levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having 5-ALA levels that are at least 40% more than 5-ALA levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having 5-ALA levels that are at least 50% more than 5-ALA levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 20%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 30%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 40%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 50%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 60%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 70%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 80%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 90%. In some embodiments, the disclosure relates to methods of inhibiting 5-ALA synthesis in vivo by at least 100%. The present application further provides use of one or more compound selected from a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a formulation for the treatment of EPP, XLPP, CEP or related syndrome thereof (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject. In some embodiments, the present application provides use of one or more compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a formulation for the treatment of EPP, XLPP, or CEP in a subject. The present application provides the use of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment of EPP, XLPP, or CEP, or related syndrome thereof (e.g., EPP-related syndrome, XLPP-related syndrome, or CEP-related syndrome) in a subject. In certain embodiments of the foregoing, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Congenital erythropoietic porphyria (CEP) is an erythropoietic cutaneous porphyria characterized by blistering cutaneous photosensitivity. Severe cases of CEP can present in utero with hydrops fetalis, or shortly after birth with severe blistering photosensitivity, red urine, splenomegaly, hemolysis, and transfusion dependence. Milder cases and later onset forms typically present with red urine, severe blistering, and hemolytic anemia. CEP individuals are often homozygous or compound heterozygous for UROS mutations. Some cases of CEP are due to mutations in the gene encoding the transcriptional regulator GATA1. These mutations result in reduced enzyme activity of uroporphyrinogen III synthase (UROIII-S), the fourth enzyme in the heme biosynthetic pathway. The decreased activity of UROIII-S leads to an accumulation of hydroxymethylbilane which spontaneously forms uroporphyrinogen I, which is further metabolized to coproporphyrinogen I. Uroporphyrinogen I and coproporphyrinogen I accumulate in the tissues. The diagnosis of CEP can be determined by analyzing the enzyme activity of uroporphyrinogen III synthase (UROIII-S), by evaluating mutations in the UROS gene, by evaluating the function of GATA-1 erythroid-specific transcription factor, by evaluating mutations in GATA1, and by determining the levels of uroporphyrin I and coproporphyrin I in the subject. In some embodiments, the subject has a mutation in UROS. In some embodiments, the subject has a gene defect in GATA-1 erythroid-specific transcription factor. In some embodiments, the method relates to methods of treating a subject, wherein the subject has decreased activity of uroporphyrinogen III synthase. In some embodiments, the increased levels of uroporphyrin I and / or coproporphyrin I are measured in the subject’s urine or red blood cells. In some embodiments, the increased levels of coproporphyrin I are measured in the subject’s stool. In certain aspects, the disclosure relates to methods of treating congenital erythropoietic porphyria (CEP) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has increased uroporphyrin I and / or coproporphyrin I levels. In some embodiments, the subject has increased levels of uroporphyrin I and / or coproporphyrin I. In some embodiments, the method relates to subjects having uroporphyrin I levels that are at least 10%, 20%, 30%, 40%, or 50% more than uroporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having uroporphyrin I levels that are at least 10% more than uroporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having uroporphyrin I levels that are at least 20% more than uroporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having uroporphyrin I levels that are at least 30% more than uroporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having uroporphyrin I levels that are at least 40% more than uroporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having uroporphyrin I levels that are at least 50% more than uroporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of treating subjects having coproporphyrin I levels that are at least 10%, 20%, 30%, 40%, or 50% more than coproporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having coproporphyrin I levels that are at least 10% more than coproporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having coproporphyrin I levels that are at least 20% more than coproporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having coproporphyrin I levels that are at least 30% more than coproporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having coproporphyrin I levels that are at least 40% more than coproporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to subjects having coproporphyrin I levels that are at least 50% more than coproporphyrin I levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of treating EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the dosage of the pharmaceutical composition does not cause a substantial reduction in heme levels. In some embodiments, the patient’s PPIX levels decrease 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 decrease by at least 55%. In some embodiments, the patient’s PPIX levels decrease by at least 60%. In some embodiments, the patient’s PPIX levels decrease by at least 65%. In some embodiments, the patient’s PPIX levels decrease by at least 70%. In some embodiments, the patient’s PPIX levels decrease by at least 75%. In some embodiments, the patient’s PPIX levels decrease by at least 80%. In some embodiments, the patient’s PPIX levels decrease by at least 85%. In some embodiments, the patient’s PPIX levels decrease by at least 90%. In some embodiments, the patient’s PPIX levels decrease by at least 95%. In some embodiments, the patient’s PPIX levels decrease by at least 100%. In some embodiments, the patient’s heme levels decrease no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient’s heme levels decrease no more than 15%. In some embodiments, the patient’s heme levels decrease no more than 20%. In some embodiments, the patient’s heme levels decrease no more than 25%. In some embodiments, the patient’s heme levels decrease no more than 30%. In some embodiments, the accumulation of one or more of the following heme intermediates is inhibited, wherein the one or more heme intermediates is selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of PPIX, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of ZPPIX, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of uroporphyrin I, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of coproporphyrin I, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of 5-ALA, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the accumulation of the one or more heme intermediates (e.g., PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA) is inhibited in a dose dependent manner.

[0011] Protoporphyrin accumulation in EPP, XLPP, and CEP can cause liver damage when the hepatic load exceeds the canalicular excretion capacity. The accumulation of PPIX in hepatocytes and bile canaliculi may result in cell damage, cholestasis, cytolysis and further retention of protoporphyrin. Excess protoporphyrin can exert cholestatic effects leading to changes in the hepatobiliary system which can range from mild inflammation to fibrosis and cirrhosis (e.g., cholelithiasis, mild liver disease, deteriorating liver disease, and terminal phase liver disease). Between 3-5% of patients with EPP or XLPP develop protoporphyria hepatopathy, a severe liver disease that can progress rapidly and require liver transplantation. Approximately 2% of patients will develop severe liver disease.

[0012] In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of liver disease associated with EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is cholelithiasis. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is mild liver disease. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is deteriorating liver disease. In some embodiments, the liver disease associated with EPP, XLPP, or CEP is terminal phase liver disease.

[0013] Liver function in patients with EPP, XLPP, and CEP can be assessed using various known clinical assays. In some embodiments, liver function tests can be used to determine the level of various biochemical parameters (e.g., raised aspartate transaminase levels, alkaline phosphatase, or γ-glutamyl transferase levels). In some embodiments, histopathology of liver biopsies may be used to assess one or more parameters (e.g., protoporphyrin deposition, fibrosis, infiltrates, portal fibrosis, and periportal fibrosis) in the subject. In some embodiments, ultrastructural studies of biopsy specimen can be used to determine if crystal containing vacuoles are present in the subject. With deterioration of liver function, urinary coproporphyrin excretion increases. In some embodiments, coproporphyrin excretion in the urine may be analyzed to assess liver function in the subject. In some embodiments, ultrasound, or magnetic resonance elastography may be used to measure liver stiffness in the subject. In certain embodiments of the methods and uses as disclosed herein, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the present application, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 100 nM. In certain embodiments of the present application, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 50 nM. In certain such embodiments, the EC50 is measured in a flow cytometry assay. In certain embodiments of the methods and uses as disclosed herein, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the present application, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 100 nM. In certain embodiments of the present application, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates PPIX inhibition with an EC50 of less than 50 nM. In certain such embodiments, the EC50 is measured in a flow cytometry assay. In certain embodiments of the methods and uses as disclosed herein, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95% cell viability is maintained. In certain such embodiments, at least 90% cell viability is maintained. Heme and Heme Intermediates Glycine is one of the key initial substrates for heme and globin synthesis. As such, decreased levels of glycine due to GlyT1 inhibition could lead to a decrease in heme synthesis. In certain aspects, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject’s heme levels decrease no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the subject’s heme levels decrease no more than 15%. In some embodiments, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the subject’s heme levels decrease no more than 20%. In some embodiments, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the subject’s heme levels decrease no more than 25%. In some embodiments, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, wherein the subject’s heme levels decrease no more than 30%. In certain aspects, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the dosage of the pharmaceutical composition does not cause a substantial reduction in heme levels. In some embodiments, the synthesis of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, wherein the one or more heme intermediates is 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 methods of inhibiting 5-aminolevulinic acid (5- ALA) synthesis in a subject, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has a hepatic porphyria, EPP, XLPP, or CEP. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin III synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting zinc-protoporphyrin IX (ZPPIX) synthesis in a subject, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject has ALA dehydratase porphyria (ADP). In some embodiments, the disclosure relates to methods of inhibiting porphobilinogen (PBG) synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting 5- aminolevulinic acid (5-ALA) and porphobilinogen (PBG) synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting hydroxymethylbilane (HMB) synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin III synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting heptacarboxyl-porphyrin synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting isocoproporphyrin synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the synthesis of the 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. In some embodiments, the accumulation of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, wherein the one or more heme intermediates is 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 the 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. In some embodiments, the subject to be treated according to the methods described herein has an elevated level of a porphyrin or a porphyrin precursor, e.g., ALA and / or PBG. In some embodiments, the subject has porphyrin precursor level that is at least 10%, 20%, 30%, 40%, or 50% more than porphyrin precursor level in a healthy subject prior to administration of the v. In some embodiments, the subject has increased levels of a porphyrin precursor. 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 increased uroporphyrin III levels (e.g., increased uroporphyrin III levels in the urine). In some embodiments, the subject has increased levels of 5-ALA (e.g., increased levels of 5- ALA in the urine or plasma). In some embodiments, the subject has increased levels of HMB. In some embodiments, the subject has increased levels of coproporphyrin III (e.g., increased levels of coproporphyrin III in the urine and stool). In some embodiments, the subject has increased levels of PBG (e.g., increased levels of PBG in the urine). In some embodiments, the subject has an increased proportion of protoporphyrin to coproporphyrin in the stool. In some embodiments, the subject has increased heptacarboxyl-porphyrin levels (e.g., increased heptacarboxyl-porphyrin levels in the urine or stool). In some embodiments, the subject has increased isocoproporphyrin levels (e.g., increased isocoproporphyrin levels in the stool). In some embodiments, the subject has increased ZPPIX levels in erythrocytes. Levels of a porphyrin or a porphyrin precursor can be assessed using methods known in the art or methods described herein. In some embodiments, the level of a porphyrin or a porphyrin precursor (e.g., ALA or PBG) in the subject is assessed based on the absolute level of the porphyrin or the porphyrin precursor, e.g., ALA or PBG in a sample from the subject. In some embodiments, the level of a porphyrin or a porphyrin precursor (e.g., ALA or PBG) in the subject is assessed based on the relative level of the 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., the level of creatinine, in a sample from the subject. In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a stool sample. An elevated level of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG) can be established by showing that the subject has a level of a porphyrin or a porphyrin precursor (e.g., a plasma or urine level of ALA and / or PBG) that is greater than, or greater than or equal to, a reference value. A physician with expertise in the treatment of porphyrias would be able to determine whether the level of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG) is elevated, e.g., for the purpose of diagnosing a hepaticporphyria, EPP, XLPP, or CEP or for determining whether a subject is at risk for developing a hepatic porphyria, EPP, XLPP, or CEP, e.g., a subject may be predisposed to an acute attack or to pathology associated with a porphyria, such as, e.g., chronic pain (e.g., neuropathic pain) and neuropathy (e.g., progressive neuropathy). As used herein, a “reference value” refers to a value from the subject when the subject is not in a disease state, or a value from a normal or healthy subject, or a value from a reference sample or population, e.g., a group of normal or healthy subjects (e.g., a group of subjects that does not carry a mutation associated with a hepatic porphyria, EPP, XLPP, or CEP and / or a group of subjects that does not suffer from symptoms associated with a hepatic porphyria, EPP, XLPP, or CEP). In some embodiments, the reference value is a pre-disease level in the same individual. In some embodiments, the reference value is a level in a reference sample or population. In some embodiments, the reference value is the mean or median value in a reference sample or population. In some embodiments, the reference value the value that is two standard deviations above the mean in a reference sample or population. In some embodiments, the reference value is the value that is 2.5, 3, 3.5, 4, 4.5, or 5 standard deviations above the mean in a reference sample or population. In some embodiments, the subject has a plasma level or a urine level of ALA or PBG that is greater than a reference value. In some embodiments, wherein the subject has an elevated level of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG) the subject has a level of ALA and / or PBG that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than a reference value. In some embodiments, the subject has a level of a porphyrin or a porphyrin precursor (e.g., ALA and / or PBG) that is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold higher than a reference value. In some embodiments, the reference value is an upper reference limit. As used herein, an “upper reference limit” refers to a 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 who do not carry a genetic mutation associated with a porphyria and / or individuals who do not suffer from a hepatic porphyria, EPP, XLPP, or CEP. Accordingly, a lower reference limit refers to a level that is the lower limit of the same 95% confidence interval. In some embodiments, the subject has an elevated level (e.g., a plasma level or a urine level) of a porphyrin or a porphyrin precursor that is greater than or equal to 2 times, 3 times, 4 times, or 5 times that of a reference value (e.g., an upper reference limit). In some embodiments, the subject has a urine level of a porphyrin or a porphyrin precursor that is greater than 4 times that of an upper reference limit. In some embodiments, the subject has a urine level of PBG that is greater than or equal to 1.4 mmol / mol creatinine. In some embodiments, the subject has a urine level of PBG that is greater than or equal to 4.8 mmol / mol creatinine. In certain embodiments, the subject has a urine level of PBG that is greater than, or greater than or equal to, about 3, 4, 5, 6, 7, or 8 mmol / mol creatinine.

[0014] In some embodiments, the reference value for plasma PBG is 0.12 μmol / L. In some embodiments, the subject has a plasma PBG level that is greater than, or greater than or equal to 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject has a plasma level of PBG that is greater than, or greater than or equal to 0.48 μmol / L.

[0015] In some embodiments, the reference value for urine PBG is 1.2 mmol / mol creatinine. In some embodiments, the reference value for urine PBG is 1.4 mmol / mol creatinine. In some embodiments, the subject has a urine PBG level that is greater than, or greater than or equal to 1.0 mmol / mol creatinine, 1.2 mmol / mol creatinine, 2.4 mmol / mol creatinine, 3.6 mmol / mol creatinine, 4.8 mmol / mol creatinine, or 6.0 mmol / mol creatinine. In some embodiments, the subject has a urine level of PBG that is greater than, or greater than or equal to 4.8 mmol / mol creatinine.

[0016] In some embodiments, the reference value for plasma ALA is 0.12 μmol / L. In some embodiments, the subject has a plasma ALA level that is greater than, or greater than or equal to 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject has a plasma ALA level that is greater than, or greater than or equal to 0.48 μmol / L.

[0017] In some embodiments, the reference value for urine ALA is 3.1 mmol / mol creatinine. In some embodiments, the reference value for urine ALA is 6.3 mmol / mol creatinine. In some embodiments, the subject has a urine ALA level that is greater than, or greater than or equal to 2.5 mmol / mol creatinine, 3.1 mmol / mol creatinine, 6.2 mmol / mol creatinine, 6.3 mmol / mol creatinine, 9.3 mmol / mol creatinine, 12.4 mmol / mol creatinine, or 15.5 mmol / mol creatinine.

[0018] In some embodiments, the reference value for urine uroporphyrin is less than 4.5 μmol / mol creatinine. In some embodiments, the subject has a urine uroporphyrin level that is greater than, or greater than or equal to 4.5 μmol / mol creatinine, 9.0 μmol / mol creatinine, 13.5 μmol / mol creatinine, 18.0 μmol / mol creatinine, 22.5 μmol / mol creatinine, 27 μmol / mol creatinine, or 31.5 μmol / mol creatinine. In some embodiments, the reference value for urine coproporphyrin is less than 20.7 μmol / mol creatinine. In some embodiments, the subject has a urine coproporphyrin level that is greater than, or greater than or equal to 20.7 μmol / mol creatinine, 41.4 μmol / mol creatinine, 62.1 μmol / mol creatinine, 82.8 μmol / mol creatinine, 103.5 μmol / mol creatinine, 124.2 μmol / mol creatinine, or 144.9 μmol / mol creatinine.

[0019] In some embodiments, the reference value for plasma porphyrin is 10 nmol / L. In some embodiments, the subject has a plasma porphyrin level that is greater than, or greater than or equal to 10 nmol / L. In some embodiments, the subject has a plasma porphyrin level that is greater than, or greater than or equal to 8, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nmol / L. In some embodiments, he subject has a plasma porphyrin level that is greater than, or greater than or equal to 40 nmol / L.

[0020] In some embodiments, the reference value for urine porphyrin is 25 μmol / mol creatinine. In some embodiments, the reference value for urine porphyrin is less than 28.4 μmol / mol creatinine. In some embodiments, the subject has a urine porphyrin level that is greater than, or greater than or equal to 25 μmol / mol creatinine. In some embodiments, the subject has a urine porphyrin level that is greater than, or equal to 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 μmol / mol creatinine.

[0021] In some embodiments, the subject has a level (e.g. , a plasma level or a urine level) of a porphyrin or a porphyrin precursor that is greater than that of 99% of individuals in a sample of healthy individuals.

[0022] In some embodiments, the subject has a level (e.g., a plasma level or a urine level) of ALA or PBG that is greater than two standard deviations above the mean level in a sample of healthy individuals.

[0023] In some embodiments, the subject has a urine level of ALA that is 1.6 or more times that of the mean level in a normal subject (e.g., a subject that does not carry a mutation associated with a porphyria). In some embodiments, the subject has a plasma level of ALA that is 2 or 3 times that of the mean level in a normal subject. In some embodiments, the subject has a urine level of PBG that is four or more times that of the mean level in a normal subject. In some embodiments, the subject has a plasma level of PBG that is four or more times that of the mean level in a normal subject.

