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EP-4739307-A2 - TARGETED EPIGENETIC THERAPIES FOR DISORDERS OF PROGRANULIN DEFICIENCY

EP4739307A2EP 4739307 A2EP4739307 A2EP 4739307A2EP-4739307-A2

Abstract

The present disclosure relates to compounds, e.g., compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof, and their use for modulating levels of progranulin.

Inventors

  • HAGGARTY, STEPHEN J.
  • ROSENTHAL, Zachary
  • MAZITSCHEK, RALPH
  • PATNAIK, DEBASIS
  • PAYNE, NEIL
  • HOOKER, Jacob M.
  • PACZEK, Michael
  • FASS, Daniel M.

Assignees

  • The General Hospital Corporation

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. WHAT IS CLAIMED IS: 1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is 5-6 membered heteroaryl or phenyl; Ring B is 6-10 membered heteroaryl, 9-14 membered heterocyclyl, or phenyl; R 1 is C1-C6 alkyl; R 2 is: (i) phenyl optionally substituted with 1-2 independently selected R 2A , (ii) 5-6 membered heteroaryl optionally substituted with 1-2 independently selected R 2A , (iii) C1-C6 alkyl, (iv) C3-C6 cycloalkyl, (v) -(C=O)(C1-C6 alkyl optionally substituted with C1-C6 alkoxyl), (vi) -(C=O)C3-C6 cycloalkyl, (vii) 4-10 membered heterocyclyl, and (viii) -NR 2B (C3-C6 cycloalkyl); R 2A is halogen or hydroxyl; R 2B is hydrogen or C1-C6 alkyl; R 3 is halogen or -NR 3A (C=O)C1-C6 alkyl; R 3A is hydrogen or C1-C6 alkyl; L is a bond, -O-, -S-, -S(=O)-, -SO 2 -, -N(R A )-, -C(R A R B )-, or -C(=O)-; R A and R 2B are each independently hydrogen or C1-C6 alkyl; R B is hydrogen, hydroxyl, or C1-C6 alkoxyl; and n is 0 or 1.
  2. 2. The compound of claim 1, wherein Ring A is 5 membered heteroaryl.
  3. 3. The compound of claim 1, wherein Ring A is 6 membered heteroaryl.
  4. 4. The compound of claim 1, wherein Ring A is phenyl.
  5. 5. The compound of any one of claims 1-4, wherein Ring B is 6-10 membered heteroaryl.
  6. 6. The compound of any one of claims 1-5, wherein Ring B is 6 membered heteroaryl.
  7. 7. The compound of any one of claims 1-5, wherein Ring B is 9-10 membered heteroaryl.
  8. 8. The compound of any one of claims 1-4, wherein Ring B is 9-14 membered heterocyclyl.
  9. 9. The compound of any one of claims 1-4, wherein Ring B is phenyl.
  10. 10. The compound of any one of claims 1-9, wherein R 1 is C3-C6 alkyl.
  11. 11. The compound of any one of claims 1-9, wherein R 1 is C1-C2 alkyl.
  12. 12. The compound of any one of claims 1-9 and 11, wherein R 1 is methyl.
  13. 13. The compound of any one of claims 1-12, wherein R 2 is phenyl optionally substituted with 1-2 independently selected R 2A .
  14. 14. The compound of any one of claims 1-13, wherein R 2 is phenyl substituted with 1-2 independently selected R 2A .
  15. 15. The compound of any one of claims 1-12, wherein R 2 is 5-6 membered heteroaryl optionally substituted with 1-2 independently selected R 2A .
  16. 16. The compound of any one of claims 1-12 and 15, wherein R 2 is 5-6 membered heteroaryl substituted with 1-2 independently selected R 2A .
  17. 17. The compound of any one of claims 1-12 and 15, wherein R 2 is unsubstituted 5-6 membered heteroaryl.
  18. 18. The compound of any one of claims 1-12, wherein R 2 is C1-C6 alkyl.
  19. 19. The compound of any one of claims 1-12, wherein R 2 is C3-C6 cycloalkyl.
  20. 20. The compound of any one of claims 1-12, wherein R 2 is -(C=O)(C1-C6 alkyl optionally substituted with C1-C6 alkoxyl).

Description

TARGETED EPIGENETIC THERAPIES FOR DISORDERS OF PROGRANULIN DEFICIENCY STATEMENT OF GOVERNMENT SUPPORT [0001] This invention was made with government support under R01NS108115 awarded by National Institute of Neurological Disorders & Stroke / National Institute of Health. The government has certain rights in the invention. PRIORITY CLAIM [0002] This application claims the benefit of priority to U.S. Provisional Application No. 63/524,837, filed on July 3, 2023 and U.S. Provisional Application No. 63/610,275, filed on December 14, 2023, each of which is incorporated by reference in its entirety, including any drawings and exhibits. FIELD [0003] The present disclosure relates to compounds, e.g., compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof, and their use for modulating levels of progranulin. BACKGROUND [0004] Frontotemporal dementia (FTD) is characterized by the selective degeneration of the frontal and temporal lobes and is the second most common cause of presenile dementia, accounting for 5-15% of all dementia cases. Clinically, frontotemporal lobar degeneration (FTLD) patients commonly present with severe personality and behavioral changes, as well as fluent or non-fluent aphasias. Pathologically, frontotemporal lobar degeneration (FTLD) cases near ubiquitously show evidence of abnormal intracellular protein aggregation, and the composition of their aggregating proteins can distinguish FTLD subtypes. [0005] One of the most significant genetic risk factors for FTLD is mutations in the GRN gene, which encodes the progranulin (PGRN) protein. FTLD caused by mutations in GRN characteristically presents with an aberrant accumulation of ubiquitin and TAR DNA-binding protein (TDP-43)-positive inclusions. GRN mutation frequency in FTLD is between 1-11%, with a large range due to significant differences in mutation frequency among various populations. By the age of sixty, over half of GRN mutation carriers are affected by FTLD; by 70, over 90% are affected. To date, at least seventy pathogenic mutations in GRN have been identified, with the majority introducing a premature stop codon. These mutations result in a reduction of GRN mRNA, and corresponding PGRN protein, resulting in PGRN haploinsufficiency. [0006] PGRN is a 68.5 kDa protein that is processed via multiple N-linked glycosylation events to produce a mature 88 kDa protein. PGRN is then secreted and cleaved either extracellularly or after re-internalization into fragments (granulins) via the actions of several proteases such as elastase, proteinase 3, and cathepsins B, D, and L. PGRN modulates a variety of biological processes, such as mediating wound repair and inflammation, promoting epithelial cell growth, and inhibiting transcriptional elongation. PGRN deficiency causes broad lysosomal dysfunction characterized by inclusion-filled lysosomes and increased expression of lysosomal proteins such as cathepsin D and LAMP1, and homozygous loss of GRN causes the lysosomal storage disorder neuronal ceroid lipofuscinosis. Reduced lysosomal function is a common feature observed in neurodegenerative diseases, and PGRN deficiency is known to cause lysosomal dysfunction through alterations in lysosomal protein composition and a reduction in lipid homeostasis. An additional mechanism by which PGRN may protect against neurodegeneration is through moderating neuroinflammation. Recent research has pointed toward the importance of microglial PGRN in CNS homeostasis. SUMMARY [0007] Some embodiments provide a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is 5-6 membered heteroaryl or phenyl; Ring B is 6-10 membered heteroaryl, 9-14 membered heterocyclyl, or phenyl; R1 is C1-C6 alkyl; R2 is: (i) phenyl optionally substituted with 1-2 independently selected R2A, (ii) 5-6 membered heteroaryl optionally substituted with 1-2 independently selected , (iii) C1-C6 alkyl, (iv) C3-C6 cycloalkyl, (v) -(C=O)(C1-C6 alkyl optionally substituted with C1-C6 alkoxyl), (vi) -(C=O)C3-C6 cycloalkyl, (vii) 4-10 membered heterocyclyl, and (viii) -NR2B(C3-C6 cycloalkyl); R2A is halogen or hydroxyl; R2B is hydrogen or C1-C6 alkyl; R3 is halogen or -NR3A(C=O)C1-C6 alkyl; R3A is hydrogen or C1-C6 alkyl; L is a bond, -O-, -S-, -S(=O)-, -SO2-, -N(RA)-, -C(RARB)-, or -C(=O)-; RA and R2B are each independently hydrogen or C1-C6 alkyl; RB is hydrogen, hydroxyl, or C1-C6 alkoxyl; and n is 0 or 1. [0008] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0009] Some embodiments provide a pharmaceutical composition comprising the compound of Formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0010] Some embodiments provide a method of treating a PGRN-associated disease in a subject in need thereof, comprising adm