US007964607B2 (12) United States Patent (10) Patent No.: US 7.964,607 B2 Verhoest et al. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO3,4-DIPYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460.077 9, 2004 WO 02085904 10, 2002 (75) Inventors: Patrick Robert Verhoest, Old Lyme, CT WO 2004037176 5, 2004 (US); Caroline Proulx-Lafrance, Ledyard, CT (US) OTHER PUBLICATIONS Wunder et al., Mol. Pharmacol., vol. 28, No. 6, (2005), pp. 1776 (73) Assignee: Pfizer Inc., New York, NY (US) 1781. van der Staay et al., Neuropharmacology, vol. 55 (2008), pp. 908 (*) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 U.S.C. 154(b) by 562 days. Primary Examiner — Susanna Moore (74) Attorney, Agent, or Firm — Jennifer A. Kispert; (21) Appl. No.: 12/118,062 Michael Herman (22) Filed: May 9, 2008 (57) ABSTRACT (65) Prior Publication Data The invention provides PDE9-inhibiting compounds of For US 2009/OO3OOO3 A1 Jan. 29, 2009 mula (I), Related U.S. Application Data (I) O (60) Provisional application No. 60/917.333, filed on May R 11, 2007. H N N N (51) Int. Cl. R3 N CO7D 487/04 (2006.01) WS M A 6LX3/59 (2006.01) s' N N A61 P 25/28 (2006.01) R N (52) U.S. Cl. ..................................... 514/262.1; 54.4/262 / (58) Field of Classification Search .................. 544/262: R 51.4/262.1 See application file for complete search history. and pharmaceutically acceptable salts thereof, wherein R. R. (56) References Cited RandR areas defined herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S. PATENT DOCUMENTS treating neurodegenerative and cognitive disorders, such as 2003. O139427 A1 7/2003 Castelhano et al. ....... 514,2611 Alzheimer's disease and Schizophrenia, are also provided. 2004/0176361 A1 9/2004 Fujio et al. ................. 514,224.2 2004/0259870 Al 12/2004 Feng et al. ................. 514,229.2 13 Claims, No Drawings US 7,964,607 B2 1. 2 PYRAZOLO3,4-DIPYRIMIDINE 47:1081-1092 (2004). Inhibition of PDE9 has been shown to COMPOUNDS increase LTP. Hendrix, BMC Pharmacol., 5(Supp. 1):55 (2005). RELATED APPLICATION Accordingly, there is a need for PDE9 inhibitors that are effective in treating conditions that may be regulated or nor This application claims the benefit under 35 U.S.C. S 119 malized by inhibition of PDE9. (e) of U.S. provisional application Ser. No. 60/917.333, filed May 11, 2007. SUMMARY OF THE INVENTION FIELD OF THE INVENTION 10 The present invention is directed to compounds of Formula (I), This invention relates to a series of novel compounds that are selective inhibitors of phosphodiesterase type 9 (“PDE9). More particularly, the invention relates to pyra (I) Zolo3,4-dipyrimidinone compounds for use in the treatment 15 O R and prevention of neurodegenerative diseases and other dis H eases and disorders influenced by modulation of PDE9. n N N BACKGROUND OF THE INVENTION R3 WSls M N s N N Cyclic nucleotides cyclic guanosine monophosphate R N (cGMP) and cyclic adenosine monophosphate (cAMP) are / important second messengers and thus are central to the con R trol and regulation of a multitude of cellular events, both physiological and pathophysiological, in a wide variety of 25 Organs. and pharmaceutically acceptable salts thereof, wherein R. R. Cyclic GMP is formed from GTP by the catalytic reaction R, and R are as defined herein. of guanylyl cyclase (GC), which is activated by nitric oxide The present invention is also directed to compositions con (NO). Cyclic GMP in turn activates cGMP-dependent protein taining a compound of Formula (I), or a pharmaceutically kinases (cGK), which mediate localized and global signaling. 30 acceptable salt thereof, and a pharmaceutically acceptable A variety of physiological processes in the cardiovascular, vehicle, carrier or diluent, and optionally further comprising nervous and immune systems are controlled by the a second pharmaceutical agent. NO/cGMP pathway, including ion channel conductance, gly The present invention is further directed to a method of cogenolysis, cellular apoptosis, and Smooth muscle relax inhibiting PDE9 in a mammal in need of such inhibition, ation. In blood vessels, relaxation of vascular Smooth muscles 35 comprising the step of administering to the mammala PDE9 leads to vasodilation and increased blood flow. inhibiting amount of a) a compound of Formula I, or a phar The phosphodiesterase (PDE) enzyme family hydrolyses maceutically acceptable salt thereof, or b) a pharmaceutical cGMP and cAMP. The PDE9 enzyme has been identified as a composition comprising a compound of Formula I, or a phar novel member of the PDE enzyme family that selectively maceutically acceptable salt thereof, and a pharmaceutically hydrolyses cGMP over cAMP. See Fisher et al., J. Biol. 40 Chem., 273 (25), 15559-15564 (1998). PDE9 has been found acceptable vehicle, carrier or diluent. to be present in a variety of human tissues, namely the testes, The present invention is further directed to a method of brain, Small intestine, skeletal muscle, heart, lung, thymus treating a neurodegenerative disease in a mammal in need of and spleen, as well as in Smooth muscle cells within the Such treatment, comprising the step of administering to the human vasculature of a variety of tissues. 