[0024] In certain embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, results in a decrease in the level of one or more porphyrins or porphyrin precursors, as described herein (e.g., ALA and / or PBG). The decrease may be measured relative to any appropriate control or reference value. For example, the decrease in the level of one or more porphyrins or porphyrin precursors may be established in an individual subject, e.g., as a decrease of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared with the level prior to treatment (e.g., immediately prior to treatment). A decrease in the level of a porphyrin precursor, a porphyrin, or a porphyrin metabolite may be measured using any method known in the art. In some embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is effective to reduce the level of ALA and / or PBG in the subject. The level of ALA or PBG in the subject can be assessed, e.g., based on the absolute level of ALA or PBG, or based on the relative level of ALA or PBG (e.g., relative to the level of another protein or compound, e.g., the level of creatinine) in a sample from the subject. In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample. In some embodiments, the method decreases 5-ALA levels in the subject. In some embodiments, the method decreases 5-ALA 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 decreases HMB levels in the subject. In some embodiments, the method decreases HMB 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 decreases coproporphyrin III levels in the subject. In some embodiments, the method decreases 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 decreases PBG levels in the subject. In some embodiments, the method decreases 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 decreases uroporphyrin III levels in the subject. In some embodiments, the method decreases uroporphyrin 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 decreases the proportion of protoporphyrin to coproporphyrin in the subject. In some embodiments, the method decreases the proportion 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 decreases heptacarboxyl-porphyrin levels in the subject. In some embodiments, the method decreases heptacarboxyl-porphyrin 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 decreases isocoproporphyrin levels in the subject. In some embodiments, the method decreases 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 decreases ZPPIX levels in the subject. In some embodiments, the method decreases 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 decreases porphyrin or porphyrin precursor (e.g., ALA or PBG) levels in the subject to a normal level. In some embodiments, the normal level is a reference value for a porphyrin or porphyrin precursor (e.g., urine ALA levels <6.3 mmol / mol creatine and urine PBG levels <1.4 mmol / mol creatine) as described herein. In certain aspects, the disclosure relates to methods of inhibiting uroporphyrin I and / or coproporphyrin I synthesis in vivo, comprising administering to a subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 20%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 30%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 40%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 50%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 60%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 70%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 80%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 90%. In some embodiments, the disclosure relates to methods of inhibiting uroporphyrin I synthesis in vivo by at least 100%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100%). In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 20%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 30%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 40%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 50%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 60%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 70%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 80%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 90%. In some embodiments, the disclosure relates to methods of inhibiting coproporphyrin I synthesis in vivo by at least 100%. Porphyrins (e.g., PPIX, ZPPIX, uroporphyrin I, and coproporphyrin I) can be found in various biological samples including the skin, urine, stool, plasma, and erythrocytes. In some embodiments, the porphyrins may be extracted from the biological sample into a solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct inspection using long wavelength ultraviolet light (e.g., 400-420 nm light). Porphyrins have the greatest absorption wavelengths near 400-420 nm, with their highest absorption peak occurring at 415 nm. The emission maxima of porphyrins is typically around 600 nm and varies slightly based on the type of porphyrins and the solvent used for analysis. In some embodiments, diagnosis of a 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. See, e.g., Heerfordt IM. Br J Dermatol.2016;175(6):1284- 1289. In some embodiments, the subject’s plasma porphyrin fluoresces at a peak of 634 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s plasma porphyrin fluoresces at a peak between 626 nm and 634 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s skin porphyrin fluoresces at a peak of 632 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject’s skin porphyrin fluoresces at a peak between 626 nm and 634 nm when illuminated with blue light (e.g., 400-420 nm light). In some embodiments, the subject has greater than 0.2 FluoDerm Units (FDU) of protoporphyrin IX levels in the skin. In some embodiments, the subject has greater than 1.0 FDU of protoporphyrin IX levels in the skin. In some embodiments, the subject has between 1.0 FDU and 2.5 FDU of protoporphyrin IX levels in the skin. In some embodiments, the subject has greater than 2.5 FDU of protoporphyrin IX levels in the skin. In some embodiments, the method decreases protoporphyrin IX levels in the skin of the subject to less than 0.5 FDU. In some embodiments, the method decreases protoporphyrin IX levels in the skin of the subject to less than 1.0 FDU. In some embodiments, the method decreases protoporphyrin IX levels in the skin of the subject to less than 1.5 FDU. In some embodiments, the method decreases protoporphyrin IX levels in the skin of the subject to less than 2.0 FDU. In some embodiments, the method decreases protoporphyrin IX levels in the skin of the subject to less than 2.5 FDU. In some embodiments, the subject has red fluorescent urine. In some embodiments, the subject has a peak between 615 nm and 620 nm using plasma porphyrin fluorescence analysis. In certain aspects, the methods provided herein comprise administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the subject’s PPIX levels decrease while the patient’s heme levels are substantially maintained. In some embodiments, the patients PPIX levels decrease 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 levels decrease no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient’s PPIX levels decrease by at least 85% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 80% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 75% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 70% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 65% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 60% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 55% and the patient’s heme levels decrease no more than 15%. In some embodiments, the patients PPIX levels decrease by at least 50% and the patient’s heme levels decrease no more than 15%. In certain aspects, the disclosure relates to methods of treating a hepatic porphyria, EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the dosage of the pharmaceutical composition does not cause a substantial reduction in heme levels. In some embodiments, the patient’s PPIX levels decrease 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 decrease by at least 55%. In some embodiments, the patient’s PPIX levels decrease by at least 60%. In some embodiments, the patient’s PPIX levels decrease by at least 65%. In some embodiments, the patient’s PPIX levels decrease by at least 70%. In some embodiments, the patient’s PPIX levels decrease by at least 75%. In some embodiments, the patient’s PPIX levels decrease by at least 80%. In some embodiments, the patient’s PPIX levels decrease by at least 85%. In some embodiments, the patient’s PPIX levels decrease by at least 90%. In some embodiments, the patient’s PPIX levels decrease by at least 95%. In some embodiments, the patient’s PPIX levels decrease by at least 100%. In some embodiments, the patient’s heme levels decrease no more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the patient’s heme levels decrease no more than 15%. In some embodiments, the patient’s heme levels decrease no more than 20%. In some embodiments, the patient’s heme levels decrease no more than 25%. In some embodiments, the patient’s heme levels decrease no more than 30%. In some embodiments, the accumulation of one or more of the following heme intermediates is inhibited, wherein the one or more heme intermediates is selected from the group consisting of PPIX, ZPPIX, uroporphyrin I, coproporphyrin I, and / or 5-ALA. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of PPIX, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of ZPPIX, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of uroporphyrin I, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of coproporphyrin I, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of inhibiting the accumulation of 5-ALA, the method comprising administering to the subject a pharmaceutical composition comprising a v. In some embodiments, the accumulation of the 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 Porphyrias In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of one or more complications of a hepatic porphyria, EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more complications of a hepatic porphyria is selected from the group consisting of: acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte disturbances, nausea, vomiting, constipation, diarrhea, difficulty urinating, ileus, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, pain associated with neuropathy, muscle paralysis, tetraparesis, decreased breathing, respiratory arrest, hyponatremia, tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive renal damage, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, deteriorating liver disease, and terminal phase liver disease. In some embodiments, the one or more complications are improved indirectly. In some embodiments, the one or more complications of EPP, XLPP, or CEP is 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, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic liver failure, erythrodontia, hypercellular bone marrow, thrombocytopenia, hydrops fetalis and / or death in utero. In some embodiments, the disclosure contemplates methods of treating one or more complications of EPP, XLPP, or CEP (e.g., acute photosensitivity, cutaneous photosensitivity, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholelithiasis, cholestasis, cytolysis, gallstones, cholestatic liver failure, erythrodontia, hypercellular bone marrow, thrombocytopenia, hydrops fetalis and / or death in utero) comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more complications are improved indirectly. In some embodiments, the disclosure contemplates methods of preventing one or more complications of a hepatic porphyria, EPP, XLPP, or CEP comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure contemplates methods of reducing the progression rate of one or more complications of a hepatic porphyria, EPP, XLPP, or CEP comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure contemplates methods of reducing the severity of one or more complications of a hepatic porphyria, EPP, XLPP, or CEP comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. Methods of treatment provided herein may serve to ameliorate one or more symptoms associated with a hepatic porphyria or to reduce the risk of developing conditions associated with porphyria (e.g., neuropathy (e.g., progressive neuropathy), hepatocellular cancer). Symptoms associated with a hepatic porphyria may include abdominal pain or cramping, headaches, effects caused by nervous system abnormalities, and light sensitivity, causing rashes, blistering, and scarring of the skin (photodermatitis). In certain embodiments, the hepatic porphyria is AIP. Symptoms of AIP include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (dysuria, urinary retention / incontinence, or dark urine), neurologic symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting the cranial nerves and / or leading to weakness in the arms or legs), seizures, neuropathic pain, progressive neuropathy, headaches, neuropsychiatric symptoms (e.g., mental confusion, anxiety, agitation, hallucination, hysteria, delirium, apathy, depression, phobias, psychosis, insomnia, somnolence, coma), autonomic nervous system involvement (resulting e.g., in cardiovascular symptoms such as tachycardia, hypertension, and / or arrhythmias, as well as other symptoms, such as, e.g., increased circulating catecholamine levels, sweating, restlessness, and / or tremor), dehydration, and electrolyte abnormalities. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered together with (e.g., before, after, or concurrent with) another treatment that may serve to alleviate one or more of the above symptoms. For example, abdominal pain may be treated, e.g., with narcotic analgesics, seizures may be treated, e.g., with anti-seizure medications, nausea / vomiting may be treated, e.g., with phenothiazines, and tachycardia / hypertension may be treated, e.g., with beta blockers. Optionally, methods disclosed herein for preventing, treating, or reducing the progression rate and / or severity of one or more complications of EPP, XLPP, or CEP in a subject, may further comprise administering to the patient one or more supportive therapies or additional active agents for treating EPP, XLPP, or CEP. For example, the patient also may be administered one or more supportive therapies or active agents selected from the group consisting of: avoiding sunlight, 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 comprise administering to the patient Afamelanotide (Scenesse ®). Porphyrin photosensitization in certain hepatic porphyrias (e.g., VP, HCP, PCT, and HEP), EPP, XLPP, and CEP produces two distinct clinical syndromes: (1) acute photosensitivity on exposure to sunlight with erythema and edema and (2) a syndrome wherein subepidermal bullae occur in sun-exposed areas of the skin. In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of EPP, XLPP, or CEP in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the method increases pain free light exposure in the subject. In some embodiments, the method increases pain free light exposure in the subject by at least 10%, 20%, 30%, 40%, or 50% more as compared to pain free light exposure prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method decreases light sensitivity in the subject. In some embodiments, the method decreases light sensitivity in the subject by at least 10%, 20%, 30%, 40%, or 50% more as compared to light sensitivity prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a history of phototoxic reactions from EPP. In some embodiments, the subject is an adult, child, infant, or pregnant woman. EC50 and Administration In certain embodiments of the methods and uses as disclosed herein, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates inhibition of a porphyrin precursor (e.g., 5-ALA or PBG) with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the present application, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates inhibition of a porphyrin precursor (e.g., 5-ALA or PBG) with an EC50 of less than 100 nM. In certain embodiments of the present application, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, demonstrates inhibition of a porphyrin precursor (e.g., 5-ALA or PBG) with an EC50 of less than 50 nM. In certain embodiments, the EC50 is measured in a flow cytometry assay. In certain embodiments, the EC50 is measured in a LC-MS / MS assay. In certain embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof is administered to prevent or reduce the severity or frequency of recurring attacks, e.g., cyclical attacks associated with a precipitating factor. In some embodiments, the precipitating factor is the menstrual cycle. In some embodiments, a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered repeatedly, e.g., at regular intervals to prevent or reduce the severity or frequency of recurring attacks, e.g., cyclical attacks associated with a precipitating factor, e.g., the menstrual cycle, e.g., a particular phase of the menstrual cycle, e.g., the luteal phase. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof is administered during a particular phase of the menstrual cycle or based on hormone levels of the patient being treated (e.g., based on hormone levels that are associated with a particular phase of the menstrual cycle). In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered on one or more particular days of the menstrual cycle, e.g., on day 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 on day 28 (or later day for subjects who have a longer menstrual cycle). In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered during the luteal phase, e.g., on one or more days between days 14-28 of the menstrual cycle (or later, in subjects who have a menstrual cycle longer than 28 days). In some embodiments, ovulation of the subject is assessed (e.g., using a blood or urine test that detects a hormone associated with ovulation, e.g., LH) and the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered at a predetermined interval after ovulation. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered immediately after ovulation. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 days after ovulation. Any of these schedules may optionally be repeated for one or more iterations. The number of iterations may depend on the achievement of a desired effect, e.g., the achievement of a therapeutic or prophylactic effect, e.g., reduce or prevent one or more symptoms associated with a hepatic porphyria, EPP, XLPP, or CEP, to reduce the frequency of attacks associated with hepatic porphyria, EPP, XLPP, or CEP. In some embodiments, an initial dose of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered and the level of ALA or PBG is tested, e.g., 1-48 hours, e.g., 2, 4, 8, 12, or 24 hours following administration of the initial dose. In some embodiments, if the level of ALA and / or PBG has decreased (e.g., to achieve a predetermined reduction, e.g., a normalization), and / or if the symptoms associated with a hepatic porphyria, EPP, XLPP, or CEP (e.g., pain) have improved (e.g., such that the patient is asymptomatic), no further dose is administered, whereas if the level of ALA and / or PBG has not decreased (e.g., has not achieved a predetermined reduction, e.g., has not normalized), a further dose of the compound of formula (I) (e.g., any one of compounds 1-60), 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 to decrease the level of ALA and / or PBG, the further dose is modified, e.g., increased to achieve a desired decrease (e.g., a predetermined reduction, e.g., a normalization) in ALA or PBG levels. In some embodiments, the predetermined reduction is a decrease of at least 10%, 20%, 30%, 40%, or 50%. In some embodiments, the predetermined reduction is a reduction that is effective to prevent or ameliorate symptoms, e.g., pain, prodromal symptoms, or recurring attacks. In some embodiments, the predetermined reduction is a reduction of at least 1, 2, 3, or more standard deviations, wherein the standard deviation is determined based on the values from a reference sample, e.g., a reference sample as described herein. In some embodiments, the predetermined reduction is a reduction that brings the level of the porphyrin or porphyrin precursor to a level that is less than, or to a level that is less than or equal to, a reference value (e.g., a reference value as described herein). As used herein, a “normalization” in ALA or PBG levels (or a “normal” or “normalized” level) refers to a level (e.g., a urine and / or plasma level) of either ALA, or PBG, or both, that is within the expected range for a healthy individual, an individual who is asymptomatic (e.g., an individual who does not experience pain and / or suffer from neuropathy), or an individual who does not have a mutation associated with a porphyria. For example, in some embodiments, a normalized level is within two standard deviations of the normal mean. In some embodiments, a normalized level is within normal reference limits, e.g., within the 95% confidence interval for an appropriate control sample, e.g., a sample of healthy individuals or individuals who do not carry a gene mutation associated with a porphyria. In some embodiments, the ALA and / or PBG level of the subject (e.g., the urine and / or plasma ALA and / or PBG level) is monitored at intervals, a further dose of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered when the level increases above the reference value. Administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may reduce porphyrin or porphyrin precursor levels, e.g., in a cell, tissue, blood, urine or other compartment of the patient 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 the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may also decrease porphyrin or porphyrin precursor levels during an acute attack of AIP. Combination Therapies Optionally, methods disclosed herein for preventing, treating, or reducing the progression rate and / or severity of one or more complications of a porphyria (e.g., hepatic porphyria, EPP, XLPP, or CEP) in a subject, may further comprise 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, the patient also may be administered one or more supportive therapies or active agents selected from the group consisting of: avoiding sunlight, topical sunscreens, skin protection, UVB phototherapy, Afamelanotide (Scenesse®), bortezomib, heme infusions, sufficient caloric support, Givosiran, RNAi mediated silencing of various enzymes (e.g., ALA synthase), avoiding precipitating factors, 4-aminoquinolines, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of PBGD gene in liver cells by viral vectors), hemodialysis, pharmacologic chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion. In some embodiments, the subject is administered a combination treatment, e.g., a compound of formula (I) (e.g., any one of compounds 1-60), 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., glucose and / or a heme product such as hemin, as described herein) or its associated symptoms. In one embodiment, a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered in combination with glucose or dextrose. For example, 10-20% dextrose in normal saline may be provided intravenously. Typically, when glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. The compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may also be administered intravenously, as part of the same infusion that is used to administer the glucose or dextrose, or as a separate infusion that is administered before, concurrently, or after the administration of the glucose or dextrose. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, is administered via a different route of administration (e.g., subcutaneously). In yet another embodiment, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered in combination with total parenteral nutrition. The compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may be administered before, concurrent with, or after the administration of total parenteral nutrition. In certain embodiments, a compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional treatments, e.g., another treatment known to be effective in treating porphyria or symptoms of porphyria. In one embodiment, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered in combination with a heme product (e.g., hemin, heme arginate, or heme albumin). In a further embodiment, the compound of formula (I) (e.g., any one of compounds 1-60), 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 total parenteral nutrition. The additional treatment(s) may be administered before, after, or concurrent with the administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. The compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent can be administered in combination in the same composition, e.g., intravenously, or the additional therapeutic agent can be administered as part of a separate composition or by another method described herein. In some embodiments, the subject has previously been treated with a heme product (e.g., hemin, heme arginate, or heme albumin), as described herein. In some embodiments, administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, or administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in combination one or more additional treatments (e.g., glucose, dextrose), decreases the frequency of acute attacks (e.g., by preventing acute attacks so that they no longer occur, or by reducing the number of attacks that occur in a certain time period, e.g., fewer attacks occur per year). In some such embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is administered according to a regular dosing regimen, e.g., b.i.d., daily, weekly, biweekly, or monthly. Anemias associated with ribosomal disorders Mutations in ribosomal protein (RP) genes or other transcription factors (e.g., GATA1) can result in the loss of erythrocyte progenitor cells and cause anemia associated with a ribosomal disorder. One example of an anemia associated with a ribosomal disorder is Diamond-Blackfan anemia (DBA), a rare blood disorder that is almost exclusively linked to RP gene haploinsufficiency. DBA affects approximately seven per million live births and is usually diagnosed during the first year of life. Classic diagnostic criteria includes: (1) macrocytic, normochromic, anemia; (2) reticulocytopenia; (3) bone marrow erythroid hypoplasia; and (4) early onset of anemia (90% present before age one year). In DBA patients, erythrocyte precursors do not mature sufficiently leading to congenital erythroid aplasia and developmental defects. Affected individuals may have physical abnormalities, such as craniofacial malformations, thumb or upper limb abnormalities, cleft palate, as well as defects of the genitalia, urinary tract, eyes and heart. In some cases, low birth weight and short stature are observed. DBA patients are also at a modest risk of developing leukemia and other malignancies. The current treatment options for DBA includes corticosteroids, blood transfusion, and bone marrow transplantation. Approximately 80% of DBA patients respond to an initial course of corticosteroids. However, the efficacy of corticosteroids can wane over time in many patients. These patients and the 20% who do not respond initially to such therapy must be maintained on a chronic blood transfusion with iron chelation. Chronic 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, are either of unproved benefit and / or seem to benefit relatively few people. Pharmacological doses of Erythropoietin (EPO) are also ineffective. Bone marrow transplantation is the sole cure for the hematologic manifestation of DBA-related anemia, but is usually only considered in corticosteroid- resistant persons because of substantial morbidity and mortality. Typically, only transplants from human leukocyte antigen (HLA)-identical sibling were considered. For many patients, the lack of a suitable donor excludes bone marrow transplantation as a therapeutic option. As such, there is a high, unmet need for effective therapies for treating anemias associated with ribosomal disorders. Accordingly, it is an object of the present application to provide methods for treating, preventing, or reducing the progression rate and / or severity of anemia associated with a ribosomal disorder. The methods and use of glycine transporter inhibitors, such as, but not limited to, a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, these needs as well as others. In certain aspects, the present application provides the use of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment of an anemia associated with a ribosomal disorder in a subject in need thereof. The present application provides methods of preventing or treating anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In part, the present application relates to methods of treating anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of one or more complications of anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the ribosomal disorder is Diamond-Blackfan anemia. In some embodiments, the ribosomal disorder is Shwachman- Diamond syndrome. In some embodiments, the ribosomal disorder is x-linked dyskeratosis congenital. In some embodiments, the ribosomal disorder is cartilage hair hypoplasia. In particular embodiments, the patient, subject or individual is a human. The present application provides methods of preventing, treating, or reducing the progression rate and / or severity of anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain embodiments of the foregoing, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The present application further provides use of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in the manufacture of a formulation for the treatment of anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia) in a subject. Diamond-Blackfan anemia Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually develops during the neonatal period. DBA is characterized by low red blood cell counts (anemia) with decreased erythroid progenitors in the bone marrow. In DBA patients, levels of other blood components such as platelets and the white blood cells are normal. This is in contrast to Shwachman-Diamond syndrome, in which the bone marrow defect results primarily in low neutrophil counts (neutropenia). Ribosomal protein mutations have been implicated in the pathophysiology of DBA. The first gene, mutated in approximately 25% of DBA patients, was identified as RPS19 (ribosomal protein S19) (Gustavsson et ah, Nat Genet.1997 Aug;l6(4):368-7l; Draptchinskaia et al, Nat Genet.1999 Feb;2l(2): 169-75). Sequencing of patient samples has identified mutations of either large (60s) or small (40s) subunit ribosomal proteins in over 50% of patients (Vlachos et al, Br J Haematol.2008 Sep; 142(6): 859-876). 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, always maintaining a wildtype copy of the affected RP gene. However, approximately 30% of people with DBA have no detectable RP mutation. Some phenotype / genotype correlations are known, relating to congenital abnormalities. Id. There are numerous subtypes of DBA, each of which are caused by different mutations in various genes. For instance, Diamond-Blackfan anemia-l (DBA1, OMIM #105650) is caused by heterozygous mutations in the RPS19 gene on chromosome l9ql3. Other forms of DBA include DBA2 (OMIM #606129), caused by mutations on chromosome 8p23-p22; DBA3 (OMIM #610629), caused by mutation in the RPS24 gene on l0q22; DBA4 (OMIM #612527), caused by mutation in the RPS17 gene on 15q; DBA5 (OMIM #612528), caused by mutation in the RPL35A gene on 3q29; DBA6 (OMIM #612561), caused by mutation in the RPL5 gene on lp22. l; DBA7 (OMIM #612562), caused by mutation in the RPL11 gene on lp36; DBA8 (OMIM #612563), caused by mutation in the RPS7 gene on 2p25; DBA9 (OMIM #613308), caused by mutation in the RPS10 gene on 6p; DBA10 (OMIM #613309), caused by mutation in the RPS26 gene on l2q; DBA11 (OMIM #614900), caused by mutation in the RPL26 gene on 17r13; DBA12 (OMIM #615550), caused by mutation in the RPL15 gene on 3p24; DBA13 (OMIM #615909), caused by mutation in the RPS29 gene on l4q; DBA 14 (OMIM #300946), caused by mutation in the / 'SR 2 gene on Xpl 1; DBA 15 (OMIM #606164), caused by mutation in the RPS28 gene on 19p 13 ; DBA 16 (OMIM #617408), caused by mutation in the RPL27 gene on chromosome 17q21; and DBA17 (OMIM #617409), caused by mutation in the RPS27 gene on chromosome lq2l . Mutations in ribosomal proteins impact ribosomal protein function, leading to ribosomal insufficiency and increased stress. Impaired ribosome biogenesis has been linked to p53 induction and cell-cycle arrest. Ribosomal protein knockdown leads to an increase of 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; l l(4):50l-8). Other ribosomal proteins may activate p53 by 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 impact of DBA on ribosomal protein function results in decreased globin synthesis, which is required to produce hemoglobin. Heme synthesis does not appear to be impacted. The imbalance between heme synthesis and globin leads to the accumulation of free heme in DBA erythroid cells (Rio S, et al. Blood.2019;133(12):1358-1370). Heme is toxic for the cells by increasing reactive oxygen species production, lipid peroxidation, and apoptosis. As a consequence, excess heme levels resulting from the heme / globin imbalance leads to deleterious effects on erythroipoiesis. Typically, a diagnosis of DBA is made through a blood count and a bone marrow biopsy. A diagnosis of DBA is made on the basis of anemia, low reticulocyte (immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells. Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified. Genetic testing is frequently used to identify mutations in ribosomal protein genes as well as some other non-ribosomal protein genes. About 20-25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene. Approximately 10-25% of DBA cases have a family history of disease, and most pedigrees suggest an autosomal dominant mode of inheritance. In certain aspects, the disclosure relates to methods of treating anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the anemia associated with a ribosomal disorder is Diamond Blackfan anemia (DBA). In some embodiments, the DBA is caused by haploinsufficiency for 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, the DBA is caused by haploinsufficiency for 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 a ribosomal protein gene. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, can be used in a method of treating anemia associated with a ribosomal disorder, wherein the subject has a mutation in ribosomal protein 19 (RPS19). The phenotype of DBA patients indicates a hematological stem cell defect specifically affecting the erythroid progenitor population. The RPS19 protein is involved in the production of ribosomes. Disease features may be related to the nature of RPS19 mutations. The disease is characterized by dominant inheritance, and therefore arises due to a partial loss of RPS19 protein function. In alternative embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, can be used in a method of treating anemia associated with a ribosomal disorder, wherein the subject has a mutation in ribosomal protein from at least one of, but 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, and 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, the subject with a ribosomal disorder has a mutation in a non-ribosomal protein selected from the group consisting of TSR2, GATA1, and EPO. In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of one or more complications of anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more complications of anemia associated with a ribosomal disorder is selected from the group consisting of: thrombocytosis, megakaryotypic hyperplasia, infections, bleeding (e.g., from the nose or gums), bruising, splenomegaly, the need for more frequent blood transfusions, the need for increased glucocorticoid use, the need for allogenic hematopoietic stem cell transplantation, the need for autologous gene therapy, marrow failure, leukemia, and acute myelogenous leukemia. In certain aspects, the disclosure relates to methods of treating splenomegaly associated with anemia associated with a ribosomal disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an increased spleen size (e.g., splenomegaly). In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, reduce splenomegaly in a subject with anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia). In some embodiments, the method reduces the subject’s spleen size. In some embodiments, the method reduces the subject’s spleen size 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 spleen size by at least 15%. In some embodiments, the method reduces the subject’s spleen size by at least 20%. In some embodiments, the method reduces the subject’s spleen size by at least 25%. In some embodiments, the method reduces the subject’s spleen size by at least 30%. In some embodiments, the method reduces the subject’s spleen size by at least 35%. In some embodiments, the method reduces the subject’s spleen size by at least 40%. In some embodiments, the method reduces the subject’s spleen size by at least 45%. In some embodiments, the method reduces the subject’s spleen size by at least 50%. In some embodiments, the method reduces the subject’s spleen size by at least 55%. In some embodiments, the method reduces the subject’s spleen size by at least 60%. In some embodiments, the method reduces the subject’s spleen size by at least 65%. In some embodiments, the method reduces the subject’s spleen size by at least 70%. In some embodiments, the method reduces the subject’s spleen size by at least 75%. In some embodiments, the method reduces the subject’s spleen size by at least 80%. In some embodiments, the method reduces the subject’s spleen size by at least 85%. In some embodiments, the method reduces the subject’s spleen size by at least 90%. In some embodiments, the method reduces the subject’s spleen size by at least 95%. In some embodiments, the method reduces the subject’s spleen size by at least 100%. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, can be used to treat a subject with a ribosomal disorder, such as DBA, wherein the subject has a symptom of macrocytic anemia and / or craniofacial abnormalities. Shwachman-Diamond syndrome Shwachman-Diamond syndrome (SDS) or Shwachman-Bodian-Diamond syndrome is a rare genetic disorder that that affects many parts of the body, particularly the pancreas, bone marrow, and skeletal system. Shwachman-Diamond syndrome is inheritated in an autosomal recessive pattern. Most cases of SDS are caused by mutations in the SBDS gene, which lies on the long arm of chromosome 7 at cytogenetic position 7ql 1. The protein encoded by SBDS is thought to play a role in RNA processing and ribosome biogenesis, although the exact mechanism of how SBDS mutations lead to the major signs and symptoms of Shwachman- Diamond syndrome is still unclear. Typical symptoms of Shwachman-Diamond syndrome include exocrine pancreatic insufficiency, decreased muscle tone, low blood neutrophil count (neutropenia), anemia, and abnormal bone development affecting the rib cage and / or bones in the arms and / or legs (metaphyseal dysostosis). Diagnosis of Shwachman-Diamond syndrome can be made based on clinical findings, including pancreatic dysfunction and characteristic hematologic abnormalities (e.g., neutropenia and thrombocytopenia). Genetic testing may be used to confirm the diagnosis. SBDS gene mutations are known to cause about 90% of cases of Shwachman-Diamond syndrome. The remaining 10% cases have unknown genetic cause, and hence genetic testing is not an option for these cases. There is no cure for Shwachman-Diamond syndrome. Treatment usually include oral pancreatic enzyme replacement, vitamin supplementation, blood and / or platelet transfusion, administration of granulocyte-colony stimulating factor (G-CSF), and / or hematopoietic stem cell transplantation. The shortage of neutrophils in subjects with Shwachman-Diamond syndrome can lead to neutropenia, which makes them more vulnerable to infections such as pneumonia. Patients with Shwachman-Diamond syndrome also have a higher than average chance of developing aplastic anemia, and leukemia (e.g., acute myeloid leukemia). In certain aspects, the disclosure relates to methods of treating Shwachman-Diamond syndrome in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of Shwachman- Diamond syndrome in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has one or more mutations in the SBDS gene. In some embodiments, the method decreases the need for hematopoietic stem cell transplant in the subject. In some embodiments, the method decreases neutropenia in the subject. In some embodiments, the method decreases thrombocytopenia in the subject. In some embodiments, the method decreases the subject’s risk of developing leukemia. In some embodiments, the method decreases the subject’s risk of developing an infection. In some embodiments, the method decreases the subject’s risk of developing pneumonia. In some embodiments, the subject has low neutrophil levels. Dyskeratosis congenita Dyskeratosis congenita, also known as Zinsser-Engman-Cole syndrome, is a rare genetic form of bone marrow failure which is classically associated with oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Inheritance is most commonly x-linked recessive. As such, males are three times more likely to be affected than females. Symptoms vary widely and may include atrophic wrinkled skin, eye disease, and bone marrow failure. Dyskeratosis congenita patients are at increased risk of developing leukemia and other cancers (e.g., cancers of the head, neck, anus, or genitals) as well as fibrosis (e.g., pulmonary fibrosis and liver fibrosis). The majority of patients have mutations in dyskerin gene (DKC1), a protein which is directly involved in stabilizing an enzyme called telomerase that is responsible for catalyzing a reaction that sustains the length of telomeres. Without proteins like dyskerin, the telomeres progressively shorten casing the 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 dyskeratosis congenita. Treatment options for patients with dyskeratosis congenita are limited. The only long-term treatment option for bone failure in dyskeratosis congenita patients is hematopoietic stem cell transplantation. However, long-term outcomes remain poor, with an estimated 10-year survival rate of 23%. Short-term treatment options include anabolic steroids (e.g., oxymetholone), granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. In certain aspects, the disclosure relates to methods of treating dyskeratosis congenita in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of dyskeratosis congenita in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has dyskeratosis congenita. In some embodiments, the dyskeratosis congenita is x-linked dyskeratosis congenita. In some embodiments, the subject has one or more mutations in the DKC1 gene. In some embodiments, the subject has one or more mutations in a gene selected from the group consisting of TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53 / TCAB1, PARN, CTC1, and RTEL1. In some embodiments, the method decreases the risk of bone marrow failure in the subject. In some embodiments, the method decreases the risk of pulmonary fibrosis in the subject. In some embodiments, the method decreases the risk of liver fibrosis in the subject. Cartilage-hair hypoplasia Cartilage-hair hypoplasia, also known as McKusick type metaphyseal chondrodysplasia, is a disorder of bone growth characterized by short stature (dwarfism) with other skeletal abnormalities; fine, sparse hair; joint hypermobility; anemia; increased risk for malignancy; gastrointestinal dysfunction; impaired spermatogenesis; and abnormal immune system function which often leads to recurrent infections. Patients with cartilage-hair hypoplasia. Most patients with cartilage-hair hypoplasia have a mutation in the RMRP gene (OMIM no.157660), with a 70A#G transition mutation commonly present. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA–processing ribonuclease, RNase MRP. Diagnosis of cartilage-hair hypoplasia is based primarily on clinical findings, characteristic radiographic findings, and in some cases, evidence of immune dysfunction, macrocytic anemia, and / or gastrointestinal problems. Molecular genetic testing can be used in patients to identify pathogenic variants by RMRP. Treatment of patients often incudes repeated blood transfusions and surgeries to fuse unstable vertebrae or to treat progressive kyphoscoliosis which compromises lung function. Corrective osteotomies may also be required to treat progressive varus deformity associated with ligament laxity in the knees. For patients with immunodeficiency, frequent treatments of underlying infections is required. Prophylatic antibiotic therapy and / or immunoglobulin replacement therapy is often required. Recurrent severe infections and / or the presence of severe combined immunodeficiency (SCID) and / or severely depressed erythropoiesis may warrant bone marrow transplantation. In certain aspects, the disclosure relates to methods of treating cartilage-hair hypoplasia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of cartilage-hair hypoplasia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the 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. Defects in erythropoiesis Erythropoiesis refers generally to the process by which red blood cells (erythrocytes) are produced from HSCs, and includes the formation of erythroid progenitor cells. Erythropoiesis is a carefully ordered sequence of events. Initially occurring in fetal hepatocytes, the process is taken over by the bone marrow in the child and adult. Although multiple cytokines and growth factors are dedicated to the proliferation of the red blood cell, the primary regulator is erythropoietin (EPO). Red blood cell development is initially regulated by stem cell factor (SCF), which commits hematopoietic stem cells to develop into erythroid progenitors. Subsequently, EPO continues to stimulate the development and terminal 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 in red blood cells (RBCs), suggesting the presence of paracrine and autocrine functions. Erythropoiesis escalates as increased expression of the EPO gene produces higher levels of circulating EPO. EPO gene expression is known to be affected by multiple factors, including hypoxemia, transition metals (Co2+, Ni2+, Mn2+), and iron chelators. However, the major influence is hypoxia, including factors of decreased oxygen tension, red blood cell loss, and increased oxygen affinity of hemoglobin. For instance, EPO production may increase as much as 1000-fold in severe hypoxia. Erythropoiesis requires the proper biosynthesis of heme and as erythroblasts mature, their demand for heme and iron dramatically increase. Erythroid cells synthesize large amounts of heme and hemoglobin while simultaneously absorbing lots of iron into the cell. A disequilibrium between the globin chain and the heme synthesis is known to occur in the erythroid cells of Diamond-Blackfan anemia patients. This imbalance leads to the accumulation of excess free heme and increased reactive oxygen species production. Blockade of erythroid differentiation and proliferation in Diamond-Blackfan anemia have been shown to affect immature progenitor cells or erythroid-Burst-Forming Unit (BFU- e) resulting in impaired hematopoiesis. Circulating EPO levels are increased in Diamond- Blackfan anemia patients, indicating the unresponsiveness of the bone marrow to anemia related EPO stimulation. An increased propensity of erythroid progenitors to apoptosis during in vitro EPO deprivation and in RPS19 deficiency has also been reported. Glycine is one of the key initial substrates for heme synthesis. As such, decreased levels of glycine due to GlyT1 inhibition could lead to a decrease in heme synthesis. In certain aspects, the disclosure relates to methods of inhibiting heme synthesis in a subject with anemia associated with a ribosomal disorder, comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the heme synthesis is inhibited in a dose dependent manner. In some embodiments, the subject with anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia) has elevated heme levels. In some embodiments, the subject has heme levels that are at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 10% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 20% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 30% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 40% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 50% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 60% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 70% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 80% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 90% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has heme levels that are at least 100% more than heme levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the method reduces the heme 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 the heme levels in the subject by at least 15%. In some embodiments, the method reduces the heme levels in the subject by at least 20%. In some embodiments, the method reduces the heme levels in the subject by at least 25%. In some embodiments, the method reduces the heme levels in the subject by at least 30%. In some embodiments, the method reduces the heme levels in the subject by at least 35%. In some embodiments, the method reduces the heme levels in the subject by at least 40%. In some embodiments, the method reduces the heme levels in the subject by at least 45%. In some embodiments, the method reduces the heme levels in the subject by at least 50%. In some embodiments, the method reduces the heme levels in the subject by at least 55%. In some embodiments, the method reduces the heme levels in the subject by at least 60%. In some embodiments, the method reduces the heme levels in the subject by at least 65%. In some embodiments, the method reduces the heme levels in the subject by at least 70%. In some embodiments, the method reduces the heme levels in the subject by at least 75%. In some embodiments, the method reduces the heme levels in the subject by at least 80%. In some embodiments, the method reduces the heme levels in the subject by at least 85%. In some embodiments, the method reduces the heme levels in the subject by at least 90%. In some embodiments, the method reduces the heme levels in the subject by at least 95%. In some embodiments, the method reduces the heme levels in the subject by at least 100%. 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 subject by at least 55%. In some embodiments, the method reduces heme synthesis in the subject by at least 60%. In some embodiments, the method reduces heme synthesis in the subject by at least 65%. In some embodiments, the method reduces heme synthesis in the subject by at least 70%. In some embodiments, the method reduces heme synthesis in the subject by at least 75%. In some embodiments, the method reduces heme synthesis in the subject by at least 80%. In some embodiments, the method reduces heme synthesis in the subject by at least 85%. In some embodiments, the method reduces heme synthesis in the subject by at least 90%. In some embodiments, the method reduces heme synthesis in the subject by at least 95%. In some embodiments, the method reduces heme synthesis in the subject by at least 100%. In some embodiments, the method reduces intracellular heme levels. In some embodiments, the method reduces intracellular heme levels in erythroid precursors. 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%. In some embodiments, the subject has liver iron overload. In some embodiments, the method reduces the risk of liver iron overload. In some embodiments, the method reduces the levels of iron in the liver. In some embodiments, the method reduces the levels 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 levels of iron in the liver by at least 15%. In some embodiments, the method reduces the levels of iron in the liver by at least 20%. In some embodiments, the method reduces the levels of iron in the liver by at least 25%. In some embodiments, the method reduces the levels of iron in the liver by at least 30%. In some embodiments, the method reduces the levels of iron in the liver by at least 35%. In some embodiments, the method reduces the levels of iron in the liver by at least 40%. In some embodiments, the method reduces the levels of iron in the liver by at least 45%. In some embodiments, the method reduces the levels of iron in the liver by at least 50%. In some embodiments, the method reduces the levels of iron in the liver by at least 55%. In some embodiments, the method reduces the levels of iron in the liver by at least 60%. In some embodiments, the method reduces the levels of iron in the liver by at least 65%. In some embodiments, the method reduces the levels of iron in the liver by at least 70%. In some embodiments, the method reduces the levels of iron in the liver by at least 75%. In some embodiments, the method reduces the levels of iron in the liver by at least 80%. In some embodiments, the method reduces the levels of iron in the liver by at least 85%. In some embodiments, the method reduces the levels of iron in the liver by at least 90%. In some embodiments, the method reduces the levels of iron in the liver by at least 95%. In some embodiments, the method reduces the levels of iron in the liver by at least 100%. 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 levels 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 levels of iron in the heart by at least 15%. In some embodiments, the method reduces the levels of iron in the heart by at least 20%. In some embodiments, the method reduces the levels of iron in the heart by at least 25%. In some embodiments, the method reduces the levels of iron in the heart by at least 30%. In some embodiments, the method reduces the levels of iron in the heart by at least 35%. In some embodiments, the method reduces the levels of iron in the heart by at least 40%. In some embodiments, the method reduces the levels of iron in the heart by at least 45%. In some embodiments, the method reduces the levels of iron in the heart by at least 50%. In some embodiments, the method reduces the levels of iron in the heart by at least 55%. In some embodiments, the method reduces the levels of iron in the heart by at least 60%. In some embodiments, the method reduces the levels of iron in the heart by at least 65%. In some embodiments, the method reduces the levels of iron in the heart by at least 70%. In some embodiments, the method reduces the levels of iron in the heart by at least 75%. In some embodiments, the method reduces the levels of iron in the heart by at least 80%. In some embodiments, the method reduces the levels of iron in the heart by at least 85%. In some embodiments, the method reduces the levels of iron in the heart by at least 90%. In some embodiments, the method reduces the levels of iron in the heart by at least 95%. In some embodiments, the method reduces the levels of iron in the heart by at least 100%. In some embodiments, the subject has decreased erythroid precursor survival as compared to a healthy subject. In some embodiments, the subject has decreased erythroid precursor differentiation into mature red blood cells as compared to a healthy subject. In some embodiments, the subject has impaired hematopoiesis. In some embodiments, the method increases the subject’s erythroid precursor survival. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the subject’s erythroid precursor survival by at least 15%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 20%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 25%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 30%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 35%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 40%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 45%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 50%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 55%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 60%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 65%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 70%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 75%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 80%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 85%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 90%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 95%. In some embodiments, the method increases the subject’s erythroid precursor survival by at least 100%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells in the subject. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells 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 erythroid precursor differentiation into mature red blood cells by at least 15%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 20%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 25%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 30%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 35%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 40%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 45%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 50%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 55%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 60%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 65%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 70%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 75%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 80%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 85%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 90%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 95%. In some embodiments, the method increases erythroid precursor differentiation into mature red blood cells by at least 100%. In some embodiments, the subject has elevated erythrocyte adenosine deaminase activity. In some embodiments, the subject has normal marrow cellularity with a paucity of red cell precursors. In some embodiments, the subject has normal neutrophil and / or platelet counts. In some embodiments, the anemia is due to a failure in erythropoiesis. In some embodiments, the method reduces anemia in the subject. In some embodiments, the method reduces anemia in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces anemia in the subject by at least 15%. In some embodiments, the method reduces anemia in the subject by at least 20%. In some embodiments, the method reduces anemia in the subject by at least 25%. In some embodiments, the method reduces anemia in the subject by at least 30%. In some embodiments, the method reduces anemia in the subject by at least 35%. In some embodiments, the method reduces anemia in the subject by at least 40%. In some embodiments, the method reduces anemia in the 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.

