USOO94471.14B2 (12) United States Patent (10) Patent No.: US 9.447,114 B2 Chenard et al. (45) Date of Patent: Sep. 20, 2016 (54) THIENO- AND 2015,0111038 A1* 4, 2015 Kadam ................ CO7D 495/04 FURO2,3-DIPYRIMIDINE-2,41H,3H-DIONE 2015,0190366 A1* 7, 2015 Hous Agik ; : DERVATIVES OuSley ............... 5.14?6.5 2016/0046624 A1 2/2016 Chenard .............. CO7D 471/04 (71) Applicant: Hydra Biosciences, Inc., Cambridge, 514,264.1 MA (US) FOREIGN PATENT DOCUMENTS (72) Inventors: Bertrand L. Chenard, Waterford, CT (US); Randall J. Gallaschun, Lebanon, JP EP 0640606 A1 * 3, 1995 ........... A61K 31.505 WO WO O2O64572 A1 * 8, 2002 ... A64K 31,517 CT (US) WO WO-2004O28634 A1 4/2004 WO WO-2008070529 A2 6, 2008 (73) Assignee: Hydra Biosciences, Inc., Cambridge, WO WO-2010017368 A2 2, 2010 MA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this CAS Registry No. 606122-61-6 (Entered STN: Oct. 17, 2003).* patent is extended or adjusted under 35 CAS Registry No. 1497903-60-2 (Entered STN: Dec. 18, 2013).* U.S.C. 154(b) by 0 days. CAS Registry Nos. (Indexed 2012).* CAS Registry Nos. (Indexed 2006).* (21) Appl. No.: 14/822,018 C. Hong et al., 138 Brain, 3030-3047 (2015).* K.D. Phelan et al., 83 Molecular Pharmacology, 429–438 (2013).* (22) Filed: Aug. 10, 2015 M. Raychaudhuri et al., 2011 International Journal of Alzheimer's Disease, 1-5 (2011).* (65) Prior Publication Data J. Richter et al., 171 British Journal of Pharmacology, 158-170 (2014).* US 2016/OO398.41 A1 Feb. 11, 2016 C-O Wong et al., 159 British Journal of Pharmacology, 1486-1496 (2010).* Related U.S. Application Data * cited by examiner (60) Provisional application No. 62/035,575, filed on Aug. Primary Examiner — Alexander R Pagano 11, 2014. (74) Attorney, Agent, or Firm — McCarter & English, LLP: (51) Int. Cl. Steven G. Davis; Kathryn M. Kizer A 6LX 3/59 (2006.01) (57) ABSTRACT CO7D 495/04 (2006.01) CO7D 49/048 (2006.01) This invention relates to novel Thieno- and Furo2,3-d CO7D 49/04 (2006.01) pyrimidine-2,41H.3H]-dione derivatives of formula I (52) U.S. Cl. CPC ........... C07D 495/04 (2013.01); C07D 491/04 (2013.01); C07D 491/048 (2013.01); A61 K 3 1/519 (2013.01) (58) Field of Classification Search CPC .............. C07D 495/04; C07D 491/04; C07D 491/048 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS and their use as TRPC5 modulators, pharmaceutical com 4,536,518 A * 8/1985 Welch, Jr. ............... CO7C 43/21 positions containing the same, and methods of using the 514,555 same as agents for the treatment of TRPC5 receptor medi 2012/0041004 A1 2/2012 Chaudhari ........... A61K 31,519 ated disorders or conditions. A. R', R, R and R have 514,462.1 meanings given in the description. 2012/0178766 A1* 7, 2012 Chaudhari ........... CO7D 495/04 514,260.1 15 Claims, No Drawings US 9,447,114 B2 1. 2 THENO- AND TRPC5-TRPC4 heteromultimer). Examples of TRPC5 in FURO 2.3-DIPYRIMIDINE-2,41H,3H-DIONE the literature include the following: Nature. 2008 Jan. 3: 451 DERVATIVES (7174):69-72: Mol Pharmacol. 2008 January: 73 (1):42-9; J Biol Chem. 2007 Nov. 16: 282 (46):33868-78; Biochem RELATED APPLICATIONS Biophys Res Commun. 2008 Jan. 11; 365 (2):239-45: J Biol Chem. 2006 Nov. 3; 281 (44):33487-96: Eur J Pharmacol. The present application is a U.S. Non-Provisional Appli 2005 Mar. 14: 510 (3):217-22; J Biol Chem. 2006 Feb. 24; cation which claims priority to U.S. Provisional Patent 281 (8):4977-82: Biochem Soc Trans. 2007 February: 35 (Pt Application No. 62/035,575, filed Aug. 11, 2014, the entirety 1): 101-4; Handb Exp Pharmacol. 2007: (179): 109-23; J Biol of which applications is hereby incorporated herein by 10 Chem. 2005 Mar. 25; 280 (12):10997-1006; J Physiol. 2006 reference. Jan. 15: 570 (Pt 2):219-35; and Nat Neurosci. (2003) 6: 837-45. FIELD OF THE INVENTION Modulating the function of TRPC5 proteins provides a This invention relates to novel Thieno- and Furo2,3-d 15 means of modulating calcium homeostasis, Sodium homeo pyrimidine-2,41H.3H]-dione derivatives and their use as Stasis, membrane polarization, and/or intracellular calcium TRPC5 modulators, pharmaceutical compositions contain levels, and compounds that can modulate TRPC5 function ing the same, and methods of using the same as agents for are useful in many aspects, including, but not limited to, the treatment of TRPC5 receptor mediated disorders or maintaining calcium homeostasis, modulating intracellular conditions. calcium levels, modulating membrane polarization, and treating or preventing diseases, disorders, or conditions BACKGROUND associated with calcium and/or sodium homeostasis or dys homeostasis. A variety of ion channel proteins exist to mediate ion flux SUMMARY OF THE INVENTION across cellular membranes. The proper expression and func 25 tion of ion channel proteins is essential for the maintenance of cell function, intracellular communication, and the like. The present invention provides compounds of Formula Numerous diseases are the result of misregulation of mem (I): brane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane 30 potential and ion flux in cells, identification of agents that Formula (I) can promote or inhibit particular ion channels are of great O R4 interest as research tools and as possible therapeutic agents. R Cation channels such as TRPC5 modulate the flux of n N N calcium and Sodium ions across cellular membranes. 35 1. R3 Sodium and calcium influx leads to a depolarization of the O A. cell. This increases the probability that Voltage-gated ion channels will reach the threshold required for activation. As R2 a result, activation of non-selective cation channels can increase electrical excitability and increase the frequency of 40 or a pharmaceutically acceptable salt thereof, wherein con Voltage-dependent events. Voltage-dependent events stituent members are provided herein. include, but are not limited to, neuronal action potentials, The present invention further provides compositions com cardiac action potentials, Smooth muscle contraction, car prising a compound of Formula (I) and a pharmaceutically diac muscle contraction, and skeletal muscle contraction. acceptable carrier. Calcium influx caused by the activation of non-selective 45 The present invention further provides methods of treat cation channels such as TRPC5 also alters the intracellular ing a TRPC5 mediated disorder in a Subject, e.g. a human free calcium concentration. Calcium is a ubiquitous second Subject, comprising administering to the Subject a compound messenger molecule within the cell and the alterations in or composition of a compound of Formula (I) or a pharma intracellular calcium levels have profound effects on signal ceutically acceptable salt thereof, to thereby treat the sub transduction and gene expression. Thus, activation of non 50 ject, e.g., a human Subject. selective cation channels such as TRPC5 can lead to changes The present invention provides methods and composi in gene expression and cellular phenotype. Gene expression tions for treating conditions such as a neuropsychiatric events include, but are not limited to, production of mRNAs disorder, a neurodegenerative disorder, nephropathy, and encoding cell Surface receptors, ion channels, and kinases. seizure disorder by modulating the activity of the transient These changes in gene expression can lead to hyperexcit 55 receptor potential cation channel subfamily C, member 5 ability in that cell. (TRPC5), which can exist in homomultimeric form as well Transient receptor potential (TRP) homomeric TRPC5 as heteromultimeric form with other ion channels such as ion channels are signal transduction gated, Ca"-permeable TRPC1 or TRPC3 (i.e., TRPC5-TRPC1 and TRPC1 channels predominantly expressed in the neurons. TRPC5 TRPC3-TRPC5). The compound of Formula (I) modulate forms homomultimeric structures such as tetramers (i.e., 60 the function of TRPC5 by inhibiting a TRPC5-mediated ion TRPC5 homomultimers) and heteromultimeric structures flux or by inhibiting the inward current, the outward current, such as tetramers (i.e., TRPC5-TRPC1 heteromultimers). or both currents mediated by TRPC5. The inhibition of a Unless expressly stated otherwise, when the term TRPC5 is particular current is the ability to inhibit or reduce such used herein, for example, when identifying a modulator of current (e.g., inward and/or outward) in an in vitro or an in TRPC5 such as a TRPC5 antagonist, the term TRPC5 is used 65 vivo assay. The activation of a particular current is the ability generically so as to include either or both of a TRPC5 to activate or increase Such current (e.g., inward and/or homomultimer or a heteromultimer (e.g., TRPC5-TPRC1 or outward) in an in vitro or an in vivo assay. US 9,447,114 B2 3 4 DETAILED DESCRIPTION OF THE In another embodiment, in the general formula I, R. R. INVENTION R. R. R. and A have the same meaning as defined in any of the preceding embodiments and R' is 3-hydroxypropyl; or The present invention provides a compound of Formula a pharmaceutically acceptable salt thereof. (I): 5 In another embodiment, in the general formula I, R. R. R. R. R. and A have the same meaning as defined in any of the preceding embodiments and R is C-C alkyl or Formula (I) C-C hydroxyalkyl, or a pharmaceutically acceptable salt O R4 thereof. R 10 In another embodiment, in the general formula I, R', R, n N N R. R. R. and A have the same meaning as defined in any 1. R3 of the preceding embodiments and R is methyl or 3-hy O A.