45 mammalatherapeutically effective amount of a compound of Recent studies have directly implicated dysfunction of Formula I, or a pharmaceutically acceptable salt thereof. NO/cGMP/cGK signaling in Alzheimer's disease. For The present invention is further directed to a method of example, disruption of Long Term Potentiation (LTP), a promoting neurorestoration in a mammal in need of Such physiological correlate of learning and memory, by amy neurorestoration, comprising the step of administering to the loid-fi peptide was shown to result from a malfunction of 50 mammalatherapeutically effective amount of a compound of NO/cGMP signaling. Puzzo et al., J. Neurosci., 25(29):6887 Formula I, or a pharmaceutically acceptable salt thereof. 6897 (2005). Moreover, in rats showing deficits in memory The present invention is still further directed to a method of tasks due to depletion in forebrain acetylcholinesterase improving cognitive deficits and treating cognitive impair (which is associated with Alzheimer's disease), administra ment in a mammal in need of such improvement or treatment, tion of a nitric oxide mimetic increased GC activity and 55 comprising the step of administering to the mammal athera reversed the cognitive deficits in memory tasks. Bennett et al., peutically effective amount of a compound of Formula I, or a Neuropsychopharmacology, 32:505-513 (2007). It is there pharmaceutically acceptable salt thereof. fore believed that therapeutic agents capable of enhancing the With the foregoing and other advantages and features of the GC/NO/cGMP/cGK signaling cascade may be useful as a invention that will become hereinafter apparent, the nature of new approach to the treatment of Alzheimer's disease and 60 the invention may be more clearly understood by reference to other neurodegenerative disorders. the following detailed description of the invention and the By reducing or preventing the hydrolysis of c(GMP by appended claims. PDE9, PDE9 inhibitors elevate the intracellular level of cGMP, thus enhancing or prolonging its effects. It has been DETAILED DESCRIPTION OF THE INVENTION found that an increase incGMP concentration in rats leads to 65 improvement in learning and memory in Social and object The present invention comprises novel selective PDE9 recognition tests. See, e.g., Boess et al., Neuropharmacology, inhibitors of Formula (I), US 7,964,607 B2 15 16 The term “aryl' is also intended to include the partially hydro 3-bipyrazinyl), pyridopyridinyl, pyrrolopyrazolyl, dihydro genated derivatives of Such ring systems, e.g. 1.2.3,4-tetrahy pyrrolopyrazolyl (e.g. dihydropyrrolo 1.2-bipyrazolyl), dronaphthyl. quinazolinyl (also known as “1,3-benzodiazinyl'), quinolinyl The term “aryloxy' denotes an aryl radical bonded to an (also known as "1-benzazinyl), isoquinolinyl (also known as oxygen atom that is attached to a core structure. Such as 5 “2-benzazinyl'), quinolizinyl, quinolyl, isoquinolyl, quinox benzyloxy. alinyl, dithianaphthalenyl, thienofuranyl (e.g. thieno3.2-b The term "cycloalkyl denotes a saturated monocyclic or furanyl), and the like. bicyclic cycloalkyl group. Examples of cycloalkyl groups Examples of 3-fused ring heteroaryls include acridinyl, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, diazaanthryl, triaZaphenanthrene, carbazolyl, carbolinyl, cycloheptyl, cyclooctyl, and the like. 10 furocinnolinyl, perimidinyl, phenanthridinyl, phenanthroli The term “halogen' or “halo represents chlorine, bro nyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazi mine, fluorine and iodine atoms and radicals. The term “haloalkyl refers to an alkyl or cycloalkyl sub nyl, thianthrenyl, Xanthenyl, and the like. stituent wherein at least one hydrogen radical is replaced with The term "heterocycloalkyl denotes a saturated monocy a halogen radical. Where more than one hydrogen is replaced 15 clic or polycyclic cycloalkyl group, in which at least one of with halogen, the halogens may be the same or different. the carbon atoms is replaced with a heteroatom such as nitro Examples of haloalkyl radicals include trifluoromethyl, 2.2, gen, oxygen or Sulfur. If the heterocycle contains more than 2-trifluoroethyl, 4.4,4-trifluorobutyl, 4.4-difluorocyclohexyl, one heteroatom, the heteroatoms may be the same or differ chloromethyl, dichloromethyl, trichloromethyl, 1-bromoet ent. The heterocycloalkyl radicals may be bonded via a car hyl, and the like. bon atom or a heteroatom. Examples of heterocycloalkyl The term “haloalkoxy” refers to an alkoxy radical in which groups include aZetidinyl, dioxacyclohexyl, 1,3-dioxolanyl. at least one hydrogen radical is replaced with a halogen radi imidazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyra cal. Where more than one hydrogen is replaced with halogen, Zolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl. the halogens may be the same or different. Examples of tetrahydrothiopyranyl, thiazanyl, and the like.