[0025] In some embodiments, the method increases red cell mass. In some embodiments, the method decreases the mean corpuscular volume of red cells. In some embodiments, the method decreases red cell adenosine deaminase. In some embodiments, the method decreases red cell adenosine deaminase in a subject with DBA. In some embodiments, the method decreases fetal hemoglobin content in red cells.

[0026] Red blood cell count and hematocrit

[0027] Certain embodiments of the present application relate to methods of administering a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject has an low red blood cell count (e.g, less than about 4.5 million red blood cells per μl of blood for men and about 4.1 million red blood cells per μl of blood for women, often by a clinically or statistically significant amount), or a low hematocrit (e.g, greater than about 38% for men or about 35% for women, often by a clinically or statistically significant amount). In some embodiments, the subject has hematocrit levels that are less than 38%. In some embodiments, the subject has hematocrit levels that are less than 35%.

[0028] In some embodiments, the subject’s hematocrit levels are at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 10% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 20% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 30% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 40% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 50% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 60% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 70% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 80% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject’s hematocrit levels are at least 90% less than hematocrit levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 10% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 20% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 30% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 40% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 50% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 60% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 70% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 80% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count that is at least 90% less than a red blood cell count in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a red blood cell count less than 4.5 x1012 / L. In some embodiments, the subject has a red blood cell count less than 4.1 x1012 / L. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, increase red blood cell synthesis (also known as erythropoiesis), and may be used to treat a condition associated with decreased red blood cells. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof may modulate red blood cell synthesis by reducing the formation of heme. In some embodiments, the disclosure relates to methods of increasing red blood cell synthesis in a subject with anemia associated with a ribosomal disorder, comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the red blood cell synthesis is increased in a dose dependent manner. In some embodiments, the red blood cell count is increased in a dose dependent manner. In some embodiments, merely by way of non-limiting example, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may be administered directly to a subject to increase red blood count, if desired. Red blood count may also be reflected by a person's hematocrit (i.e., packed cell volume (PCV) or erythrocyte volume fraction (EVF)), which is the proportion or percentage of blood volume that is occupied by red blood cells. A normal hematocrit is normally about 49% for men and about 48% for women. A lower hematocrit value indicates a lower number of red blood cells. In certain embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, to such a subject increases their red blood cell count or hematocrit. Also included are methods of increasing red blood cells in a subject, and methods of increasing hematocrit in a subject, including a subject that has a lower than normal red blood cell count or hematocrit, or is at risk for developing such a condition, comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, and thereby increasing red blood cell count or hematocrit in the subject. In some embodiments, the method increases the subject’s red blood cell count. In some embodiments, the method increases the subject’s red blood cell count by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the subject’s red blood cell count by at least 15%. In some embodiments, the method increases the subject’s red blood cell count by at least 20%. In some embodiments, the method increases the subject’s red blood cell count by at least 25%. In some embodiments, the method increases the subject’s red blood cell count by at least 30%. In some embodiments, the method increases the subject’s red blood cell count by at least 35%. In some embodiments, the method increases the subject’s red blood cell count by at least 40%. In some embodiments, the method increases the subject’s red blood cell count by at least 45%. In some embodiments, the method increases the subject’s red blood cell count by at least 50%. In some embodiments, the method increases the subject’s red blood cell count by at least 55%. In some embodiments, the method increases the subject’s red blood cell count by at least 60%. In some embodiments, the method increases the subject’s red blood cell count by at least 65%. In some embodiments, the method increases the subject’s red blood cell count by at least 70%. In some embodiments, the method increases the subject’s red blood cell count by at least 75%. In some embodiments, the method increases the subject’s red blood cell count by at least 80%. In some embodiments, the method increases the subject’s red blood cell count by at least 85%. In some embodiments, the method increases the subject’s red blood cell count by at least 90%. In some embodiments, the method increases the subject’s red blood cell count by at least 95%. In some embodiments, the method increases the subject’s red blood cell count by at least 100%. In some embodiments, the method increases the subject’s red blood cell count to normal levels. In some embodiments, the method increases the subject’s red blood cell count to between 4.5-5.9 x1012 / L. In some embodiments, the method increases the subject’s red blood cell count to between 4.1-5.1 x1012 / L. In some embodiments, the method increases the subject’s hematocrit levels. In some embodiments, the method increases the subject’s hematocrit levels by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the subject’s hematocrit levels by at least 15%. In some embodiments, the method increases the subject’s hematocrit levels by at least 20%. In some embodiments, the method increases the subject’s hematocrit levels by at least 25%. In some embodiments, the method increases the subject’s hematocrit levels by at least 30%. In some embodiments, the method increases the subject’s hematocrit levels by at least 35%. In some embodiments, the method increases the subject’s hematocrit levels by at least 40%. In some embodiments, the method increases the subject’s hematocrit levels by at least 45%. In some embodiments, the method increases the subject’s hematocrit levels by at least 50%. In some embodiments, the method increases the subject’s hematocrit levels by at least 55%. In some embodiments, the method increases the subject’s hematocrit levels by at least 60%. In some embodiments, the method increases the subject’s hematocrit levels by at least 65%. In some embodiments, the method increases the subject’s hematocrit levels by at least 70%. In some embodiments, the method increases the subject’s hematocrit levels by at least 75%. In some embodiments, the method increases the subject’s hematocrit levels by at least 80%. In some embodiments, the method increases the subject’s hematocrit levels by at least 85%. In some embodiments, the method increases the subject’s hematocrit levels by at least 90%. In some embodiments, the method increases the subject’s hematocrit levels by at least 95%. In some embodiments, the method increases the subject’s hematocrit levels by at least 100%. In some embodiments, the method increases the subject’s hematocrit levels to at least 38%. In some embodiments, the method increases the subject’s hematocrit levels to at least 35%. Reticulocyte count and hemoglobin In certain embodiments, the present application relates to methods of administering a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has a decreased reticulocyte (e.g., less than 1%, often by a clinically or statistically significant amount), or decreased hemoglobin levels (e.g., less than about 13.2 g / dL for men or about 11.6 g / dL for women, often by a clinically or statistically significant amount). In some embodiments, the subject has hemoglobin levels that are at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 10% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 20% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 30% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 40% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 50% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 60% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 70% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 80% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are at least 90% less than hemoglobin levels in a healthy subject prior to administration of the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has hemoglobin levels that are less than 13 g / dL. In some embodiments, the subject has hemoglobin levels that are less than 11 g / dL. In some embodiments, the subject has elevated fetal hemoglobin levels. In some embodiments, the subject has a low reticulocyte count, also known as reticulocytopenia. 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 subject has a reticulocyte count of less than 0.5%. In some embodiments, the subject has a reticulocyte count of less than 0.4%. In some embodiments, the subject has a reticulocyte count of less than 0.3%. In some embodiments, the subject has a reticulocyte count of less than 0.2%. In some embodiments, the subject has a reticulocyte count of less than 0.1%. In certain embodiments, administration of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, to such a subject increases their reticulocyte or hemoglobin levels. Also included are methods of increasing reticulocytes in a subject, and methods of increasing hemoglobin levels in a subject, including a subject that has a lower than normal reticulocyte or hemoglobin levels, or is at risk for developing such a condition, comprising administering to the subject a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, and thereby reducing reticulocyte or hemoglobin levels in the subject. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1- 60), or a pharmaceutically acceptable salt thereof, increase hemoglobin synthesis in a subject with anemia associated with a ribosomal disorder, and may be used to treat a condition associated with decreased red blood cells. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, may modulate hemoglobin synthesis by reducing the formation of heme. In some embodiments, the disclosure relates to methods of increasing hemoglobin synthesis in a subject with anemia associated with a ribosomal disorder, comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof. In some embodiments, the hemoglobin synthesis is increased in a dose dependent manner. In some embodiments, the method increases the subject’s hemoglobin levels. In some embodiments, the method increases the subject’s hemoglobin levels by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the subject’s hemoglobin levels by at least 15%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 20%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 25%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 30%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 35%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 40%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 45%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 50%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 55%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 60%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 65%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 70%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 75%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 80%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 85%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 90%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 95%. In some embodiments, the method increases the subject’s hemoglobin levels by at least 100%. In some embodiments, the method increases the subject’s hemoglobin levels to at least 13 g / dL. In some embodiments, the method increases the subject’s hemoglobin levels to at least 11 g / dL. In some embodiments, the method increases the subject’s reticulocyte count. In some embodiments, the method increases the subject’s reticulocyte count to between 1% to 2%. In some embodiments, the method increases the subject’s reticulocyte count to at least 0.5%. In some embodiments, the method increases the subject’s reticulocyte count to at least 0.6%. In some embodiments, the method increases the subject’s reticulocyte count to at least 0.7%. In some embodiments, the method increases the subject’s reticulocyte count to at least 0.8%. In some embodiments, the method increases the subject’s reticulocyte count to at least 0.9%. In some embodiments, the method increases the subject’s reticulocyte count to at least 1%. In some embodiments, the method increases the subject’s reticulocyte count to at least 1.5%. In some embodiments, the method increases the subject’s reticulocyte count to at least 2%. In some embodiments, the method increases the subject’s reticulocyte count by 0.5%. In some embodiments, the method increases the subject’s reticulocyte count by 1%. Combination Therapies Certain embodiments may include combination therapies for treating anemia associated with a ribosomal disorder, including the administration of compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, in combination with other therapeutic agents or treatment modalities. Examples of combination therapies include, without limitation, any one or more additional active agents and / or supportive therapies selected from the group consisting of: trifluoperazine, HDAC inhibitors, glucocorticoids, sotatercept, luspatercept, iron chelators, blood transfusion, platelet transfusion, allogeneic hematopoietic stem cell transplant, autologous gene therapy, lenalidomide (REVLIMID®), and antibiotics. In some embodiments, the method further comprises administering another therapeutic agent to treat the ribosomal protein defect, selected from the group consisting of: corticosteroids and bone marrow transplants and other treatments known to persons of ordinary skill in the art. For instance, corticosteroids can be used to treat anemia associated with a ribosomal disorder, such as DBA. Blood transfusions can also be used to treat severe anemia associated with a ribosomal disorder, such as DBA. Periods of remission may occur, during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can treat hematological aspects of DBA. However, adverse events in transfusion patients can occur. In some embodiments, the method reduces the need for corticosteroid treatments in the subject. In some embodiments, the method reduces the dose of corticosteroid treatment needed in the subject. In some embodiments, the corticosteroid is a glucocorticoid steroid. As described above, a common therapy for treating anemia associated with a ribosomal disorder includes the use of regularly scheduled blood transfusions. In some embodiments, the compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, is useful in treating a subject who has anemia associated with a ribosomal disorder (e.g., Diamond-Blackfan anemia) requiring blood transfusions. In some embodiments, the method reduces the subject’s need for blood transfusions. In some embodiments, the method reduces the subject’s need for blood 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 blood transfusions by at least 15%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 20%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 25%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 30%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 35%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 40%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 45%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 50%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 55%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 60%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 65%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 70%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 75%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 80%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 85%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 90%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 95%. In some embodiments, the method reduces the subject’s need for blood transfusions by at least 100%. In some embodiments, the method eliminates the subject’s need for blood transfusions. Quality of Life and Survival In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of anemia associated with a ribosomal disorder (e.g., treating, preventing, or reducing the progression rate and / or severity of one or more complications of anemia associated with a ribosomal disorder) comprising administering to a patient in need thereof an effective amount of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt 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, the method relates to increasing the patient’s quality of life by at least 85%. In some embodiments, the method relates to increasing the patient’s quality of life by at least 90%. In some embodiments, the method relates to increasing the patient’s quality of life by at least 95%. In some embodiments, the method relates to increasing the patient’s quality of life by at least 100%. In some embodiments, the patients has a low quality of life. In some embodiments, the patient’s quality of life is measured using the Functional Assessment of Cancer Therapy Anemia (FACT-An). In some embodiments, the patient’s quality of life is measured using the Functional Assessment of Cancer Therapy Fatigue (FACT-Fatigue). In some embodiments, the patient’s quality of life is measured using the Functional Assessment of Chronic Illness Therapy (FACIT). In some embodiments, the patient’s quality of life is measured using the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue). In some embodiments, the patient’s quality of life is measured using the Functional Assessment of Chronic Illness Therapy Anemia (FACIT- Anemia). In some embodiments, the patient’s quality of life is measured using the SF-36 generic PRO tool. In some embodiments, the patient’s quality of life is measured using the SF-6D generic PRO tool. In some embodiments, the patient’s quality of life is measured using the linear analog scale assessment (LASA). In certain aspects, the disclosure relates to methods of preventing, treating, or reducing the progression rate and / or severity of anemia associated with a ribosomal disorder (e.g., treating, preventing, or reducing the progression rate and / or severity of one or more complications of anemia associated with a ribosomal disorder) comprising administering to a patient in need thereof an effective amount of a compound of formula (I) (e.g., any one of compounds 1-60), or a pharmaceutically acceptable salt thereof, wherein the method increases the patient’s survival by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method increases the patient’s survival. In some embodiments, the method increases the patient’s survival by at least 15%. In some embodiments, the method increases the patient’s survival by at least 20%. In some embodiments, the method increases the patient’s survival by at least 25%. In some embodiments, the method increases the patient’s survival by at least 30%. In some embodiments, the method increases the patient’s survival by at least 35%. In some embodiments, the method increases the patient’s survival by at least 40%. In some embodiments, the method increases the patient’s survival by at least 45%. In some embodiments, the method increases the patient’s survival by at least 50%. In some embodiments, the method increases the patient’s survival by at least 55%. In some embodiments, the method increases the patient’s survival by at least 60%. In some embodiments, the method increases the patient’s survival by at least 65%. In some embodiments, the method increases the patient’s survival by at least 70%. In some embodiments, the method increases the patient’s survival by at least 75%. In some embodiments, the method increases the patient’s survival by at least 80%. In some embodiments, the method increases the patient’s survival by at least 85%. In some embodiments, the method increases the patient’s survival by at least 90%. In some embodiments, the method increases the patient’s survival by at least 95%. In some embodiments, the method increases the patient’s survival by at least 100%.

[0029] In some embodiments, the method increases the patient’s survival by at least 1 month. In some embodiments, the method increases the patient’s survival by at least 2 months. In some embodiments, the method increases the patient's survival by at least 3 months. In some embodiments, the method increases the patient’s survival by at least 4 months. In some embodiments, the method increases the patient’s survival by at least 5 months. In some embodiments, the method increases the patient’s survival by at least 6 months. In some embodiments, the method increases the patient’s survival by at least 7 months. In some embodiments, the method increases the patient’s survival by at least 8 months. In some embodiments, the method increases the patient’s survival by at least 9 months. In some embodiments, the method increases the patient’s survival by at least 10 months. In some embodiments, the method increases the patient’s survival by at least 11 months.

[0030] In some embodiments, the method increases the patient’s survival by at least 1 year. In some embodiments, the method increases the patient’s survival by at least 2 years. In some embodiments, the method increases the patient’s survival by at least 3 years. In some embodiments, the method increases the patient’s survival by at least 4 years. In some embodiments, the method increases the patient’s survival by at least 5 years. In some embodiments, the method increases the patient’s survival by at least 6 years. In some embodiments, the method increases the patient’s survival by at least 7 years. In some embodiments, the method increases the patient’s survival by at least 8 years. In some embodiments, the method increases the patient’s survival by at least 9 years. In some embodiments, the method increases the patient’s survival by at least 10 years.

[0031] Polycythemia

[0032] Polycythemia, or erythrocytosis, is a disease characterized by an abnormally high le...

Claims

Claims 1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein: A is an aryl or heteroaryl ring system wherein the aryl or heteroaryl ring system is optionally substitued one or more times with R1; B is a 4- to 8-membered non-aromatic carbocycle or a 4- to 8-membered non-aromatic heterocyle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the non-aromatic carbocycle or heterocyle is optionally substituted one or more times with R2; R1is independently for each occurrence selected from the group consisting of OH, halogen, - CF3, -OCF3, -OCH2F, -OCHF2, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, -SC1-8alkyl, -CN, =O, -C(O)H, -(CH2)nNRaRb, -(CH2)nNRaaC(O)Rbb, -C(O)NRaRb, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -NRaRb, - (CH2)mC(O)OC1-8alkyl, -S(O)2-NRaRb, -S(O)2-C1-8alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C1-8alkyl, -OC1-8alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CN, -C1-8alkyl, -C1-8alkylheterocyclyl, -C1-8alkylheteroaryl, -OC1-8alkyl, aryl, and monocyclic heteroaryl; R2is independently for each occurrence selected from the group consisting of OH, halogen, - CF3, -OCF3, -OCH2F, -OCHF2, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, -OC1-8alkyl, -SC1-8alkyl, -CN, =O, -C(O)H, -(CH2)nNRaRb, -(CH2)nNRaaC(O)Rbb, -C(O)NRaRb, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -NRaRb, - (CH2)mC(O)OC1-8alkyl, -S(O)2-NRaRb, -S(O)2-C1-8alkyl, -S(O)2-aryl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl, wherein -C1-8alkyl, -OC1-8alkyl, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclicnon-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CN, -C1-8alkyl, -C1-8alkylheterocyclyl, -C1-8alkylheteroaryl, -OC1-8alkyl, aryl, and monocyclic heteroaryl; R3is selected from the group consisting of OH, -C1-8alkyl, -OC1-8alkyl, -Oaryl, -Oheteroaryl, and – OC0-8alkylC3-8cycloalkyl, wherein -C1-8alkyl and -OC1-8alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, haloalkyl (e.g., CH2F, CHF2, CF3), aryl, heterocyclyl, and –C3-8cycloalkyl; R4is H; or R3and R4together with the carbon atoms to which they are attached form cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl can be optionally substituted 1 or 2 times with a substituent selected independently at each occurrence from the group consisting of CN, -C1-8alkyl, aryl, and heterocyclyl, wherein -C1-8alkyl, aryl, and heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen; R5is selected from the group consisting of H, -OH, -C1-8alkyl, and NH2; R6is selected from the group consisting of -C1-8alkyl, aryl, and heteroaryl, wherein -C1-8alkyl, aryl, and heteroaryl, can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of deuterium, H or - C1-8alkyl, wherein -C1-8alkyl can be optionally substituted with -CONH2, -S(O)2NH2, - S(O)2-C1-8alkyl, aryl, or heterocyclyl; or R5and R6together with the atoms to which they are attached form optionally substituted heterocyclyl; R7is deuterium; Rais H or -C1-8alkyl; Rbis H or -C1-8alkyl, wherein -C1-8alkyl can be optionally substituted with -CONH2, - S(O)2NH2, -S(O)2-C1-8alkyl, aryl, or heterocyclyl; or Raand Rbtogether with the nitrogen atom to which they are attached form non-aromatic heterocyclyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of OH, =O, halogen, CF3, - OCF3, -OCH2F, -OCHF2, -C(O)H, -C1-8alkyl, –C3-8cycloalkyl, –C4-16cycloalkylalkyl, - OC1-8alkyl, -SC1-8alkyl, -NRaRb, -CN, -C(O)OC1-8alkyl, -C(O)OH, -(CH2)kCOC1-8alkyl, -(CH2)nOC1-8alkyl, -NHC(O)OC1-8alkyl, -(CH2)mC(O)OC1-8alkyl, -S(O)2-C1-8alkyl, - S(O)2-aryl, -S(O)2NRaRb, aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocyclyl; Raais H or -C1-8alkyl; Rbbis -C1-8alkyl, -C4-8cycloalkylmethyl, or monocyclic non-aromatic heterocyclyl, wherein - C1-8alkyl and -C4-8cycloalkylmethyl can be optionally substituted with NH2, halogen, or CN; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, 5, or 6; and l is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, pyrimidine, pyridine, and thiazole, wherein the phenyl, pyrimidine, pyridine, and thiazole, is optionally substituted one or more times with R1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is halogen.

4. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic carbocycle optionally substituted one or more times with R2.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic carbocycle optionally substituted one or more times with R2.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic heterocyle comprising an oxygen atom wherein the non-aromatic heterocyle is optionally substituted one or more times with R2.

7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic heterocyle comprising a sulfur atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2.

8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 5-membered non-aromatic heterocyle comprising a nitrogen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2.

9. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic heterocyle comprising a nitrogen atom and an oxygen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2.

10. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic heterocyle comprising one nitrogen atom, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2.

11. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered non-aromatic heterocyle comprising two nitrogen atoms, wherein the non-aromatic heterocyle is optionally substituted one or more times with R2.

12. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R2is independently selected from halogen, =O, -C1-8alkyl, C(O)OC1-8alkyl, and - S(O)2-NRaRb.

13. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R3is -OC1-8alkyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of halogen, CH2F, CHF2, CF3, aryl, heterocyclyl, and –C3-8cycloalkyl.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is -OC1-8alkyl optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from halogen.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R3is –OCH(CH3)CF3.

16. The compound of claim 15, wherein R3has (S) configuration.

17. The compound of claim 15, wherein R3has (R) configuration.

18. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R4is H.

19. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R5is H.

20. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R6is C1-8alkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R6is Me 22. A compound selected from any one of compounds 1-60, and pharmaceutically acceptable salts thereof.

23. The compound of claim 22, wherein the compound is compound 1,or a pharmaceutically acceptable salt thereof.

24. The compound of claim 22, wherein the compound is compound 11,or a pharmaceutically acceptable salt thereof.

25. The compound of claim 22, wherein the compound is compound 17,or a pharmaceutically acceptable salt thereof.

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

27. The compound of claim 22, wherein the compound is compound 53,or a pharmaceutically acceptable salt thereof.

28. The compound of claim 22, wherein the compound is compound 54,or a pharmaceutically acceptable salt thereof.

29. The compound of claim 22, wherein the compound is compound 55,or a pharmaceutically acceptable salt thereof.

30. The compound of claim 22, wherein the compound is compound 56,or a pharmaceutically acceptable salt thereof.

31. The compound of claim 22, wherein the compound is compound 57,or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising (a) a compound of any preceding claim; and (b) a pharmaceutically acceptable excipient.

33. A compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 for use as a medicament.

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

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

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

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

38. The method of claim 37, wherein the one or more complications of hepatic porphyria is selected from the group consisting of: acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte disturbances, nausea, vomiting, constipation, diarrhea, difficulty urinating, ileus, paresthesia, insomnia, restlessness, agitation, anxiety, confusion, hallucinations, psychosis, convulsions, pain associated with neuropathy, muscle paralysis, tetraparesis, decreased breathing, respiratory arrest, hyponatremia, tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive renal damage, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, deteriorating liver disease, and terminal phase liver disease.

39. The method of any one of claims 36-38, wherein the hepatic porphyria is an acute hepatic porphyria, acute intermittent porphyria (AIP), ALA dehydratase porphyria (ADP), variegate porphyria (VP), hereditary coproporphyria (HCP), or harderoporphyria.

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

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

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

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

44. The method of claim 43, wherein the one or more complications of EPP, XLPP, or CEP is 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, bullae, lesions, scarring, deformities, loss of fingernails, loss of digits, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, deteriorating liver disease, terminal phase liver disease, erythrodontia, hypercellular bone marrow, thrombocytopenia, hydrops fetalis and / or death in utero.

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

46. A method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject in need thereof, comprising administering a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 to the subject 47. A method of inhibiting coproporphyrin III synthesis in vivo, comprising administering a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 to a subject.

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

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

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

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

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

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

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

55. A method of inhibiting synthesis of a porphyrin or porphyrin precursor in vivo, comprising administering a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 to a subject, wherein the porphyrin or porphyrin precursor is selected from the group consisting of: s. 5-ALA t. PBG u. Hydroxymethylbilane v. PPIX w. ZPPIX x. Uroporphyrinogen I y. Uroporphyrinogen III z. Heptacarboxyporphyrinogen I aa. Heptacarboxyporphyrinogen III bb. Hexacarboxyporphyrinogen Icc. Hexacarboxyporphyrinogen III dd. Pentacarboxyporphyrinogen I ee. Pentacarboxyporphyrinogen III ff. Coproporphyrinogen I gg. Coproporphyrinogen III hh. Isocoproporphyrin ii. Porphobilinogen; and jj. Protoporphyrinogen IX.

56. The method of any one of claims 34-55, wherein accumulation of one or more heme intermediates is inhibited, and wherein 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.

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

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

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

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

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

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

63. The method of any one of claims 35-62, comprising further administering to the subject an additional active agent and / or supportive therapy.

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

65. The method of claim 63, wherein the additional active agent and / or supportive therapy is selected from the group consisting of: avoiding sunlight, topical sunscreens, skin protection, UVB phototherapy, Afamelanotide (Scenesse®), bortezomib, heme infusions, sufficient caloric support, Givosiran, RNAi mediated silencing of various enzymes (e.g., ALA synthase), avoiding precipitating factors, 4-aminoquinolines, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of PBGD gene in liver cells by viral vectors), hemodialysis, pharmacologic chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion.

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

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

68. The method of any one of claims 66-67, wherein the anemia associated with a ribosomal disorder is Diamond-Blackfan anemia.

69. The method of claim 68, wherein the subject is haploinsufficient for 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 of claim 68, wherein the subject is haploinsufficient for 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), 60Sribosomal protein L27 (RPL27), 60S ribosomal protein L31 (RPL31), 40S ribosomal protein S15a (RPS15a), 40S ribosomal protein S20 (RPS20), 40S ribosomal protein S27 (RPS27), 40S ribosomal protein S28 (RPS28), and 40S ribosomal protein S29 (RPS29).

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

72. The method of claim 68, wherein the subject has one or more mutations in a ribosomal protein gene selected from the 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 of 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 of claim 66 or claim 67, wherein the anemia associated with a ribosomal disorder is Shwachman-Diamond syndrome.

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

76. The method of claim 66 or claim 67, wherein the anemia associated with a ribosomal disorder is dyskeratosis congenita.

77. The method of claim 76, wherein the dyskeratosis congenita is x-linked dyskeratosis congenita.

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

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

80. The method of claim 66 or claim 67, wherein the anemia associated with a ribosomal disorder is cartilage hair hypoplasia.

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

82. The method of claim 67, wherein the one or more complications of anemia associated with a ribosomal disorder is selected from the group consisting of: thrombocytosis, megakaryotypic hyperplasia, infections, bleeding (e.g., from the nose or gums), bruising, splenomegaly, the need for more frequent blood transfusions, the need for increased glucocorticoid use, the need for allogenic hematopoietic stem cell transplantation, the need for autologous gene therapy, marrow failure, leukemia, and acute myelogenous leukemia.

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

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

85. The method of any one of claims 66-84, comprising further administering to the subject an additional active agent and / or supportive therapy.

86. The method of claim 85, wherein the additional active agent and / or supportive therapy is selected from the group consisting of: trifluoperazine, lenalidomide, HDAC inhibitors, glucocorticoids, sotatercept, luspatercept, iron chelators, blood transfusion, platelet transfusion, 87. A method of treating polycythemia in a subject in need thereof, comprising administering a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 to the subject.

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

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

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

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

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

93. The method of claim 92, wherein the secondary polycythemia is associated with a disorder selected from the group consisting of hypoxia, central hypoxic process, lung disease, right-to-left cardiopulmonary vascular shunts (congenital or acquired), heart disease, heart failure, carbon monoxide poisoning, smoker’s erythrocytosis, high-altitude habitat, renal disease, kidney transplant, hemoglobinopathy with high-oxygen-affinity, decreased levels of erythrocyte 2,3,-DPG, bisphosphoglycerate mutase deficiency, methemoglobinemia, hereditary ATP increase, oxygen sensing pathway gene mutations, tumor, drug-induced secondary polycythemia, adrenal cortical hypersecretion, and idiopathic polycythemia.

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

95. The method of claim 94, wherein the relative polycythemia is selected from the group consisting of Gaisbock’s syndrome, spurious polycythemia, or stress erythrocytosis.

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

97. The method of claim 88, wherein the one or more complications of polycythemia is selected from the group consisting of: pulmonary embolisms, transient ischemic attacks, transient visual defects, deep vein thrombosis, splenomegaly, hepatomegaly, myelofibrosis, and acute myeloid leukemia.

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

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

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

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

102. A method of inhibiting red blood cell synthesis in a subject with polycythemia, comprising administering a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 to the subject.

103. The method of claim 102, wherein the red blood cell synthesis is inhibited in a dose dependent manner.

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

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

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

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

108. The method of claim 107, wherein the additional active agent and / or supportive therapy is selected from the group consisting of: Hydroxyruea (e.g., Droxia®, Hydrea®), Interferon alpha, Interferon alpha-2b (e.g., Intron® A), Ruxolitinib (e.g., Jakafi®), Busulfan (e.g., Busulfex®, Myleran®), radiation treatment, hepcidin mimetics (e.g., PTG-300), matriptase-2 inhibitors, ferroportin inhibitors, JAK inhibitors, BET inhibitors, MDM2 inhibitors, and HDAC inhibitors.

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