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EP-4735422-A1 - SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF TREATING PHENYLKETONURIA AND OTHER AMINO ACIDURIAS

EP4735422A1EP 4735422 A1EP4735422 A1EP 4735422A1EP-4735422-A1

Abstract

The present disclosure relates generally compounds that inhibit SLC6A19 and can be used for the treatment of patients with phenylketonuria ("PKU") and other amino acidurias, as well as compositions containing the same and methods of using the same…

Inventors

  • KANE, JR., JOHN L.
  • TERRANOVA, Kristen
  • HIRTH, BRADFORD H.
  • DAVIS, HEATHER
  • CZEKAJ, MARK
  • SHUM, PATRICK WAI-KWOK
  • WEI, LINLI
  • RUF, SVEN
  • MUELLER, PAUL JUSTIN
  • DEBENEDETTO, Mikkel
  • MANSS, Annette
  • MERRIMAN, GREGORY HAROLD
  • BECKER, CHRISTOPHER J.

Assignees

  • Sanofi

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. WHAT IS CLAIMED IS: wherein R1 and R2 are independently selected from H or CH 3 ; wherein each R3 is independently selected from H, OH, CH 3 , 0-CH 3 , CHF2, F, or Cl, wherein at least two R3 are H; or a pharmaceutically acceptable salt thereof.
  2. 2. A compound of the formula: wherein R1 and R2 are independently selected from H or CH 3 ; wherein each R3 is independently selected from H, OH, CH 3 , 0-CH 3 , CH 2 F2, F, or Cl, wherein at least two R3 are H; wherein n is 0, 1, 2, or 3; wherein each occurrence of R4 is independently selected from CH 3 , CF3, O-CH 3 , F, Cl, -CN, iso-propyl, or cyclopropyl; wherein R 6 is H, -CH 2 CH 2 OH, or -CH 2 CH 2 N(CH 3 )2; Rs is: , , , , , , , , , l; provided that n cannot be 0 when R5 is: or a pharmaceutically acceptable salt thereof.
  3. 3. A compound of the formula: each of W1 and W4 is independently selected from N, C, or CH; each of W2, W3, W5, and W6 is independently selected from N, NH, CH, or CH 2 ; n is 0, 1, 2, or 3; each occurrence of R4 is, independently, cyclopropyl, Cl, F, CH 3 , isopropyl, CF3, -CN or OCH 3 ; m is 0, 1, 2, or 3; each occurrence of R 6 is, independently, F, Cl, or CH 3 ; wherein R1 and R2 are independently selected from H or CH 3 ;
  4. 4. A compound of the formula: wherein R1 and R2 are independently selected from H or CH 3 ; wherein each R3 is independently selected from H, OH, CH 3 , O-CH 3 , CHF2, F, or Cl, wherein at least two R3 are H; wherein n is 0, 1, or 2; wherein each occurrence of Ro1 is, independently, methyl, F, OH, H, OCH 3 , CH 3 , or cyclopropyl; wherein X is H or CF 3 ; and wherein the bicycle is a bicyclic ring that includes 8-10 constituent ring atoms, wherein 1-4 of the atoms are heteroatoms independently selected from N, 0, or S, and wherein each of the two rings is independently a saturated, unsaturated, or aromatic ring; or a pharmaceutically acceptable salt thereof.
  5. 5. A compound having the formula: R11 is -(CH 2 ) m -A m is 0, 1, 2, or 3; R12 is H; R13 is H, -CH 2 CH 2 OH, or -CH 2 CH 2 N(CH 3 ) 2 ; nis 0, 1, 2, or 3; each occurrence of Ro1 is, independently, cyclopropyl, Cl, F, CH 3 , or OCH 3 ; each R3 is independently selected from H, OH, CH 3 , O-CH 3 , CHF 2 , F, or Cl, wherein at least two R3 are H; and X1 isHorCF 3 ; X1isHorF; or Rn and R12 together with the nitrogen atom to which each is attached forms: or a pharmaceutically acceptable salt thereof.
  6. 6. A compound having the formula: wherein each of R 61 , R.62, R.63, and R.64 is independently selected from H and CH 3 , or a pharmaceutically acceptable salt thereof.
  7. 7. A compound having the formula: each of R71 and R72 is independently selected from H and CH 3 , or a pharmaceutically acceptable salt thereof.
  8. 8. A compound having the formula: wherein Q is (CH 2 ) where in a ring and n is 1, 2, or 3 thereby forming a 5, 6 or 7 membered ring, or a pharmaceutically acceptable salt thereof.
  9. or a pharmaceutically acceptable salt thereof.
  10. 10. A pharmaceudcal composition, comprising a compound of any one of the preceding ciaims, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient,
  11. 11. A compound for use in the treatment of a disease or disorder associated with a genetic defect in phenylalanine hydroxylase, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 10.
  12. 12. A compound for use in the treatment of phenylketonuria, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 10.
  13. 13. compound for use in the treatment of hyperphenylalaninemia, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 -9 or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 10.
  14. 14. A compound for use in the treatment of the diseases recited in any of claims 11, 12, or 13 wherein the compound reduces systemic phenylalanine levels in the subject.
  15. 15. A compound for use in the treatment of the di seases recited in any of claims 11, 12, or 13, wherein the compound inhibits SLC6A19 in the subject.

Description

SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF TREATING PHENYLKETONURIA AND OTHER AMINO ACIDURIAS TECHNICAL FIELD The present disclosure relates generally compounds that may be used for the treatment of patients with phenylketonuria (PKU) and other amino acidurias, as well as methods of using the same. BACKGROUND Phenylalanine hydroxylase (PAH) is an enzyme that converts phenylalanine (Phe) consumed in food into tyrosine (Tyr) primarily in the liver. Loss of PAH function leads to toxic accumulation of Phe in the body, which is manifest by lower levels of Tyr and tryptophan and high levels of Phe (and Phe-derived metabolites such as phenolketones and phenolpyruvate) in the blood and brain, (van Spronsen et.aL, Phenylketonuria. Nat Rev Dis Primers 7, 35 (2021 )). In the brain, such high levels of Phe can lead to reduced levels of dopamine and serotonin, reduced levels of neutral amino acids, white matter disruption, reduced glucose metabolism, and even amyloid-like fibril formation. PKU is caused by an autosomal-recessive inborn defect in PAH that results in loss of function and accumulation of Phe in the brain. Untreated PKU patients develop severe intellectual disability, epilepsy and behavioral, psychiatric and/or movement problems. PKU occurs in about 1 in every 15,000 births in North America and Europe and there are about 50,000 patients currently living with PKU in the United States and Europe. Current treatment for PKU involves the use of a Phe -restricted diet, meaning that patients much watch the amount of Phe that is found in their foods. However, compliance with unpalatable restricted diets is challenging for many adult and adolescent patients. Thus, patients who struggle to comply with a Phe-restricted diet need a new treatment option. Some doctors have begun treating PKU by administering PALYNZIQ®, a recombinant phenylalanine ammonia lyase (PAL) enzyme, to patients. However, some patients are allergic to this product, which can cause such patients anaphylaxis that may be life- threatening. As such, new treatments are needed. SLC6A19 (sometimes called B°AT1) is an amino acid transporter that is expressed only in the kidney and small intestine. SLC6A19 mediates greater than 95% of the free neutral amino acid absorption from the diet, including Phe. Thus, inhibition (and even selective inhibition) of SLC6A19 causes the amount of neutral amino acids (including Phe) obtained from food to be drastically reduced. In this manner, elevated amounts of Phe and other neutral amino acids would be excreted and eliminated from the body. Such inhibition, especially if a small molecule, could be easy for patients to take, and would treat PKU and other rare genetic disorders of amino acid and nitrogen metabolism. Moreover, human genetic SLC6A19 deficiency (Hartnup Disorder, frequency about 1:3,000) is typically benign and rare symptoms of such disease are treatable with niacin supplementation. It has been shown that genetically inhibiting SLC6A19 in PKU mouse models reduces plasma and brain Phe levels, normalizes neurotransmitter levels, improves neuronal morphology defects and rescues behavioural symptoms. Belanger, Adam M. et al., Inhibiting neutral amino acid transport for the treatment of phenylketonuria, JCI Insight. 2018; 3(14): el21762. Thus, inhibitors of SLC61A19 are an interesting target for treatment of PKU. See WO 2022/192370; Desai, Jigar, et. al., Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19), Bioorg. Med. Chem. Let. 53 (2021) 128421; Yadav, Aditya, et. al. (2020) Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases, Front. Pharmacol. 11:140. Thus, the present embodiments provide compounds that can be used to inhibit SLC6A19, and thereby treat PKU and other aminoacidurias. SUMMARY The present disclosure relates generally compounds that inhibit SLC6A19 and can be used for the treatment of patients with phenylketonuria (“PKU”) and other amino acidurias, as well as compositions containing the same and methods of using the same. In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured: in which R1, R2, and R3 can be as defined anywhere herein. In another aspect, compounds of Formula (II), or a pharmaceutically acceptable salt thereof, are featured: in which R1, R2, R3, R4, n, R5, and R6 can be as defined anywhere herein. In a further aspect, compounds of Formula (III), or a pharmaceutically acceptable salt thereof, are featured: in which R,1 R2, R4, R6, n, m, W1, W2, W3, W4, W5, W6, and X can be as defined anywhere herein. In one aspect, compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, are featured: in which R1, R2, R3, R10, n, bicycle, and X can be as defined anywhere herein. In another aspect, compounds of Formula (V), or a pharmaceutically acceptable salt thereof, are featured: i