US007964607B2 (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest et a1. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO[3,4-D]PYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460077 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 a1, M01. PharmacoL, v01. 28, N0. 6, (2005), pp. 1776 (73) Assignee: P?zer Inc., New York, NY (U S) 1781. van der Staay et a1, Neuropharmacology, v01. 55 (2008), pp. 908 ( * ) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 USC 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 2009/0030003 A1 Jan. 29, 2009 mula (I), Related US. Application Data (60) Provisional application No. 60/917,333, ?led on May 11, 2007. (51) Int. Cl. C07D 48 7/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01) (52) US. Cl. ................................... .. 514/262.1; 544/262 (58) Field of Classi?cation Search ................ .. 544/262; 5 1 4/2 62 .1 See application ?le for complete search history. and pharmaceutically acceptable salts thereof, Wherein R, R1, (56) References Cited R2 and R3 are as de?ned herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S. PATENT DOCUMENTS treating neurodegenerative and cognitive disorders, such as 2003/0139427 A1 7/2003 Castelhano et a1. ..... .. 514/2611 AlZheimer’s disease and schizophrenia, are also provided. 2004/0176361 A1 9/2004 Fujio et a1. ............... .. 514/2242 2004/0259870 A1 12/2004 Feng et a1. ............... .. 514/2292 13 Claims, No Drawings US 7,964,607 B2 1 2 PYRAZOLO[3,4-D]PYRIMIDINE 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 bene?t under 35 U.S.C. §119 maliZed by inhibition of PDE9. (e) of Us. provisional application Ser. No. 60/917,333, ?led May 11, 2007. SUMMARY OF THE INVENTION FIELD OF THE INVENTION 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) Zolo[3,4-d]pyrimidinone compounds for use in the treatment and prevention of neurodegenerative diseases and other dis eases and disorders in?uenced by modulation of PDE9. BACKGROUND OF THE INVENTION 20 Cyclic nucleotides cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) are important second messengers and thus are central to the con 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, R1, Cyclic GMP is formed from GTP by the catalytic reaction R2, and R3 are as de?ned 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. Inblood vessels, relaxation of vascular smooth muscles 35 comprising the step of administering to the mammal a PDE9 leads to vasodilation and increased blood How. 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 identi?ed 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 acceptable vehicle, carrier or diluent. Chem, 273(25), 15559-15564 (1998). PDE9 has been found 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 mammal a therapeutically 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-[3 peptide Was shoWn to result from a malfunction of 50 mammal a therapeutically 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 de?cits in memory The present invention is still further directed to a method of tasks due to depletion in forebrain acetylcholinesterase improving cognitive de?cits 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 a thera reversed the cognitive de?cits in memory tasks. Bennett et al., peutically effective amount of a compound of Formula I, or a Neuropsychopharmacology, 321505-513 (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 cGMP 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 in cGMP 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 1 3 1 4 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(4-methyl-3,4 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-propylpyri dihydro-2H-1,4-benZoxaZin-7-yl)methyl]pyrrolidin-3-yl} midin-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyra 1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimidin-4 -one; Zolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(3 -phenylpro 1 -cyclopentyl-6-{(3,4-trans)-1-[(1-ethyl-1H-pyraZol-5 pyl)pyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo [3 ,4-d]pyrimi 5 yl)methyl] -4 -methylpyrrolidin-3 -yl} - 1 , 5 -dihydro -4H-pyra din-4-one; Zolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[2-(tri?uorom 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[2-(tri?uo ethyl)benZyl]pyrrolidin-3 -yl} - 1 ,5 -dihydro-4H-pyraZolo [3, romethoxy)benZyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyra 4-d]pyrimidin-4 -one; Zolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(4,4,4-tri?uo 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(tri?uorom robutyl)pyrrolidin-3-yl]-1,5 -dihydro-4H -pyraZolo [3 ,4-d]py ethyl)benZyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyraZolo[3, rimidin-4-one; 4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-1-(3-methoxybenZyl)-4-me 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(1-methyl-1H thylpyrrolidin-3 -yl]-1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimi imidaZo[4,5-c]pyridin-2-yl)methyl]pyrrolidin-3-yl}-1,5-di din-4-one; hydro-4H-pyraZolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-1-(cyclopentylmethyl)-4 1-cyclopentyl-6-[(3,4-trans)-1-(3,5-di?uorobenZyl)-4 methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py methylpyrrolidin-3 -yl]-1,5-dihydro-4H-pyraZolo[3,4-d]py rimidin-4-one; rimidin-4-one; or 1-cyclopentyl-6-[(3,4-trans)-1-(2,4-dimethoxybenZyl)-4 20 1-cyclopentyl-6-[(3,4-trans)-1-(5,6-dihydro-4H-pyrrolo methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py [1 ,2-b]pyraZol-3 -ylmethyl)-4-methylpyrrolidin-3-yl] -1 ,5 rimidin-4-one; dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(morpholin or a pharmaceutically acceptable salt thereof.