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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 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. 4-ylmethyl)benZyl]pyrrolidin-3-yl } -1 ,5 -dihydro -4H-pyra The compounds of the invention have been surprising ZOlO [3 ,4-d]pyrimidin-4 -one; 25 found to shoW pharmacological activity including in selec 6-[(3,4-trans)-1-(2,1,3 -benZothiadiaZol-5 -ylmethyl)-4 tively inhibiting PDE9 that makes them suitable for the treat methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyra ment, prevention and/ or control of in treating conditions that ZOlO [3 ,4-d]pyrimidin-4 -one; may be regulated or normaliZed by inhibition of PDE9. 6- { (3 ,4-trans)-1 -[2-(benZyloxy)ethyl] -4 -methylpyrroli The compounds and intermediates of the present invention din-3 -yl}-1-cyclopentyl-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py 30 may be named according to either the IUPAC (International rimidin-4-one; Union for Pure and Applied Chemistry) or CAS (Chemical 1-cyclopentyl-6-[(3,4-trans)-1-(2,6-di?uorobenZyl)-4 Abstracts Service, Columbus, OH) nomenclature systems. methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py rimidin-4-one; De?nitions 1-cyclopentyl-6-[(3,4-trans)-1-(2-methoxybenZyl)-4-me 35 thylpyrrolidin-3 -yl]-1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimi Certain terms used herein are generally de?ned as folloWs: din-4-one; The carbon atom content of the various hydrocarbon-con 1-cyclopentyl-6-{ (3,4-trans)-4-methyl-1 -[(3 ,5 ,6-trimeth taining moieties herein may be indicated by a pre?x desig ylpyraZin-2-yl)methyl]pyrrolidin-3 -yl}-1,5 -dihydro-4H nating the minimum and maximum number of carbon atoms pyraZolo [3 ,4-d]pyrimidin-4 -one; 40 in the moiety. Thus, for example, (Cl-C6)alkyl refers to an 1-cyclopentyl-6-[(3,4-trans)-1-(2,4-dichlorobenZyl)-4 alkyl group of one to six carbon atoms inclusive. methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py The term “alkoxy” refers to a straight or branched, rimidin-4-one; monovalent, saturated aliphatic hydrocarbon radical bonded 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(5,6,7,8-tetrahy to an oxygen atom that is attached to a core structure. dro-4H-pyraZolo[1,5-a]aZepin-3 -ylmethyl)pyrrolidin-3 -yl] - 45 Examples of alkoxy groups include methoxy, ethoxy, pro 1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimidin-4 -one; poxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 1-cyclopentyl-6-[(3,4-trans)-1-(3-?uorobenZyl)-4-meth and the like. ylpyrrolidin-3 -yl]-1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimi The term “alkyl” means a saturated monovalent straight or din-4-one; branched aliphatic hydrocarbon radical. Examples of alkyl 1-cyclopentyl-6-[(3,4-trans)-1-(2,3 -dihydro-1-benZofu 50 groups include methyl, ethyl, propyl, isopropyl, butyl, isobu ran-5 -ylmethyl) -4 -methylpyrrolidin-3 -yl]-1,5 -dihydro -4H tyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, pyraZolo [3 ,4-d]pyrimidin-4 -one; isohexyl, and the like. 1-cyclopentyl-6-[(3 ,4-trans)-1 -(2-methoxy-5 -methylben The term “alkenyl” means a partially unsaturated straight Zyl)-4-methylpyrrolidin-3 -yl]-1,5-dihydro-4H-pyraZolo[3, or branched aliphatic hydrocarbon radical having one or more 4-d]pyrimidin-4 -one; 55 double bonds. Examples of alkenyl groups include ethenyl 1-cyclopentyl-6-[(3,4-trans)-1-(2-?uorobenZyl)-4-meth (also knoWn as “vinyl”), allyl, 1-propenyl, isopropenyl, ylpyrrolidin-3 -yl]-1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimi n-butenyl, n-pentenyl, and the like. The term “alkenyl” din-4-one; embraces radicals having “cis” and “trans” orientations, or 6- [(3,4-trans)-1 -(2 -chlorobenZyl)-4-methylpyrrolidin-3 - alternatively, “Z” and “E” orientations. yl]-1-cyclopentyl-1,5 -dihydro-4H-pyraZolo[3 ,4-d]pyrimi 60 The term “alkynyl” means a partially unsaturated straight din-4-one; or branched aliphatic hydrocarbon radical having one or more 1-cyclopentyl-6-[(3,4-trans)-1-(3,4-dichlorobenZyl)-4 double bonds. Examples of alkynyl groups include 1-propy methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py nyl, 2-propynyl (also knoWn as “propargyl”), 1-butynyl, rimidin-4-one; 2-butynyl, 1-pentynyl, and the like. 6-[(3,4-trans)-1-(2,1,3 -benZothiadiaZol-4-ylmethyl)-4 65 The term “aryl” denotes a monocyclic or polycyclic aro methylpyrrolidin-3-yl]-1-cyclopentyl-1,5-dihydro-4H-pyra matic ring system, for example, anthracenyl, benZyl, ?uore ZOlO [3 ,4-d]pyrimidin-4 -one; nyl, indenyl, naphthyl, phenanthrenyl, phenyl and the like. US 7,964,607 B2 15 16 The term “aryl” is also intended to include the partially hydro 3-b]pyraZinyl), pyridopyridinyl, pyrrolopyraZolyl, dihydro genated derivatives of such ring systems, eg 1,2,3,4-tetrahy pyrrolopyraZolyl (e.g. dihydropyrrolo[1,2-b]pyraZolyl), dro nap hthyl . 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 “2-benZaZinyl”), quinoliZinyl, quinolyl, isoquinolyl, quinox benZyloxy. alinyl, dithianaphthalenyl, thienofuranyl (e.g. thieno[3,2-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. furocinnolinyl, perimidinyl, phenanthridinyl, phenanthroli The term “halogen” or “halo” represents chlorine, bro nyl, phenaZinyl, phenothiaZinyl, phenoxathiinyl, phenoxaZi mine, ?uorine 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 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 tri?uoromethyl, 2,2, gen, oxygen or sulfur. If the heterocycle contains more than 2-tri?uoroethyl, 4,4,4-tri?uorobutyl, 4,4-di?uorocyclohexyl, 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. 20 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. haloalkoxy radicals include di?uoromethoxy, tri?uo 25 A cyclic group may be bonded to another group in more romethoxy, 2,2,2-tri?uoroethoxy, chloromethoxy, bro than one Way. If no particular bonding arrangement is speci momethoxy, and the like. ?ed, then all possible arrangements are intended. For The term “heteroaryl” as used herein includes heterocyclic example, the term “pyridyl” includes 2-, 3- or 4-pyridyl (2-, unsaturated ring systems containing one or more heteroatoms 3-, or 4-pyridinyl). such as nitrogen, oxygen, and sulfur. If the heteroaryl group 30 The term “mammal” means animals including, for contains more than one heteroatom, the heteroatoms may be example, dogs, cats, coWs, sheep, goats, horses and humans. the same or different. The heteroaryl radicals may be bonded Preferred mammals include humans. via a carbon atom or a heteroatom. The term “heteroaryl” is The term “oxo” means a carbonyl group formed by the also intended to include the partially hydrogenated deriva combination of a carbon atom and an oxygen atom. tives of such ring systems. Examples of heteroaryl groups 35 The term “patient” includes both human and non-human include furanyl (also knoWn as “furyl”), imidaZolinyl, imida patients. Zolyl (also knoWn as “1,3-diaZolyl”), indolyl, oxadiaZolyl, The phrase “pharmaceutically acceptable” indicates that oxaZinyl, oxaZolyl, isoxaZolyl, pyranyl, pyraZinyl (also the designated carrier, vehicle, diluent, and/or salt is generally knoWn as “1,4-diaZinyl”), pyraZolyl (also knoWn as “1,2 chemically and/or physically compatible With the other ingre diaZolyl”), pyraZolinyl, pyraZyl, pyridaZinyl (also knoWn as 40 dients comprising the formulation, and physiologically com “1,2-diaZinyl”), pyridyl (also knoWn as pyridinyl), pyrimidi patible With the recipient thereof. nyl (also knoWn as “1,3 diaZinyl” and “pyrimidyl”), pyrrolyl, The term “salts” refers to both organic and inorganic salts thiadiaZinyl, thiadiaZolyl, thiatriaZolyl, thiaZolyl, isothiaZ of a compound of Formula (1). Such salts can be prepared in olyl, thienyl, thiofuranyl (also knoWn as “thiophenyl”), thi situ during the ?nal isolation and puri?cation of a compound, opyranyl, triaZinyl, triaZolyl, and the like. 45 or by separately reacting a compound, or stereoiso The term “heteroaryl” also embraces radicals in Which 2 or mer of Formula (I) With a suitable organic or inorganic acid or 3 rings are fused together, Wherein at least on such ring base and isolating the salt thus formed. Representative contains a heteroatom as a ring atom, including radicals anionic salts include hydrobromide, hydrochloride, hydroio Wherein (a) a heterocycloalkyl ring is fused With an aryl or dide, sulfate, bisulfate, nitrate, acetate, tri?uoroacetate, heteroaryl ring, or (b) a cycloalkyl ring is fused With a het 50 oxalate, besylate, palmitate, pamoate, malonate, stearate, lau eroaryl ring. Examples of 2-fused ring heteroaryls include rate, malate, borate, benZoate, lactate, phosphate, hexa?uo benZodioxinyl, dihydrobenZodioxinyl, benZofuranyl, dihy rophosphate, sulfonate, tosylate, formate, citrate, drobenZofuranyl, isobenZofuranyl, benZimidaZolyl, ben maleate, fumarate, succinate, tartrate, naphthylate, mesylate, ZothiadiaZolyl, tetrahydrobenZothiadiaZolyl, benZothiaZolyl, glucoheptonate, lactobionate and laurylsulphonate salts and benZothienyl (also knoWn as “benZothiophenyl,” “thionaph 55 the like. Representative cationic salts include sodium, potas thenyl,” and “benZothiofuranyl”), benZoxaZinyl, dihydroben sium, calcium, and salts and the like. See gener ZoxaZinyl, benZoxaZolyl, chromanyl, isochromanyl, chrome ally, e.g., Berge, et al., J. Pharm. Sci., 66, 1-19 (1977). nyl, cinnolinyl (also knoWn as “1,2-benZodiaZinyl”), A salt of a compound of Formula (I) may be readily pre imidaZopyridinyl (e. g. imidaZo[1,2-a]pyridinyl or imidaZo [4, pared by mixing together solutions of a compound of Formula 5-c]pyridinyl), indaZolyl, indolinyl, isoindolinyl, indoliZinyl, 60 (I) and the desired acid or base, as appropriate. The salt may indolyl, isoindolyl, naphthyridinyl, oxathiolopyrrolyl, pte precipitate from solution and be collected by ?ltration or may ridinyl, pthalaZinyl, purinyl (also knoWn as “imidaZo[4,5-d] be recovered by evaporation of the solvent. pyrimidinyl”), pyranopyrrolyl, pyraZoloaZepinyl, tetrahydro The term “radical” denotes a group of atoms that behaves pyraZoloaZepinyl (e.g. tetrahydropyraZolo[1,5-a]aZepinyl), as a single reactant in a chemical reaction, e. g., an organic pyraZolopyridinyl, tetrahydropyraZolopyridinyl (e.g. tetrahy 65 radical is a group of atoms that imparts characteristic prop dropyraZolo[1,5-a]pyridinyl), pyraZolopyrimidinyl (e.g. erties to a compound containing it, or Which remains pyraZolo[3,4-d]pyrimidinyl), pyridopyraZinyl (e.g. pyrido [2, unchanged during a series of reactions or transformations. US 7,964,607 B2 17 18 The symbol “i” represents a covalent bond. metabolism or hydrolysis) during its residence time in the The phrase “reaction-inert solvent” or “inert solvent” body. A discussion of the preparation and use of is refers to a solvent, or mixture of solvents, that does not provided by Higuchi & Stella, “Prodrugs as Novel Delivery interact With starting materials, reagents, intermediates or Systems”, Vol. 14 of the ACS Symposium Series, and in products in a manner that adversely affects their desired prop “Bioreversible Carriers in Drug Design,” ed. EdWard B. er‘ties. Roche, American Pharmaceutical Association and Pergamon The terms “treat, treating,” “treated” or “treatment” as Press, 1987. All prodrugs of the various compounds of For used herein includes preventative (e.g., prophylactic), pallia mula (I) are Within the scope of the present invention. tive or curative uses or results. The present invention also embraces isotopically-labeled The compounds of Formula (I) may contain asymmetric or compounds of Formula (I) that are identical to those recited herein, but for the fact that one or more atoms are replaced by chiral centers and, therefore, exist in different stereoisomeric an atom having an atomic mass or mass number different forms. Those skilled in the art Will appreciate that, unless from the atomic mass or mass number usually found in otherWise speci?ed, all stereoisomers (e.g., enantiomers and nature. Examples of isotopes that can be incorporated into diastereoisomers, and racemic mixtures thereof) of the novel compounds of Formula (I) include isotopes of hydrogen, compounds and intermediates described, illustrated and/or carbon, nitrogen, oxygen, phosphorus, ?uorine, and chlorine, discussed herein are Within the scope of the claimed inven Such as 2H’ 3H’ 13C’ 14C’ ISN, 180, 170’ 31R 32R 35S’ 18F and tion. In addition, unless otherWise speci?ed, the present 36Cl, respectively. The compounds of Formula (I), and phar invention embraces all geometric and positional isomers. The maceutically acceptable salts thereof, that contain the afore (3S,4S) enantiomer of the core pyrrolidinyl con?guration is 20 mentioned isotopes and/or other isotopes of the other atoms preferred. are Within the scope of the instant invention. Diasteriomeric mixtures can be separated into their indi Certain isotopically-labeled compounds of Formula (I), for vidual diastereomers on the basis of their physical chemical example those into Which radioactive isotopes such as 3H and differences by methods Well-knoWn to those of ordinary skill 14C are incorporated, are useful in drug and/or substrate tissue in the art, such as by chromatography and/ or fractional crys 25 distribution assays. Tritiated, i.e., 3H and 14C, isotopes are talliZation. Enantiomers can be separated by converting the particularly preferred for their ease of preparation and detect enantiomeric mixture into a diasteriomeric mixture by reac ability. Furthermore, substitution With heavier isotopes such tion With an appropriate optically active compound (e.g., as deuterium, i.e., 2H, may afford certain therapeutic advan ), separating the diastereomers and converting (e.g., tages resulting from greater metabolic stability, for example, hydrolyZing) the individual diastereomers to the correspond 30 increased in vivo half-life, or reduced dosage requirements ing pure enantiomers. Additional methods include resolution and, hence, may be preferred in some circumstances. Isoto of racemic mixtures using chiral salts, as Well as chiral chro pically-labeled compounds of Formula (I), and pharmaceuti matography. cally acceptable salts thereof, can be generally prepared by Those skilled in the art Will further recogniZe that the carrying out analogous procedures to those disclosed in the compounds of Formula (I) can exist in crystalline form as 35 Schemes and/or in the Examples beloW, by substituting a hydrates Wherein molecules of Water are incorporated Within readily available isotopically-labeled reagent for a non-iso the crystal structure thereof and as solvates Wherein mol topically labeled reagent. ecules of a solvent are incorporated therein. All such hydrate The invention also includes pharmaceutical compositions and solvate forms are considered part of this invention. comprising an amount of a compound of Formula (I), or a Practitioners Will appreciate that certain compounds of 40 pharmaceutically acceptable salt of the compound, and Formula (I) may exist as tautomeric isomers, i.e., that equi optionally a pharmaceutically acceptable vehicle, carrier or librium exists betWeen tWo isomers Which are in rapid equi diluent. In a preferred embodiment, the pharmaceutical com librium With each other. A common example of tautomerism position is of an amount effective at inhibiting the enZyme is keto-enol tautomerism, i.e., PDE9 in a mammal. In another preferred embodiment, the 45 mammal is a human. The present invention includes the use of a combination of a PDE9 inhibitor compound as provided in Formula (I) and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may 50 be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accord ingly, the present invention also includes pharmaceutical compositions comprising an amount of: (a) a ?rst agent com prising a compound of Formula (I) or a pharmaceutically The degree to Which one tautomer is present over the other 55 acceptable salt of the compound; (b) a second pharmaceuti depends upon various factors, including substitution pattern cally active agent; and (c) a pharmaceutically acceptable car and solvent type. Other examples in accordance With the rier, vehicle or diluent. present invention Will be recogniZed by those skilled in the Various pharmaceutically active agents may be selected for art. All tautomeric forms of Formula (I) are included Within use in conjunction With the compounds of Formula (I), the scope of the invention unless otherWise speci?ed. 60 depending on the disease, disorder, or condition to be treated. The present invention also includes prodrugs of the com Pharmaceutically active agents that may be used in combina pounds of the invention. The term “prodrug” refers to a drug tion With the compositions of the present invention include, precursor Which, folloWing administration, releases the drug Without limitation: in vivo via a chemical or physiological process (e.g., upon (i) acetylcholinesterase inhibitors, such as being brought to physiological pH or through enZymatic 65 hydrochloride (E2020, ARICEPT, MEMAC), physostigmine activity). The prodrug may itself be biologically active, or salicylate (ANTILIRIUM), physostigmine sulfate (ES may be converted to a biologically active compound (eg by ERINE), metrifonate, neostigmine, pyridostigmine (MESTI US 7,964,607 B2 19 20 NON), ambenonium (MYTELASE), demarcarium, (DETROL), (DITROPAN, LYRINEL Debio992 (also known as ZT-l), (EXELON), XL, OXYTROL), penthienate bromide, propantheline (PRO ladostigil (also known as TV3326), NP-0361, BANTHINE), , hydrochloride (TOF hydrobromide (RAZADYNE, RIMINYL, NIVALIN), RANIL), imipramine maleate (SURMONTIL), , (COGNEX), velnacrine maleate, memoquin, (NORPRAMIN), (SINEQUAN, (HUP-A), phenserine, and edrophonium (EN ZONALON), (SURMONTIL), and glycopyr LON, TENSILON); rolate (ROBINUL); (ii) amyloid-[3 (or fragments thereof), such as A6145 con (viii) anticonvulsants, such as carbamaZepine (TEGRE jugated to pan HLA DR-binding epitope (PADRE), ACC TOL, CARBATROL), oxcarbaZepine (TRILEPTAL), pheny 001, ACl-Ol, ACl-24, AN-1792, Af?tope AD-Ol, CAD106, toin sodium (PHENYTEK), fosphenytoin (CEREBYX, and V-950; PRODILANTIN), divalproex sodium (DEPAKOTE), gabap (iii) antibodies to amyloid-[3 (or fragments thereof), such as entin (NEURONTIN), pregabalin (LYRICA), topirimate bapineuZumab (also knoWn as AAB-001), AAB-002, ACI (TOPAMAX), valproic acid (DEPAKENE), valproate 01-Ab7, BAN-2401, intravenous lg (GAMMAGARD), sodium (DEPACON), 1-benZyl-5-bromouracil, progabide, LY2062430 (humanized m266), PF-04360365 (also knoWn beclamide, and primidone (MYSOLINE); as RN-1219), RN-6G, R-1450, ACU-5A5, huC091, and those (ix) , such as (also knoWn as disclosed in International Patent Publication Nos WO04/ SM-13496), (ABILIFY), 032868, WO05/025616, WO06/036291, WO06/069081, (THORAZINE), (HALDOL), ?upentixol WO06/118959, in US Patent Publication Nos US2003/ decanoate (DEPIXOL, FLUANXOL), (SER 0073655, US2004/0192898, US2005/0048049, US2005/ 20 PLAN), (ORAP), ?uphenaZine decanoate, 0019328, in European Patent Publication Nos EP0994728 ?uphenaZine hydrochloride, (COMPRO), and 1257584, and in US. Pat. No. 5,750,349; , (LOXITANE), , molindone (iv) amyloid-lowering or -inhibiting agents (including (MOBAN), , , thiothixine, tri?uop those that reduce amyloid accumulation and ?brilliZation) eraZine (STELAZINE), (CLOZARIL), norcloZap such as bisnorcymserine (also knoWn as BNC), pioglitaZone, 25 ine (ACP-104), (RISPERDAL), PBT2, ?urbiprofen (ANSAID, FROBEN) and its R-enanti (INVEGA), , (ZYPREXA), omer taren?urbil (also knoWn as MPC-7869; FLURIZAN), (SEROQUEL), , sulpiride (MERESA, DOG nitro?urbiprofen, fenoprofen (FENOPRON, NALFON), ibu MATYL, SULPITIL), , (GEODON), profen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysinate, (LONASEN), and ; meclofenamic acid, meclofenamate sodium (MECLOMEN), 30 (x) calcium channel blockers such as nilvadipine (ESCOR, indomethacin (INDOCIN), diclofenac sodium NIVADIL), amlodipine (NORVASC, ISTIN, AMLODIN), (VOLTAREN), diclofenac potassium, sulindac (CLINO felodipine (PLENDIL), nicardipine (CARDENE), nifedipine RIL), sulindac sul?de, di?unisal (DOLOBID), naproxen (ADALAT, PROCARDIA), MEM 1003 and its parent com (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), pound nimodipine (NIMOTOP), nisoldipine (SULAR), insulin-degrading enZyme (also knoWn as insulysin), the 35 nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine gingko biloba extract EGb-761 (ROKAN, TEBONIN), tra (ZANIDIP), diltiaZem (CARDIZEM), verapamil (CALAN, miprosate (NC-758, CEREBRIL, ALZHEMED), eprodisate VERELAN), and enecadin (also knoWn as NS-7); (NC-503, FIBRILLEX, KIACTA), compound W (3,5-bis(4 (xi) catechol O-methyltransferase (COMT) inhibitors, nitrophenoxy)benZoic acid), NGX-96992, neprilysin (also such as tolcapone (TASMAR), entacapone (COMTAN), and knoWn as neutral endopeptidase (N EP)), scyllo-inositol (also 40 tropolone; knoWn as scyllitol, ELND005, AZD-103), atorvastatin (LIPI (xii) central nervous system stimulants, such as , TOR), simvastatin (ZOCOR), KLVFF-(EEX)3, and RAGE phenmetraZine, phendimetraZine, pemoline, fencamfamine ( for advanced glycation end-products) inhibitors; (GLUCOENERGAN, REACTIVAN), fenethylline (CAP (v) - receptor , such as TAGON), pipradol (MERETRAN), deanol (also knoWn as (CATAPRES), (ARAMINE), (AL 45 dimethylaminoethanol), (DAYTRANA), DOMET, DOPAMET, NOVOMEDOPA), methylphenidate hydrochloride (RITALIN), dexmeth (ZANAFLEX), (also knoWn as neosyneph ylphenidate (FOCALIN), (alone or in combi rine), , , (INTUNIV), nation With other CNS stimulants, e.g. ADDERALL (am , , moda?nil (PROVIGIL), adra?nil, and phetamine aspartate, amphetamine sulfate, armoda?nil (NUVIGIL); 50 dextroamphetamine saccharate, and dextroamphetamine sul (vi) beta- blocking agents (beta block fate)), dextroamphetamine sulfate (DEXEDRINE, DEX ers), such as , esmolol (BREVIBLOC), TROSTAT), (DESOXYN), lisdexamfe (NORMODYNE, TRANDATE), (LARACOR, tamine (VYVANSE), and benZphetamine (DIDREX); TRASACOR), (V ISKEN), propanolol (IN (xiii) corticosteroids, such as prednisone (STERAPRED, DERAL), (BETAPACE, SOTALEX, SOTACOR), 55 DELTASONE), prednisolone (PRELONE), predisolone (BLOCADREN, TIMOPTIC), (SEC acetate (OMNIPRED, PRED MILD, PRED FORTE), pred TRAL, PRENT), (CORGARD), tartrate nisolone sodium phosphate (ORAPRED ODT), methylpred (LOPRESSOR), metoprolol succinate (TOPROL-XL), nisolone (MEDROL); methylprednisolone acetate (DEPO (TENORMIN), butoxamine, and SR 59230A MEDROL), and methylprednisolone sodium succinate (Sano?); 60 (A-METHAPRED, SOLU-MEDROL); (vii) , such as amitniptyline (ELAVIL, (xiv) receptor agonists, such as ENDEP), , benZtropine mesylate (COGENTIN), (APOKYN), (PARLODEL), (ARTANE), (DOSTINEX), dihydrexidine, , (BENADRYL), (NORFLEX), , fenoldopam (CORLOPAM), (DOPERGIN), per (ATROPEN), (TRANSDERM 65 golide (PERMAX), (TRIVASTAL, TRASTAL), SCOP), scopolamine methylbromide (PARMINE), dicyclo (MIRAPEX), quinpirole, (REQUIP), verine (BENTYL, BYCLOMINE, DIBENT, DILOMINE, and (NEUPRO); US 7,964,607 B2 21 22 (xv) dopamine receptor antagonists, such as (xxiv) muscarinic receptor (particularly M1 subtype) ago (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperi nists, such as bethanechol chloride (DUVOID, URECHO dol (INAPSINE, DRIDOL, DROPLETAN), domperidone LINE), pilocarpine (SALAGEN), NGX267, , (MOTILIUM), L-741742, L-745870, raclopride, SCH L-687306, L-689660, furtrethonium iodide (FURAMON, 23390, ecopipam, SKF-83566, and FURANOL), furtrethonium benZensulfonate, furtrethonium (REGLAN); p-toluenesulfonate, McN-A-343, oxotremorine, and carba (xvi) dopamine reuptake inhibitors such as chol (CARBASTAT, MIOSTAT, CARBOPTIC); maleate (MERITAL), (also known as GBR (xxv) nicotinic receptor agonists, such as , 12909) and its decanoate ester DBL-583, and ; ABT-089, ABT-594, AZD-0328, R4996 (also known as (xvii) gamma-amino-butyric acid (GABA) receptor ago MEM-63908), TC-5619, and EVP-6124; nists, such as baclofen (LIORESAL, KEMSTRO), pentobar (xxVi) neuroprotective drugs such as 2,3,4,9-tetrahydro bital (NEMBUTAL), progabide (GABRENE), and clom 1H-carbaZol-3-one oxime, AL-108, ACD3480 (also known ethiaZole; as TC-1734), bis(4-[3-D-glucopyranosyloxybenZyl)-2-[3-D (xviii) immunomodulators such as glatiramer acetate (also glucopyranosyl-2-isobutyltartrate (also known as dactylorhin known as copolymer- 1; COPAXONE), MBP-8298 (synthetic B or DHB), @(APRILA), dimeboline hydrochlo myelin basic protein peptide), dimethyl fumarate, ?ngolimod ride (DIMEBON), disufenton (NXY-059, CEROVIVE), (also known as FTY720), roquinimex (LINOMIDE), laqui arundic acid (ONO-2506, PROGLIA, CEREACT), nimod (also known as ABR-215062 and SAIK-MS), ABT (also known as 5'-diphosphocholine), edaravone 874 (human anti-IL-12 antibody), rituximab (RITUXAN), 20 (RADICUT), AEOL-10150, AGY-94806 (also known as alemtuZumab (CAMPATH), dacliZumab (ZENAPAX), and SA-450 and Msc-l), granulocyte-colony simulating factor nataliZumab TSABRI); (AX-200), BAY-387271 (also known as KN-387271), DP (xix) immunosuppressants such as methotrexate (TREX b99, HF-0220 (17-[3-hydroxyepiandrosterone), HF-0420 ALL, RHEUMATREX), mitoxantrone (N OVANTRONE), (also known as oligotropin), pyridoxal 5'-phosphate (also mycophenolate mofetil (CELLCEPT), mycophenolate 25 known as MC-l), microplasmin, S-18986, (also sodium (MYFORTIC), aZathioprine (AZASAN, IMURAN), known as SUN-N4057), NP031 1 12, L-seryl-L-methionyl-L mercaptopurine (PURI-NETHOL), cyclophosphamide alanyl-L-lysyl-L-glutamyl-glycyl-L-Valine, and SUN (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), N8075; cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, (xxvii) (noradrenaline) reuptake inhibi etanercept (ENBREL), and 4-benZyloxy-5-((5-undecyl-2H 30 tors, such as (STRATTERA), doxepin pyrrol-2-ylidene)methyl)-2,2'-bi-lH-pyrrole (also known as (APONAL, ADAPIN, SINEQUAN), (AVEN PNU-l 5 6804); TYL, PAMELOR, NORTRILEN), (ASENDIN, (xx) interferons, including interferon beta-1a (AVONEX, DEMOLOX, MOXIDIL), (EDRONAX, VES REBIF) and interferon beta-1b (BETASERON, TRA), (V IVALAN), (DEPRILEPT, BETAFERON); 35 LUDIOMIL, PSYMION), (WELLBUTRIN), and (xxi) levodopa (or its methyl or ethyl ester), alone or in radaxa?ne; combination with a DOPA decarboxylase inhibitor (e.g. car (xxviii) other PDE9 inhibitors, such as BAY 73-6691 and bidopa (SINEMET, CARBILEV, PARCOPA, V1512), those disclosed in US Patent Publication Nos US2003/ benseraZide (MADOPAR), ot-methyldopa, mono?urometh 0195205, US2004/02201 86, US2006/01 1 1372, and US2006/ yldopa, di?uoromethyldopa, brocresine, or m-hydroxyben 40 0106035; ZylhydraZine); (xxix) other phosphodiesterase (PDE) inhibitors, including (xxii) N-methyl-D-aspartate (NMDA) receptor antago (a) PDEl inhibitors (e. g. (CAVINTON, CERAC nists, such as (NAMENDA, AXURA, EBIXA), TIN, INTELECTOL) and those disclosed in US. Pat. No. (SYMMETREL), acamprosate (CAMPRAL), 6,235,742), (b) PDE2 inhibitors (e.g. erythro-9-(2-hydroxy (also known as PD-196,860 or CI-1041), ket 45 3-nonyl)adenine (EHNA), BAY 60-7550, and those amine (KETALAR), (also known as NPS 1506), described in US. Pat. No. 6,174,884), (c) PDE4 inhibitors (also known as HU-211), , (e.g. , Ro 20-1724, (KETAS), , (also known as CP-101,606), (also known as RP73401), CDP840, (ARIFLO), himantane, idantadol (also known as V-3381), lancicemine ro?umilast, to?milast, oglemilast (also known as GRC 3886), (also known as AR-R 15896), (DROMORAN), 50 tetomilast (also known as OPC-6535), lirimifast, theophyl , (DOLOPHINE), (also known as line (UNIPHYL, THEOLAIR), (also known as MRZ 2/579), , , tianeptine LAS-31025), , RPR-122818, or ), (STABLON), (also known as MK-801), , and (d) PDE5 inhibitors (e.g. sildena?l (VIAGRA, REVA , , riluZole (RILUTEK), TIO), tadala?l (CIALIS), Vardena?l (LEVITRA, (CERESTAT), , and remacimide; 55 VIVANZA), udena?l, avana?l, (PERSAN (xxiii) monoamine oxidase (MAO) inhibitors, such as sel TINE), E-4010, E-4021, E-8010, , P13489791, egiline (EMSAM), selegiline hydrochloride (I-deprenyl, UK-357903, DA-8159, and those disclosed in International ELDEPRYL, ZELAPAR), dimethylselegilene, brofaromine, Patent Applications WO05/049616, WO06/ 120552, and phenelZine (NARDIL), tranylcypromine (PARNATE), WO07/122466); moclobemide (AURORIX, MANERIX), be?oxatone, sa?na 60 (xxx) quinolines, such as quinine (including its hydrochlo mide (also known as PNU-151774E), isocarboxaZid (MAR ride, dihydrochloride, sulfate, bisulfate and gluconate salts), PLAN), nialamide (NIAMID), rasageline (AZILECT), ipro chloroquine, hydroxychloroquine (PLAQUENIL), me?o niaZide (MARSILID, IPROZID, IPRONID), iprocloZide, quine (LARIAM), and amodiaquine (CAMOQUIN, FLA toloxatone (HUMORYL, PERENUM), , desox VOQUINE); ypeganine, (also known as telepathine or banaster 65 (xxxi) [3-secretase inhibitors, such as WY-25105, (+) ine), , lineZolid (ZYVOX, ZYVOXID), and par phenserine tartrate (POSIPHEN), LSN-2434074 (also known gyline (EUDATIN, SUPIRDYL); as LY-2434074), PNU-33312, KMI-574, SCH-745966, Ac US 7,964,607 B2 23 24 rER (N2-acetyl-D-arginyl-L-arginine), loxistatin (also aphasia), Gerstmann-Straiissler-Scheinker disease, glau known as E64d), and CA074Me; coma, Huntington’s disease (chorea), HIV-associated (xxxii) y-secretase inhibitors, such as LY-411,575,LY-685, , hyperkinesias, Kennedy’s disease, Korsakoff s 458, ELAN-G, ELAN-Z, 4-chloro-N-[2-ethyl-1(S)-(hy syndrome (amnesic-confabulatory syndrome), Krabbe’s dis droxymethyl)butyl]benZenesulfon-amide; ease, Lewy body dementia, logopenic progressive aphasia, (xxxiii) (5-hydroxytryptamine) 1A (5-HTlA) Machado-Joseph disease (spinocerebellar ataxia type 3), receptor antagonists, such as , levo-pindolol, BMY multiple sclerosis, multiple system atrophy (olivopontocer 7378, NAD-299, S(—)-UH-301, NAN 190, WAY 100635, ebellar atrophy), myasthenia gravis, Parkinson’ s disease, Pel (also known as SRA-333); iZaeus-MerZbacher disease, Pick’s disease, pre-senile (xxxiv) serotonin (5 -hydroxytryptamine) 6 (5-HT6) recep dementia (mild cognitive impairment), primary lateral scle tor antagonists, such as (TORVOL, BOLVIDON, rosis, primary progressive aphasia, radiation-induced demen NORVAL), methiothepin (also known as ), tia, Refsum’s disease (phytanic acid storage disease), Sand ,ALX-1161,ALX-1175, MS-245, LY-483518 (also hoff disease, Schilder’s disease, schizophrenia, semantic known as SGS518), MS-245, Ro 04-6790, RO 43-68544, Ro dementia, senile dementia, Shy-Drager syndrome, spinocer 63-0563, RO 65-7199, Ro 65-7674, SB-399885, SB-214111, ebellar ataxias, spinal muscular atrophies, Steele-Richard SB-258510, SB-271046, SB-357134, SB-699929, son-OlsZewski disease (progressive supranuclear palsy), SB-271046, SB-742457 and PRX-07034; tabes dorsalis, tardive dyskinesia, vascular amyloidosis, and (xxxv) serotonin (5-HT) reuptake inhibitors such as ala vascular dementia (multi-infarct dementia). proclate, (CELEXA, CIPRAMIL), Preferably the neurodegenerative disease or disorder is (LEXAPRO, CIPRALEX), (ANAFRANIL), 20 AlZheimer’s disease. (CYMBALTA), (MALEXIL), fen?u Other conditions and disorders associated with PDE9 that ramine (PONDIMIN), norfen?uramine, ?uoxetine may be treated or controlled by the methods of the present (PROZAC), ?uvoxamine (LUVOX), , invention include disorders of the urogenital system such as (IXEL), (PAXIL, SEROXAT), sexual dysfunction, attention de?cit disorder (ADD), atten (ZOLOFT, LUSTRAL), (DESYREL, MOLI 25 tion de?cit hyperactivity disorder (ADHD), diabetes, cardio PAXIN), (EFFEXOR), (NORMUD, vascular disorders or diseases such as systemic hypertension, ZELMID), , (PRISTIQ), bra pulmonary hypertension, congestive heart failure, coronary sofensine, and ; artery disease, atherosclerosis, , thrombosis, conditions (xxxvi) trophic factors, such as nerve growth factor (NGF), of reduced blood vessel patency (e.g. post-percutaneous basic ?broblast growth factor (bFGF), neurotrophin-3 (NT 30 transluminal coronary angioplasty), peripheral vascular dis 3), brain-derived neurotrophic factor (BDNF), and glial-de ease, renal disease, angina (including stable, unstable, and rived neurotrophic factor (GDNF), and agents that stimulate variant (Prinzmetal) angina), and any condition where local production of trophic factors, such as , improved blood ?ow leads to improved end organ function. idebenone, and AlT-082 (N EOTROFIN); and the like. The present invention also relates to methods for promot The invention also includes methods of inhibiting PDE9 in 35 ing neurorestoration and functional recovery in patients suf a mammal comprising administering to the mammal in need fering from traumatic or non-traumatic injury to the brain, of such inhibition a PDE9 inhibiting amount of: (a) a com spinal cord or peripheral nerves. Traumatic brain injuries pound of Formula (I), or a pharmaceutically acceptable salt include both closed head injuries (in which the skull is not thereof; or (b) a pharmaceutical composition comprising a broken) and open, or penetrating, head injuries (in which an compound of Formula (I), or a pharmaceutically acceptable 40 object pierces the skull and breaches the dura mater), wherein salt thereof, in a pharmaceutically acceptable vehicle, carrier sudden trauma (e.g., accidents, falls, assaults) causes damage or diluent; either alone or in combination with a second agent to the brain tissue by tearing, stretching, bruising, or swelling. as described above. Causes of non-traumatic brain injuries include aneurism, The invention also includes methods of treating conditions stroke, meningitis, oxygen deprivation due to anoxia, mediated by PDE9 inhibition in a mammal comprising 45 hypoxia, or ischemia, brain tumor, infection (e.g. encephali administering to the mammal in need of such treatment a tis), poisoning, substance abuse, and the like. The present therapeutically effective amount of: (a) a compound of For invention is useful for the treatment of cognitive impairment mula (I), or a pharmaceutically acceptable salt thereof; or (b) and cognitive dysfunction resulting from brain injuries as a pharmaceutical composition comprising a compound of well as from neurodegenerative diseases and disorders. Formula (I), or a pharmaceutically acceptable salt thereof, in 50 The present invention also relates to methods for prevent a pharmaceutically acceptable vehicle, carrier or diluent; ing the above-described conditions in a mammal, including either alone or in combination with a second agent described human, comprising the steps of administering to the mammal above. an amount of: (a) a compound of Formula (I), or a pharma Conditions that may be treated, controlled or prevented by ceutically acceptable salt thereof; or (b) a pharmaceutical the methods of the present invention include diseases and 55 composition comprising a compound of Formula (I), or a disorders associated with neurodegeneration such as: Alex pharmaceutically acceptable salt thereof, in a pharmaceuti ander disease, Alper’s disease, AlZheimer’s disease, amyo cally acceptable vehicle, carrier or diluent; either alone or in trophic lateral sclerosis (ALS; also known as Lou Gehrig’s combination with a second agent as described above, as part disease or motor neuron disease), ataxia-telangiectasia, Bat of an appropriate dosage regimen designed to prevent said ten disease (also known as Spielmeyer-Vogt-Sjogren-Batten 60 condition. disease), Binswanger’s dementia (subcortical arteriosclerotic The present invention also relates to methods for improv encephalopathy), bipolar disorders, bovine spongiform ing cognitive de?cits, including de?cits in perception, con encephalopathy (BSE), Canavan disease, chemotherapy-in centration, learning, memory, communication, reasoning, duced dementia, Cockayne syndrome, corticobasal degenera and problem-solving. tion, CreutZfeldt-Jakob disease, depression, Down syndrome, 65 The appropriate dosage regimen, the amount of each dose frontotemporal lobar degeneration (including frontotemporal administered and the intervals between doses of the com dementia, semantic dementia, and progressive non?uent pound will depend, among others, upon the compound of US 7,964,607 B2 25 26 Formula (I) of this invention being used, the type of pharma sulfate or mixtures thereof. In the case of capsules and tablets, ceutical compositions being used, the characteristics of the the dosage forms may further comprise buffering agents. subject being treated and the type and severity of the condi Solid dosage forms may be formulated as modi?ed release tions to be treated. In general, an effective dose for com and pulsatile release dosage forms containing excipients such pounds of Formula (I) or pharmaceutically acceptable salts as those detailed above for immediate release dosage forms thereof, is in the range of from about 0.1 mg to about 3,500 mg together With additional excipients that act as release rate per day. For a normal adult human having a body mass of modi?ers, these being coated on and/ or included in the body about 70 kg, a dosage in the range of from about 0.01 mg to of the device. Release rate modi?ers include, but are not about 50 mg per kg body mass is typically suf?cient, and limited to, hydroxypropylmethyl cellulose, methyl cellulose, preferably from about 0.2 to 2.5 mg per kg, in single or sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, ammoni divided doses daily. Administration may be in single (e.g., omethacrylate copolymer, hydrogenated castor oil, carnauba once daily) or multiple doses or via constant infusion. Wax, paraf?n Wax, cellulose acetate phthalate, hydroxypro Some variability in the general dosage range may be pylmethyl cellulose phthalate, methacrylic acid copolymer required depending upon the age and mass of the subject and mixtures thereof. Modi?ed release and pulsatile release being treated, the intended route of administration, the par dosage forms may contain one or a combination of release ticular compound being administered, and the like. The deter rate modifying excipients. mination of dosage ranges and optimal dosages for a particu The pharmaceutical compositions of the invention may lar mammalian subject is Within the ability of a skilled person further comprise fast dispersing or dissolving dosage formu having bene?t of the instant disclosure. 20 lations (FDDFs). The terms dispersing or dissolving as used The compounds of Formula (I) may be administered by a herein to describe FDDFs are dependent upon the solubility variety of conventional routes of administration, including of the drug substance used i.e., Where the drug substance is oral, buccal, sublingual, ocular, topical (e.g., transdermal), insoluble, a fast dispersing dosage form may be prepared, and parenteral (e. g., intravenous, intramuscular, or subcutane Where the drug substance is soluble, a fast dissolving dosage ous), rectal, intracisternal, intravaginal, intraperitoneal, intra 25 form may be prepared. vesical, local (e.g., poWder, ointment, or drop), nasal and/or Solid compositions of a similar type may also be employed inhalation dosage forms or using a “?ash” formulation, i.e., as ?llers in soft or hard ?lled gelatin capsules using such alloWing the to dissolve in the mouth Without the excipients as lactose or milk sugar, as Well as high molecular need to use Water. As Will be recogniZed by one of skill in the Weight polyethylene glycols and the like. art, the appropriate dosage regimen, the amount of each dose 30 Solid dosage forms such as tablets, dragees, capsules, and administered and the intervals betWeen doses of the com granules can be prepared With coatings and shells, such as pound Will depend upon the compound of Formula (I), or the enteric coatings and others Well-known to one of ordinary prodrug thereof, being used, the type of pharmaceutical com skill in the art. They may also comprise opacifying agents, positions being used, the characteristics of the subject being and can also be of such composition that they release the treated, and/or the severity of the conditions being treated. 35 active compound(s) in a delayed, sustained or controlled Methods of preparing various pharmaceutical composi manner. Examples of embedding compositions that can be tions With amounts of active ingredients are knoWn, or Will be employed are polymeric substances and Waxes. The active apparent in light of this disclosure, to those skilled in this art. compound(s) can also be in micro-encapsulated form, if See, for example, Remington’s Pharmaceutical Sciences, appropriate, With one or more of the above-mentioned excipi Mack Publishing Co., Easton, Pa., 19th Ed. (1995). 40 ents. Suitable pharmaceutical carriers, vehicles and diluents for Liquid dosage forms for oral administration include phar such compositions include inert solid diluents or ?llers, ster maceutically acceptable emulsions, solutions, suspensions, ile aqueous solutions and various organic solvents. The phar syrups, and elixirs. In addition to the active compounds, the maceutical compositions formed by combining a compound liquid dosage form may contain inert diluents commonly of this invention and pharmaceutically acceptable carriers, 45 used in the art, such as Water or other solvents, solubiliZing vehicles or diluents are readily administered in a variety of agents and emulsi?ers, as for example, ethanol, isopropanol, dosage forms such as tablets, poWders, loZenges, syrups, ethyl carbonate, benZyl benZoate, propylene glycol, 1,3-bu inj ectable solutions and the like. tylene glycol, oils (in particular, cottonseed oil, groundnut oil, Solid dosage forms for oral administration include cap corn germ oil, olive oil, castor oil, and sesame seed oil), sules, tablets, poWders, and granules. In such solid dosage 50 glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols forms, the active compound is admixed With at least one inert and fatty acid esters of sorbitan, or mixtures of these sub conventional pharmaceutical excipient (or carrier) such as stances, and the like. sodium citrate, calcium carbonate, or dicalcium phosphate, or In addition to the active compound(s), the pharmaceutical (a) ?llers or extenders, such as for example, starches, lactose, composition may further include suspending agents, such as sucrose, mannitol and silicic acid; (b) binders, such as for 55 for example, ethoxylated isostearyl , polyoxyethyl example, carboxymethylcellulose, alginates, gelatin, polyvi ene sorbitol and sorbitan esters, microcrystalline cellulose, nylpyrrolidone, sucrose and acacia; (c) humectants, such as aluminum metahydroxide, bentonite, agar-agar, and traga for example, glycerol; (d) disintegrating agents, such as for canth, or mixtures of these substances, and the like. SWeet example, agar-agar, calcium carbonate, potato or tapioca eners, ?avoring, and perfuming agents may also be included. starch, alginic acid, certain complex silicates, and sodium 60 The pharmaceutical compositions of the invention may carbonate; (e) solution retarders, such as for example, paraf further comprise adjuvants, such as preserving, Wetting, ?n; (f) absorption accelerators, such as for example, quater emulsifying and dispersing agents. Prevention of microor nary ammonium compounds; (g) Wetting agents, such as for ganism contamination of the instant compositions can be example, cetyl alcohol and glycerol monostearate; (h) adsor accomplished With various antibacterial and antifungal bents, such as for example, kaolin and bentonite; and/or (i) 65 agents, for example, parabens, chlorobutanol, phenol, sorbic lubricants, such as for example, talc, calcium stearate, mag acid and the like. It may also be desirable to include isotonic nesium stearate, solid polyethylene glycols, sodium lauryl agents, for example, sugars, sodium chloride and the like. US 7,964,607 B2 27 2 8 Prolonged absorption of inj ectable pharmaceutical composi -continued tions may be affected by the use of agents capable of delaying dd4doublet of doublets MPLCimedium pressure liquid absorption, for example, aluminum mono stearate and gelatin. chromatography For parenteral administration, solutions in sesame or pea DMF4dimethylformamide MSimass spectroscopy nut oil, aqueous propylene glycol, or in sterile aqueous solu DMSO4dimethyl sulfoxide NMRinuclear magnetic resonance dt4doublet of triplets ppmiparts per million tions may be employed. Such aqueous solutions should be EtOAc4ethyl acetate psiipounds per square inch suitably buffered if necessary and the liquid diluent ?rst ren EtOH4ethanol sisinglet dered isotonic With su?icient saline or glucose. These aque h (e. g., 1 h, 2 h)ihour(s) SPAiscintillation proximity assay H (e.g., 1H, 2H)ihydrogen(s) titriplet ous solutions are especially suitable for intravenous, intra Hzihertz THFitetrahydrofuran muscular, subcutaneous and intraperitoneal administration. IPAiisopropyl alcohol Trisitris (hydroxymethyl)amino In this connection, the sterile aqueous media employed are all methane Jispin-spin coupling constant readily available by standard techniques knoWn to those LCiliquid chromatography skilled in the art. For intranasal administration or administration by inhala tion, the compounds of Formula (I) are conveniently deliv The methods disclosed in the instant Schemes and ered in the form of a solution or suspension from a pump Examples are intended for purposes of exemplifying the spray container that is squeezed or pumped by the patient or instant invention only and are not to be construed as limita as an aerosol spray presentation from a pressurized container 20 tions thereon. or a nebulizer, With the use of a suitable propellant, e.g., Scheme 1 exempli?es multiple Ways to form aliphatic dichlorodi?uoromethane, trichloro?uoromethane, dichlo hydrazines that can utilized to prepare compounds in this rotetra?uoroethane, carbon dioxide or other suitable gas. In patent. Ketones can be converted to the hydrazide imine and the case of a pressurized aerosol, the dosage unit may be 25 reduced With borane or sodium cyanoborohydride. Other determined by providing a valve to deliver a metered amount. reducing agents can also be utilized. The boc group can then The pressurized container or nebulizer may contain a solution be removed With acid to form the desired hydrazine interrne or suspension of a compound of this invention. Capsules and diate. Alternatively aliphatic alcohols can be converted to cartridges (made, for example, from gelatin) for use in an boc-protected hydrazines by treatment With triphenyl phos inhaler or insulator may be formulated containing a poWder 30 phine and di-t-butyl diazacarboxylate. The boc groups can mix of a compound or compounds of the invention and a again be removed With acid to liberate the hydrazine. Aro suitable poWder base such as lactose or starch. matic hydrazine synthesis is Well knoWn in the literature by Pharmaceutical compositions of the present invention may also be con?gured for treatments in veterinary use, Where a converting anilines to hydrazines through diazotization compound of the present invention, or a veterinarily accept 35 chemistry folloWed by reduction. able salt thereof, or veterinarily acceptable solvate or pro drug thereof, is administered as a suitably acceptable forrnu Schemel lation in accordance With normal veterinary practice and the HZN veterinary practitioner Will determine the dosing regimen and 40 \ route of administration Which Will be most appropriate for a O H2N\ /Boc NH particular animal. 1) H BZH6 or NaCNBH3 In general, the compounds of Formula (I), and pharmaceu 2) HCl tically acceptable salts thereof, may be prepared according to the exemplary routes disclosed in the Schemes and Examples 45 0 O HZN beloW, as Well as by other conventional preparative proce OH \NH dures knoWn, or apparent in light of the instant disclosure, to /Boc one of ordinary skill in the art. These processes form further l) PPh3 Boc /N§N aspects of the invention. 50 2)HC1 Some of the starting compounds for the reactions described in the Schemes and Examples are prepared as illustrated O O herein. All other starting compounds may be obtained from general commercial sources, such as Sigma-Aldrich Corpo The pyrrolidine intermediates can be formed by coupling ration, St. Louis, Mo. 55 alpha-beta unsaturated esters With N-(methoxymethyl)(phe Unless indicated otherWise, the folloWing experimental nyl)-N-(trimethylsilyl)methyl)methanamine Which is com abbreviations have the indicated meanings: mercially available by catalysis With acid. This chemistry is exempli?ed in the experimental section beloW and also by 60 numerous literature examples such as Hosomi et al., Chem. mimultiplet Len. 13(7) 1117-1120, 1984. The pyrrolidines have also been bdibroad doublet MHzimegahertz synthesized in an enantiomeric pure fashion by either bmibroad multiplet Min(s)iminute(s) BOCit-butoxycarbonyl MeOHimethanol employing chiral auxiliaries on the ester (see Nichols et al., bsibroad singlet Mgimilligram Org. Lett, 8(7), 1495-1498, 2006) or by utilizing a chiral CDCl3ideuterated mlimilliliter 65 CD3OD4deuterated methanol mmolimillimoles benzyl amine in the cycloaddition chemistry (see Haight et al., Org. Proc. Res. Dev, 8(6), 897-902, 2004). US 7,964,607 B2 29 30 -continued Schemel 0 R1 R / TFA,CH2Cl2 H 3\/\ \ N \ COZMe Me3Si/\N/\OMe R3 I N

N qCOzMe R3 5

N

The benZyl group can then be removed via standard hydro genation conditions to provide the secondary amine that is ready for further functionaliZation. The amine can be alky 20 lated With alkyl halides in the presence of base or reductive amination chemistry utiliZing a variety of hydride reducing HydraZines can then be coupled in the presence of a base agents can provide the desired compounds. such as sodium methoxide or triethylamine With 2-(ethoxym ethylene)malononitrile or substituted variants to afford the 25 desired amino cyano pyraZoles. The cyano group can be oxidized by a variety of reagent but tWo conditions have been utilized to prepare compounds for this patent. Concentrated sulfuric acid or hydrogen peroxide With ammonium hydrox ide has afforded the amino-amide-pyraZoles. The amino 30 amide pyraZoles can then be coupled With esters in the pres ence of a base such as potassium t-butoxide With heated. The solvent of choice for this reaction has been tetrahydrofuran and in some cases dehydrating agents such as molecular sieves can be employed to improve upon the yields of the 35 coupling.

Scheme} 40 EtOH, Base (OEt or Et3N) R\ /NH2 — NH NC | CN

Rl OEt R1 NC H202, NH4OH | \ N or H2804 RZ-X (Br, 1, Cl, ect.) / Base (Cs2CO3), DMF or THF HZN N\ R 0 R1 Base such as KOtBu HZN I \ in THF 60° c. /N bCOZMe HZN N\ R3 ~’ R 60

65 US 7,964,607 B2 31 32 EXAMPLES (c) (3,4-trans)-methyl 1-benZyl-4-methylpyrrolidine 3-carboxylate The Examples below are intended to illustrate particular embodiments of the invention and preparations thereto and are not intended to limit the speci?cation, including the 5 claims, in any manner. Unless otherWise noted, all reagents employed Were obtained commercially. Example 1 N (a) 5 -amino-1 -(2-methoxyphenyl)-1H-pyraZole-4 carbonitrile

NC | \ N / To a solution of(E)-methyl but-2-enoate (1.6 g) Was added HZN N (30 mL), N-(methoxymethyl)(phenyl)-N-((trimeth OMe 20 ylsilyl)methyl)methanamine (3.7 g) and tri?uoroacetic acide (1.5 g). The reaction mixture Was heated at 500 C. for 18 h. The reaction mixture Was concentrated, quenched With satu rated sodium bicarbonate, extracted With methylene chloride, dried With magnesium sulfate, ?ltered and concentrated. 25 Puri?cation via MPLC chromatography eluting With 20-30% To a solution of 1-(2-methoxyphenyl)hydraZine hydrogen ethyl acetate/hexanes provided the title compound (1.5 g). chloride (3 g, 0.017 mol) in ethanol (50 mL) Was added 2-(methoxymethylene)malononitrile (1.89 g, 0.9 eq.) and 400 MHZ 1H NMR (CDCl3) 6 7.33-7.20 (m, 5H), 4.15-4.08 sodium methoxide (1 .92 g, 2.1 eq). The reaction mixture Was (m, 1H), 3.66-3.53 (m, 2H), 2.87-2.74 (m, 2H), 2.53-2.44 (m, heated at re?ux for 18 h and concentrated. The reaction mix 30 2H), 2.23-2.19 (m, 1H), 1.23 (t, J:7.1 HZ, 3H), 1.11 (d, 1:66 ture Was partitioned betWeen brine and ethyl acetate. The HZ, 3H). organic layer Was separated, dried With magnesium sulfate, ?ltered and concentrated. MPLC Biotage chromatography (d) 6-[(3,4-trans)-1-benZyl-4-methylpyrrolidin-3-yl] eluting With 20-60% ethyl acetate/hexanes afforded the title 1 -(2-methoxyphenyl)- 1 ,5 -dihydro-4H -pyraZolo [3 ,4 compound in 53% yield (1.9 g). 400 MHZ 1H NMR (CDCl3) 35 d]pyrimidin-4-one 6 7.64 (m, 1 H), 7.40 (m, 2H), 7.08 (m,2H), 4.51 (bs, 2H), 3.87 (s, 3 H); MS: (M+H m/Z:215.2). (b) 5 -amino-1 -(2-methoxyphenyl)-1H-pyraZole-4 @] carboxamide 40 H,

on-,,I N N @ '11, / \ HZN I N N I / HZN OMe 50

To (3,4-trans)-methyl 1-benZyl-4-methylpyrrolidine-3car boxylate (241 mg) and 5-amino-1-(2-methoxyphenyl)-1H pyraZole-4-carboxamide (200 mg) Was added a solution of To a solution of 5-amino-1-(2-methoxyphenyl)-1H-pyra 55 Zole-4-carbonitrile (1.53 g) in saturated ammonium hydrox potassium t-butoxide in (1M) in THF (4.31 mL, 5 eq.) The reaction mixture Was heated at re?ux for 16 h and poured into ide (30 mL) Was added 30% hydrogen peroxide solution (6 saturated sodium bicarbonate. The aqueous layer Was mL). The reaction stirred for 18 h at ambient temperature and Was sloWly quenched With 60 mL of a saturated sodium extracted With ethyl acetate, dried With magnesium sulfate, ?ltered and concentrated. MPLC Biotage chromatography sulfate solution. The aqueous layer Was extracted With ethyl 60 acetate, dried With magnesium sulfate, ?ltered and concen eluting With 1-4% methanol/methylene chloride With 0.5% trated. MPLC Biotage chromatography eluting With 2-6% saturated ammonium hydroxide provided 79 mg of the title methanol/methylene chloride provided the title compound compound. 400 MHZ 1H NMR (DMSO) 6 8.16 (d, J:7.9 HZ, 1.38 g (84%). 400 MHZ 1H NMR (DMSO) 6 7.79 (s, 1 H), 1H), 7.92 (s, 1 H), 7.34 (m, 5H), 7.09 (m, 1H), 6.92 (m, 2H), 7.42 (m, 1H), 7.25 (d, 1:75 HZ, 2H), 7.19 (d, 1:83 HZ, 2 H), 65 3.89 (s, 3H), 3.84 (m, 1H), 3.71 (m, 1H), 3.37 (t, 1:91 HZ, 7.03 (t, 1:62 HZ, 1H), 5.83 (s,2H), 3.76 (s, 3 H); MS: (M+H 1H), 3.09 (m, 1H), 2.85 (m, 1H), 2.65 (m, 1H), 2.47 (m, 1H), m/Z:233.2). 2.03 (m, 2H), 1.19 (d, J:7.1 HZ, 3H); MS: (M+H m/Z:416.1). US 7,964,607 B2 33 34 Example 2 Example 4

(a) 1-cyclopentyl-6-[(3 ,4-trans-4-methylpyrrolidin-3 - 6-[(3,4-trans)-1-benZyl-4-methylpyrrolidin-3-yl]-1 yl]-1H-pyraZolo[3,4-d]pyrimidin-4(5H)-one cyclopentyl- 1 , 5 -dihydro-4H-pyraZolo[3 ,4-d]pyrimi din-4-one

A solution of 6-[(3,4-trans)-1-benZyl-4-methylpyrrolidin 20 3 -yl]-1-cyclopentyl-1,5 -dihydro-4H-pyraZolo[3 ,4-d]pyrimi din-4-one (970 mg) in ethanol 25 mL Was added to a Parr bottle. Acetic acid (2.5 mL) and Pd(OH)2 (500 mg) Was Following the procedure for the preparation of 6-[(3,4 added. The reaction mixture Was placed on a hydrogenator trans)- 1 -benZyl-4 -methylpyrrolidin-3 -yl] -1 -(2-methoxyphe under 40 PS1 for 16 h. The reaction mixture Was ?ltered nyl)-1,5-dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one but 25 through Celite and concentrated. The reaction mixture Was substituting 5 -amino-1-cyclopentyl-1H-pyraZole-4-carboxa partitioned betWeen saturated bicarbonate solution and meth mide provided the title compound. 400 MHZ 1H NMR ylene chloride. The layers Were separated and the aqueous layer Was extracted 6>< With methylene chloride. The organic (CD3OD) 6 8.00 (s, 1H), 7.38-7.23 (m, 5H), 5.14-5.10 (m, layer Was dried With magnesium sulfate, ?ltered and concen 1H), 3.80-3.57 (m, 2H), 3.34 (t, 1:83 HZ, 1H), 2.97 (d, 1:99 30 trated to provide 429 mg of the title compound. 400 MHZ 1H HZ, 1H), 2.80-2.78 (m, 1H), 2.53-2.49 (m, 1H), 2.41-2.38 (m, NMR (CD3OD) 6 9.25 (brs, 1H), 8.02 (s, 1H), 5.20-5.17 (m, 1H), 2.10-1.89 (m, 7H), 1.70-1.66 (m, 2H), 1.17 (d, J:6.6 HZ, 1H), 3.91 (m, 1H), 3.77-3.68 (m, 2H), 3.46-3.44 (m, 1H), 3.10 3H). MS: (M+H m/Z:378.1). (m, 1H), 2.89 (m, 1H), 2.13-1.87 (m, 6H), 1.74-1.65 (m, 2H), 1.20 (d, 1:62 HZ, 3H). MS: (M+H m/Z:288.1). Example 3 35 (b) 1-cyclopentyl-6- { (3 ,4-trans) -4 -methyl- 1 - [4-(trif luoromethyl)pyrimidin-2 -yl]pyrrolidin-3 -yl}-1,5 6-[(3 S,4S)-1-benZyl-4-methylpyrrolidin-3-yl]-1 dihydro -4H-pyraZolo [3 ,4-d]pyrimidin-4-one cyclopentyl- 1 , 5 -dihydro-4H-pyraZolo[3 ,4-d]pyrimi din-4-one 40

50

0

55 To a solution of 1 -cyclopentyl-6-[(3,4-trans)-4-methylpyr The racemate Was separated on Chiralcel OD chiral HPLC rolidin-3 -yl]-1H-pyraZolo[3,4-d]pyrimidin-4(5H)-one (40 column, Mobile Phase 90/10 Heptane/EtOH, TR:6.807, to mg) in dimethylformamide (1 ml) Was added cesium carbon provide the enantiomer. 400 MHZ lHNMR (CDCl3) 6 8.00 (s, ate (2 eq.) and 2-chloro-4-(tri?uoromethyl)pyrimidine (1.2 1H), 7.38-7.22 (m, 5H), 5.27-5.10 (m, 1H), 3.78 (d, 1:125 60 eq.) and the reaction mixture Was heated at 600 C. for 90 min. HZ, 1H), 3.6 (d, 1:125 HZ, 1H), 3.34 (t, 1:83 HZ, 1H), 2.97 The reaction mixture Was poured into saturated sodium bicar bonate, extracted With methylene chloride, dried With mag (d, 1:99 HZ, 1H), 2.80-2.78 (m, 1H), 2.52-2.48 (m, 1H), nesium sulfate, ?ltered and concentrated. Puri?cation via 2.41-2.38 (m, 1H), 2.10-1.89 (m, 7H), 1.70-1.66 (m, 2H), MPLC Biotage chromatography eluting With 20-60% ethyl 1.18(d, 1:66 HZ, 3H). MS: (M+H m/Z:378.1). 65 acetate/hexanes provided 40 mg of the title compound. 400 Chiralcel OD, Mobile Phase 90/10 Heptane/IPA, MHZ 1H NMR (CDCl3) 6 8.51 (d, 1:50 HZ, 1H), 8.02 (m, TR:9.433. 1H), 6.79 (d, 1:46 HZ, 1H), 5.16-5.08 (m, 1H), 4.243.97 (m, US 7,964,607 B2 35 36 3H), 3.37-3.32 (m, 1H), 3.20-3.14 (m, 1H), 2.09-2.05 (m, Vided the title compound (27 mg). 400 MHZ 1H NMR 3H), 1.96-1.90 (m, 1H), 1.73-1.56 (m, 5H), 1.24 (d, J:6.6 HZ, (CDCl3) 6 8.06-8.03 (m, 1H), 7.57-7.50 (m, 2H), 7.43-7.37 3H). MS: (M+H m/Z:434.1). (m, 3H), 5.20-5.13 (m, 1H), 4.16-4.03 (m,1H), 3.92 (d, 1:83 HZ, 1H), 3.81-3.76 (m, 1H), 3.47-3.29 (m, 1H), 3.17-3.03 (m, Example 5 1H), 2.84-2.67 (m, 1H), 2.11-1.80 (m, 3H), 1.79-1.72 (m, 1H), 1.56-1.30 (m, 4H), 1.21-1.11 (m, 3H). MS: (M+H 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-pyrimidin 2-ylpyrrolidin-3 -yl]-1,5 -dihydro -4H-pyraZolo [3 ,4-d] m/Z:392.1). pyrimidin-4-one Example 7

1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3 - [E] ylmethyl)pyrrolidin-3-yl] - 1 ,5 -dihydro-4H-pyraZolo O [3,4-d]pyrimidin-4-one

N \ I .N @]

N 20 N N

NA .. N N \ / 25 Following the procedure for the preparation of 1 -cyclopen tyl-6-{(3,4-trans)-4-methyl-1-[4-(tri?uoromethyl)pyrimi / din-2-yl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyraZolo[3,4-d] N pyrimidin-4-one but substituting 2-chloropyrimidine provided the title compound. 400 MHZ 1H NMR (CD3OD) 6 30 To a solution of 1-cyclopentyl-6-[(3,4-trans)-4-methylpyrro 8.29 (d, 1:50 HZ, 2H), 7.96 (s, 1H), 6.60 (t, 1:50 HZ, 1H), lidin-3 -yl] -1H-pyraZolo[3,4-d]pyrimidin-4(5H)-one (40 mg) 5.08-5.04 (m, 1H), 4.06-3.87 (m, 3H), 3.23-3.18 (m, 1H), in 1,2-dichloroethane (2 mL) Was added acetic acid (2 eq.), 3.12 (q, 1:79 HZ, 1H), 2.80-2.76 (m, 1H), 2.05-1.98 (m, 4), nicotinaldehyde (1.5 eq.) and sodium triacetoxy borohydride 1.90-1.82 (m, 2H), 1.66-1.61 (m, 2H), 1.17 (d, J:7.1 HZ, 3H). (58 mg). The reaction mixture Was heated at 400 C. for 4 h, MS: (M+H m/Z:366.1). 35 poured into saturated sodium bicarbonate, extracted With methylene chloride, dried With magnesium sulfate, ?ltered Example 6 and concentrated. Puri?cation Via Biotage MPLC chroma tography eluting With 1-4% methanol/methylene chloride/ 6-[(3,4-trans)-1-benZoyl-4-methylpyrrolidin-3-yl]-1 0.5% ammonium hydroxide provided the title compound (47 cyclopentyl- 1 , 5 -dihydro-4H-pyraZolo[3 ,4-d]pyrimi 40 mg). 400 MHZ 1H NMR (CDCl3) 6 8.55 (m, 2H), 2.02 (s, 1H), din-4-one 7.84 (m, 1H), 7.36 (m, 1H), 5.16-5.09 (m, 1H), 3.82-3.60 (m, 2H), 3.36 (m, 1H), 3.05-2.38 (m, 4H), 2.13-1.89 (m, 7H), 1.73-1.68 (m, 2H), 1.21 (m, J:7.1 HZ, 3H). MS: (M+H [E] m/Z:379.1). O 45 Example 8 \ N N / 1-cyclopentyl-6- { (3 ,4-trans)-4-methyl-1 -[3 -(tri?uo L \ N romethyl)benZyl]pyrrolidin-3 -yl } -1 ,5 -dihydro -4H e‘\\\N pyraZolo[3 ,4-d]pyrimidin-4 -one

N

O 55

To a solution of 1-cyclopentyl-6-[(3,4-trans)-4-methylpyrro lidin-3 -yl] -1H-pyraZolo[3,4-d]pyrimidin-4(5H)-one (40 mg) 60 in methylene chloride (1 ml) Was added triethyl amine (2.5 eq.) and benZoyl chloride (1.2 eq.) and the reaction mixture Was stirred at ambient temperature for 1 h. The reaction mixture Was poured into saturated sodium bicarbonate, extracted With methylene chloride, dried With magnesium 65 sulfate, ?ltered and concentrated. Biotage MPLC chromatog FolloWing the procedure for the preparation of 1 -cyclopen raphy eluting With 2-4% methanol/methylene chloride pro tyl-6-[(3 ,4-trans)-4-methyl-1 -(pyridin-3 -ylmethyl)pyrroli US 7,964,607 B2 37 38 din-3 -yl]-1,5-dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one compound. 400 MHZ 1H NMR (CDCl3) 6 8.92-8.89 (m, 1H), but substituting 3-(tri?uoromethyl)benZaldehyde provided 8.27-8.25 (m, 1H), 8.18-8.16 (m, 1H), 8.00 (s, 1H), 7.80-7.74 the title compound. 400 MHZ 1H NMR (CDCl3) 6 8.02 (s, (m, 2H), 7.63-7.50 (m, 1H), 5.14-5.07 (m, 1H), 4.18 (m, 2H), 1H), 7.66 (s, 1H), 7.53-7.50 (m, 3H), 5.16-5.09 (m, 1H), 3.80 3.37 (m, 1H), 3.10-2.30 (m, 5H), 2.15-1.93 (m, 6H), 1.74 (m, 1H), 3.69-3.66 (m, 1H), 3.35 (m, 1H), 2.99 (m, 1H), 2.83 5 1.64 (m, 2H), 1.21 (d, 1:66 HZ, 3H). MS: (M+HII1/Z:429.1). (m, 1H), 2.42 (m, 1H), 2.12-1.93 (m, 7), 1.74-1.68 (m, 2H), 1.56 (m, 1H), 1.21 (d, 1:66 HZ, 3H). MS: (M+HII1/Z:446.0). Example 11 Example 9 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-{[6-(tri?uo romethyl)pyridin-3-yl]methyl}pyrrolidin-3-yl] -1 ,5 - 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinolin-2 dihydro -4H-pyraZolo [3 ,4-d]pyrimidin-4-one ylmethyl)pyrrolidin-3 -yl] -1 ,5 -dihydro-4H-pyraZolo [3,4-d]pyrimidin-4-one [E]

N N

N FF/\ / N F / FolloWing the procedure for the preparation of 1 -cyclopen Following the procedure for the preparation of 1 -cyclopen 30 tyl- 6 - [ (3 ,4 -trans)-4 -methyl -1 -(pyridin-3 -ylmethyl)pyrroli tyl-6-[(3 ,4-trans) -4 -methyl-1 -(pyridin-3 -ylmethyl)pyrroli din-3 -yl]-1,5 -dihydro -4H-pyraZolo [3,4-d]pyrimidin-4-one din-3-yl]-1,5-dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one but substituting 6-(tri?uoromethyl)nicotinaldehyde provided but substituting quinoline-2-carbaldehyde provided the title the title compound. 400 MHZ 1H NMR (CDCl3) 6 8.63 (m, compound. 400 MHZ 1H NMR (CDCl3) 6 8.22-8.15 (m, 2H), 1H), 8.01 (s, 1H), 7.7 (d, 1:780 HZ, 1H), 5.12 (m, 1H), 4.82 8.07 (s, 1H), 7.80 (d, J:7.9 HZ, 1H), 7.71 (t:8.3 HZ, 1H), 35 (m, 1H), 3.79 (q, 1:132, 16.2, HZ, 2H), 3.32 (t, 1:85 HZ, 7.69-7.50 (m, 2H), 5.18-5.11 (m, 1H), 4.25 (m, 1H), 3.91 (m, 1H), 3.02 (m, 1H), 2.86 (m, 1H), 2.63 (m, 1H), 2.45 (m, 1H), 1H), 3.71 (m, 1H), 3.49 (m, 1H), 3.17 (m, 1H), 2.87 (m, 1H), 2.12-2.88 (m, 6H), ), 1.74-1.64 (m, 3H), 1.32 (d, 1:705 HZ, 2.73-2.45 (m, 2H), 2.13-1.94 (m, 6H), 1.75-1.68 (m, 2H), 3H). MS: (M+H m/Z:447.0). 1.23 (d, J:7.1 HZ, 3H). MS: (M+H m/Z:429.1). 40 Example 12 Example 10 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinoxalin 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(quinolin-4 2-ylmethyl)pyrrolidin-3 -yl] -1 ,5-dihydro -4H-pyra ylmethyl)pyrrolidin-3 -yl] -1 ,5 -dihydro-4H-pyraZolo Zolo[3 ,4-d]pyrimidin-4-one [3,4-d]pyrimidin-4-one 45

[E]

O

N N N \

N N

N N

Q N/Y

FolloWing the procedure for the preparation of 1 -cyclopen FolloWing the procedure for the preparation of 1 -cyclopen tyl- 6 - [ (3 ,4 -trans)-4 -methyl -1 -(pyridin-3 -ylmethyl)pyrroli tyl-6-[(3 ,4-trans) -4 -methyl-1 -(pyridin-3 -ylmethyl)pyrroli 65 din-3-yl]-1,5-dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one din-3 -yl]-1,5-dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one but substituting quinoxaline-2-carbaldehyde provided the but substituting quinoline-4 -carbaldehyde provided the title title compound. 400 MHZ 1H NMR (CDCl3) 6 8.86 (s, 1H),