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EP-3761989-B1 - IMIDAZODIAZEPINEDIONES AND METHODS OF USE THEREOF

EP3761989B1EP 3761989 B1EP3761989 B1EP 3761989B1EP-3761989-B1

Inventors

  • DANIELS, MATTHEW, H.
  • YU, MAOLIN
  • HARMANGE, Jean-Christophe, P.
  • TIBBITTS, THOMAS, T.
  • LEDEBOER, MARK, W.
  • CASTLE, NEIL, A.
  • MALOJCIC, Goran

Dates

Publication Date
20260513
Application Date
20190305

Claims (14)

  1. A compound of Formula (I) or (II), or a tautomer or a pharmaceutically acceptable salt thereof, wherein A' is N; and A is CR; or A is N and A' is CR; R is L-R 1 ; L is O, CH 2 , SO 2 , or NR 2 , or is absent; R 1 is selected from optionally substituted aryl, and optionally substituted heteroaryl; each R 2 is independently alkyl or H; R 3 is selected from optionally substituted alkyl, optionally substituted alkylene-OR 2 , optionally substituted cycloalkylene-OR 2 , optionally substituted alkylene-N(R 7 ) 2 , optionally substituted cycloalkylene-N(R 7 ) 2 , optionally substituted alkylene-C(O)N(R 2 ) 2 , optionally substituted cycloalkylene-C(O)N(R 2 ) 2 , optionally substituted alkylene-S(O) 2 N(R 2 ) 2 , and optionally substituted cycloalkylene-S(O) 2 N(R 2 ) 2 ; R 4 is selected from optionally substituted alkylene-aryl, alkyl, and optionally substituted alkylene-heteroaryl; each R 5 is independently selected from H, N(R 2 ) 2 , and OR 2 ; each R 7 is independently selected from H, alkyl, (alkyl)C(O)-, (aryl)C(O)-, (alkyl)S(O) 2 -, and (aryl)S(O) 2 -; X is -C(O)-, CH 2 , CHR 6 , or C(R 6 ) 2 ; each R 6 is independently selected from alkyl, and optionally substituted alkylene-OH; X' is -C(O)-, CH 2 , CHR 3' , C(R 3' ) 2 , or X' is taken together with R 3 to form a 5- or 6-membered ring; each R 3' is independently selected from optionally substituted alkyl, optionally substituted alkylene-OR 2 , optionally substituted cycloalkylene-OR 2 , optionally substituted alkylene-N(R 7 ) 2 , optionally substituted cycloalkylene-N(R 7 ) 2 , optionally substituted alkylene-C(O)N(R 2 ) 2 , optionally substituted cycloalkylene-C(O)N(R 2 ) 2 , optionally substituted alkylene-S(O) 2 N(R 2 ) 2 , and optionally substituted cycloalkylene-S(O) 2 N(R 2 ) 2 ; and Z is absent, CH 2 , CHR 5 , O, -NR 2 -, or -SO 2 -; provided that X and X' are not both -C(O)-, and R 5 is H when Z is O, NR or SO 2 .
  2. The compound of claim 1, wherein A is CR and A' is N.
  3. The compound of claim 1 or 2, wherein L is O.
  4. The compound of any one of claims 1-3, wherein R 1 is phenyl substituted with one or more substituents independently selected from halogen, -CF 3 , -C(H)F 2 , and -OCF 3 .
  5. The compound of any one of claims 1-4, wherein the R 2 depicted in Formula (I) is alkyl.
  6. The compound of any one of claims 1-5, wherein R 3 is optionally substituted alkylene-OH, preferably wherein R 3 is selected from
  7. The compound of any one of claims 1-6, wherein R 4 is optionally substituted alkylene-aryl, wherein the aryl of alkylene-aryl is phenyl substituted with one or more instances of halogen, preferably wherein R 4 is
  8. The compound of any one of claims 1-7, wherein each R 5 is H.
  9. The compound of any one of claims 1-8, wherein X is -C(O)- and X' is CH 2 , or X' is -C(O)- and X is CH 2 .
  10. The compound of any one of claims 1-9, wherein Z is absent.
  11. The compound of claim 1, wherein the compound is selected from:
  12. A composition, comprising a compound of any one of claims 1-11 or a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  13. The composition of claim 12 for use in treating, or the reducing risk of developing, a kidney disease, diabetic retinopathy, anxiety, depression, or cancer.
  14. The composition of claim 13 for use in treating a kidney disease, preferably wherein the kidney disease is Focal Segmental Glomerulosclerosis (FSGS), Diabetic nephropathy, Alport syndrome, hypertensive kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, Lupus nephritis, postinfectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, IgA nephropathy, proteinuric kidney disease, microalbuminuria or macroalbuminuria kidney disease.

Description

BACKGROUND Proteinuria is a condition in which an excessive amount of protein in the blood leaks into the urine. Proteinuria can progress from a loss of 30 mg of protein in the urine over a 24-hour period (called microalbuminuria) to >300 mg/day (called macroalbuminuria), before reaching levels of 3.5 grams of protein or more over a 24-hour period, or 25 times the normal amount. Proteinuria occurs when there is a malfunction in the kidney's glomeruli, causing fluid to accumulate in the body (edema). Prolonged protein leakage has been shown to result in kidney failure. Nephrotic Syndrome (NS) disease accounts for approximately 12% of prevalent end stage renal disease cases at an annual cost in the United States of more than $3 billion. Approximately 5 out of every 100,000 children are diagnosed with NS each year, and 15 out of every 100,000 children are living with it today. Even for patients who respond positively to treatment the relapse frequency is extremely high. About 90% of children with Nephrotic Syndrome will respond to treatment; however, an estimated 75% will relapse. Therefore, more effective methods of treating, or reducing risk of developing, kidney disease, e.g., proteinuria, are required. Mammalian TRP channel proteins form six-transmembrane cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cell functions and are considered to play an important role in the pathophysiology of many diseases. Many TRPs are expressed in kidney along different parts of the nephron, and growing evidence suggest that these channels are involved in hereditary as well as acquired kidney disorders. For example, TRPC6, TRPM6, and TRPP2 have been implicated in hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively. TRPC5 has also been reported to contribute to the mechanisms underlying regulation of innate fear responses. (J Neurosci. 2014 Mar 5; 34(10): 3653-3667). Hence, there is a need for additional inhibitors of TRPC5. SUMMARY The invention is based, at least in part, on the discovery that Transient Receptor Potential Cation Channel, subfamily C, member 5 (TRPC5) activity abolishes actin stress fibers and diminishes focal adhesion formation, rendering a motile, migratory podocyte phenotype. The invention is defined in the appended claims. The invention relates to small molecule TRPC5 modulators. In some embodiments, the invention relates to small molecule TRPC5 inhibitors and the use of such inhibitors in methods of treating, or reducing risk of developing, kidney disease (e.g., proteinuria, microalbuminuria, macroalbuminuria), anxiety, depression, or cancer, comprising administering to a subject in need thereof. In some embodiments, the invention relates to small molecule TRPC5 agonists and the use of such agonists in methods of treating, or reducing risk of developing, obesity. The interaction of small molecule ligands with proteins can lead to agonist or antagonist (inhibitory) activity. The structural determinants that lead to agonistic or antagonistic activity are often not well understood. Opposing effects of closely related molecules, even enantiomers, on the activity of their biological target has been observed in multiple cases over decades of research. It is particularly common in membrane signaling proteins, such as ion channels and GPCR's (X. Huang et al., ACS Med. Chem. Lett. 2018, 9, 679-684; R. Recio et al., Eur J Med Chem 2017, 138, 644-660; Y. Kim et al., Eur J Med Chem 2016, 123, 180-190). Examples of this behavior include the modulation of calcium channels, such as DHP receptors (G.C. Rovnyak et al., J Med Chem. 1995, 38(1):119-29, from Neil's email), calcium channels in heart cells (RS Kass, Circ Res 1987, 61(4 Pt 2), I1-5 and others (R.P. Hof et al., J Cardiovasc Pharmacol. 1985, 7(4):689-93). These references highlight how small structural features govern whether a compound can act as either an agonist or antagonist. Very recently, such a phenomenon was described for TRPC1/4/5 channels (H.N. Rubaiy et al., Br J Pharmacol. 2018, 175(5):830-839. doi: 10.1111/bph.14128. Epub 2018 Jan 25). In accordance with such literature reports, we found that Formula I and Formula II described herein include both agonists and inhibitors. One of ordinary skill in the art can easily determine if a compound of Formula I or Formula II is a TRPC5 agonist or inhibitor by testing it in the FLIPR assays described herein or any other assays that can determine if a compound is a TRPC5 inhibitor or a TRPC5 agonist. Ivanov É. I, Chemistry of Heterocyclic Compounds, vol. 34, no. 6, 1998, pp719-722 discloses the synthesis of a cyclic homolog of caffeine. Daly J.W. et al., J. Med. Chem., 1990, 33, 2818-2821 discloses imidazodiazepinediones: