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US-20260125363-A1 - PROCESSES FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

US20260125363A1US 20260125363 A1US20260125363 A1US 20260125363A1US-20260125363-A1

Abstract

The disclosure provides processes for preparing a compound of Formula (I):

Inventors

  • Paul T. Angell
  • John Studley
  • Cristian Harrison
  • Robert M. Hughes
  • Berenice Lewandowski
  • Benjamin J. Littler
  • Vito Melillo
  • William A. Nugent
  • David Andrew Siesel
  • David Smith

Assignees

  • VERTEX PHARMACEUTICALS INCORPORATED

Dates

Publication Date
20260507
Application Date
20250820

Claims (7)

  1. 1 - 186 . (canceled)
  2. 187 . A compound chosen from: wherein —R 1 is and —Ring A is phenyl or or a salt thereof, or a deuterated derivative of any of the foregoing.
  3. 188 - 209 . (canceled)
  4. 210 . The compound according to claim 187 , wherein the compound is a salt thereof, or a deuterated derivative of any of the foregoing.
  5. 211 . The compound according to claim 187 , wherein the compound is a salt thereof, or a deuterated derivative of any of the foregoing.
  6. 212 . The compound according to claim 187 , wherein the compound is and wherein —R 1 is or a salt thereof, or a deuterated derivative of any of the foregoing.
  7. 213 . The compound according to claim 187 , wherein the compound is and wherein —Ring A is phenyl or or a salt thereof, or a deuterated derivative of any of the foregoing.

Description

This application claims the benefit of U.S. Provisional Application No. 62/596,452, filed Dec. 8, 2017, U.S. Provisional Application No. 62/623,725, filed Jan. 30, 2018, and U.S. Provisional Application No. 62/649,970, filed Mar. 29, 2018, all of which are incorporated herein by reference in their entirety. SEQUENCE LISTING The instant application contains a sequence listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The Sequence Listing XML, created on Mar. 6, 2023, is named 10275.0133-01000 SL.xml and is 716 bytes in size. The invention provides processes for preparing compounds useful for treating a cystic fibrosis transmembrane conductance regulator (“CFTR”) mediated disease such as cystic fibrosis, intermediates useful in those processes, and processes for making those intermediates. Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure. In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis. Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with severe disease. The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR, i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity. CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking. Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and Cl− channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl− channels, resulting in a vectorial transport. Arrangement of Na+/2Cl−/K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels