United States Patent (10) Patent No.: US 7,723,348 B2 Hopper Et Al
US007723348B2
(12) United States Patent (10) Patent No.: US 7,723,348 B2 Hopper et al. (45) Date of Patent: May 25, 2010
(54) PHOSPHODIESTERASE 4 INHIBITORS JP 10724.15 3, 1998 WO WO92, 19594 11, 1992 (75) Inventors: Allen Hopper, Glen Rock, NJ (US); Robert F. Dunn,s Towaco, sNJ (US); sErik WO WO93/07 141 4f1993 Mikal Kuester, Rochester, MN (US); WO WO 93,255.17 12/1993 Richard D. Conticello, Ossining, NY WO WO94f14742 T 1994 (US) WO WO95/28926 11, 1995 WO WO95/35282 12/1995 (73) Assignee: Memory Pharmaceuticals WO WO 97.12884 A1 * 4f1997 Corporation, Montvale, NJ (US) WO WO 97.25312 7/1997 (*) Notice: Subject to any disclaimer, the term of this WO WO 97/497O2 12/1997 patent is extended or adjusted under 35 WO WO 98.58901 12/1998 U.S.C. 154(b) by 0 days. WO WOOOf 66562 11, 2000 (21) Appl. No.: 12/108,833 WO WOO1.40216 6, 2001 WO WOO140216 6, 2001 (22) Filed: Apr. 24, 2008 WO WOO1, 58.895 8, 2001 (65) Prior Publication Data WO WOO1? 68600 9, 2001 WO WOO2,45749 6, 2002 US 2008/O2O766O A1 Aug. 28, 2008 WO WOO3,087062 10, 2003 Related U.S. Application Data WO WOO4/OO7463 1, 2004 (62) Division- - - of application No. 1 1/249,769, filed on Oct. WO WO 2004/OO7463 1, 2004 14, 2005, now Pat. No. 7,432,266. WO WO 2004/094411 11, 2004 (60) Provisional application No. 60/618,725, filed on Oct. 15, 2004. (51) Int. Cl OTHER PUBLICATIONS A6 IK3I/506 (2006.01) Vippagunta, et al., Crystalline solids, 2001, Advanced Drug Delivery A6 IK 3/437 (2006.01) Reviews, 48, pp. 3 and 18.* A6 IK 3L/454 (2006.01) Barad et al. Proc. Natl. Acad. Sci., USA, Dec. 1998 vol. 95, pp. A6 IK 3/4I55 (2006.01) 15020-15025. (52) U.S. Cl...... 514/275: 514/303; E. Christensen et al. J.Med. Chem, 1998, vol. 41, pp. 821-835. (58) Field of Classification Search ...... s1427s, Crossland, Drugs of the Future, 1998, vol. 13, No. 1. 514/406, 407, 303, 341 Database Caplus, XP002294352, Journal of the Chemical Society, See application file for complete search history. Perkins Transactions 1, 1997, vol. 12, pp. 1477-1500 Accession No. 1978-6818. (56) References Cited Database Caplus, XP002294353, Synthetic Communication, 1996, U.S. PATENT DOCUMENTS vol. 26, No. 14, pp. 2603-2611. 4.012.495 A 3, 1977 Schmiechen etal Database Beilstein, XP002294354, 1996, Acta Crystallographica W .. 4 CeCe a Sect. B., vol. 52, No. 4, pp. 746-752. 4,193.926 A 3, 1980 Schmiechen et al. CC WO O. 4, pp 4,219,551 A 8, 1980 Seidelmann et al. 5,539,111 A 7, 1996 Petzoldt et al. 5,814,651 A 9/1998 Duplantier et al. (Continued) 5,846,514 A 12, 1998 Foster et al. Primary Examiner Kamal A Saeed 2: E. East al. Assistant Examiner—Kristin Bianchi 6.136.82. A 10/2000 FIS (74) Attorney, Agent, or Firm—Millen, White, Zelano, 6,235,736 B1 5/2001 Ina et al. Branigan, P.C. 6,258,833 B1 7/2001 Martins et al. 6,334,997 B1 1/2002 Foster et al. (57) ABSTRACT 6,372,777 B1 4/2002 Martins et al. 6,403,597 B1 6, 2002 Wilson et al. 3. R S. Main t al. Selective PDE4 inhibition is achieved by aryland heteroaryl 726930 B2 62007 Foret al. pyrazole compounds. The compounds exhibit improved 20070254913 A 2007 Dunnet al...... 514303 PDE4 inhibition as compared to compounds such as rolipram and show selectivity with regard to inhibition of other classes FOREIGN PATENT DOCUMENTS of PDEs. EP 1 251 126 10, 2002 EP 1251 126 10, 2002 61 Claims, No Drawings US 7,723,348 B2 Page 2
OTHER PUBLICATIONS Nagakura et al. British Journal of Pharmacology, 2002, 135, pp. 1783-1793. Demnitz et al. Molecules, 1998, vol. 3 pp. 107-119. Osby et al. Tetrahedron Letters, 1985, vol. 26, No. 52, pp. 6413-6416. Egawa et al Jpn. J Pharmacol, 1997, Nov. 75, (3) pp. 275-281. Patent Abstracts of Japan, vol. 2000, No. 19, Jun. 5, 2001 & JP 2001 Halrow et al. Polyhedron, 1997, vol. 16, No. 24, pp. 4257-4264. 039954 A (Tomono Agrica Co.Ltd.), Feb. 13, 2001 p. 123. Houslay et al. 1998, Advance in Pharmacology, 1998, vol. 44, pp. Robichaud et al. Neuropharmacology, 1999, 38, pp. 289-297. 225-342. Schmiechen et al. Psychopharmacology, 1990, 102 (1) pp. 17-20. Japanese Patent Abstract No. 2001-039954, (Feb. 13, 2001). Wang et al. Biochemical & Biophysical Research Communciations, 1997, pp. 234,320-324. Keller et al. Chem. Pharm. Bull, 2001, 49 (8) 1009-1017. Int'l Search Report and the Written Opinion of the Int'l Searching Krause et al Xenobiotica, 1998, vol. 18, No. 5, pp. 561-571. Authority, issued Feb. 27, 2006 in PCT Application No. PCT/ Kusters et al. Journal of Chromatopgraphy, 1996, vol. 737, pp. 333 US2005/0368O1 337. Database Caplus, XP-002294354, Copyright 1988-2001. Langlois et al., 1997. Synthetic Communicaitons, 27 (18), pp. 3133 Malcolm A. Halcrow, et al. "Metal complexes of sterically hindered 3.144. pyrazolylpyridines . . . . Polyhedron, vol. 16, No. 124, pp. 4257 Lourenco et al. Nuclear Medicine & Biology, 2001, vol. 28, pp. 4264, 1997. 347-358. Database Caplus, XP-002367781, Copyright 1988-2005. Marivet et al. J. Med. Chem. 1989, 32, pp. 1450-1457. Cancer and Metastasis Reviews (1998), 17(1), 91-106. Martin, Idrugs, 2001, 4(3), pp. 312-338. A. Maureen Rouhi, Chemical & Engineering News, Feb. 24, 2003, Meyers et al. J. Org. Chem., 1993, vol. 58, pp. 36-42. pp. 32-35. Accession No. 1993:531492 Caplus; Comparison of the effect of US Pharmacopia #23, national formulary #18, pp. 1843-1844 (1995). isobutylmethylxanthine and phosphodiesterase-selective inhibitors Zhang et al. Neuropsychopharmacology, 2000, 23, pp. 198-204. on cAMP levels in SH-SY5Y neuroblastoma cells; Anthony J. Mor Zhang et al. Psychopharmacology DOI, 2000, 10. gan et al. * cited by examiner US 7,723,348 B2 1. 2 PHOSPHODESTERASE 4 INHIBITORS processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 This application is a divisional of U.S. patent application and arifilo are powerful anti-inflammatory agents and there Ser. No. 1 1/249,769, filed Oct. 14, 2005 now U.S. Pat. No. fore may be useful in treating diseases where inflammation is 7.432.266, which is incorporated by reference herein. problematic Such as asthma or arthritis. Further, rolipram This application claims the benefit of U.S. Provisional improves the cognitive performance of rats and mice in learn Application Ser. No. 60/618,725, filed Oct. 15, 2004, the ing paradigms. entire disclosure of which is hereby incorporated by refer CCC. This application is related to copending U.S. application 10 1. O Ser. No. 10/825,611, filed Apr. 16, 2004, which claims the benefit of U.S. Provisional Application Ser. No. 60/463,725, filed Apr. 18, 2003, the entire disclosures of each of which are O hereby incorporated by reference. O 15 N FIELD OF THE INVENTION H
The present invention relates generally to the field of phos rolipram phodiesterase 4 (PDE4) enzyme inhibition. More specifi O cally, this invention relates to selective PDE4 inhibition by 1. C novel compounds, e.g., aryland heteroaryl Substituted pyra Zole compounds, methods of preparing Such compounds, O N compositions containing Such compounds, and methods of O N use thereof. C 2 25 BACKGROUND OF THE INVENTION piclaimilast The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP 30 In addition to Such compounds as rolipram, Xanthine and coMP). These cyclic nucleotides act as second messen derivatives such as pentoxifylline, denbufylline, and theo gers within cells, and as messengers, carry impulses from cell phylline inhibit PDE4 and have received attention of late for Surface receptors having bound various hormones and neu their cognition enhancing effects. cAMP and ccjMP are sec rotransmitters. PDEs act to regulate the level of cyclic nucle ond messengers that mediate cellular responses to many dif otides within cells and maintain cyclic nucleotide homeosta 35 ferent hormones and neurotransmitters. Thus, therapeutically sis by degrading Such cyclic mononucleotides resulting in significant effects may result from PDE inhibition and the termination of their messenger role. resulting increase in intracellular cAMP or cGMP in key PDE enzymes can be grouped into eleven families accord cells, such as those located in the nervous system and else ing to their specificity toward hydrolysis of cAMP or cGMP. where in the body. their sensitivity to regulation by calcium, calmodulin or 40 Rolipram, previously in development as an antidepressant, cGMP, and their selective inhibition by various compounds. selectively inhibits the PDE4 enzyme and has become a stan For example, PDE1 is stimulated by Ca/calmodulin. PDE2 dard agent in the classification of PDE enzyme subtypes. is cGMP-dependent, and is found in the heart and adrenals. Early work in the PDE4 field focused on depression and PDE3 is coiMP-inhibited, and inhibition of this enzyme cre inflammation, and has subsequently been extended to include ates positive inotropic activity. PDE4 is cAMP specific, and 45 indications such as dementia. see “The PDE IV Family Of its inhibition causes airway relaxation, anti-inflammatory and Calcium-Phosphodiesterases Enzymes. John A. Lowe, III, et antidepressant activity. PDE5 appears to be important in al., Drugs of the Future 1992, 17(9):799-807 for a general regulating c(3MP content in vascular Smooth muscle, and review. Further clinical developments of rolipram and other therefore PDE5 inhibitors may have cardiovascular activity. first-generation PDE4 inhibitors were terminated due to the Since the PDEs possess distinct biochemical properties, it is 50 side effect profile of these compounds. The primary side likely that they are subject to a variety of different forms of effect in primates is emesis, while the primary side effects in regulation. rodents are testicular degranulation, weakening of vascular PDE4 is distinguished by various kinetic properties includ Smooth muscle, psychotrophic effects, increased gastric acid ing low Michaelis constant for cAMP and sensitivity to cer secretion, and stomach erosion. In humans, the primary side tain drugs. The PDE4 enzyme family consists of four genes, 55 effect is nausea and emesis. Thus, there is a continuing need which produce 4 isoforms of the PDE4 enzyme designated to develop selective PDE4 inhibitors with improved side PDE4A, PDE4B, PDE4C, and PDE4D Wang et al., Expres effect profiles (e.g., are relatively non-emetic) while retaining sion, Purification, and Characterization of Human cAMP therapeutic utility. Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234, 320-324 (1997). In 60 SUMMARY OF THE INVENTION addition, various splice variants of each PDE4 isoform have been identified. The present invention relates to novel compounds that PDE4 isoenzymes are localized in the cytosol of cells and inhibit, preferably selectively, PDE4 enzymes, and especially are unassociated with any known membranous structures. have improved side effect profiles, e.g., are relatively non PDE4 isoenzymes specifically inactivate cAMP by cata 65 emetic (e.g., as compared to the previously discussed prior art lyzing its hydrolysis to adenosine 5'-monophosphate (AMP). compounds). In particular, the present invention relates to Regulation of cAMP activity is important in many biological aryl and heteroaryl Substituted pyrazole compounds. The US 7,723,348 B2 3 compounds of this invention at the same time facilitate entry into cells, especially cells of the nervous system. - Still further, the present invention provides methods for V synthesizing compounds with Such activity and selectivity, as well as methods of and corresponding pharmaceutical com positions for treating a patient, e.g., mammals, including humans, in need of PDE inhibition. Treatment is preferably for a disease state that involves elevated intracellular PDE4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with depression 10 and/or memory impairment, most especially major depres sion and/or longterm memory impairment. In particular, Such VI depression and/or memory impairment is due at least in part to catabolism of intracellular cAMP levels by PDE4 enzymes or where Such an impaired condition can be improved by 15 increasing cAMP levels. In a preferred aspect, the compounds of the inventions improve such diseases by inhibiting PDE4 enzymes at doses that do not induce emesis or other side effects.
DETAILED DESCRIPTION OF THE INVENTION
VII The present invention relates to selective PDE4 inhibition by novel compounds, e.g., aryl and heteroaryl Substituted pyrazole compounds, methods of preparing Such compounds, 25 compositions containing Such compounds, and methods of use thereof. The present invention includes compounds selected from Formulas I, II, III, IV, V,VI,VII, VIII, IX or X:
VIII 30
35
DX
II 40
45
X
III 50
55
IV wherein 60 X is CH or N: L is a single bond; C-C straight chain or branched alky lene, wherein a CH2 group is optionally replaced by O. NH, NR", or S, which is unsubstituted or substituted one 65 or more times by Oxo, halogen (preferably F), hydroxy, cyano or combinations thereof (CH2)CONH; (CH), OCONH; (CH2)CON(C-alkyl); (CH)NHCO: US 7,723,348 B2 5 6 (CH),CONHSO; (CH), SONH; (CH),SO; or trifluoromethyl), nitro, Oxo, amino, alkylamino, (CH) CO, (e.g., a bond, CHCONH, SO, CHCO, dialkylamino, carboxy or combinations thereof and/ CHCO); or Substituted in the alkyl portion by halogen, OXo, n is 0 to 3: cyano, or combinations thereof, or R" is alkyl having 1 to 4 carbon atoms, which is unsubsti 5 cycloalkylalkyl having 4 to 16 carbonatoms (e.g., cyclo tuted or Substituted one or more times by halogen (e.g., pentylethyl and cyclopropylmethyl), which is unsub CH, CHF); stituted or Substituted one or more times by halogen, R is H, oxo, alkyl or combinations thereof; alkyl having 1 to 8 carbon atoms, which is unsubstituted R is H, or Substituted one or more times by halogen, oxo or 10 alkyl having 1 to 8 carbon atoms, which is unsubstituted combinations thereof wherein optionally one or more or Substituted one or more times, by halogen, Oxo, or —CH2CH2— groups are replaced in each case by combinations thereof wherein optionally one or more —CH=CH- or —C=C- groups (e.g., CH, —CH2CH2— groups are replaced in each case by CHF), —CH=CH- or —C=C- groups (e.g., CHs. cycloalkyl having 3 to 8 carbon atoms, which is unsub 15 CH(CH), n-propyl. n-butyl, t-butyl), stituted or Substituted one or more times by halogen, cycloalkyl having 3 to 8 carbon atoms, which is unsub oxo, alkyl having 1 to 4 carbonatoms or combinations stituted or Substituted one or more times by halogen, thereof (e.g., cyclopentyl), oxo, alkyl, or combinations thereof (e.g., cyclopentyl, a heterocyclic group, which is Saturated, partially Satu cyclohexyl), rated or fully unsaturated, having 5 to 10 ring atoms in aryl having 6 to 14 carbon atoms, which is unsubstituted which at least 1 ring atom is an N, O or Satom (e.g., or Substituted one or more times by halogen, alkyl, 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is hydroxy, alkoxy, halogenated alkyl, halogenated unsubstituted or substituted one or more times by alkoxy (e.g., OCF), nitro, methylenedioxy, ethylene halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl dioxy, amino, alkylamino, dialkylamino. —CO—N (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, 25 (R'), -SO. N(R'), hydroxyalkyl, hydroxy dialkylamino, or combinations thereof (e.g., tetrahy alkoxy (e.g., —OCHHCOH), alkoxyalkoxy (e.g., drofuranyl), methoxyethoxy (CHOCH2CH2O ), alkoxyalkoxy aryl having 6 to 14 carbon atoms, which is unsubstituted alkyl (e.g., CHOCH2CHOCH2—), carboxy, cyano, or Substituted one or more times by halogen, CF acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyl OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, 30 Sulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, ethylenedioxy, amino, alkylamino, dialkylamino, phenyl, halogenated phenyl, phenoxy, benzyloxy, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfo furanyl which is unsubstituted or substituted by halo nyl, phenoxy, acylamido (e.g., acetamido), and acy gen, Ca-alkyl, Ca-alkoxy, C2-s-alkoxycarbonyl, loxy (e.g., acetoxy), or combinations thereof, 35 and/or benzyl, pyrrolyl which is unsubstituted or sub arylalkyl having 7 to 16 carbon atoms, which is unsub stituted by halogen, Ca-alkyl, C-alkoxy, C2-s- stituted or substituted, preferably in the aryl portion, alkoxycarbonyl, and/or benzyl, pyrazolyl which is one or more times by halogen, CF. OCF, alkyl, unsubstituted or Substituted by halogen, C-alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylene C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, dioxy, amino, alkylamino, dialkylamino, hydroxy 40 isoxazolyl which is unsubstituted or substituted by alkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxy halogen, Ca-alkyl, Calkoxy, C2-s-alkoxycarbo carbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, nyl, and/or benzyl, imidazolyl which is unsubstituted phenoxy, acylamido (e.g., acetamido), and acyloxy or Substituted by halogen, C-alkyl, C-alkoxy, (e.g., acetoxy), or combinations thereof (e.g., benzyl, Cs-alkoxycarbonyl, and/or benzyl, pyridinyl which difluorobenzyl), 45 is unsubstituted or Substituted by halogen, C-alkyl, a partially unsaturated carbocyclic group having 5 to 14 C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, carbon atoms, (e.g., cyclohexenyl, cyclohexadienyl, pyrimidinyl which is unsubstituted or substituted by indanyl, and tetrahydronaphthenyl), which is unsub halogen, Ca-alkyl, C-alkoxy, C2-s-alkoxycarbo stituted or Substituted one or more times by halogen, nyl, and/or benzyl, morpholinyl which is unsubsti alkyl, alkoxy, nitro, cyano, oxo, or combinations 50 tuted or Substituted by C-alkyl, C-s-alkoxycarbo thereof, nyl, and/or benzyl, piperadinyl which is unsubstituted arylalkenyl having 8 to 16 carbon atoms, wherein the or Substituted by C-alkyl, C-s-alkoxycarbonyl, alkenyl portion has up to 5 carbon atoms, which is and/or benzyl, piperazinyl which is unsubstituted or unsubstituted or substituted, preferably in the aryl Substituted by C-alkyl, C-s-alkoxycarbonyl, and/ portion, one or more times by halogen, alkyl, hydroxy, 55 or benzyl, tetrazolyl which is unsubstituted or substi alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, tuted by C-alkyl, C-s-alkoxycarbonyl, and/or ben alkylamino, dialkylamino, hydroxyalkyl, hydroxy Zyl, alkylsulphonimide (e.g., CHSO. NHCO ), alkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alky arylsulphonimide (e.g., CHSO. NHCO ) lthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acyla wherein the aryl portion is optionally substituted by mido (e.g., acetamido), and acyloxy (e.g., acetoxy), or 60 halogen, C-alkyl, C-alkoxy, or combinations combinations thereof, thereof (e.g., phenyl, bromophenyl, cyanophenyl, a heterocyclic-alkyl group, which is saturated, partially nitrophenyl, fluorophenyl, difluorophenyl, trifluo saturated or fully unsaturated, having 5 to 10 ring romethoxyphenyl, methylphenyl, dimethylphenyl, atoms in which at least 1 ring atom is an N, O or S methoxyphenyl, biphenyl substituted by —CONH2, atom, which is unsubstituted or substituted one or 65 and phenyl substituted by biphenyl or CONH2). more times in the heterocyclic portion by halogen, heterocyclic group, which is Saturated, partially satu aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., rated or fully unsaturated, having 5 to 10 ring atoms in US 7,723,348 B2 7 8 which at least 1 ring atom is an N, O or Satom, which hydroxy or combinations thereof wherein optionally is unsubstituted or substituted one or more times by one or more —CH2CH2— groups are replaced in halogen, alkyl, hydroxy, alkoxy, halogenated alkyl each case by —CH=CH- or —C=C- groups, (e.g., trifluoromethyl), halogenated alkoxy, nitro, alkoxyalkyl having 2 to 6 carbon atoms (e.g., methoxy methylenedioxy, ethylenedioxy, amino, alkylamino, ethyl (CHCHOCH), ethoxymethyl dialkylamino, hydroxyalkyl, hydroxyalkoxy, car (CHOCH2CH)), which is unsubstituted or substi boxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkyl tuted one or more times by halogen, oxo, or combi sulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phe nations thereof; nyl, halogenated phenyl, phenoxy, acyloxy, alkoxycarbonyl ( C(=O)C)-alkyl) having 2 to 6 car tetrazolyl, alkylsulphonimide, arylsulphonimide, 10 bon atoms (e.g., —C(=O)CCH(CH)); aryl, oxo, acylamido (e.g., acetamido), or combina CO NR'?: tions thereof (e.g., pyridyl, methylpyridyl, benzothia cycloalkyl having 3 to 8 carbon atoms, which is unsub Zolyl), stituted or Substituted one or more times by halogen, arylalkyl having 7 to 16 carbon atoms, which is unsub oxo, alkyl, or combinations thereof (e.g., cyclopen stituted or substituted, preferably in the aryl portion, 15 tyl), one or more times by halogen, alkyl, hydroxy, alkoxy, cycloalkylalkyl having 4 to 16 carbonatoms (e.g., cyclo halogenated alkyl (e.g. CF), halogenated alkoxy pentylethyl and cyclopropylmethyl), which is unsub (e.g. OCF), nitro, methylenedioxy, ethylenedioxy, stituted or Substituted one or more times by halogen, amino, alkylamino, dialkylamino, hydroxyalkyl, oxo, alkyl or combinations thereof, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo aryl having 6 to 14 carbon atoms, which is unsubstituted nyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfi or substituted one or more times by halogen, CF nyl, arylsulfonyl, phenyl, halogenated phenyl, phe OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, noxy, acyloxy (e.g., acetoxy), acylamido (e.g., ethylenedioxy, amino, alkylamino, dialkylamino, acetamido), tetrazolyl, alkylsulphonimide, arylsul hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, phonimide, or combinations thereof and/or substi 25 alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfo tuted in the alkyl portion by halogen, Oxo, cyano, or nyl, phenoxy, acylamido (e.g., acetamido), and acy combinations thereof (e.g., benzyl, methylbenzyl, loxy (e.g., acetoxy), or combinations thereof, t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, arylalkyl having 7 to 16 carbon atoms, which is unsub fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, stituted or substituted, preferably in the aryl portion, trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl, 30 one or more times by halogen, CF. OCF, alkyl, nitrobenzyl, methoxycarbonylbenzyl, methylsulfo hydroxy, alkoxy, nitro, methylenedioxy, ethylene nylbenzyl, phenethyl, phenpropyl), dioxy, a heterocyclic-alkyl group, which is saturated, partially amino, alkylamino, dialkylamino, hydroxyalkyl, saturated or fully unsaturated, having 5 to 10 ring hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo atoms in which at least 1 ring atom is an N, O or S 35 nyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, atom, which is unsubstituted or substituted one or acylamido (e.g., acetamido), and acyloxy (e.g., more times in the heterocyclic portion by halogen, acetoxy), or combinations thereof, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trif a heterocyclic group, which is saturated, partially satu luoromethyl), halogenated alkoxy, nitro, methylene rated or fully unsaturated, having 5 to 10 ring atoms in dioxy, ethylenedioxy, amino, alkylamino, dialky 40 which at least 1 ring atom is an N, O or Satom (e.g., lamino, hydroxyalkyl, hydroxyalkoxy, carboxy, 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 2-pyrimidi cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, nyl, 4-tetrahydropyranyl), which is unsubstituted or alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl, halo Substituted one or more times by halogen, aryl, alkyl, genated phenyl, phenoxy, acyloxy, tetrazolyl, alkyl alkoxy, alkoxycarbonyl, cyano, halogenated alkyl Sulphonimide, arylsulphonimide, aryl, Oxo, or com 45 (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, binations thereof and/or substituted in the alkyl dialkylamino, or combinations thereof, or portion by halogen, Oxo, cyano, or combinations a heterocyclic-alkyl group, which is saturated; partially thereof (e.g., pyridylmethyl), saturated or fully unsaturated, having 5 to 10 ring cycloalkylalkyl having 4 to 16 carbonatoms (e.g., cyclo atoms in which at least 1 ring atom is an N, O or S pentylethyl and cyclopropylmethyl), which is unsub 50 atom, which is unsubstituted or substituted one or stituted or Substituted one or more times by halogen, more times in the heterocyclic portion by halogen, oxo, alkyl or combinations thereof, or aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., alkoxyalkyl having 3 to 8 carbon atoms; trifluoromethyl), nitro, Oxo, amino, alkylamino, R is alkyl having, 1 to 6 carbon atoms, which is unsubsti dialkylamino, carboxy or combinations thereof and/ tuted or Substituted one or more times by halogen, OXo, 55 or Substituted in the alkyl portion by halogen, OXo, or combinations thereof wherein optionally one or more cyano, or combinations thereof; —CH2CH2— groups are replaced in each case by R’ is H, halogen, or alkyl having 1 to 6 carbon atoms —CH=CH- or —C=C- groups (e.g., CH); wherein optionally one or more —CH2CH2— groups R is H, or are replaced in each case by —CH=CH or alkyl having 1 to 6 carbonatoms, which is unsubstituted 60 —C=C-groups and wherein the alkyl is unsubstituted or Substituted one or more times by halogen wherein or Substituted one or more times by halogen; optionally one or more —CH2CH2— groups are R is H, halogen, alkyl having 1 to 6 carbonatoms wherein replaced in each case by —CH=CH- or —C=C optionally one or more —CH2CH2— groups are groups (e.g., CH, CHs); replaced in each case by —CH=CH or C=C R is H, 65 groups and wherein the alkyl is unsubstituted or Substi alkyl having 1 to 6 carbonatoms, which is unsubstituted tuted one or more times by halogen or hydroxyl (e.g., or Substituted one or more times by halogen, OXo, CH, CH5, CF, hydroxymethyl 2-(2-hydroxy)propyl. US 7,723,348 B2 10 hydroxymethyl), carboxy, alkoxycarbonyl having 2 to 6 or benzyl, pyrrolyl which is unsubstituted or substituted by carbon atoms (e.g., ethoxycarbonyl), —CO-alkyl hav halogen, C-alkyl, C-alkoxy, Cis-alkoxycarbonyl, and/ ing 2 to 6 carbon atoms (e.g., CH-CO), or phenyl: or benzyl, pyrazolyl which is substituted by halogen, Ca R is halogen (e.g., F); and alkyl, C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, isox R is H. 5 azolyl which is unsubstituted or substituted by halogen, Ca alkyl having 1 to 8 carbon atoms, which is unsubstituted alkyl, C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, or Substituted one or more times by halogen, oxo or imidazolyl which is substituted by halogen, C-alkyl, Ca combinations thereof wherein optionally one or more alkoxy, Cis-alkoxycarbonyl, and/or benzyl, pyridinyl which —CH2CH2— groups are replaced in each case by is Substituted by halogen, C-alkyl, C-alkoxy, Cis —CH=CH- or —C=C- groups (e.g., CH, 10 alkoxycarbonyl, and/or benzyl, pyrimidinyl which is unsub CHF), or alkoxy having 2 to 8 carbon atoms, which is unsubsti stituted or substituted by halogen, C-alkyl, C-alkoxy, tuted or Substituted one or more times by halogen; Cs-alkoxycarbonyl, and/or benzyl, morpholinyl which is R'' is H, Substituted by C-alkyl, C-salkoxycarbonyl, and/or benzyl, alkyl having 1 to 6 carbonatoms (e.g., methyl, ethylpro 15 piperadinyl which is substituted by C-alkyl, C-s-alkoxy pyl), which is unsubstituted or substituted one or more carbonyl, and/or benzyl, piperazinyl which is substituted by times by halogen, oxo, or combinations thereof C-alkyl, C-s-alkoxycarbonyl, and/or benzyl, tetrazolyl wherein optionally one or more —CH2CH2—groups which is unsubstituted or substituted by C-alkyl, C-s- are replaced in each case by —CH=CH or alkoxycarbonyl, and/or benzyl, or arylsulphonimide (e.g., —C=C- groups (e.g., CH, CHs), or CHSO. NHCO ) wherein the aryl portion is substituted a heterocyclic-alkyl group, which is saturated, partially by halogen or C-alkoxy. saturated or fully unsaturated, having 5 to 10 ring According to a further compound aspect of the invention, atoms in which at least 1 ring atom is an N, O or S the compounds are of Formula IX or X, e.g., Formula IX. atom, which is unsubstituted or substituted one or According to a further compound aspect of the invention, more times in the heterocyclic portion by halogen, 25 aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., the compounds are of formulas I, II, III, IV, V,VI,VII or VIII, trifluoromethyl), nitro, Oxo, amino, alkylamino, particularly IV and VI, wherein R is aryl substituted at least dialkylamino, carboxy or combinations thereof and/ once by -SO. N(R'), alkoxyalkoxy (e.g., methoxy or Substituted in the alkyl portion by halogen, OXo, ethoxy), alkoxyalkoxyalkyl (e.g., CHOCHCHOCH ) cyano, or combinations thereof (e.g., tetrahydro-2H 30 or benzyloxy. pyranylmethyl, pyrollidinylethyl; According to a further compound aspect of the invention, R" is H, the compounds are of formulas III or VI, wherein R is alkyl alkyl having 1 to 6 carbonatoms (e.g., methyl, ethylpro having 1 to 6 carbon atoms which is Substituted at least once pyl), which is unsubstituted or substituted one or more by hydroxy; alkoxyalkyl having 2 to 6 carbon atoms (e.g., times by halogen, oxo, or combinations thereof 35 methoxyethyl, ethoxymethyl), which is unsubstituted or sub wherein optionally one or more —CH2CH2—groups stituted one or more times by halogen, oxo, or combinations are replaced in each case by —CH=CH or thereof, alkoxycarbonyl ( C(=O)C-alkyl) having 2 to 6 —C=C- groups (e.g., CH, CHs), carbon atoms (e.g., —C(=O)CCH(CH); or —CO— cycloalkyl having, 3 to 8 carbon atoms, which is unsub NRSR 12. stituted or Substituted one or more times by halogen, 40 oxo, alkyl, or combinations thereof (e.g., cyclopen In accordance with the method aspect of the invention, tyl), or there is provided a method of treating a patient (e.g., a mam a heterocyclic-alkyl group, which is saturated, partially mal Such as a human) Suffering from a disease state (e.g., saturated or fully unsaturated, having, 5 to 10 ring memory impairment) involving decreased cAMP levels and/ atoms in which at least 1 ring atom is an N, O or S 45 or increased intracellular PDE4 levels, comprising adminis atom, which is unsubstituted or substituted one or tering to the patient a compound selected from Formulas I, II, more times in the heterocyclic portion by halogen, III, IV, V, VI, VII, VIII, IX or X: aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, Oxo, amino, alkylamino,
dialkylamino, carboxy or combinations thereof and/ 50 or Substituted in the alkyl portion by halogen, OXo, cyano, or combinations thereof (e.g., furylmethyl); and pharmaceutically acceptable salts or Solvates (e.g., hydrates) thereof, or Solvates of pharmaceutically acceptable salts thereof. 55 According to a further compound aspect of the invention, the compounds are of formulas I, II, III, IV, V,VI,VII or VIII, wherein L is (CH), OCONH, particularly compounds of for II mula IV wherein L is (CH), OCONH. According to a further compound aspect of the invention, 60 the compounds are of formulas I, II, III, IV, V,VI,VII or VIII, particularly IV and VI, wherein R is aryl having 6 to 14 carbonatoms (particularly phenyl or biphenyl), which is Sub stituted by at least one substituent selected from —CO N (R') (wherein R' is preferably, H, alkyl or alkoxy), ami 65 nosulfonyl, furanyl which is unsubstituted or substituted by halogen, Ca-alkyl, Ca-alkoxy, C2-s-alkoxycarbonyl and/ US 7,723,348 B2 11 12
-continued -continued
III
10
IV wherein 15 X is CH or N: L is a single bond; C-C straight chain or branched alky lene, wherein a CH group is optionally replaced by O. NH, NR", or S, which is unsubstituted or substituted one or more times by Oxo, halogen (preferably F), hydroxy, 2O cyano or combinations thereof (CH2)CONH; (CH), OCONH; (CH2)CON(C-alkyl); (CH)NHCO: (CH),CONHSO; (CH), SONH; (CH),SO; or (CH2)CO (e.g., a bond, CHCONH, SO, CHCO, CHCO); 25 n is 0 to 3: R" is alkyl having 1 to 4 carbon atoms, which is unsubsti tuted or Substituted one or more times by halogen (e.g., CH, CHF); 30 R is H, VI alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more —CH2CH2— groups are replaced in each case by —CH=CH- or —C=C- groups (e.g., CH, 35 CHF), cycloalkyl having 3 to 8 carbon atoms, which is unsub stituted or Substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbonatoms or combinations
VII 40 thereof (e.g., cyclopentyl), a heterocyclic group, which is saturated, partially satu rated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or Satom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is 45 unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, ammo, alkylamino, VIII dialkylamino, or combinations thereof (e.g., tetrahy drofuranyl), 50 aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, 55 alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfo nyl, phenoxy, acylamido (e.g., acetamido), and acyl IX oxy (e.g., acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsub stituted or substituted, preferably in the aryl portion, 60 one or more times by halogen, CF. OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylene dioxy, amino, alkylamino, dialkylamino, hydroxy alkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxy carbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, 65 phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof (e.g., benzyl, difluorobenzyl), US 7,723,348 B2 13 14 a partially unsaturated carbocyclic group having 5 to 14 C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, carbon atoms, (e.g., cyclohexenyl, cyclohexadienyl, pyridinyl which is unsubstituted or substituted by indanyl, and tetrahydronaphthenyl), which is unsub halo-en, Ca-alkyl, Ca-alkoxy, C2-s-alkoxycarbo stituted or Substituted one or more times by halogen, nyl, and/or benzyl, morpholinyl which is unsubsti alkyl, alkoxy, nitro, cyano, oxo, or combinations tuted or Substituted by C-alkyl, C-s-alkoxycarbo thereof, nyl, and/or benzyl, piperadinyl which is unsubstituted arylalkenyl having 8 to 16 carbon atoms, wherein the or substituted by C-alkyl, C-s-alkoxycarbonyl, alkenyl portion has up to 5 carbon atoms, which is and/or benzyl, piperazinyl which is unsubstituted or unsubstituted or substituted, preferably in the aryl Substituted by C-alkyl, C-s-alkoxycarbonyl, and/ portion, one or more times by halogen, alkyl, hydroxy, 10 or benzyl, tetrazolyl which is unsubstituted or substi alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, tuted by C-alkyl, C-s-alkoxycarbonyl, and/or ben alkylamino, dialkylamino, hydroxyalkyl, hydroxy Zyl, alkylsulphonimide (e.g., CHSO. NHCO ), alkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alky arylsulphonimide (e.g., CHSO. NHCO ) lthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acyla wherein the aryl portion is optionally substituted by mido (e.g., acetamido), and acyloxy (e.g., acetoxy), or 15 halogen, C-alkyl, C-alkoxy, or combinations combinations thereof, thereof (e.g., phenyl, bromophenyl, cyanophenyl, a heterocyclic-alkyl group, which is saturated, partially nitrophenyl, fluorophenyl, difluorophenyl, trifluo saturated or fully unsaturated, having 5 to 10 ring romethoxyphenyl, methylphenyl, dimethylphenyl, atoms in which at least 1 ring atom is an N, O or S methoxyphenyl, biphenyl substituted by —CONH2, atom, which is unsubstituted or substituted one or and phenyl substituted by biphenyl or CONH2). more times in the heterocyclic portion by halogen, heterocyclic group, which is Saturated, partially satu aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., rated or fully unsaturated, having 5 to 10 ring atoms in trifluoromethyl), nitro, Oxo, amino, alkylamino, which at least 1 ring atom is an N, O or Satom, which dialkylamino, carboxy or combinations thereof and/ is unsubstituted or substituted one or more times by or Substituted in the alkyl portion by halogen, OXo, 25 halogen, alkyl, hydroxy, alkoxy, halogenated alkyl cyano, or combinations thereof, or (e.g., trifluoromethyl), halogenated alkoxy, nitro, cycloalkylalkyl having 4 to 16 carbonatoms (e.g., cyclo methylenedioxy, ethylenedioxy, amino, alkylamino, pentylethyl and cyclopropylmethyl), which is unsub dialkylamino, hydroxyalkyl, hydroxyalkoxy, car stituted or Substituted one or more times by halogen, boxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkyl oxo, alkyl or combinations thereof; 30 sulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phe R is H, nyl, halogenated phenyl, phenoxy, acyloxy, alkyl having 1 to 8 carbon atoms, which is unsubstituted tetrazolyl, alkylsulphonimide, arylsulphonimide, or Substituted one or more times by halogen, oxo; or aryl, oxo, acylamido (e.g., acetamido), or combina combinations thereof wherein optionally one or more tions thereof (e.g., pyridyl, methylpyridyl, benzothia —CH2CH2— groups are replaced in each case by 35 Zolyl), —CH=CH- or —C=C- groups (e.g., CHs. arylalkyl having 7 to 16 carbon atoms, which is unsub CH(CH), n-propyl. n-butyl, t.-butyl), stituted or substituted, preferably in the aryl portion, cycloalkyl having 3 to 8 carbon atoms, which is unsub one or more times by halogen, alkyl, hydroxy, alkoxy, stituted or Substituted one or more times by halogen, halogenated alkyl (e.g. CF), halogenated alkoxy oxo, alkyl, or combinations thereof (e.g., cyclopentyl, 40 (e.g. OCF), nitro, methylenedioxy, ethylenedioxy, cyclohexyl), amino, alkylamino, dialkylamino, hydroxyalkyl, aryl having 6 to 14 carbon atoms, which is unsubstituted hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo or Substituted one or more times by halogen, alkyl, nyl, alkylthio, alkylsulfinyl, alkylsulfanyl, arylsulfi hydroxy, alkoxy, halogenated alkyl, halogenated nyl, arylsulfonyl, phenyl, halogenated phenyl, phe alkoxy (e.g., OCF), nitro, methylenedioxy, ethylene 45 noxy, acyloxy (e.g., acetoxy), acylamido (e.g., dioxy, amino, alkylamino, dialkylamino. —CO—N acetamido), tetrazolyl, alkylsulphonimide, arylsul (R'), SO. N(R'), hydroxyalkyl, hydroxy phonimide, or combinations thereof and/or substi alkoxy (e.g., —OCHHCOH), alkoxyalkoxy (e.g., tuted in the alkyl portion by halogen, oxo, cyano, or methoxyethoxy (CHOCHCHO ), alkoxyalkoxy combinations thereof (e.g., benzyl, methylbenzyl, alkyl (e.g., CHOCH2CHOCH2—), carboxy, cyano, 50 t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyl fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, Sulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl, phenyl, halogenated phenyl, phenoxy, benzyloxy, nitrobenzyl, methoxycarbonylbenzyl, methylsulfo acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), nylbenzyl, phenethyl, phenpropyl). furanyl which is unsubstituted or substituted by halo 55 a heterocyclic-alkyl group, which is saturated, partially gen, Ca-alkyl, C-alkoxy, Cis-alkoxycarbonyl, saturated or fully unsaturated, having 5 to 10 ring and/or benzyl, pyrrolyl which is unsubstituted or sub atoms in which at least 1 ring atom is an N, O or S stituted by halogen, Ca-alkyl, Ca-alkoxy, C2-s- atom, which is unsubstituted or substituted one or alkoxycarbonyl, and/or benzyl, pyrazolyl which is more times in the heterocyclic portion by halogen, unsubstituted or Substituted by halogen, C-alkyl, 60 alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trif Calkoxy, Cisalkoxycarbonyl, and/or benzyl, isox luoromethyl), halogenated alkoxy, nitro, methylene azolyl which is unsubstituted or substituted by halo dioxy, ethylenedioxy, amino, alkylamino, dialky gen, Ca-alkyl, C-alkoxy, Cis-alkoxycarbonyl, lamino, hydroxyalkyl, hydroxyalkoxy, carboxy, and/or benzyl, imidazolyl which is unsubstituted or cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, Substituted by halogen, C-alkyl, C-alkoxy, Cis 65 alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl, halo alkoxycarbonyl, and/or benzyl, pyridinyl which is genated phenyl, phenoxy, acyloxy, tetrazolyl, alkyl unsubstituted or Substituted by halogen, Calkyl, Sulphonimide, arylsulphonimide, aryl, oxo, or com US 7,723,348 B2 15 16 binations thereof and/or substituted in the alkyl a heterocyclic-alkyl group, which is saturated, partially portion by halogen, Oxo, cyano, or combinations saturated or fully unsaturated, having-5 to 10 ring thereof (e.g., pyridylmethyl), atoms in which at least 1 ring atom is an N, O or S cycloalkylalkyl having 4 to 16 carbonatoms (e.g., cyclo atom, which is unsubstituted or substituted one or pentylethyl and cyclopropylmethyl), which is unsub more times in the heterocyclic portion by halogen, stituted or Substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., oxo, alkyl or combinations thereof, or trifluoromethyl), nitro, Oxo, amino, alkylamino, alkoxyalkyl having 3 to 8 carbon atoms; dialkylamino, carboxy or combinations thereof and/ R is alkyl having 1 to 6 carbon atoms, which is unsubsti or Substituted in the alkyl portion by halogen, OXo, tuted or Substituted one or more times by halogen, oxo, 10 cyano, or combinations thereof; or combinations thereof wherein optionally one or more R’ is H, halogen, or alkyl having 1 to 6 carbon atoms —CH2CH2— groups are replaced in each case by wherein optionally one or more —CH2CH2— groups —CH=CH- or —C=C- groups (e.g., CH); are replaced in each case by —CH=CH or R is H, or —C=C-groups and wherein the alkyl is unsubstituted alkyl having 1 to 6 carbon atoms, which is unsubstituted 15 or Substituted one or more times by halogen; or Substituted one or more times by halogen wherein R is H. halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more —CH2CH2— groups are optionally one or more —CH2CH2—groups are replaced in replaced in each case by —CH=CH- or —C=C each case by —CH=CH- or —C=C- groups and groups (e.g., CH, CHs); wherein the alkyl is unsubstituted or substituted one or more R is H, 20 times by halogen or hydroxyl (e.g., CH, CH5, CF alkyl having 1 to 6 carbonatoms, which is unsubstituted hydroxymethyl 2-(2-hydroxy)propyl, hydroxymethyl), car or Substituted one or more times by halogen, OXo, boxy, alkoxycarbonyl having 2 to 6 carbon atoms (e.g., hydroxy or combinations thereof wherein optionally ethoxycarbonyl), —CO-alkyl having 2 to 6 carbon atoms one or more —CH2CH2— groups are replaced in (e.g., CH-CO), or phenyl: each case by -CH=CH- or -C=C- groups, 25 R is halogen (e.g., F); and alkoxyalkyl having 2 to 6 carbon atoms (e.g., methoxy- R" is H, ethyl (CHCHOCH), ethoxymethyl alkyl having 1 to 8 carbon atoms, which is unsubstituted (CHOCHCH)), which is unsubstituted or substi or Substituted one or more times by halogen, oxo or tuted one or more times by halogen, oxo, or combi combinations thereof wherein optionally one or more nations thereof; 30 —CH2CH2— groups are replaced in each case by alkoxycarbonyl ( C(=O)C)-alkyl) having 2 to 6 car- —CH=CH- or —C=C- groups (e.g., CH, bon atoms (e.g., —C(=O)CCH(CH)); CHF), or CO NRSR'2; alkoxy having 2 to 8 carbon atoms, which is unsubsti cycloalkyl having 3 to 8 carbon atoms, which is unsub- tuted or Substituted one or more times by halogen; stituted or substituted one or more times by halogen, 35 R'' is H. oxo, alkyl, or combinations thereof (e.g., cyclopen- alkyl having 1 to 6 carbonatoms (e.g., methyl, ethylpro tyl), pyl), which is unsubstituted or substituted one or more cycloalkylalkyl having 4 to 16 carbonatoms (e.g., cyclo- times by halogen, oxo, or combinations thereof pentylethyl and cyclopropylmethyl), which is unsub- wherein optionally one or more —CH2CH2—groups stituted or Substituted one or more times by halogen, 40 are replaced in each case by —CH=CH or oxo, alkyl or combinations thereof, —C=C- groups (e.g., CH, CHs), or aryl having 6 to 14 carbon atoms, which is unsubstituted a heterocyclic-alkyl group, which is saturated, partially or Substituted one or more times by halogen, CF saturated or fully unsaturated, having 5 to 10 ring OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, atoms in which at least 1 ring atom is an N, O or S ethylenedioxy, amino, alkylamino, dialkylamino, 45 atom, which is unsubstituted or substituted one or hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, more times in the heterocyclic portion by halogen, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfo- aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., nyl, phenoxy, acylamido (e.g., acetamido), and acy- trifluoromethyl), nitro, Oxo, amino, alkylamino, loxy (e.g., acetoxy), or combinations thereof, dialkylamino, carboxy or combinations thereof and/ arylalkyl having 7 to 16 carbon atoms, which is unsub- 50 or Substituted in the alkyl portion by halogen, OXo, stituted or substituted, preferably in the aryl portion, cyano, or combinations thereof (e.g., tetrahydro-2H one or more times by halogen, CF. OCF, alkyl, pyranylmethyl, pyrollidinylethyl; hydroxy, alkoxy, nitro, methylenedioxy, ethylene- R" is H, dioxy, amino, alkylamino, dialkylamino, hydroxy- alkyl having 1 to 6 carbonatoms (e.g., methyl, ethylpro alkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxy- 55 pyl), which is unsubstituted or substituted one or more carbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, times by halogen, oxo, or combinations thereof phenoxy, acylamido (e.g., acetamido), and acyloxy wherein optionally one or more —CH2CH2—groups (e.g., acetoxy), or combinations thereof, are replaced in each case by —CH=CH or a heterocyclic group, which is Saturated, partially Satu-
US 7,723,348 B2 37 38
-continued -continued
5) 9)
10
15
6) 10)
30
35 7) 11)
40
45
50 8) 12)
55
60
65 US 7,723,348 B2 39 40
-continued -continued
13) 17)
10
15 18)
14) 25 \/\/
30 19)
35 15) ~~~~)~~~~)~~~~)• 40 N,Z> 45 S»S,S, 20) 50 N/*Z 16) 55 60 65 US 7,723,348 B2 41 42 -continued -continued 25) 21) N N 10 C - 15 O U/N/ 26) 22) N ^ N M 25 e N e y NN,A C) C 30 O C “\, > 35 23) 27) ^ M 40 e N e NN,A C) C 45 O C o N/ 50 28) 24) / 55 e A e DC,NN, NN, 60 O 65 US 7,723,348 B2 43 44 -continued -continued 29) 34) 10 15 30) 25 35) 30 31) 35 40 32) 45 36) 50 33) 55 60 65 US 7,723,348 B2 45 46 -continued -continued 37) 39) 10 15 25 40) 30 35 40 41) 38) 45 50 55 42) 60 65 US 7,723,348 B2 47 48 -continued -continued 43) 47) ()--C O -- CN " (, 44) 20 48) No / \ 25 No c'eNO Sr. O r) F 30 49) ( \, 45) 35 N O No N-N- re. O i). O 50 No r) S-r 46) 55 51) ( \, 60 No O 65 US 7,723,348 B2 49 50 -continued -continued 52) 57) 10 F C 15 58 ) s 53) ( \, 2O O O r ro 25 so) 54) ( \, N N- NN-1a O r 35 O O 60) 40 55) ( \, Sr. -r 45 O 50 61) 56) 55 60 65 US 7,723,348 B2 51 52 -continued -continued 65) 62) 10 15 66) 25 63) 35 67) 40 45 64) 50 68) 55 60 65 US 7,723,348 B2 53 54 -continued -continued 74) -N 5 N N No N- O O 2 O O O 10 () NN,/ N N N-N- 75) ( \, O O i). r Ol 2O c'e r 25 71) O 76) O 2 O O 2 ()-- N \, O 35 cy NN N^ N. O 72) 40 N O 2 45 () N/ N N-N- O 77) c'e a^ 50 raroO \, 73) W \ 55 or " No r) Sir O) US 7,723,348 B2 55 56 -continued -continued 79) 84) ( \, 5 i). re, 10 80) ( \, 15 85) ro O 25 81) 86) 35 40 82) 87) 45 50 88) 55 83) 60 Cl C 65 US 7,723,348 B2 61 62 -continued -continued 105) 109) CH ^ N -Q,N \ / H3C 106) CH3 2O 110) CH3 ^ 25 N - N N 30 Qu O HC 107) CH 35 111) 40 45 50 108) 112) CH3 55 60 //N 65 US 7,723,348 B2 63 64 -continued -continued 113) CH 117) 10 15 114) CH3 20 118) 25 30 35 119) 115) 40 45 50 120) 116) 55 60 65 US 7,723,348 B2 67 68 -continued -continued 130) 134) CH ( 10 N / N-N 15 135) CH3 131) CH3 W 25 4 N (SO 30 136) 35 132) CH ( 40 N \ N 4 N-N 45 137) CH3 O 50 ^ N 133) CH3 N e 55 4 N/ 7 NN 7 N-N O 60 /S \, 65 o US 7,723,348 B2 69 70 -continued -continued 138) 10 15 139) 143) 25 N t 30 140) HO 35 144) 40 45 50 141) 145) 55 60 CH3 65 OH US 7,723,348 B2 71 72 -continued -continued 146) CH3 149) CH 10 15 2O 150) CH3 25 147) CH3 30 35 151) CH3 40 45 148) CH3 50 152) 55 60 65 US 7,723,348 B2 75 76 -continued -continued 161) 162) 163) 168) 164) 55 60 65 US 7,723,348 B2 77 78 -continued -continued 169) 172) 10 15 HC 173) 170) 25 30 174) O 35 O 45 171) 50 175) 55 60 65 HC US 7,723,348 B2 79 80 Preparation of starting materials: -continued 176) Scheme 1 RO N 1A) RBr, base 1B) ROH, PPh3, DEAD -- 2 HO X Z 10 1 RO N O 2 R2O X Z 15 2 O Z = CHO, COCH, B(OR"), or halogen RI HO O O N EtO l NHT 1) Base 177) 2 -- too 'S-s-NHT ---A O X EtO 4 25 R2 O 3 30 Ho-MO 35 Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceu tically acceptable carrier and, optionally, another active agent The starting materials for Formulas I and IV are prepared as discussed below. A further preferred aspect includes a 40 as shown in Scheme 1. Thus, appropriately substituted ben method of inhibiting a PDE4 enzyme, especially an isoen Zaldehydes 3 (X—CH, N) are subjected to Horner-Wad Zyme, e.g., as determined by a conventional assay or one sworth-Emmons conditions with phosphonate 2. The result described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); a method ing olefin is not isolated, but heated to induce cyclization of treating a psychiatric or neurological syndrome, e.g., 45 Almirante, N.; Cerri, A.; Fedrizzi, G.; Marazzi, G.; Santa depression and loss of memory, especially major depression gostino, M. Tetrahedron Lett., 1998, 39, 3287-3290 to pro and long-term memory, cognitive impairment or decline, vide the corresponding pyrazoles 5. memory impairment, etc.; a method of treating a disease state modulated by PDE4 activity, in a mammal, e.g., a human, Alternatively, 3-substituted pyrazoles can be made from e.g., those disease states mentioned herein. 50 beta-ketoaldehydes and hydrazine Murray, W.; Wachter, M.: Methods of the invention include, but are not limited to, Barton, D.; Forenro-Kelly, Y. Synthesis, 1991, 18 or from methods of enhancing cognition in a patient in whom Such enhancement is desired, methods of treating a patient Suffer various palladium couplings using a pyrazole aptly Substi ing from cognition impairment or decline, methods of treat tuted in the 3 position, for example with a bromine or a boron. ing a patient having a disease involving decreased cAMP 55 Cacchi, S. Fabrizi, G.; Carnaio, A. Syn. Lett. 1997, 959 levels, methods of inhibiting PDE4 enzyme activity in a 961. patient, methods of treating a patient Suffering from memory impairment due to neurodegenerative disease, methods of Substitution on the pyrazole nitrogen is accomplished by treating a patient Suffering from depression, methods of treat treatment of the pyrazole 5 with an appropriate base Such as ing a patient Suffering from an allergic or inflammatory dis 60 ease. All methods comprise administering to the patient an NaH, LDA or KCO in a polar aprotic solvent. This is fol effective amount of a compound of the invention. Preferably, lowed by the addition of electrophile R-L-X, where X is a the patient is human. Suitable leaving group Such as a halogen or Sulfonate (C1, Br, The compounds of the present invention may be prepared methanesulfonyl, etc.). A mixture of Substituted pyrazoles 6a conventionally. Some of the known processes that can be used 65 and 6b are obtained with the major isomer being the 1,3- are described below. All starting materials are known or can disubstituted pyrazoles (6a). These isomers can be separated be conventionally prepared from known starting materials. by HPLC. US 7,723,348 B2 81 82 He1) Base 1a) RX He1b) ROH 1c) R2-B(OH), Po Reaction of pyrazole 5 with alkyl bromoacetate (preferably t-butyl bromoacetate) gives pyrazole Substituted acetate esters. These esters are Saponified to acetic acid derivatives 6a and 6b (L=CHCO, R=H) by treatment with either an acid, 30 Such as trifluoroacetic acid, or use of a base. Such as sodium hydroxide. Treatment of the resultant acetic acid products with thionyl chloride or oxalyl chloride generates the corre sponding acid chloride. Subsequent reaction with a nucleo phile Such as an amine (e.g., aniline) gives the acetamide 35 derivatives 6a and 6b (e.g., L=CHCONH, R-phenyl). Simi larly, the acetic acid derivative (L=CHCO, R=H) can be treated with HBTU or a suitable coupling reagent (i.e., DCC, HOBT, etc) and an amine compound to give the desired acetamide analogues 6a and 6b. 40 Alternatively, (Scheme 3) compounds of the type 6a where R°-arylalkyl, alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocyclic or heterocyclic-alkyl groups can be prepared by either Mitsunobu reaction between phenol 7b and an appro 45 Compounds of Formulas II and V are synthesized in a priate alcohol (ROH) or alkylation with a suitable electro phile, R X (X" is a suitable leaving group such as a halogen similar manner starting from aldehyde 8. For these reactions, or Sulfonate (C1, Br, methanesulfonyl etc.)), and an appropri the ketone should be protected before pyrazole formation and ate base (i.e., KCO, NaH, NaOH). (R-arylalkyl, alkyl, can be deprotected afterwards. Suitable protecting groups cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocyclic and 50 include, but are not limited to, ketals and cyclic ketals. heterocyclic-alkyl groups.) 3-Aryloxy 3-heteroaryloxypyrazole derivatives of the type 6a (i.e., where R is aryl or heteroaryl) are prepared by cross coupling reaction of phenol 7b with arylboronic acids using a copper catalyst in the presence of an amine base. Suitable 55 copper catalysts include copper diacetate, copper (II) chlo ride, etc. Generally, halogenated Solvents are utilized. Such as chloroform, dichloromethane, 1,2-dichloroethane, and the like. Commonly used bases include triethylamine, diisopro pylethylamine, and pyrrolidine. Alternatively, 3-aryloxy and 60 3-heteroaryloxy pyrazole compounds can be synthesized in an analogous method as described previously for 3-pheny loxyrolipram, which utilizes an Ullman type coupling reac tion starting with iodobenzene and 3-hydroxyrolipram 65 Compounds of Formulas III and VI are synthesized in a Schmiechen, R. et al., U.S. Pat. No. 4,193.926. The other similar manner starting from aldehyde 9. Marfat, A., et al., regioisomer 6b may be formed in an analogous manner. U.S. Pat. No. 6,262,040. US 7,723,348 B2 83 Scheme 5 RO N 4) HS(CH2)SH, BF-Et2O -- 2 R2O X CHO 3 10 RO O Synthesis of 1.5-pyrazoles N SAN 2 S - R A. Cross-Coupling Reactions R2O X BuLi, HMPA 15 Alternatively, the 1,5-disubstituted compounds of Formula S IV through VII can be prepared from 1-hydroxypyrazole 10 (Scheme 4) (Eskildsen, J., Vedso, P. Begtrup, M., Synthesis, 13 2001, 1053-1056. Eskildsen, J., Kristensen, J., Vedso, P., OH RO N 6) Dess Martin Ox Begtrup, M.J. Org. Chem., 2001, 66,8654-8656. Paulson, A. 7) RLNHNH2-HX S., Eskildsen.J., Vedso, P. Begtrup, M. J. Org. Chem., 2002, 2 S R 8 -Toluene, heatHe 67,3904-3907). Thus, warning a solution of 1-hydroxypyra R2O X Zole 10 with an electrophile such as a benzyl bromide or C.-bromoacetate in CHCl to 60 to 100° C. provides 2-substi S tuted-pyrazol-1-oxides 11. Subsequent treatment with POCl. 25 14 or POBr, in a halogenated solvent such as CHCl yields 5-halo-1-substituted pyrazoles 12. Such 5-halo-1-substituted pyrazoles can undergo cross-coupling type reaction with aryl boronic acids 2 (Z=B(OH)) or can be metalated (e.g., halo gen-magnesium exchange, transmetalation with ZnCl2) for a 30 Negishi-type reaction with an aryl halide 2 (Z=halogen). Scheme 4 35 N RLX', CHCl, 2 \ He-50 to 100 C. / HerPOX's. CHCI N- N / N Another method to prepare 1,5-disubstituted pyrazoles of OH R3L O type 6b is through condensation reaction between 1,3-diketo 10 11 40 derivative 16 and a substituted hydrazine (Nakamura, Toshio, et al., J. Med Chem, 2003, 46, 5416: Penning, T. D., et al., J. X 2 f SuzukiiCross-coupling or Negishi He Med. Chem., 1997, 40, 1347-1365.) The selectivity of this - N RO reaction for 1.5 versus 1,3-disubstituted pyrazoles varies R3L 45 pending the substitution at R. Formation of the 1,5-disubsti 12 2 tuted pyrazoles are favored when R is an electron withdraw R2O DOX Z. ing group Such as carboxylate or trifluoromethyl, or a small RO-N-4 \ group Such as hydrogen. Starting 1,3-diketo derivatives 16 are Sa. a prepared from acetophenone derivatives 15 by reaction with X f 50 Sodium hydride and an appropriately Substituted ethyl R2O N-N RI/ acetate. Scheme 6 Alternatively, 1,5-disubstituted pyrazoles 6b can be pre 55 pared from 2-aryldithianes 13 in a three step synthesis. Thus, RO N 8) R'CHMgCl;7 PCC dithiane intermediate 13 can be prepared by reaction of alde Ho hyde 3 with propane dithiol and a Lewis acid catalyst Such as 2 R2O X CHO BF-EtO in an aprotic solvent (Hatch, R.P., Shringarpure, J., 60 Weinreb, S. M., J. Org. Chem., 1978, 43, 4172-4177). Sub 3 sequent reaction of the alkyl lithium produced dithiane anion RO N 9) NaH, RCH2COEt8 with appropriately substituted epoxides provides-2,2-disub He stituted dithianes 14. Oxidation of alcohol 14 to the protected 2 B-keto dithiane followed by treatment with an appropriately 65 R2O X COCHR substituted hydrazine salt provides 1,5-disubstituted pyra 15 Zoles 6b. US 7,723,348 B2 86 -continued RO N R7 Scheme 8 10) R3LNHNH-HX 13) LDA, R5CHO 2 R8 --> N 14) PCC, CHCI R2O X --- 2 O O F N F 18 10 O N R5 15)) R6NHNH 2 2 15 F N F 19 R5 16) NaCN, DMSO TBAB N 7 | N He17) PHPCHR7Br, BuLi, THF Y 2 In a similar fashion, enamines of the type 17 undergo A N F reaction with appropriately substituted hydrazines to provide R6 target pyrazoles 6b (Yang, Ji, et al., J. Med. Chem. 2004, 47(6), 1547). 25 Scheme 7 RO N 11) (MeO)2CR8N(CH3)2 30 Ho 2 R2O X COCHR 15 35 Azaindazole analogs of formulae VI where X=N are pre pared in a similar fashion as described above in Scheme 7 starting with 6-ketoaZaindazole analog 21. This starting RO N R7 material is prepared from 2,6-dihalogenated pyridines of the 12) RLNHNH2-HX type 18 by selective lithiation at the 3-position by a sterically 2 N 40 hindered non-nucleophilic base such as LDA followed by R2O X N N treatment with an appropriate Substituted aldehyde Such as O R8 propionaldehyde to generate the corresponding secondary 17 alcohol. (Radinov, R.; Chanev, C.; Haimova, M., Lithiation of 45 polychloropyrimidines and dichloropyridines. J. Org. Chem. 1991, 5, 4793-4796.). Oxidation to the corresponding ketone can be performed by a number of methods such as with PCC in chloroform to generate 3-ketosubstituted pyridine 19. Reaction of pyridine 19 with a substituted hydrazine provides 50 6-halo-azaindazole 20. Treatment with NaCN produces the 6-cyano derivative which can then be converted to target 21 by reaction with phosphoranes. (Reference: Taber, D. F.; Cai, L., Preparation of ketones from nitriles and phosphoranes. J. 55 Org. Chem. 2005, 70,4887-4888.) Scheme 9 Compounds of Formula VIII can also be prepared using the R5 general procedure described above. Subsequent reaction with the appropriately substituted iso N 2N1s 18) tBuOK, R6-Br cyanates in halogenated solvents provides the desired car NN 2 NS M X O bamates. Compounds of formulas I-VIII where L is H CHCHOCONHR can be prepared by the reaction of 65 O hydroxyethyl hydrazine with an enamine of the type 17 to 22 form the ethanol derivative 6b (L=CHCH-OH). US 7,723,348 B2 87 88 -continued -continued N N 2 n He 10 23 19) R7CH2MgX HO 26 15 24 (minor component) 25 27 In addition, a variety of ethers can be synthesized by alky 30 lation of phenolic analogs 26 by reaction with various alkyl 21 bromides to provide targets 27. In addition these phenols can be functionalized by Mitsunobu reaction with an appropriate alcohol to provide compounds where R=OAlkyl. Still fur ther, reaction with trifluoromethylsulfonyl chloride provides 35 the triflate (R—CFSO, ) which can readily undergo Alternatively, target compounds of formula VI or IX can be Suzuki type reactions with boronic acids or Buchwald reac prepared from 6-keto-indazole intermediates of the type 21 or tions with amines to generate biaryls (R9-aryl or heteroaryl) 24 as described in Scheme 7. Thus, Weinreb amide analog 22 and amino substituted compounds (R—N(R).) respectively. is prepared by conventional methods from the previously 40 One of ordinary skill in the art will recognize that some of described carboxylic acid. Treatment of 22 with a strong base the compounds of Formulas I, II, III, IV, V, VI, VII, VIII, IX and X can exist in different geometrical isomeric forms. In such as potassium tert-butoxide followed by addition of a addition, some of the compounds of the present invention suitable R-bromide provides primarily 1-substituted inda possess one or more asymmetric atoms and are thus capable Zoles 23 with minor amounts of the 2-substituted analogs 24. 45 of existing in the form of optical isomers, as well as in the Treatment of the Weinreb amide analog 23 with a Grignard form of racemic or nonracemic mixtures thereof, and in the reagent provides key intermediate 21. form of diastereomers and diastereomeric mixtures interalia. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, Substantially pure, and pure enantiomers, are 50 within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the correspond ing opposite enantiomer, preferably no more than 2%, most preferably no more than 1%. 55 The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereomeric salts using an 20). H., 10% Pd/C optically active acid or base or formation of covalent diaste COCS. 60 Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or BO chemical differences by methods known to those skilled in 25 65 the art, for example, by chromatography or fractional crys tallization. The optically active bases or acids are then liber ated from the separated diastereomeric salts. US 7,723,348 B2 89 90 A different process for separation of optical isomers For example, the pharmaceutically acceptable salt can be a involves the use of chiral chromatography (e.g., chiral HPLC hydrochloride, a hydroformate, hydrobromide, or a maleate. columns), with or without conventional derivation, optimally Preferably, the salts formed are pharmaceutically accept chosen to maximize the separation of the enantiomers. Suit able for administration to mammals. However, pharmaceuti able chiral HPLC columns are manufactured by Diacel, e.g., 5 cally unacceptable salts of the compounds are suitable as Chiracel OD and Chiracel OJ among many others, all rou intermediates, for example, for isolating the compound as a tinely selectable. Enzymatic separations, with or without salt and then converting the salt back to the free base com derivitization, are also useful. The optically active com pound by treatment with an alkaline reagent. The free base pounds of Formulas I-X can likewise be obtained by utilizing can then, if desired, be converted to a pharmaceutically optically active starting materials in chiral syntheses pro 10 acceptable acid addition salt. cesses under reaction conditions which do not cause racem One of ordinary skill in the art will also recognize that some ization. of the compounds of Formulas I-X can exist in different In addition, one of ordinary skill in the art will recognize polymorphic forms. As known in the art, polymorphism is an that the compounds can be used in different enriched isotopic ability of a compound to crystallize as more than one distinct forms, e.g., enriched in the content of H. H. ''C, 'Cand/or 15 crystalline or “polymorphic species. A polymorph is a solid '''C. In one particular embodiment, the compounds are deu crystalline phase of a compound with at least two different terated. Such deuterated forms can be made by the procedure arrangements or polymorphic forms of that compound mol described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As ecule in the solid state. Polymorphic forms of any given described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deutera compound are defined by the same chemical formula or com tion can improve the efficacy and increase the duration of position and areas distinct in chemical structure as crystalline action of drugs. structures of two different chemical compounds. Deuterium Substituted compounds can be synthesized One of ordinary skill in the art will further recognize that using various methods such as described in: Dean, Dennis C.; compounds of Formulas I-X can exist in different solvate Editor. Recent Advances in the Synthesis and Applications of forms. Solvates of the compounds of the invention may also Radiolabeled Compounds for Drug Discovery and Develop 25 form when solvent molecules are incorporated into the crys ment. In: Curr., Pharm. Des., 2000; 6(10) (2000), 110 pp. talline lattice structure of the compound molecule during the CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, crystallization process. For example, Suitable Solvates George W.; Varma, Rajender S. The Synthesis of Radiola include hydrates, e.g., monohydrates, dihydrates, sesquihy beled Compounds via Organometallic Intermediates. Tetra drates, and hemihydrates. hedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN: 30 The compounds of the invention can be administered alone 0040-4020. CAN 112:20527AN 1990:20527 CAPLUS; and or as an active ingredient of a formulation. Thus, the present Evans, E. Anthony. Synthesis of radiolabeled compounds, J. invention also includes pharmaceutical compositions of one Radioanal. Chem. (1981), 64(1-2), 9-32. CODEN:JRACBN or more compounds of Formulas I, II, III, IV, V,VI,VII, VIII, ISSN: 0022-4081, CAN 95:76229 AN 1981:476229 IX and X containing, for example, one or more pharmaceu CAPLUS. 35 tically acceptable carriers. The present invention also relates to useful forms of the Numerous standard references are available that describe compounds as disclosed herein, such as pharmaceutically procedures for preparing various formulations Suitable for acceptable salts or prodrugs of all the compounds of the administering the compounds according to the invention. present invention for which salts or prodrugs can be prepared. Examples of potential formulations and preparations are con Pharmaceutically acceptable salts include those obtained by 40 tained, for example, in the Handbook of Pharmaceutical reacting the main compound, functioning as a base, with an Excipients, American Pharmaceutical Association (current inorganic or organic acid to form a salt, for example, salts of edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, hydrochloric acid, Sulfuric acid, phosphoric acid, methane Lachman and Schwartz, editors) current edition, published by Sulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, Marcel Dekker, Inc., as well as Remington's Pharmaceutical Succinic acid and citric acid. Pharmaceutically acceptable 45 Sciences (Arthur Osol, editor), 1553-1593 (current edition). salts also include those in which the main compound func In view of their high degree of selective PDE4 inhibition, tions as an acid and is reacted with an appropriate base to the compounds of the present invention can be administered form, e.g., sodium, potassium, calcium, magnesium, ammo to anyone requiring PDE4 inhibition. Administration may be nium, and choline salts. Those skilled in the art will further accomplished according to patient needs, for example, orally, recognize that acid addition salts of the claimed compounds 50 nasally, parenterally (Subcutaneously, intravenously, intra may be prepared by reaction of the compounds with the muscularly, intrasternally and by infusion) by inhalation, rec appropriate inorganic or organic acid via any of a number of tally, vaginally, topically and by ocular administration. known methods. Alternatively, alkali and alkaline earth metal Various solid oral dosage forms can be used for adminis salts are prepared by reacting the compounds of the invention tering compounds of the invention including such solid forms with the appropriate base via a variety of known methods. 55 as tablets, gelcaps, capsules, caplets, granules, lozenges and The following are further examples of acid salts that can be bulk powders. The compounds of the present invention can be obtained by reaction with inorganic or organic acids: acetates, administered alone or combined with various pharmaceuti adipates, alginates, citrates, aspartates, benzoates, benzene cally acceptable carriers, diluents (such as Sucrose, mannitol, Sulfonates, bisulfates, butyrates, camphorates, digluconates, lactose, starches) and excipients known in the art, including cyclopentanepropionates, dodecylsulfates, ethanesulfonates, 60 but not limited to Suspending agents, Solubilizers, buffering glucoheptanoates, glycerophosphates, hemisulfates, hep agents, binders, disintegrants, preservatives, colorants, fla tanoates, hexanoates, fumarates, hydrobromides, hydroio Vorants, lubricants and the like. Time release capsules, tablets dides, 2-hydroxy-ethanesulfonates, lactates, maleates, meth and gels are also advantageous in administering the com anesulfonates, nicotinates, 2-naphthalenesulfonates, pounds of the present invention. oxalates, palmoates, pectinates, persulfates, 3-phenylpropi 65 Various liquid oral dosage forms can also be used for onates, picrates, pivalates, propionates, succinates, tartrates, administering compounds of the inventions, including aque thiocyanates, tosylates, mesylates and undecanoates. ous and non-aqueous solutions, emulsions, Suspensions, Syr US 7,723,348 B2 91 92 ups, and elixirs. Such dosage forms can also contain Suitable neurodegenerative dementias (Alzheimer's, Parkinson's dis inert diluents known in the art such as water and suitable ease, Pick's disease), vascular (Infarcts, Hemorrhage, Car excipients known in the art Such as preservatives, wetting diac Disorders), mixed vascular and Alzheimer's, bacterial agents, Sweeteners, flavorants, as well as agents for emulsi meningitis, Creutzfeld-Jacob Disease, multiple Sclerosis, fying and/or suspending the compounds of the invention. The 5 traumatic (subdural hematoma or traumatic brain injury), compounds of the present invention may be injected, for infectious (HIV), toxic (heavy metals, alcohol, medications), example, intravenously, in the form of an isotonic sterile metabolic (Vitamin B or folate deficiency), CNS hypoxia, Solution. Other preparations are also possible. Cushing's disease, psychiatric (depression and Schizophre Suppositories for rectal administration of the compounds nia) and hydrocephalus. of the present invention can be prepared by mixing the com- 10 pound with a suitable excipient Such as cocoa butter, salicy The present invention also includes methods for treating lates and polyethylene glycols. Formulations for vaginal memory loss separate from dementias, including mild cogni administration can be in the form of a pessary, tampon, cream, tive impairment (MCI) and age-related cognitive decline. The gel, paste, foam, or spray formula containing, in addition to present invention includes methods of treatment for memory the active ingredient, Such Suitable carriers as are known in 15 impairment as a result of disease including Huntington's the art. disease and Down's syndrome. According to another aspect, For topical administration, the pharmaceutical composi the invention includes methods for treating memory loss from tion can be in the form of creams, ointments, liniments, anesthetics, chemotherapy, radiation treatment, post-Surgical lotions, emulsions, Suspensions, gels, Solutions, pastes, pow trauma, post-traumatic stress disorder (PTSD), obesity, and ders, sprays, and drops suitable for administration to the skin, 20 diabetes. eye, ear or nose. Topical administration may also involve The compounds of the invention can also be used to treat transdermal administration via means such as transdermal Schizophrenia, bipolar or manic depression, major depres patches. sion, and drug addiction. PDE4 inhibitors can be used to raise Aerosol formulations suitable for administering via inha cAMP levels and prevent neurons from undergoing apopto lation also can be made. For example, for treatment of disor- 25 sis. PDE4 inhibitors are also known to be anti-inflammatory. ders of the respiratory tract, the compounds according to the The combination of preventing neuronal apoptosis and inhib invention can be administered by inhalation in the form of a iting inflammatory responses make these compounds useful powder (e.g., micronized) or in the form of atomized solu to treat neurodegeneration resulting from any disease or tions or Suspensions. The aerosol formulation can be placed injury, including stroke, Alzheimer's disease, multiple scle into a pressurized acceptable, propellant. 30 rosis, amyolaterosclerosis (ALS), and multiple systems atro The compounds can be administered as the sole active phy (MSA), as well as spinal injury. agent or in combination with other pharmaceutical agents PDE4 inhibitors have been shown to produce antidepres Such as other agents used in the treatment of cognitive impair sant effects in humans and antidepressant-like effects in ani ment and/or in the treatment of psychosis, e.g., other PDE4 mal models of depression. Clinical studies in humans Suffer inhibitors, calcium channel blockers, chloinergic drugs, 35 ing from major depression have demonstrated efficacy of the adenosine receptor modulators, ampakines, NMDA-R modu PDE4 inhibitor, rolipram, with comparable results in some of lators, mGluR modulators, and cholinesterase inhibitors these studies to those of desipramine Bobon D. Breulet M. (e.g., donepezil, rivastigimine, and galanthamine). In Such Gerard-Vandenhove MA, Guito-Goffioul F. Plomteux G, combinations, each active ingredient can be administered Satre-Heinandez M, Schratzer M, Troisfontaines B, Von either in accordance with their usual dosage range or a dose 40 Frenckell R. Wachtel H (1988) Is Phosphodiesterase Inhibi below their usual dosage range. tion a New Mechanism of Antidepressant Action? Eur Arch The present invention further includes methods of treat Psychiatr Neurol Sci., 238:2-6; Meya U, Wachtel H, Sastre ment that involve inhibition of PDE4 enzymes. Thus, the Hernandez M (1991) inhibition of Phosphodiesterase as an present invention includes methods of selective inhibition of Antidepressive Mechanism: Clinical Properties of Rolipram. PDE4 enzymes in patients, such as animals, e.g., mammals, 45 In Ansseau M. von Frenckell, Franck G (eds) Biological especially humans, wherein Such inhibition has a therapeutic Markers of Depression: State of the art, Elsevier Science effect, such as where such inhibition may relieve conditions Publishers B. V., Pp: 209-213; Zhu J, Mix E. Winblad B involving neurological syndromes, such as the loss of (2001) The Antidepressant and Anti-inflammatory Effects of memory, especially long-term memory. Such methods com Rolipram in the Central Nervous System. CNS Drug Reviews, prise administering to a patient in need thereof. Such as an 50 7:387-398. Rolipram was active in a number of biochemical animal, especially a mammal, most especially a human, an and behavioral preclinical models of antidepressant activity inhibitory amount of a compound, alone or as part of a for Wachtel H (1983) Potential Antidepressant Activity of mulation, as disclosed herein. Rolipram and other Selective Cyclic Adenosine 3',5'-Mono The condition of memory impairment is manifested by phosphate Phosphodiesterase Inhibitors. Neuropharmacol impairment of the ability to learn new information and/or the 55 ogy, 22: 267-272; and Wachtel H., Schneider H H (1986) inability to recall previously learned information. Memory Rolipram, a novel antidepressant drug, reverses the hypoth impairment is a primary symptom of dementia and can also be ermia and hypokinesia of monoamine-depleted mice by an a symptom associated with Such diseases as Alzheimer's action beyond postsynaptic monoamine receptors. Neurop disease, Schizophrenia, Parkinson's disease, Huntington's harmacology, 25: 1119-1126. More recently, studies with disease, Pick's disease, Creutzfeld-Jakob disease, HIV, car- 60 rolipram have demonstrated efficacy of this compound in the diovascular disease, head trauma as well as age-related cog tail Suspension and forced Swimming models of antidepres nitive decline. sant activity; these effects were eliminated in animals trans Dementias are diseases that include memory loss and addi genically modified to lack the PDE4D Subtype suggesting tional intellectual impairment separate from memory. The that the antidepressant effects of rolipram are mediated by its present invention includes methods for treating patients Suf- 65 inhibition of the PDE4 enzyme, specifically the PDE4D sub fering from memory impairment in all forms of dementia. type Zhang H-T, Huang Y. Jin S-L, Frith SA, Suvarna N. Dementias are classified according to their cause and include: Conti M. O'Donnell J M (2002) Antidepressant-like Profile US 7,723,348 B2 93 94 and Reduced Sensitivity to Rolipram in Mice Deficient in the regeneration. The compounds can also be used to treat psy PDE4D Phosphodiesterase Enzyme, Neuropsychopharma chosis characterized by elevated levels of PDE4, for example, cology, 27:587-595). various forms of depression, Such as manic depression, major Thus, in accordance with a preferred embodiment, the depression, and depression associated with psychiatric and present invention includes methods of treating patients Suf neurological disorders. The compounds may additionally be fering from memory impairment due to, for example, mild used for neurogenesis. cognitive impairment due to aging, Alzheimer's disease, The use of trisubstituted phenyl derivatives for treating Schizophrenia, Parkinson's disease, Huntington's disease, asthma, chronic bronchitis, psoriasis, allergic rhinitis, and Pick's disease, Creutzfeld-Jakob disease, depression, aging, other inflammatory diseases, and for inhibiting tumor necro head trauma, stroke, CNS hypoxia, cerebral senility, multiin 10 sis factor is known within the art. See, e.g., WO 98/58901, JP farct dementia and other neurological conditions, as well as 11-189577, JP 10-072415, WO 93/25517, WO 94/14742, HIV and cardiovascular diseases, comprising administering U.S. Pat. No. 5,814,651, and U.S. Pat. No. 5,935,978. These an effective amount of a compound according to Formulas I. references describe 1,3,4-trisubstituted phenyl compounds II, III, IV, V, VI, VII, VIII, IX and X or a pharmaceutically said to exhibit PDE4 inhibition activity. They also describe acceptable salt or Solvate (e.g., hydrate) thereof, or a solvate 15 assays for determining PDE4 inhibition activity, and methods of a pharmaceutically acceptable salt thereof. for synthesizing Such compounds. The entire disclosures of A Subject or patient in whom administration of the thera these documents are hereby incorporated by reference. peutic compound is an effective therapeutic regimen for a PDE4 inhibitors may be used to prevent or ameliorate disease or disorder is preferably a human, but can be any osteoporosis, as an antibiotic, for treatment of cardiovascular animal, including a laboratory animal in the context of a disease by mobilizing cholesterol from atherosclerotic clinical trial or screening or activity experiment. Thus, as can lesions, to treat rheumatoid arthritis (RA), for long-term inhi be readily appreciated by one of ordinary skill in the art, the bition of mesenchymal-cell proliferation after transplanta methods, compounds and compositions of the present inven tion, for treatment of urinary obstruction secondary to benign tion are particularly Suited to administration to any animal, prostatic hyperplasia, for Suppression of chemotaxis and particularly a mammal, and including, but by no means lim 25 reduction of invasion of colon cancer cells, for treatment ofB ited to, humans, domestic animals, such as feline or canine cell chronic lymphocytic leukemia (B-CLL), for inhibition of Subjects, farm animals, such as but not limited to bovine, uterine contractions, to attenuate pulmonary vascular equine, caprine, Ovine, and porcine Subjects, wild animals ischemia-reperfusion injury (IRI), for corneal hydration, for (whether in the wild or in a Zoological garden), research inhibition of IL-2R expression and thereby abolishing HIV-1 animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, 30 DNA nuclear import into memory T cells, for augmentation cats, etc., avian species, such as chickens, turkeys, Songbirds, of glucose-induced insulin secretion, in both the prevention etc., i.e., for veterinary medical use. and treatment of colitis, and to inhibit mast cell degranulation. As mentioned, the compounds of the invention also exhibit The invention is also suitable for use in the treatment of a anti-inflammatory activity. As a result, the inventive com class of disorders known as polyglutamine-repeat diseases. pounds are useful in the treatment of a variety of allergic and 35 These diseases share a common pathogenic mutation. The inflammatory diseases, particularly disease states character expansion of a CAG repeat, which encodes the amino acid ized by decreased cyclic AMP levels and/or elevated phos glutamine, within the genome leads to production of a mutant phodiesterase 4 levels. Thus, in accordance with a further protein having an expanded polyglutamine region. For embodiment of the invention, there is provided a method of example, Huntington's disease has been linked to a mutation treating allergic and inflammatory disease states, comprising 40 of the protein huntingtin. In individuals who do not have administering an effective amount of a compound according Huntington's disease, huntingtin has a polyglutamine region to Formulas I, I, III, IV, V, VI, VII, VIII, IX and X or a containing about 8 to 31 glutamine residues. For individuals pharmaceutically acceptable salt or Solvate (e.g., hydrate) who have Huntington's disease, huntingtin has a poly thereof, or a solvate of a pharmaceutically acceptable salt glutamine region with over 37 glutamine residues. Aside thereof. Such disease states include: asthma, chronic bron 45 from Huntington's disease (HD), other known poly chitis, chronic obstructive pulmonary disease (COPD), atopic glutamine-repeat diseases and the associated proteins are: dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, dentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1); Vernal conjunctivitis, esoniophilic granuloma, psoriasis, spinocerebellar ataxia type-1 (ataxin-1); spinocerebellar inflammatory arthritis, rheumatoid arthritis, septic shock, ataxia type-2 (ataxin-2); spinocerebellar ataxia type-3 also ulcerative colitis, Crohn's disease, reperfusion injury of the 50 called Machado-Joseph disease, MJD (ataxin-3); spinocer myocardium and brain, chronic glomerulonephritis, endot ebellar ataxia type-6 (alpha la-Voltage dependent calcium oxic shock, adult respiratory distress syndrome, cystic fibro channel); spinocerebellar ataxia type-7 (ataxin-7); and spinal sis, emphysema, arterial restenosis, artherosclerosis, kerato and bulbar muscularatrophy, SBMA, also known as Kennedy sis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes disease (androgen receptor). mellitus, pneumoconiosis, chronic obstructive airways dis 55 Thus, in accordance with a further aspect of the invention, ease, chronic obstructive pulmonary disease, toxic and aller there is provided a method of treating a polyglutamine-repeat gic contact eczema, atopic eczema, seborrheic eczema, lichen disease or CAG repeat expansion disease comprising admin simplex, Sunburn, pruritis in the anogenital area, alopecia istering to a patient, especially a human, a therapeutically areata, hypertrophic scars, discoid lupus erythematosus, fol effective amount of a compound according to Formulas I-X or licular and wide-area pyodermias, endogenous and exog 60 a pharmaceutically acceptable salt or Solvate (e.g., hydrate) enous acne, acne rosacea, Beghet's disease, anaphylactoid thereof, or a solvate of a pharmaceutically acceptable salt purpura nephritis, inflammatory bowel disease, leukemia, thereof. In accordance with a further embodiment, there is multiple Sclerosis, gastrointestinal diseases, autoimmune dis provided a method of treating Huntington's disease (HD), eases, osteoporosis, and the like. The compounds can also be dentatorubral-pallidoluysian atrophy (DRPLA), spinocer used in a method of treating patients suffering from disease 65 ebellar ataxia type-1, spinocerebellar ataxia type-2, spinoc states characterized by decreased NMDA function, such as erebellar ataxia type-3 (Machado-Joseph disease), spinocer Schizophrenia. The compounds may also be used for neuronal ebellar ataxia type-6, spinocerebellar ataxia type-7, or spinal US 7,723,348 B2 95 96 and bulbar muscular atrophy, comprising administering to a tion, diffuse pleural thickening, round atelectasis, and bron patient, especially a human, a therapeutically effective chogenic carcinoma, comprising administering to a patient, amount of a compound according to Formulas I-X or a phar Such as a mammal, e.g., a human, a therapeutically effective maceutically acceptable salt or Solvate (e.g., hydrate) thereof, amount of a compound of the invention (e.g., in the form of a or a Solvate of a pharmaceutically acceptable Salt thereof. pharmaceutically acceptable salt or Solvate (e.g., hydrate) The compounds of the present invention can be adminis thereof). tered as the Sole active agent or in combination with other The compounds of the present invention may also be pharmaceutical agents such as other agents used in the treat administered in combination with other known therapeutics ment of cognitive impairment and/or in the treatment of psy for the treatment of asbestos-related diseases or disorders chosis, e.g., other PDE4 inhibitors, PDE10 inhibitors, cal 10 including, but not limited to, other PDE-4 inhibitors, anti cium channel blockers, chloinergic drugs, adenosine receptor cancer agents, antibiotics, anti-inflammatory agents, cytok modulators, ampakines, NMDA-R modulators, mGluR ines, steroids, immunomodulatory agents, immunosuppres modulators, and cholinesterase inhibitors (e.g., donepezil, sive agents, and combinations thereof. In addition, the rivastigimine, and galanthamine). In such combinations, each compounds of the present invention can be used in combina active ingredient can be administered either in accordance 15 tion with conventional therapies used to treat, prevent, or with their usual dosage range or a dose below their usual manage asbestos-related diseases or disorders, including, but dosage range. not limited to, chemotherapy, Surgery, radiation therapy, pho The compounds of Formulas I-X can be administered as todynamic therapy, and combinations thereof. the Sole active agent or in combination with other pharma When used in combination with one or more additional ceutical agents such as other agents used in the treatment of pharmaceutical agent or agents for the treatment of asbestos allergic and/or inflammatory conditions, e.g. respiratory con related diseases or disorders, the compounds of the present ditions. Suitable examples of other pharmaceutical agents invention may be administered prior to, concurrently with, or which may be used in combination with the compounds of the following administration of the additional pharmaceutical present invention include, but are not limited to, other PDE-4 agent or agents. When used in combination with one or more inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxyge 25 conventional therapies for the treatment of asbestos-related nase activating protein (FLAP) antagonists (e.g., Zileuton, diseases or disorders, the compounds of the present invention fenleuton), leukotriene antagonists (LTRAS) including, may be administered prior to, concurrently with, or following antagonists of a LTB, LTC, LTD, and LTE (e.g., ontazo the conventional therapy. last, ablukast, pranlukast, Verlukast, Zariflukast, montelukast, The dosages of the compounds of the present invention Zileuton), histaminic receptor antagonists, including H1 and 30 depend upon a variety of factors including the particular H3 antagonists (e.g., cetirizine, loratidine, desloratidine, fex syndrome to be treated, the severity of the symptoms, the ofenadine, astemizole, azelastine, chlorpheniramine, cimeti route of administration, the frequency of the dosage interval, dine, ranitidine, famotidine, nizatidine), C. and Cadreno the particular compound utilized, the efficacy, toxicology ceptor agonist vasoconstrictor sympathomimetic agents for profile, pharmacokinetic profile of the compound, and the decongestant use (e.g., propylhexedrine, phenylephrine, phe 35 presence of any deleterious side-effects, among other consid nylpropanolamine, pseudoephedrine, naphazoline hydro erations. chloride), muscarinic receptor (M1, M2, and M3) antagonists The compounds of the invention are typically administered (e.g., ipratropium salts, namely bromide, tiotropium salts, at dosage levels and in a mammal customary for PDE4 inhibi namely bromide, oxitropium salts, namely bromide, peren tors such as those known compounds mentioned above. For Zepine, and telenZepine), anticholinergic agents, f to fa (e.g. 40 example, the compounds can be administered, in single or B) adrenoceptor agonists (e.g., isoprenaline, albuterol, Salb multiple doses, by oral administration at a dosage level of utamol, formoterol, salmeterol), COX-1 inhibitors NSAIDs), generally 0.001-100 mg/kg/day, for example, 0.01-100 COX-2 selective inhibitors, nitric oxide NSAIDs, oral or mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 inhaled glucocorticosteroids (e.g., prednisone, prednisolone, mg/kg/day. Unit dosage forms can contain generally 0.01 flunisolide, triamcinolone acetonide, beclomethasone 45 1000 mg of active compound, for example, 0.1-50 mg of diproprionate), acetylcholinesterase inhibitors (e.g., aricept), active compound. For intravenous administration, the com and adenosine A2a receptor agonists. Further examples of pounds can be administered, in single or multiple dosages, at Suitable other pharmaceutical agents which may be used in a dosage level of, for example, 0.001-50 mg/kg/day, prefer combination with the compounds of the present invention are ably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit disclosed in U.S. Pat. Nos. 6,559,168 and 6,756,392, which 50 dosage forms can contain, for example, 0.1-10 mg of active are hereby incorporated by reference in their entireties. In compound. Such combinations, each active ingredient can be adminis In carrying out the procedures of the present invention, it is tered either in accordance with their usual dosage range or a of course to be understood that reference to particular buffers, dose below its usual dosage range. media, reagents, cells, culture conditions and the like are not The compounds of the invention are also suitable for use in 55 intended to be limiting, but are to be read so as to include all the treatment of asbestos-related diseases or disorders. See, related materials that one of ordinary skill in the art would for example, U.S. Published Application No. 2005/0142104, recognize as being of interest or value in the particular context which is hereby incorporated by reference in its entirety. in which that discussion is presented. For example, it is often Thus, in accordance with a further aspect of the invention, possible to substitute one buffer system or culture medium for there is provided a method of treating asbestos-related dis 60 another and still achieve similar, if not identical, results. eases or disorders comprising administering to a patient, Such Those of skill in the art will have sufficient knowledge of such as a mammal, e.g., a human, a therapeutically effective systems and methodologies so as to be able, without undue amount of a compound of the invention (e.g., in the form of a experimentation, to make Such substitutions as will optimally pharmaceutically acceptable salt or Solvate (e.g., hydrate) serve their purposes in using the methods and procedures thereof). In accordance with a further embodiment, there is 65 disclosed herein. provided a method of treating, for example, mesothelioma, The present invention will now be further described by way asbestosis, pleural effusion, pleural plaque, pleural calcifica of the following non-limiting examples. In applying the dis US 7,723,348 B2 97 98 closure of these examples, it should be kept clearly in mind extracted twice with 20% aqueous sodium bisulfite (150 that other and different embodiments of the methods dis mL/extraction). The extracts were pooled and washed with closed according to the present invention will no doubt Sug ethyl acetate (75 mL). The aqueous layer was basified with gest themselves to those of skill in the relevant art. solid sodium hydroxide (26 g) and then extracted with 3x150 In the foregoing and in the following examples, all tem mL of ethyl acetate (150 mL/extraction). The organic extracts peratures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by were pooled, washed with 40 mL of brine, dried (NaSO), weight. and concentrated to afford 7.4 g (66%) of a pale yellow oil. H The entire disclosures of all applications; patents and pub NMR (CDC1:300 MHz) & 2.2-2.4 (m, 2H); 3.8-4.1 (m, 7H): lications, cited above and below, are hereby incorporated by 10 5.0 (m. 1H); 7.0 (d. 1H); 7.4 (s, 1H); 7.5 (d. 1H): 9.9 (s, 1H). reference in their entirety. ES-MS M+H+=223.2 The following compounds were prepared in a similar fash EXAMPLES ion with different starting materials: 1-Bromo-4-methoxy-3-(3R)-tetrahydrofuranyloxybenzene. All spectra were recorded at 300 MHz on a Bruker Instru 15 ments NMR unless otherwise stated. Coupling constants (J) 4-Methoxy-3-(3S)-tetrahydrofuryloxybenzaldehyde. are in Hertz (Hz) and peaks are listed relative to TMS (8 0.00 ppm). Sulfonic acid ion exchange resins (SCX) were pur Example 1B chased from Varian Technologies. Analytical HPLC was per formed on 4.6 mmx100 mm Waters Sunfire RPC18.5 um Synthesis of 3-4-Methoxy-3-(3R)-tetrahydrofurany column using (i) a gradient of 20/80 to 80/20 acetonitrile loxyphenyl)-1H-pyrazole (0.1% formic acid)/water (0.1% formic acid) over 6 min (Method A), (ii) a gradient of 20/80 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) over 8 min (Method B), (iii) a gradient of 40/60 to 80/20 acetonitrile 25 (0.1% formic acid)/water (0.1% formic acid) over 6 min (Method C), (iv) a gradient of 40/60 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) over 8 min (Method D), (v) an isocratic eluent of 80/20 acetonitrile/water (0.1% formic acid) over 8 minutes (Method E), (vi) or a 30 gradient of 10/90 to 90/10 acetonitrile (0.1% formic acid)/ water (0.1% formic acid) over 6 min (Method F). Preparative HPLC was performed on 30 mmx100 mm Xtera Prep RP 5u columns using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid). 35 Example 1 Sodium hydride (60% in mineral oil, 1.51 g, 37.7 mmol) was suspended in THF (20 mL) and cooled to 5°C. followed Example 1A by addition of diethoxyphosphorylacetaldehyde tosylhydra 40 Zone (6.51 g, 18.7 mmol) in THF (20 mL) over 10 minutes. Synthesis of After stirring for 30 minutes at 5°C., the yellow suspension 4-Methoxy-3-(3R)-tetrahydrofuryloxybenzaldehyde was treated with a solution of 4-methoxy-3-(3R)-tetrahydro furyloxybenzaldehyde (2.84g, 12.8 mmol) in TBTf (20 mL) 45 and stirred for 1 hour at room temperature and 16 hours at 80° C. in an oil bath. After cooling to room temperature, the reaction was poured into 5% aqueous NaH2PO and extracted with ethyl acetate. The extract was washed with water and brine, dried over NaSO and concentrated to afford a yellow 50 solid. Recrystallization from ethyl acetate furnished 1.9 g, (57%) of 3-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphe nyl)-1H-pyrazole in two crops as light yellow solids. (mp 149-151° C); H NMR (CDC1, 300 MHz) & 2.23 (m, 2H), O 55 3.85-4.10 (nm 4H), 3.89 (s.3H), 5.02 (m, 1H), 6.54 (m, 1H), 6.92 (m. 1H), 7.25 (m, 2H), 7.60 (m, 1H); MS M+H=261. 3-Hydroxy-4-methoxybenzaldehyde (7.6 g.: 50 mmol) was The following compounds were prepared in a similar fash dissolved in THF (200 mL) followed by addition of (S)-3- ion with different starting materials: hydroxytetrahydrofuran (6.0 mL. 75 mmol) and triph 3-(3,4-Dimethoxyphenyl)-1H-pyrazole enylphosphine (19.7 g; 75 mmol). The resulting solution was 60 cooled to 5° C. and diisopropyl azodicarboxylate (14.8 mL.; 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1H-pyrazole 75 mmol) was added dropwise over 10 minutes. The clear 3-3,4-Bis(difluoromethoxy)phenyl)-1H-pyrazole orange solution was stirred at ambient temperature for 16 3-1-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphe hours. Thin layer chromatography analysis using a 1:1 mix nyl)-1H-pyrazole ture of hexane/ethyl acetate determined the reaction to be 65 complete. The solvent was removed under reduced pressure 3-(3-Benzyloxy-4-methoxyphenyl)pyrazole and the residue was taken up in ethyl acetate (60 mL) and 3-3-(2,3-Difluorobenzyloxy)-4-methoxyphenylpyrazole US 7,723,348 B2 101 102 Example 3 orless oils. Both peaks exhibit M+H=357. HNMR for peak A (CDC1,300 MHz) & 0.80 (m, 2H), 1.1-1.3 (m,3H), 1.4-1.7 1-Cyclohexylmethyl-3-(4-methoxy-3-(3R)-tetrahy (m, 5H), 1.9 (m. 1H), 2.2 (m, 2H), 3.8-4.2 (m, 9H), 4.97 (s, drofuranyloxyphenyl)-1H-pyrazole 1H), 6.22 (s, 1H), 6.82 (s, 1H), 6.96 (s. 2H), 7.55 (s, 1H). H NMR of peak B (CDC1,300 MHz) & 0.80 (m, 2H), 1.1-1.3 (m,3H), 1.4-1.7(m, 5H), 1.9 (m. 1H), 2.2 (m. 2H), 3.8-4.2 (m, 9H), 5.08 (s, 1H), 6.44 (s, 1H), 6.9 (d. 1H), 7.35 (m, 3H). The following compounds were prepared in a similar fash ion with different starting materials: 10 1-Cyclohexylmethyl-5-4-methoxy-3-(3S)-tetrahydrofura nyloxyphenyl)-1H-pyrazole, Isopropyl 2-5-4-methoxy-3-(3R)-tetrahydrofuranylphe nyl-pyrazol-1-yl)acetate, 1-(2,3-Difluorobenzyl)-5-4-methoxy-3-(3R)-tetrahydro Oc. 15 furanylphenyl)-1H-pyrazole, 1-(4-fluorobenzyl)-2-(4-methoxy-3-((3R)-tetrahydrofuran 3-yloxyphenyl)-1H-pyrrole 3 Example 4 Intermediate B: Synthesis of and 1-Cyclohexylmethyl-5-4-methoxy-3-(3R)-tetrahydro 2-Acetyl-4-bromo-7-methoxybenzofuran furanyloxyphenyl)-1H-pyrazole 2-Acetyl-7-methoxybenzofuran (1.0g, 5.3 mmol) was dis 25 solved in glacial acetic acid (29 mL) followed by addition of sodium acetate (1.3g, 15.8 mmol). The reaction was treated dropwise with a solution of bromine (0.26 mL, 5.26 mmol) in glacial acetic acid (10 mL) at room temperature followed by stirring for one hour. The solvent was removed under vacuum. 30 The residue was dissolved in water and extracted three times with dichloromethane. The combined organic extracts were Ol.N-N washed with 2% aqueous sodium bicarbonate, dried over Sodium Sulfate and concentrated under vacuum. The residue O was purified on silica gel using a 50-100% dichloromethane/ 35 hexane gradient affording 1.00 g (75%) of the product as a white solid. "H NMR (CDC1,300 MHz) & 7.44 (s, 1H), 7.32 (d. 1H), 6.80 (d. 1H), 4.0 (s, 3H), 2.62 (s, 3H). Intermediate C: Synthesis of 4-bromo-7-methoxy-2- A solution of 3-4-methoxy-3-(3R)-tetrahydrofuranylox 40 2-methyl-(1,3-dioxolan)-2-ylbenzofuran yphenyl)-1H-pyrazole (78 mg, 0.3 mmol) in DMF (2 mL) was treated with sodium hydride (60% in oil, 24 mg. 0.6 A solution of 2-acetyl-4-bromo-7-methoxybenzofuran mmol) and stirred at room temperature for three hours. The (0.50 g, 1.86 mmol), 5 mL of ethylene glycol, and PPTS (46 reaction mixture was then treated with a solution of (bromom mg, 0.186 mmol) was refluxed overnight in benzene (37 mL) ethyl)cyclohexane (0.13 mL, 0.9 mmol) in DMF (0.8 mL) and 45 using a Dean Stark apparatus. The reaction was cooled to stirred at ambient temperature for 16 hours. The mixture was room temperature, washed with aqueous sodium bicarbonate, diluted with ethyl acetate (60 mL) and washed with water dried over Sodium sulfate and evaporated under vacuum to (2x20 mL) and brine (1x15 mL), dried (NaSO) and con afford 293 mg (50%) of 4-bromo-7-methoxy-2-[2-methyl-(1, centrated to 250 mg of an oil, which was chromatographed 3-dioxolan)-2-yl)benzofuran as an oil. "H NMR (CDC1,300 over silica gel using a 10-30% ethyl acetate/hexane gradient. 50 MHz) & 7.28 (d. 1H), 6.74 (s, 1H), 6.69 (d. 1H), 4.04 (m, 4H), Concentration of fractions afforded 92 mg of an oil consisting 1.84 (s, 3H). of a mixture of regioisomers in a ratio of 3.5:1 as determined by LCMS. The mixture of regioisomers was taken in 1 mL of Intermediate D: Synthesis of 7-methoxy-2-2-me acetonitrile/water (3:2 with 0.1% formic acid) and resolved thyl-(1,3-dioxolan)-2-yl)-benzofuran-4-carboxalde by preparative hplc using a Waters C18, 5um, 30x100 mm 55 hyde column with a flow rate of 45 mL/min. A gradient of 35-80% acetonitrile/water containing 0.1% formic acid over 6 min 4-Bromo-7-methoxy-2-2-methyl-(1,3-dioxolan)-2-yl) utes was employed and a Waters 2996 PDA detector was benzofuran (666 mg, 2.1 mmol) was dissolved in THF (21 utilized to trigger collection at 248 nm. Baseline resolution mL), cooled to -60° C. under an argon atmosphere, and was achieved with peak A eluting at 7.61 min and peak B 60 t-butyl lithium (2.6 mL, 1.7 M) was added with stirring at eluting at 8.15 min. Tubes containing each regioisomer were -60°C. The mixture was stirred at-60° C. for one hour, DMF concentrated on a Genevac HT4 Series II Evaporator supply (0.82 mL, 10.6 mmol) in THF (20 mL) was added, and the ing 14 mg of (peak A. retention time 7.61 minutes) 1-cyclo reaction was stirred at ambient temperature overnight. The hexylmethyl-5-4-methoxy-3-(3R)-tetrahydrofuranylox reaction was poured into aqueous Sodium bicarbonate and yphenyl)-1H-pyrazole and 54 mg of (peak B; retention 65 extracted three times with ethyl acetate. The combined time=8.15 minutes) 1-cyclohexylmethyl-3-(4-methoxy-3- extracts were washed once with water, once with brine, and (3R)-tetrahydrofuranyloxyphenyl)-1H-pyrazole, each as col dried over sodium sulfate. Evaporation of the solvent under US 7,723,348 B2 103 104 reduced pressure followed by purification on silica gel using isolated in 24% yield (6.62g). H NMR (CDC1,400MHz) & a 10-50% ethyl acetate/hexane gradient afforded 7-methoxy 6.1 (brs, 1H), 6.48-6.85 (t, 1HOCHF), 7.26 (d. 1H), 7.44 (d. 2-2-methyl-(1,3-dioxolan)-2-yl)-benzofuran-4-carboxalde 1H), 7.55 (s, 1H), 9.91 (s, 1H). hyde (399 mg: 72%) as an oil. H NMR (CDC1,300 MHz) & 10.01 (s, 1H), 7.66 (d. 1H), 7.45 (s, 1H), 6.88 (d. 1H), 4.08 (m, 5 Intermediate F: Synthesis of tert-Butyl 2-3-4-dif 7H), 1.84 (s, 3H). luoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl Example 5 pyrazol-1-yl)acetate Synthesis of 10 3-4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphe 3-(2-Acetyl-7-methoxybenzofuran-4-yl)pyrazole nyl)-1H-pyrazole (199 mg, 0.67 mmol) was dissolved in DMF (9 mL). Sodium hydride (60% in oil, 54 mg, 1.34 mmol) was added at room temperature and stirred for 1 hour fol lowed by addition of tert-butyl bromoacetate (0.30 mL 2.01 15 mmol) in DMF (1 mL). The reaction was stirred for 16 hours at room temperature, diluted with ethyl acetate, and washed with water twice and brine once. The solvent was dried over sodium sulfate and concentrated to 500 mg of a pale yellow oil, which was purified on silica gel using a 20-50% ethyl acetate/hexane gradient to afford tert-butyl 2-3-4-difluo romethoxy-3-(3R)-tetrahydrofuranyloxyphenylpyrazol-1- yl)acetate as a colorless oil (145 mg, 53%). MS M+H=411. "H NMR (DMSO300MHz) & 1.42 (s.9H), 2.05 (m. 1H), 2.23 25 (m. 1H), 3.8-4.0 (m, 4H), 4.98 (s. 2H), 5.18 (br 5, 1H), A suspension of sodium hydride (60% in oil, 174 mg. 4.36 6.78-7.28 (t, 1H OCHF), 6.80 (s, 1H), 7.21 (d. 1H), 7.38 (d. mmol) in THF (5 mL) was cooled to 0°C. under argon, and 1H), 7.45 (s, 1H), 7.77 (s, 1H). then treated with a solution of diethoxyphosphorylacetalde hyde tosylhydrazone (75.9 mg, 2.2 mmol) in THF (7 mL). 30 After stirring at 0°C. for 30 minutes a solution of 7-methoxy Synthesis of 2-3-4-difluoromethoxy-3-(3R)-tet 2-(2-methyl-1,3dioxolan-2-yl)benzofuran-4-carboxalde rahydrofuranyloxyphenylpyrazole-1-yl)acetic acid hyde (381 mg, 1.45 mmol) in THF (5 mL) was added and the reaction stirred at room temperature overnight followed by stirring at 65° C. for 5 hours. After cooling to room tempera 35 ture, the reaction was poured into 5% aqueous NaH2PO and extracted with ethyl acetate. The extract was washed with water, washed with brine, dried over NaSO, and concen trated. The residue was chromatographed on silica gel using a O 25-50% ethyl acetate/hexane gradient to afford the dioxolane 40 protected pyrazole (306 mg, 70%). The masked ketone (306 mg) was taken in 3M HCl in THF (10 mL) and stirred at room O N temperature for 2 hours. The solution was neutralized with sodium bicarbonate and extracted with ethyl acetate three NNN O times. The combined extracts were washed with water, 45 washed with brine, dried over sodium sulfate and concen O ( trated under vacuum. The residue was purified on silica gel O using hexane/ethyl acetate (1:1; V/v) to isolate 3-(2-Acetyl 7-methoxybenzofuran-4-yl)pyrazole (192 mg, 74%) as a yel tert-Butyl 2-3-4-difluoromethoxy-3-(3R)-tetrahydro low solid. "H NMR (CDC13,300 MHz) & 8.09 (s, 1H), 7.70 50 (d. 1H), 7.53 (d. 1H), 6.98 (d. 1H), 6.70 (d. 1H), 4.07 (s.3H), furanyloxyphenylpyrazol-1-yl)acetate (762 mg, 1.85 mmol) 2.65 (s.3H). was stirred in dichloromethane (11 mL) and treated with trifluoroacetic acid (11 mL) with stirring for 90 minutes. The Example 6 Solvent was removed under reduced pressure and partitioned 55 between ethyl acetate/water. The organic layer was washed Intermediate E: Synthesis of with water three times and brine once. After drying over 4-difluoromethoxy-3-hydroxybenzaldehyde sodium sulfate, the solvent was stripped to furnish 2-3-4- difluoromethoxy-3-(tetrahydrofuryloxy)phenylpyrazole-1- 3,4-Dihydroxybenzaldehyde (20g, 145 mmol), chlorodif yl)acetic acid as a semisolid (657 mg, 100%) MS M+H= luoroacetic acid sodium salt (55.19 g,362 mmol) and sodium 60 355. "H NMR (CDC1300 MHz) & 2.25 (m, 2H), 4.02 (m, hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 4H), 5.07 (m, 2H), 5.2 (brs, 1H), 6.31-6.81 (t, 1H OCHF), mL) at 55° C. under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10% aqueous HCl followed 6.61 (s, 1H), 7.19-7.28 (m, 3H), 7.29 (s, 1H), 7.52 (s, 1H). by extraction with ethyl acetate (3x500 mL). The combined extracts were evaporated under vacuum. The residue was 65 2-3-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl) purified on silica gel using a 10-20% ethyl acetate/hexane pyrazole-1-yl)acetic acid was synthesized in a similar man gradient. 4-difluoromethoxy-3-hydroxybenzaldehyde was ner with different starting materials. US 7,723,348 B2 105 106 Example 7 Example 8 Synthesis of 2-3-4-Difluoromethoxy-3-(3R)-tet Intermediate G: Methyl rahydrofuranyloxyphenyl-pyrazol-1-yl)-N-(2,3- 3-ethyl-1H-indazol-6-yl-carboxylate difluorophenyl)acetamide To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol 6-yl-carboxylic acid, Marfat, A., et al., U.S. Pat. No. 6,262, 040, 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) 10 of DMAP in 60 mL of CHC1 was added 1.5 g (7.8 mmol) of EDCI-HC1. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried 15 (NaSO), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl carboxylate. "H NMR (CDC1) & 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s.3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H). Intermediate H: Methyl 1-Cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate 25 2-3-4-difluoromethoxy-3-(3R)-tetrahydrofuranylox To a flask containing 337 mg (8.4 mmol) of NaH (60% in yphenylpyrazol-1-yl)acetic acid (84 mg. 0.23 mmol) was mineral oil), 1.7 mL (8.4 mmol) of 15-crown-5 and 42 mL of dissolved in dichloromethane (2 mL), cooled to 5° C. and DMF was added 860 mg (4.2 mmol) of methyl 3-ethyl-1H treated the oxalyl chloride (2M in dichloromethane, 0.13 mL, 30 indazol-6-yl-carboxylate. This mixture was stirred at room 0.26 mmol) and stirred for 90 minutes. In a separate flask, temperature for 3 hours and then 1.35 mL (12.6 mmol) of 2,3-difluoroaniline (0.35 mL, 0.35 mmol) in THF (2 mL) was cyclopentylbromide was added and the reaction was stirred at treated with sodium hydride (60% in oil, 22 mg 0.56 mmol) room temperature overnight. The solvent was removed and and stirred for 90 minutes. The solvent from the initial flask the residue was dissolved in 40 mL ethylacetate, washed with was removed under reduced pressure. The residue was taken 35 30 mL of water and 30 mL of brine, dried (NaSO), and in THF (2 mL), cooled to 5° C. and treated with the difluo concentrated. The residue was purified by column chroma roaniline/hydride suspension followed by stirring at ambient tography over SiO, using a step gradient of 10% ethyl acetate temperature for 16 hours. The solvent was removed under in hexanes until the first compound eluted and then 50% ethyl vacuum and the residue was partitioned between ethyl acetate in hexanes to provide 662 mg (2.4 mmol) of methyl 40 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate as a acetate?water. The organic layer was washed with water and clear oil along with 144 mg (0.53 mmol) methyl 2-(cyclopen brine, dried over sodium sulfate and evaporated to afford 57 tyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellow oil. mg of a brown oil. This was adsorbed onto a preparative thin 'H-NMR (CDC1) & 8.17 (s, 1H), 7.71 (dd, J1=8.4 Hz, J2=6.7 layer chromatography silica gel plate (20x20 cm, 2000 Hz, 2H), 5.0 (p.J=7.5 Hz, 1H), 3.97 (s.3H), 3.00(q, J–7.5 Hz, micron) using ethyl acetate/hexane (1:1 V/v) to elute. The 45 product was isolated from the plate by scraping and Suspend 2H), 2.16 (m, 4H), 1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J–7.6 ing the silica gel in ethyl acetate following by filtering Hz, 3H). through a bed of Celite. Evaporation of the solvent afforded Intermediate I: 2-3-4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphe 1-Cyclopentyl-3-ethyl-6-hydroxymethyl-1H-indazole nyl-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide as a 50 white foam (15 mg, 14%) MSM+H=446; H NMR (CDC1, DIBAL (10 mL, 1M in toluene) was slowly added with 300 MHz) & 2.28 (m, 2H), 4.05 (m, 4H), 4.98 (s. 2H). 5.1 (s, stirring at -50° C. to a solution of 886 mg (3.25 mmol) of 1H), 6.3-6.7 (t, 1HOCHF) 6.65 (s, 1H), 6.8 (1H, 1H)6.9 (m, methyl 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate 1H), 7.25 (m, 2H), 7.56 (s. 2H) 8.3 (t, 1H), 9.8 (s, 1H). 55 in 32 mL of CHC1. The reaction stirred at -50° C. for 1 hour The following compounds were prepared in a similar fash and was quenched by the slow addition of 4 mL of MeCH and then, with stirring, poured into a saturated Rochelle’s salt and ion with different starting materials: ethyl acetate mixture (60 each). Stirring continued at room 2-3-3,4-Bis(difluoromethoxy)-phenyl-pyrazol-1-yl)-N- temperature until both layers were clear. The organic layer (2-methylphenyl)acetamide, 60 was separated and the aqueous layer was extracted with 3x40 2-3-3,4-Bis(difluoromethoxy)-phenyl-pyrazol-1-yl)-N- mL of ethyl acetate. The organic fractions were combined, (2,3-difluorophenyl)acetamide, dried (Na2SO4), and concentrated. The compound was puri 1-N-(2-cyanophenyl)-2-3-4-difluoromethoxy-3-(3R)-tet fied via column chromatography over SiO, using a 1:4 solu tion of EtOAc in hexanes as eluant to yield 427 mg (1.75 rahydrofuranyloxyphenylpyrazol-1-yl)acetamide, 65 mmol) of 1-cyclopentyl-3-ethyl-6-hydroxymethanol-1H-in 2-3-4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphe dazole as a clear oil. "H-NMR (CDC1) & 7.66 (d. J=8.2 Hz, nyl-pyrazol-1-yl)-N-2-(6-methylpyridyl)acetamide. 1H), 7.42 (s, 1H), 7.07 (d. J=8.2 Hz), 4.92 (p, J–7.7 Hz, 1H), US 7,723,348 B2 107 108 4.84 (d. J=5.5 Hz, 2H), 2.99 (q, J=7.6 Hz, 2H), 2.15 (m, 4H), A solution of 31.8 mg (0.11 mmol) of 3-(1-cyclopentyl 2.04 (m, 2H), 11.73 (m, 2H), 1.38 (t, J=1.6 Hz, 3H). 3-ethylindazol)-6-yl)-1H-pyrazole in 1 mL of DMF was added to a flask containing 12.9 mg (0.32 mmol) of NaH Intermediate J: 1-Cyclopentyl-3-ethyl-1H-indazol-6- (60% in mineral oil) and 1 mL of DMF. This was stirred at yl-carboxaldehyde room temperature for 3 hours. Then, a solution of 43 uL (0.33 mmol) of 2,3-difluorobenzyl bromide in 1 mL of DMF was To a solution of 427 mg (1.75 mmol) 1-cyclopentyl-3- added and the reaction was stirred at room temperature over ethyl-6-hydroxymethanol-1-1H-indazole in 58 mL of CHCl night. The mixture was poured into a mixture of 10 mL of was added 2.1 g (24.1 mmol) of MnO. The reaction was water and 10 mL of ethyl acetate. The organic layer was stirred at room temperature for 6 hours, the solids were 10 washed with 2x10 mL of water and 1x10 mL of brine. The removed by filtration and the filtrate was concentrated. The organic layer was then dried over NaSO, filtered and the residue was purified via column chromatography over SiO, solvent was removed under reduced pressure. Purification via using 3% ethyl acetate in hexanes as eluant to give 332 mg column chromatography over 4 g of silica using 5% ethyl (1.37 mmol) of 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-car acetate in hexanes to 10% ethyl acetate in hexanes gradient boxaldehyde as a clear oil. H-NMR (CDC1) & 10.13 (s, 1H), 15 over 10 minutes to give 24 mg (0.06 mmol. 52% yield) of 7.94 (s, 1H), 7.78 (d. J=8.2 Hz, 1H), 7.61 (d. J=8.2 Hz, 1H), 3-(1-cyclopentyl-3-ethylindazol)-6-yl)-1-(2,3-difluoroben 5.02 (p, J=7.4 Hz, 1H), 3.02 (q, J=7.5 Hz, 2H), 2.19 (m, 4H), Zyl)-1H-pyrazole as a clear oil. H-NMR (CDC1) & 7.84 (s, 2.02 (m, 2H), 1.76 (m, 2H), 1.40 (t, J–7.5 Hz, 3H). 1H), 7.69 (d. J=8.3 Hz, 1H), 7.54 (d. J=8.3 Hz, 1H), 7.50 (s, 1H), 7.15-7.04 (m, 3H), 6.68 (s, 1H), 5.48 (s. 2H), 4.99 (p, 3-(1-Cyclopentyl-3-ethylindazol)-6-yl)-1H-pyrazole J=7.6 Hz, 1H), 3.01 (q, J–7.4 Hz, 2H), 2.12 (s, 4H), 1.98 (s, 2H), 1.75-1.72 (m, 2H), 1.40 (t, 7.4 Hz, 3H). A flask containing 165 mg (4.12 mmol) of NaH (60% in The following compounds were synthesized in a similar mineral oil) and 4 mL of THF was placed under Arand cooled manner with different starting materials: to 0°C. A solution of 716 mg (2.06 mmol) of diethoxyphos 3-(1-Cyclopentyl-3-ethylindazol)-6-yl)-1-(2,3-difluo phorylacetaldehyde tosylhydrazone in 7 mL of THF was 25 rophenyl)-1H-pyrazole added over 5 minutes. The reaction stirred at 0° C. for 30 3-(5-Cyclopentyl-3-ethylindazol)-6-yl)-1-(2-methylben minutes followed by the addition of a solution of 332 mg Zyl)-1H-pyrazole (1.37 mmol) of 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-car 3-(1-Cyclopentyl-3-ethylindazol)-6-yl)-1-(4-methylsulfo boxaldehyde in 4.5 mL THF. The ice bath was removed and 30 nylbenzyl)-1H-pyrazole the solution was stirred at room temperature for 4 hours, and 3-(1-Cyclopentyl-3-ethylindazol)-6-yl)-1-(2-pyridylm then heated to 65° C. overnight. The reaction mixture was cooled to room temperature, poured into 50 mL of 5% ethyl)-1H-pyrazole. NaH2PO and extracted with 3x25 mL of ethyl acetate. The organic layers were combined, dried over NaSO, concen Example 10 trated, and purified by column chromatography over SiO, 35 using a gradient from 10% to 50% ethyl acetate in hexanes Synthesis of 2-4-Methoxy-3-(3R)tetrahydrofurany over 20 minutes to yield 185 mg (0.66 mmol) of 1-cyclopen loxyphenyl-1,3-dithiane tyl-3-ethyl-6-(1H-pyrazol-3-yl)-1H-indazole as a white foam. H-NMR (CDC1) & 7.80 (s, 1H), 7.69 (d. J=8.3 Hz, 1H), 7.65 (s, 1H), 7.5 (d. J=8.3 Hz, 1H), 6.7 (s, 1H)4.90 (p. 40 J=-7.5 Hz, 1H), 3.00 (q, J=7.5 Hz, 2H), 2.13 (m, 4H), 2.00 (m. 2H), 1.71 (m, 2H), 1.40 (t, J–7.5, 3H). Example 9 45 3-(1-Cyclopentyl-3-ethylindazol)-6-yl)-1-(2,3-dif luorobenzyl)-1H-pyrazole Cr) 50 4-Methoxy-3-(3R)-tetrahydrofuranyloxybenzaldehyde (8.37 g; 37.6 mmol) was dissolved in dichloromethane (120 mL) followed by addition of 1,3-propanedithiol (11.3 mL.; 55 113 mmol) and borontrifluoride etherate (0.6 mL). The reac (N N tion mixture became mildly exothermic and turbid. Reaction \ monitoring by LC-MS showed complete conversion taking N-N place in 90 minutes. The reaction was washed with 30 mL of water and 30 mL of brine, dried over anhydrous sodium 60 sulfate and concentrated. Trituration of the residue with ether produced a white solid that was collected by filtration and dried yielding 9.09 g (77%) of 2-4-methoxy-3-(3R)-tetrahy F drofuranyloxyphenyl-1,3-dithiane. 'H-NMR (CDC1: 300 MHz) & 1.85-2.25 (m, 4H); 2.85-2.95 (m, 2H); 3.0-3.1 (m, F 65 2H); 3.85 (s.3H); 3.9–4.1 (m, 4H); 4.95-5.00 (m, 1H); 5.1 (s, 1H); 6.85 (d. 1H); 7.00 (d. 1H); 7.05 (d. 1H). ES-MSM--H+ =313.2 US 7,723,348 B2 109 110 Example 11 mmol) and stirred at room temperature for 15 minutes. The Solvent was concentrated under reduced pressure and the Synthesis of 2-2-4-Methoxy-3-(3R)-tetrahydro residue was loaded onto a column of silica gel and eluted with furanyloxyphenyl-1,3-dithian-2-yl)propanol a 20-60% ethyl acetate/hexane gradient. The product was isolated as an oil (23 mg: 15%). "H NMR (CDC1300 MHz) 82.0 (s.3H); 2.1-2.5 (m, 4H); 2.8 (m, 4H);3.2 (s.2H); 3.8-4.2 (m, 7H); 5.0 (m. 1H); 6.9 (m, 1H): 7.5 (m, 2H). ES-MS M+H+=369.1. The following compound was synthesized in a similar 10 manner with different starting materials: 1-2-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-1,3- OH dithian-2-yl)butan-2-one. Alternative Method for Example 12 Nu 15 1-2-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-1, 3-dithian-2-yl)propan-2-ol (119 mg 0.32 mmol) was stirred in dichloromethane (5 mL) and treated with Dess-Martin Solid 2-4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl periodinane (15% solution in dichloromethane; 173 mg 0.41 1,3-dithiane (2.5 g; 8 mmol) was added to an oven-dried flask mmol) and stirred at room temperature for 10 minutes. Upon equipped with a stir bar, septum and an inert gas line. Dry formation of a precipitate, thin layer chromatography analy tetrahydrofuran (40 mL) was added and stirred at -40°C. sis using hexane/ethyl acetate (1:1 V/v) determined the reac using an acetonitrile/dry ice bath. To the resulting Solution tion to be complete. The reaction was diluted with dichlo was added n-butyl lithium (2.5M in hexanes; 4.2 mL. 10.4 romethane (40 mL) and washed with 20 mL portions of mmol) via syringe over 15 minutes. After stifling at 40°C. for 25 aqueous Sodium bicarbonate and brine. The organic layer was thirty minutes, HMPA (1.4 mL; 8 mmol) was injected over dried over anhydrous sodium sulfate and evaporated to a two minutes and stirred for 10 minutes followed by rapid addition of propylene oxide (0.62 mL; 8.8 mmol). After stir crude Solid, which was used as such in Example 7. ring at -40°C. for 1 hour, the reaction was quenched with Example 13 aqueous ammonium chloride (5 mL), diluted with water (30 30 mL) and extracted with ethyl acetate (70 mL). The organic Synthesis of 1-(2-Methoxybenzyl)-5-4-methoxy-3- layer was washed with 25 mL of water and 25 mL of brine, 3R)-tetrahydrofuranyloxy-phenyl-3-methyl-1H dried over anhydrous sodium sulfate and evaporated to yield pyrazole 3.5g of a viscous yellow oil. The crude alcohol was purified by flash chromatography on silica gel using a 20-60% ethyl 35 acetate/hexane gradient affording the product as a colorless, viscous oil (2.7 g.: 91%). "H NMR (CDC1:300 MHz) & 1.1 (d,3H); 2.0-2.5 (m, 7H); 2.75 (m, 4H); 3.8 (s.3H);3.9–4. 1 (m, 5H); 5.0 (m, 1H) 6.9 (d. 1H): 7.5 (m, 2H). ES-MS M+H+ =371.2 40 The following compound was synthesized in a similar O manner with different starting materials: 1-2-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-1,3- dithian-2-yl)butan-2-ol. O 2 f 45 Example 12 N-N Synthesis of 1-2-4-Methoxy-3-(3R)-tetrahydro furanyloxyphenyl-1,3-dithian-2-yl)propan-2-one 50 55 1-2-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-1, 3-dithian-2-yl)propan-2-one (115 mg, 0.32 mmol) was reconstituted in toluene (5 mL) and treated with 2-methoxy benzyl hydrazine dihydrochloride (144 mg. 0.64 mmol) and 60 molecular sieves (4A: 500 mg). The reaction was heated at 100° C. for two hours and cooled to room temperature. O Molecular sieves were removed via filtration and the filtrate was diluted with ethyl acetate (50 mL), washed with 20 mL 1-2-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-1, portions of water and brine. The organic layer was dried over 3-dithian-2-yl)propan-2-ol (158 mg 0.42 mmol) was stirred 65 anhydrous sodium sulfate and concentrated to an oil. The in dichloromethane (5 mL) and treated with Dess Martin product was isolated by flash chromatography on silica gel periodinane (15% solution in dichloromethane: 356 mg; 0.84 using a 20-50% ethyl acetate/hexane gradient to afford 57 mg US 7,723,348 B2 113 114 1-(3-Methoxybenzyl)-5-4-methoxy-3-(3R)-tetrahydrofura Example 16 nyloxyphenyl)-1H-pyrazole; 1-(4-Fluorobenzyl)-5-4-methoxy-3-(3R)-tetrahydrofurany Synthesis of 1-4-Methoxy-3-(3R)-tetrahydrofurany loxyphenyl)-1H-pyrazole; loxyphenylethanol 1-(3,4-Difluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H pyrazole; 5-(3-Fluoro-4-methoxyphenyl)1-(4-methoxycarbonylben Zyl)-1H-pyrazole; pyrazole; 1-(2,6-Difluorobenzyl)-5-4-methoxy-3-(3R)-tetrahydro 10 furanyloxyphenyl 1H-pyrazole; 1-(4-Fluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H pyrazole; and 44) 1-(4-fluorobenzyl)-5-4-methoxy-3-((3R)-tetrahydrofu 15 OH ran-3-yloxyphenyl-4-methyl-1H-pyrazole LC/MS (EI) to 4.2 (Method C), m/z383.1 (M"+1). Example 15 A flask containing 1.7 g (7.5 mmol) of 4-methoxy-3-(3R)- tetrahydrofuranyloxybenzaldehyde and 75 mL of THF was Synthesis of 2-4-Methoxy-3-(3R)-tetrahydrofurany cooled to -78°C. under argon and 5.0 mL (3M) of MeMgCl loxyphenyl-5,5-dimethyl-1,3,2dioxaborinane was slowly added. The reaction was stirred at room tempera ture for 12 hours and was quenched by the addition of 100 mL 25 of saturated aqueous NHaCl. The aqueous layer was extracted with 3x50 mL of ethyl acetate and the combined organic extracts were dried over NaSO filtered and concentrated. Purification by silica gel column chromatography using a 30 gradient elution from 50% to 100% ethyl acetate in hexanes yielded 1.46 g (80%) of 1-4-methoxy-3-(3R)-tetrahydro furanyloxyphenyl-ethanol as a white solid. 'H-NMR (CDC1, 300 MHz) & 6.9 (m, 3H), 5.0 (m. 1H), 4.8 (m. 1H), 4.0-3.8 (m, 4H), 3.8 (s, 3H), 2.1 (m, 2H), 1.4 (d. 3H). 35 O (M-H2O+1)-221.2 Example 17 40 Synthesis of 1-4-Methoxy-3-(3R)-tetrahydrofurany loxyphenylethanone 1-Bromo-4-methoxy-3-(3R)-tetrahydrofuranyloxyben Zene (500 mg, 1.83 mmol) was added to a flask containing 10 mL of THF. This was cooled to -78° C. under argon and 45 butyllithium (1.5 mL, 2.5 M) was slowly added. After stirring at -78°C. for 1.5 hours, trimethylborate (0.41 mL, 3.7 mmol) in 10 mL of THF was added and the mixture was allowed to warm to room temperature overnight. The reaction was 50 quenched by the addition of 20 mL of an aqueous Saturated solution of NHCl and 20 mL of diethyl ether. The organic layer was washed with 10 mL of water, 10 mL of brine, dried over NaSO, and concentrated. The residue was dissolved in 18 mL of toluene and 270 mg of (2.6 mmol) 2,2-dimethyl 55 propane-1,3-diol was added. This was heated to reflux for 4 hours, concentrated, and diluted with hexanes. The insoluble Pyridium chlorochromate (2.8 g; 12.3 mmol) was added to material was washed three times with hexanes. The combined a flask containing 1.46 g (6.1 mmol) of 1-4-methoxy-3-(3R)- organic layer was removed and the product was purified using tetrahydrofuranyloxyphenyl]ethanol and 65 mL of CHC1. column chromatography using a gradient elution from 10% to 60 The mixture was stirred at room temperature for one hour and 100% ethyl acetate in hexanes to give 198 mg (35%) of the solids were filtered through silica gel, rinsing with 200 mL 2-4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-5.5- ethyl acetate. The solvent was removed and the residue was dimethyl-1,3,2-dioxaboriane as a clear oil. H-NMR purified by column chromatography using a gradient elution (CDC1,300 MHz) & 7.4 (d. 1H), 7.3 (d. 1H), 6.9 (d. 1H), 5.0 65 from 20% to 50% ethyl acetate in hexanes to give 1.2 g (83%) (m. 1H), 4.0 (m,3H), 3.9-3.8 (n 4H), 3.7. (s, 4H), 2.1 (m, 2H) of 1-4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyletha 1.0 (s, 6H). none as a white solid. 'H-NMR (CDC1,300 MHz) & 7.5 (d. US 7,723,348 B2 115 116 1H), 7.4 (d. 1H), 6.8 (d. 1H); 4.9 (m, 1H), 4.0-3.9 (m,3H), 3.8 quenched by the addition of 25 mL of water. The mixture was (m, 4H), 2.5 (s.3H), 2.1 (m, 2H). (M+1)=237.2. extracted with 4x25 mL of ethyl acetate and the combined organic fractions were dried over NaSO, filtered and con Example 18 centrated. Purification by column chromatography oversilica gel using a gradient elution from 100% CHCl to 90:10:5:: Synthesis of 3-4-Methoxy-3-(3R)-tetrahydrofurany CHC1:MeOH:NH-OH provided 257 mg (56%) of 3-dim loxyphenyl-3-oxopropionaldehyde ethylamino-1-(4-methoxy-3-(3R)-tetrahydrofuranyloxyphe nylpropenone as a yellow oil and 115 mg of the starting ketone. 'H-NMR (CDC1, 300 MHz) & 8.0 (s, 1H), 7.7 (d. 10 1H), 7.5 (m, 2H), 6.9 (d. 1H), 5.7 (d. 1H), 5.1 (m, 1H), 4.0 (m, 3H), 3.9 (s, 4H), 2.9 (s.3H), 2.8 (s.3H), 2.2 (m, 2H). (M+1)= 292.1 The following compounds were synthesized in a similar manner with different starting materials: 15 (2E)-3-(dimethylamino)-1-(3-fluoro-4-methoxyphenyl) prop-2-en-1-one; (2E)-1-(3,4-dimethoxyphenyl)-3-(dimethylamino)prop-2- en-1-one; O (E)-1-(3-Bromo-4-methoxy-phenyl)-3-dimethylamino-pro penone; (2E)-1-3,4-bis(difluoromethoxy)phenyl-3-(dimethy A suspension of Sodium hydride (60% suspension in min lamino)prop-2-en-1-one; eral oil, 210 mg, 5.25 mmol) in 4 mL of THF under argon was (2E)-1-4-(difluoromethoxy)-3-methoxyphenyl-3-(dim treated sequentially with 0.4 mL (4.77 mmol) of ethyl for ethylamino)prop-2-en-1-one. mate and a solution of 939 mg (3.98 mmol) of 1-4-methoxy 25 3-(3R)-tetrahydrofuranyloxyphenylethanone in 2 mL of THF. The resulting mixture was stirred at room temperature Example 20 for 4 hours, and then acidified with 0.5 NHCl to pH 2 and Synthesis of 1-(4-Methoxyphenyl)-5-4-methoxy-3- extracted with 3x10 mL of ethyl acetate. The organic layer (3R)-tetrahydrofuranyloxy-phenyl)-1H-pyrazole was dried over NaSO filtered and the solvent removed. 30 Purification by column chromatography on silica gel using a gradient elution from 20% to 50% ethyl acetate in hexanes famished 218 mg (21%) of 3-4-methoxy-3-(3R)-tetrahydro furanyloxyphenyl-3-oxopropionaldehyde as a yellow solid. 'H-NMR (CDC1, 300 MHz) & 8.0 (s, 1H), 7.6-7.5 (m, 2H), 35 7.4 (d. 1H), 6.1 (d. 1H), 5.0 (m. 1H), 4.0 (m, 4H), 3.9 (s.3H), 2.2 (m, 2H). (M+1)=265.2 The following compounds were synthesized in a similar manner with different starting materials: 4,4,4-trifluoro-1-(4-methoxy-3-((3R)-tetrahydrofuran-3- 40 yloxyphenylbutane-1,3-dione; Ethyl 1-4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-1, 3-dionebutanoate. Example 19 45 Synthesis of 3-Dimethylamino-1-(4-methoxy-3- (3R)-tetrahydrofuranyloxyphenylpropenone 3-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-3- Oxopropionaldehyde (45 mg, 0.17 mmol), 4-methoxyphenyl 50 hydrazine hydrochloride (36 mg, 0.20 mmol) and 1.7 mL of ethanol were combined in a 0.5-2.0 mL Smith Process Vial. The vial was sealed and heated to 140° C. for 300 seconds using a Personal Chemistry Emrys Optimizer. The solvent was removed and purification by silica gel column chroma 55 tography using a gradient elution from 20% to 100% ethyl acetate in hexanes provided 40 mg (65%) of 1-(4-methox yphenyl)-5-4-methoxy-3-(3R)-tetrahydrofuranyloxyphe nyl)-1H-pyrazole as a brown solid. 'H-NMR (CDC1, 300 MHz) & 7.6 (d. 1H), 7.2 (m, 2H), 6.9 (m, 4H), 6.5 (d. 1H, 6.4 60 (d. 1H, 4.6 (m, 1H, 3.9-3.7 (m. 10H, 1.9 (m, 2H). (M+1)= 3672 The following compounds were synthesized in a similar To a solution of 440 mg (1.86 mmol) of 1-4-methoxy-3- manner with different starting materials: (3R)-tetrahydrofuranyloxyphenyl-ethanone in 15 mL of Ethyl 1-Benzyl-5-4-methoxy-3-(3R)-tetrahydrofuranylox DMF was added 0.30 mL (2.24 mmol) of N,N-dimethylfor 65 yphenyl)-1H-pyrazole-3-carboxylate: mamide dimethyl acetal. The resulting mixture was heated to 1-Benzyl-5-4-methoxy-3-(3R)-tetrahydrofuranyloxyphe 140° C. for 16 hours, then cooled to room temperature and nyl-3-trifluoromethyl-1H-pyrazole; US 7,723,348 B2 123 124 Example 23 mg, 0.13 mmol) in 2 mL of DMF was treated with HOBt (33 mg, 0.22 mmol), diisopropylethylamine (38 uL, 0.22 mmol), Synthesis of 5-4-Methoxy-3-(3R)-tetrahydrofura 3-fluoroaniline (21 uL, 0.22 mmol), and EDCI (38 u, 0.22 nyloxyphenyl-3-trifluoromethyl-1H-pyrazol-1- mmol) and was then stirred at room temperature for 16 h. The yl)acetic acid reaction was diluted with 10 mL of ethyl acetate; the organic layer was separated and sequentially washed with 10 mL of water, 10 mL of 1 NHCl, 10 mL of saturated NaHCO, and 10 mL of brine, dried (NaSO) and concentrated. Purification by silica gel column chromatography using 10% ethylacetate O 10 in hexanes provided 21 mg of N-(3-fluorophenyl)-2-5-4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-3-trifluorom ethyl-pyrazol-1-yl)acetamide as a white solid. 'H-NMR F O e (CDC1, 300 MHz) & 8.6 (s, 1H), 7.5 (d. 1H), 7.3 (m, 1H), F 7.1-7.0 (m,3H), 7.0-6.8 (m, 2H), 6.6 (s, 1H), 5.0 (m, 1H), 4.9 N-4 15 (s. 2H), 4.0-3.9 (m, 7H), 2.2 (m, 2H). N F The following compounds were synthesized in a similar O manner with different starting materials: OH N-Cyclopropyl-2-5-4-methoxy-3-(3R)-tetrahydrofurany O loxyphenyl-pyrazol-1-yl)acetamide; N-Isopropyl-2-5-4-methoxy-3-(3R)-tetrahydrofuranylox {5-4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl-3- yphenyl-pyrazol-1-yl)acetamide: trifluoromethyl-pyrazol-1-yl)-acetic acid ethyl ester (239 N-Phenyl-2-5-4-methoxy-3-(3R)-tetrahydrofuranylox mg, 0.58 mmol) was dissolved in 5 mL of a solution made of yphenyl-pyrazol-1-yl)acetamide: 35g KOH in 25 mL water. The reaction mixture was diluted N,N-Diethyl-2-5-4-methoxy-3-(3R)-tetrahydrofuranylox with 100 mL of methanol, heated to 100° C. for 1 hour, and 25 yphenyl-pyrazol-1-yl)acetamide: cooled to room temperature. Acidification with 1N HCl resulted in the formation of a white solid, which was isolated by filtration to give 100mg of 5-4-methoxy-3-(3R)-tetrahy Example 25 drofuranyloxyphenyl-3-trifluoromethyl-1H-pyrazol-1- Synthesis of 2-1-Benzyl-5-4-methoxy-3-(3R)tet yl)acetic acid. 'H-NMR (CDC1,300MHz) & 6.9 (s. 2H), 6.8 30 rahydrofuranyloxyphenyl)-1H-pyrazol-3-yl)propan (s, 1H), 6.5 (s, 1H), 4.9 (m, 4H), 4.0 (s, 4H), 3.9 (s.3H); 2.2 2-ol (A) and 1-1-Benzyl-5-4-methoxy-3-(3R)tet (s. 2H). (M+1) rahydro-furanyloxyphenyl)-1H-pyrazol-3- The following compounds were synthesized in a similar yl)ethanone (B) manner with different starting materials: 1-Benzyl-5-4-methoxy-3-(3R)-tetrahydrofuranyloxyphe 35 nyl)-1H-pyrazole-3-carboxylic acid; 1-(4-Carboxybenzyl)-5-4-methoxy-3-(3R)-tetrahydrofura nyloxyphenyl)-1H-pyrazole; 1-(4-Carboxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H O pyrazole. 40 OH Example 24 O e A Synthesis of N-(3-Fluorophenyl)-2-5-4-methoxy NN N 3-(3R)-tetrahydrofuranyloxyphenyl-3-trifluorom 45 ethylpyrazol-1-yl)acetamide O 50 O O F O e O 55 N NN/ F NN O O N O 60 F A solution of 1-benzyl-5-4-methoxy-3-(3R)-tetrahydro 65 furanyloxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl A solution of 5-4-methoxy-3-(3R)-tetrahydrofuranylox ester (144 mg. 0.34 mmol) in 3 mL of THF was cooled to -78° yphenyl-3-trifluoromethyl-1H-pyrazol-1-yl)acetic acid (50 C. under argon and MeMgCl (0.34 mL, 3.0M) was added US 7,723,348 B2 125 126 slowly. The solution was warmed to room temperature over 2 1-(2-Hydroxyethyl)-5-4-methoxy-3-(3R)-tetrahydrofura hours and then 10 mL of saturated aqueous NHCl was added. nyloxyphenyl)-1H-pyrazole. The mixture was extracted with 3x10 mL of ethyl acetate and the combined organic fractions were dried over NaSO, Example 27 filtered and concentrated. Purification by silica gel column chromatography using a gradient elution from 20% to 50% Synthesis of ethyl acetate in hexanes yielded 55 mg of 2-1-benzyl-5-4- 5-Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-1H-pyrazol 3-yl)propan-2-ol A as a clear oil and 20 mg of 1-1-benzyl 10 Step 1: 2-(2,6-Difluorobenzyl)-1-hydroxy-1H-pyrazole 5-(4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-1H 1-Hydroxypyrazole (49.3 mg, 0.59 mmol. 1.0 eq) was pyrazol-3-yl)ethanone Bas a clear oil." H-NMR (CDC1,300 mixed with 165.8 mg (0.80 mmol. 1.36 eq) of 2,6-difluo MHz) A & 7.3 (m, 3H), 7.0 (d. 2H), 6.9 (m, 2H), 6.6 (d. 1H), robenzyl bromide in ~1-2 mL of anhydrous CHCl under 6.2 (s, 1H), 5.3 (s. 2H), 4.6 (m, 1H), 4.0-3.7 (m, 7H), 2.0 (m, argon. The mixture was heated at 80°C. for 18 b tinder inert 2H), 1.6 (s, 6H). 'H-NMR (CDC1, 300 MHz) B 8 7.3 (m, 15 atmosphere in a sealed flask without condenser. The residue 3H), 7.0 (d. 2H), 6.9 (s. 2H), 6.8 (s, 1H), 6.6 (s, 1H), 5.3 (s, was partitioned between 37 weight percent aqueous HCl and 2H), 4.6 (m, 1H), 4.0-3.7 (m, 7H), 2.6 (s, 3H), 1.9 (m, 2H), toluene. The aqueous layer was collected and the toluene (M+1) A409.2 B 393.2. fraction extracted again with 37 weight percent aqueous HC1. The following compound was synthesized in a similar The combined aqueous HCL fractions were neutralized with manner with different starting materials: 5N aqueous NaOH to pH-11-12 and then back-extracted with 3x30 mL of CHC1. The organic layers were combined, 145) 2-(4-5-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H washed with brine, dried over NaSO and concentrated pyrazolo 3,4-bipyridin-6-yl)-1H-pyrazol-1-yl)phenyl) under reduced pressure to yield 86.3 mg (70.1% yield) of propan-2-ol, LC/MS (EI) to 4.73 (Method A), m/z. 432.2 25 2-(2,6-difluorobenzyl)-1-hydroxy-1H-pyrazole as a tan (M+1) brown solid. "H NMR (CDC 300 MHz) & 7.37 (m, 1H), 7.18 (d. 1H), 6.95 (t, 2H), 6.85 (d. 1H), 6.11 (t, 1H), 5.43 (s.2.00H) Example 26 LC/MS (ES) M+1=211.2 Synthesis of {1-Benzyl-5-4-methoxy-3-(3R)-tet 30 Step 2: 5Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole rahydrofuranyloxyphenyl)-1H-pyrazol-3- 2-(2,6-Difluorobenzyl)-1-hydroxy-1H-pyrazole (81.2 mg, yl)methanol 0.386 mmol. 1.0 eq) and 5 of anhydrous CHCl were com bined in a flame-dried 25 mL round-bottom flask under argon and cooled in an ice/water bath. A solution of POBr. (398.1 35 mg, 1.39 mmol. 3.60 eq) in 3 mL of CHCl was added using a syringe in aliquots over an hour period with stirring. The O reaction solution was warmed to room temperature and stirred for 16 hours. The CHCl was removed in vacuo and the resulting orange mixture was neutralized with Saturated aque O e 40 ous NaHCO and extracted with 3x30 mL of diethyl ether. / The combined ether fractions were washed with brine, dried NN, OH over NaSO and concentrated in vacuo to yield 101.5 mg (96.7% yield) of 5-bromo-1-(2,6-difluorobenzyl)-1H-pyra O 45 zole as a hygroscopic orange-tan colored solid. "H NMR (CDC1300 MHz) & 7.51 (d. 1H), 7.34 (m, 1H), 6.94 (t, 2H), 6.29 (d. 1H), 5.50 (s. 2H). LC/MS (ES) M+1=273.1, 275.1 The following compounds were synthesized in a similar manner with different starting materials: A solution of 1-benzyl-5-4-methoxy-3-(3R)-tetrahydro 50 5-Bromo-1-(4-trifluoromethoxybenzyl)-1H-pyrazole; furanyloxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl 5-Bromo-1-(2,3-difluorobenzyl)-1H-pyrazole; ester (62 mg, 0.15 mmol) in 3 mL THF was cooled to 0°C. 5-Bromo-1-(4-methylbenzyl)-1H-pyrazole; under argon. LAH (0.25 mL, 1M) was added and after stirring for 1 hour the reaction was quenched by the slow addition of 5-Bromo-1-(4-tert-butylbenzyl)-1H-pyrazole; 5 mL of methanol and 5 mL of 0.1 NHC1. The aqueous layer 55 5-Bromo-1-(4-trifluoromethylbenzyl)-1H-pyrazole; was extracted with 2x10 mL of ethyl acetate and the com 5-Bromo-1-(3,4-difluorobenzyl)-1H-pyrazole; bined organic factions were concentrated. Purification by 5-Bromo-1-(2-fluorobenzyl)-1H-pyrazole; silica gel column chromatography using a gradient elution 5-Bromo-1-(3-nitrobenzyl)-1H-pyrazole; from 50% to 100% ethyl acetate in hexanes yielded 20 mg of 5-Bromo-1-(4-methoxycarbonylbenzyl)-1H-pyrazole; {1-Benzyl-5-4-methoxy-3-(3R)-tetrahydrofuranyloxyphe nyl)-1H-pyrazol-3-yl)methanol as a clear oil. H-NMR 5-Bromo-1-(3-fluorobenzyl)-1H-pyrazole; (CDC1,300 MHz) & 7.3 (m,3H), 7.0 (d. 2H), 6.9 (m, 2H), 6.6 5-Bromo-1-(3,5-dimethoxybenzyl)-1H-pyrazole; (d. 1H), 6.3 (s, 1H), 5.3 (s. 2H), 4.7 (s. 2H), 4.6 (m. 1H), 1-Benzyl-5-bromo-1H-pyrazole; 3.9-3.7 (m, 7H), 2.5 (s, 1H), 2.0-1.4 (m, 2H). (M+1)-381.2 65 5-Bromo-1-(3-methoxybenzyl)-1H-pyrazole; The following compounds were synthesized in a similar 5-Bromo-1-(4-fluorobenzyl)-1H-pyrazole; manner with different starting materials: 5-Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole. US 7,723,348 B2 129 130 Example 31 4-dimethylaminopyridine (19.3 mg, 0.158 mmol), 4-meth oxybenzenesulphonamide (29.5 mg, 0.158 mmol) and 2 mL Synthesis of (2E)-1-(1-Cyclopentyl-3-ethyl-1H-inda of methylene chloride. The reaction was stirred overnight at Zol-6-yl)-3-(dimethylamino)prop-2-en-1-one room temperature, poured into 10 mL of water and 10 mL of ethyl acetate and the pH of the aqueous layer was adjusted to pH-6 by adding saturated aqueous NaHCO. The organic layer was dried over sodium sulfate, filtered and approxi mately 1 g of silica gel was added and the mixture was evaporated to dryness under reduced pressure. The residue 10 was purified by column chromatography on silica gel using a gradient elution going from 0% to 10% methanol in dichlo romethane over 20 minutes to give N-(4-methoxyphenyl) sulfonyl)-4-(5-(4-methoxy-3-((3R)-tetrahydrofuran-3- yloxyphenyl)-1H-pyrazol-1-yl)methylbenzamide (53 mg, 15 74%) as a yellow foam. LC/MS (EI) to 5.22 (Method C), m/z 564.2 (M-1). 'HNMR (CDC1300 MHz) & 1.8-2.0 (m,2H): 2.6 (brs, 2H); 3.6 (m, 2H); 3.8 (m, 2H); 3.9 (s.3H); 44 (brs, 1H); 5.2 (s. 2H); 6.3 (s, 1H); 6.4 (s, 1H); 6.9 (m, 3H): 7.2-7.6 Under argon 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl) (m, 3H); 7.7 (t, 2H); 7.8 (d. 2H); 7.9 (d. 2H). ethanone (815 mg, 3.18 mmol), N,N-dimethylformamide The following compounds were synthesized in a similar dimethyl acetal (0.634 mL, 4.77 mmol) and 30 mL of N.N- manner with different starting materials: dimethylformamide were combined and warmed to 140°C. 36) 4-(5-(4-methoxy-3-((3R)-tetrahydrofuran-3-yloxy overnight. The reaction mixture was poured into 50 mL of phenyl)-1H-pyrazol-1-yl)methyl-N-(phenylsulfonyl) water and extracted with 3x75 mL of ethyl acetate. The com benzamide: LC/MS (EI) to 534.5 (Method C), m/z 2.7 bined organic fractions were dried over sodium sulfate and 25 (M+1) concentrated under reduced pressure. The residue was puri 38) N-(4-fluorophenyl)sulfonyl)-4-(5-(4-methoxy-3- fied by column chromatography over silica gel eluting with (3R)-tetrahydrofuran-3-yloxyphenyl)-1H-pyrazol-1-yl) CHCl, for 10 minutes and then with a linear gradient over 30 methylbenzamide: LC/MS (EI) to 5.45 (Method C), m/z. minutes to 100% of 10% MeOH in CHCl with 0.1% 552.1 (M"+1) NHOH to give 954 mg (3.18 mmol, 96%) of (2E)-1-(1- 30 19) 4-5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyra cyclopentyl-3-ethyl-1H-indazol-6-yl)-3-(dimethylamino) Zol-1-yl-N-(methylsulfonyl)benzamide: LC/MS (EI) to prop-2-en-1-one as a yellow oil. LCMS m/z. 312.2 (M+1). 5.04, m/z 478.2 (M"+1) 20) 4-5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyra Example 32 Zol-1-yl-N-(ethylsulfonyl)benzamide LC/MS (EI) to 35 5.19, m/z 492.2 (M"+1). 37) N-(4-Methoxyphenyl)sulfonyl)-4-(5-(4-meth oxy-3-((3R)-tetrahydrofuran-3-yloxyphenyl)-1H Example 33 pyrazol-1-yl)methylbenzamide 53) 2-(5-4-Methoxy-3-((3R)-tetrahydrofuran-3- 40 yloxyphenyl)-1H-pyrazol-1-yl)ethyl phenylcarbam ate O 45 O e NN,M O e 50 O N/ O O VNH O 2S 55 2 ( O O 9 H 2-(5-4-Methoxy-3-((3R)-tetrahydrofuran-3-yloxylphe 60 nyl)-1H-pyrazol-1-yl)ethanol (20 mg, 0.066 mmol), 0.50 mL O of methylene chloride, phenyl isocyanate (30 uI, 0.28 mmol) / were combined in a test tube and stirred for 3 days at room temperature. Trisamine scavenger resin (Argonaut P/N Into a vial was added 4-(5-(4-methoxy-3-((3R)-tetrahy 800228, -3-5 equiv) was added and the mixture was stirred drofuran-3-yloxyphenyl)-1H-pyrazol-1-yl)methylbenzoic 65 for 2-3 hours, filtered through an Acro Disc (0.45 um) filter acid (50.0 mg, 0.127 mmol), N-(3-dimethylaminopropyl)-N'- and concentrated to yield 29.3 mg of a light yellow solid. The ethylcarbodiimide hydrochloride (30.2 mg 0.158 mmol), crude product was recrystallized from 0.5 mL of methanol to US 7,723,348 B2 135 136 bottom flask and stirred at room temperature for two hours. Into a 1-neck round-bottom flask was added 1-(1-cyclo The mixture was treated with 10 mL of saturated aqueous pentyl-3-ethyl-1H-indazol-6-yl)ethanol (1.06 g. 4.10 mmol), NaHCO and 10 mL of ethyl acetate. The organic layer was pyridinium chlorochromate (1.77g, 8.20 mmol) and 40 mL of separated, dried over Sodium sulfate, filtered and approxi methylene chloride. The reaction was stirred at room tem mately 500 mg of silica gel was added. The mixture was evaporated to dryness under reduced pressure and the residue perature for 1 hour, filtered through Celite, and rinsed with was purified by column chromatography over silica gel elut 200 mL of ethyl acetate. Approximately 20g of silica gel were ing with a gradient of 10% ethyl acetate in hexanes for 5 added and the mixture was evaporated to dryness under minutes and then increasing linearly to 100% ethyl acetate at reduced pressure. The residue was purified by column chro 25 minutes to yield 4-5-(1-cyclopentyl-3-ethyl-1H-indazol 10 matography over silica gel eluting with 20% ethyl acetate in 6-yl)-1H-pyrazol-1-ylbenzamide (5 mg, 62%) as a white hexanes to yield 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl) solid. LC/MS (EI) to 4.09(Method C), m/z 400.2 (M"+1). "H ethanone (809 mg, 77%). NMR (CDC1300 MHz) & 1.4 (t, 3H); 1.6 (m, 2H); 1.8 (m, 2H); 2.1 (m, 4H); 3.0 (q, 2H); 4.8 (m, 1H); 5.7 (brs, 1H); 6.0 (brs, 1H); 6.6 (s, 1H); 6.9 (d. 1H); 7.3-7.5 (m, 3H); 7.6 (d. 15 Example 40 1H); 7.8 (m, 3H). 24) 1-4-5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)- Example 38 1H-pyrazol-1-yl)phenylethanone Synthesis of 1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol 25 30 N M N e OH NN,A 35 A solution of 1-cyclopentyl-3-ethyl-1H-indazole-6-car boxaldehyde (1.00 g, 4.13 mmol) in 40 mL of tetrahydrofuran O under argon was cooled to -78° C. and with stirring treated with 3 mL of 3 M methylmagnesium chloride in tetrahydro furan. The reaction was stirred at -78°C. for 1 hour, slowly 40 warmed to room temperature overnight and then quenched by addition of 100 mL of saturated aqueous NHC1. The mixture was extracted with 3x50 mL of ethyl acetate and the com bined organic fractions were dried over sodium sulfate and concentrated to give 1-(1-cyclopentyl-3-ethyl-1H-indazol-6- 45 4-5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyra yl)ethanol as a yellow solid. The crude residue was not puri Zol-1-yl)-N-methoxy-N-methylbenzamide (66 mg, 0.15 fied but used as such in the next step. mmol) and 2 mL of tetrahydrofuran were combined in a one-necked round-bottom, placed under an atmosphere of Example 39 50 argon, cooled to -78°C., and 0.10 mL of 3 M methylmagne sium chloride in tetrahydrofuran was slowly added. The reac Synthesis of 1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanone tion was stirred at -78°C. for 30 minutes, warmed to 0°C. for 60 minutes and another 0.2 mL of 3 M methylmagnesium chloride in THF was added. The reaction was allowed to stir 55 at 0°C. for 30 minutes and 10 mL of saturated aqueous NHCl was added and the mixture was allowed to warm to room temperature. The aqueous layer was extracted with 20 mL of ethyl acetate and the separated organic layer was dried over Sodium sulfate, filtered and concentrated under reduced pres 60 sure to yield 1-4-5-(1-cyclopentyl-3-ethyl-1H-indazol-6- yl)-1H-pyrazol-1-ylphenylethanone (35 mg, 59%) as a white solid. LC/MS (EI) to 5.68 (Method C), m/z 399.1 (M"+ 1). "H NMR (CDC1300 MHz) & 1.3 (t,3H); 1.6 (m, 2H); 1.9 65 (m. 2H); 2.0 (m, 4H); 2.5 (s.3H); 3.0 (t, 2H); 4.8 (m. 1H); 6.5 (s, 1H); 6.8 (d. 1H): 7.2 (s, 1H); 7.3 (d. 2H); 7.4 (d. 1H); 7.7 (s, 1H): 7.6 (d. 2H). US 7,723,348 B2 137 138 Example 41 (11.0 mg 0.0120 mmol). The reaction was placed under an atmosphere of argon, 0.4 mL of 1.00 M lithium bis(trimeth 81) 5-1-(4-Fluorophenyl)-1H-pyrazol-5-yl)-2-meth ylsilyl)amide in tetrahydrofuran was added and the mixture oxyphenol was heated to 65° C. for 16 hours. After cooling to room temperature, 30 mL of saturated aqueous NHCl solution was added and the aqueous layer was extracted with 30 mL ethyl acetate. The separated organic layer was dried over sodium O Sulfate, filtered, and approximately 1 g silica gel was added 10 and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatogra phy on silica gel eluting with 20% ethyl acetate in hexanes to HO e yield tert-butyl 4-4-(5-(4-methoxy-3-((3R)-tetrahydrofu NN,M ran-3-yloxyphenyl)-1H-pyrazol-1-yl)phenylpiperazine-1- 15 carboxylate (21 mg, 34%) as a yellow oil. LC/MS (EI) to 4.62 (Method C), m/z. 521.3 (M+1). H NMR (CDC1300 MHz) & 1.5 (s, 9H); 1.9 (m, 2H); 3.1 (m, 4H); 3.6 (m, 4H); 3.7-3.9 F (m, 4H); 3.9 (s.3H); 4.6 (m. 1H); 6.4 (s, 1 h); 6.6 (s, 1H): 6.9-7.1 (m, 4H); 7.2 (d. 2H): 7.6 (S. 1H). Into a 1-neck round-bottom flask was added 5-3-(benzy The following compound was synthesized in a similar loxy)-4-methoxyphenyl-1-(4-fluorophenyl)-1H-pyrazole manner with different starting materials: (3.5 g., 9.3 mmol) and 100 mL of ethanol. The flask was flushed with nitrogen for 10 minutes and 350 mg of 10% Pd/C 27) 4-4-(5-(4-methoxy-3-((3R)-tetrahydrofuran-3-yloxy was added. The reaction was then stirred under one atmo 25 phenyl)-1H-pyrazol-1-yl)phenylmorpholine LC/MS (EI) sphere of hydrogen at room temperature overnight. The reac to 3.45 (Method C), m/z 422.2 (M"+1). tion was degassed under reduced pressure, flushed with argon for 5 minutes, filtered through Celite and concentrated to Example 43 yield 2.6 g (98%) of 5-1-(4-fluorophenyl)-1H-pyrazol-5-yl)- 2-methoxyphenol as a grey oil. m/z 285.0 (M"+1). "H NMR 30 Synthesis of 4-(5-(4-methoxy-3-((3R)-tetrahydrofu (CDC1300 MHz) & 3.9 (s.3H); 5.6 (s, 1H); 6.4 (s, 1H); 6.8 ran-3-yloxyphenyl)-1H-pyrazol-1-yl)methylben (d. 1H); 7.0 (d. 2H); 7.4 (d. 2H): 7.6 (m, 2H); 7.7 (s, 1H). Zoic acid Example 42 39) Tert-butyl 4-4-(5-(4-methoxy-3-((3R)-tetrahy 35 drofuran-3-yloxyphenyl)-1H-pyrazol-1-yl)phenyl piperazine-1-carboxylate O 40 O e / O NN 45 O O1 na na O N/ OH O 50 Into a 1-neck round-bottom flask was added methyl 4-(5- {4-methoxy-3-((3R)-tetrahydrofuran-3-yloxyphenyl)-1H pyrazol-1-yl)methylbenzoate (330 mg. 0.808 mmol), 5 mL r of 1,4-dioxane, 20 mL of water and 8 mL of 2 M aqueous 55 sodium hydroxide. The reaction was heated at 90°C. for 1.5 hours, acidified with 1N HCl until pH-3 and extracted with -- 3x20 mLCH.Cl. The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-(5-(4-methoxy-3-((3R)-tetrahydrofuran 60 3-yloxyphenyl)-1H-pyrazol-1-yl)methylbenzoic acid (260 mg, 81%) as a brown solid. LCMS M+1=395.2 Into a 1-neck round-bottom flask was added 2-dicyclo hexylphosphino-2'-(N,N-dimethylamino)biphenyl (4.74 mg. The following compound was synthesized in a similar 0.0120 mmol), 1-(4-bromophenyl)-5-4-methoxy-3-((3R)- manner with different starting materials: tetrahydrofuran-3-yloxyphenyl)-1H-pyrazole (50.0 mg. 65 28) 4-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl) 0.120 mmol), tert-butyl 1-piperazinecarboxylate (26.9 mg, methylbenzoic acid LC/MS (EI) to 3.49 (Method C), m/z. 0.144 mmol) and tris(dibenzylideneacetone) dipalladium(0) 327.2 (M"+1). US 7,723,348 B2 139 140 Example 44 treated with potassium hydroxide (6.64g, 118 mmol) and the reaction was stirred at room temperature for one hour. The 85) 5-(3,4-Dimethoxyphenyl)-1-(4-fluorophenyl)- reaction mixture was cooled with a dry ice/acetone bath to 1H-pyrazole maintain an internal temperature <25° C. and chlorodifluo roacetic acid (5.57 mL, 65.7 mmol) was slowly added and the reaction was then allowed to warm to room temperature for one hour. The reaction was heated to 65° C. overnight and after cooling to room temperature, the reaction was diluted 10 with 400 mL of water and extracted with 3x150 mL methyl t-butyl ether making sure the water layer was pH-3. The organic layer was extracted with 3x100 mL of 1 NNaOH. To obtain 1-3,4-bis(difluoromethoxy)phenylethanone, the separated organic layer was dried over Sodium sulfate, fil 15 tered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 10% ethyl acetate in hexanes to 100% ethyl acetate over 30 minutes to yield 1-3,4-bis(difluoromethoxy) phenyl]ethanone (531 mg, 16%). 5-1-(4-Fluorophenyl)-1H-pyrazol-5-yl)-2-methoxyphe To obtain 1-4-(difluoromethoxy)-3-hydroxyphenyletha nol (50.0 mg 0.176 mmol), 5 mL of N,N-dimethylformamide none, the NaOH solution was acidified with 1N HCl and and methyl iodide (16.4 uI, 0.264 mmol) were combined in a extracted with 3x100 mL diethyl ether. The combined organic vial and stirred at room temperature overnight. An additional fractions were dried over sodium sulfate, filtered and concen 0.5 mL of methyl iodide was added and stirring continued for 25 2 days at room temperature and then 10 mL of ethyl acetate trated under reduced pressure. The residue was purified by and 10 mL of water were added. The organic layer was column chromatography on silica gel eluting with a gradient separated, dried over sodium Sulfate, filtered and concen of 10% ethyl acetate in hexanes to 100% ethyl acetate over 30 trated under reduced pressure. The residue was purified by minutes to yield 1-4-(difluoromethoxy)-3-hydroxyphenyl column chromatography on silica gel eluting with a gradient 30 ethanone (314 mg, 12%). of 10% ethyl acetate in hexanes to 50% ethyl acetate in hexanes over 20 minutes to give 5-(3,4-dimethoxyphenyl)-1- Example 46 (4-fluorophenyl)-1H-pyrazole (25 mg, 48%) as a white solid. LC/MS (EI) to 4.14, m/z 299.1 (M+1). "H NMR (CDC1300 Synthesis of (2E)-1-4-(Difluoromethoxy)-3-meth MHz) 83.7 (s.3H); 3.9 (s.3H); 6.5 (s, 1H); 6.7 (s, 1H); 7.0 (s, 35 oxyphenyl-3-(dimethylamino)prop-2-en-1-one 2H); 7.1 (m, 2H); 7.3 (m, 2H); 7.7 (s, 1H). The following compounds were synthesized in a similar manner with different starting materials: 86) 5-(3-ethoxy-4-methoxyphenyl)-1-(4-fluorophenyl)-1H pyrazole; LC/MS (EI) to 4.41, m/z. 313.2 (M"+1) 40 87) 5-3-(cyclopropylmethoxy)-4-methoxyphenyl-1-(4- fluorophenyl)-1H-pyrazole; LC/MS (EI) to 4.69, m/z 339.1 (M+1) 88) 5-3-(cyclopentyloxy)-4-methoxyphenyl-1-(4-fluo rophenyl)-1H-pyrazole LC/MS (EI) to 5.11 (Method C), 45 m/z. 353.2 (M+1) Example 45 Synthesis of 1-4-(Difluoromethoxy)-3-hydroxyphenylethanone 50 and 1-3,4-bis(difluoromethoxy)phenylethanone Into a 1-necked flask were added 1-4-(difluoromethoxy)- 55 3-hydroxyphenylethanone (0.317 g, 1.57 mmol), 16 mL of N,N-dimethylformamide, and N,N-dimethylformamide dim N ethy acetal (0.25 mL, 1.9 mmol). The mixture was heated to O O 140° C. overnight and after cooling to room temperature, poured into 50 mL water and extracted 3x50 mL ethyl acetate. The combined organic fractions were dried over sodium sul HO O fate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Fu F : eluting with a gradient of 50% ethyl acetate in hexanes to 65 100% ethyl acetate over 30 minutes to give (2E)-1-4-(dif A solution of 1-(3,4-dihydroxyphenyl)ethan-1-one (2.00 luoromethoxy)-3-methoxyphenyl-3-dimethylamino)prop g, 13.1 mmol) in 200 mL of N,N-dimethylformamide was 2-en-1-one (51 mg 0.188 mmol) as a yellow oil. US 7,723,348 B2 141 142 Example 47 lyl)ethoxymethyl-2H-indazole-6-carboxamide, which was used without further purification. Synthesis of 3-Ethyl-N-methoxy-N-methyl-1H-inda Zole-6-carboxamide Example 49 Synthesis of 1-(3-Ethyl-1-(2-(trimethylsilyl)ethoxy methyl)-1H-indazol-6-yl)ethanone 10 N N No N 15 M N 3-ethyl-1H-indazole-6-carboxylic acid (3.9 g, 0.020 mol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydro chloride (4.3 g, 0.022 mol) and 4-dimethylaminopyridine O N (3.11 g, 0.0254 mol), N.O-dimethylhydroxylamin hydro SiMe3 chloride (2.8 g., 0.028 mol) were dissolved in methylene chlo ride (200 mL) and N,N-dimethylformamide (20 mid) and the solution stirred at room temperature for one hour. The result Methylmagnesium chloride (7.7 mL, 3M in tetrahydrofu 25 ran) was added dropwise at -78°C. under an atmosphere of ing mixture was poured in iced water. The aqueous layer was argon to a solution of 3-Ethyl-N-methoxy-N-methyl-1-(2- removed, and extracted with ethyl acetate (2x50 mL). The (trimethylsilyl)ethoxymethyl)-1H-indazole-6-carboxamide combined organics were washed with 1 NHCl, 2N NaOH, (4.0 g, 0.011 mol) in tetrahydrofuran (114 mL). The resulting water, and brine, then dried. The solvent was removed in mixture was allowed to warm slowly to room temperature. vacuo, and the residue was purified by column chromatogra 30 The reaction was then quenched by the addition of a saturated phy on silica gel eluting with a gradient of 50% ethyl acetate solution of ammonium chloride. Ethyl acetate (150 mL) and in hexanes to 100% ethyl acetate over 30 minutes to give 1.6 water (100 mL) were then added, and the organic layer was g (33%) of 3-ethyl-N-methoxy-N-methyl-1H-indazole-6- separated, washed with water and with brine, and then dried carboxamide. (sodium sulfate). After filtration, the solvent was concen 35 trated, and the residue was purified by column chromatogra phy on silica gel, eluting with a gradient of 50% ethyl acetate Example 48 in hexanes to 100% ethyl acetate over 30 minutes, to give 3.5 g (quantitative yield) of 1-(3-Ethyl-1-(2-(trimethylsilyl) Synthesis of 3-Ethyl-N-methoxy-N-methyl-2-2- ethoxymethyl)-1H-indazol-6-yl)ethanone. "H NMR (trimethylsilyl)ethoxymethyl-2H-indazole-6-car 40 (CDC1) & 0.0 (m. 1H), 1.0 (t, 3H), 1.1-1.4 (m, 2H), 2.7 (s, boxamide 3H), 2.9-3.1 (m, 2H), 3.5 (1,2H), 5.7 (s. 2H), 7.5 (m, 2H), 8.0 (s, 1H). Example 50 45 Synthesis of (2E)-3-(Dimethylamino)-1-(3-Ethyl-1- 2-(trimethylsilyl)ethoxymethyl)-1H-indazol-6-yl) prop-2-en-1-one \ SiMe3 NaH (1.3 g. 60% dispersion in mineral oil, 0.033 mol) and tetrahydrofuran (223 mL) were mixed in a 1-necked flaskand 55 cooled to 0°C. To this was added dropwise a mixture of 3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide (2.6 g., 0.011 mol) in tetrahydrofuran (60 mL), and the mix ture was stirred at 0°C. for 1 hour. B-(Trimethylsilyl)ethoxy 60 methyl chloride (2.4 mL, 0.013 mol) was then added and the reaction mixture was allowed to warm to room temperature. s/ The resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the N organics were washed with brine (25 mL), dried (sodium 65 Sulfate) and concentrated in vacuo to afford 4.0 g (quantitative Under an atmosphere of argon, 1,1-Dimethoxy-N,N-dim yield) of 3-ethyl-N-methoxy-N-methyl-2-[2-(trimethylsi ethylmethanamine (4.4 mL, 0.033 mol) and 1-(3-Ethyl-1- US 7,723,348 B2 143 144 2-(trimethylsilyl)ethoxymethyl)-1H-indazol-6-yl)etha Example 52 none (3.5 g., 0.011 mol) were mixed in N.N- dimethylformamide (110 mL) and the resulting mixture was heated at 140° C. for 16 hours. After cooling to room tem 99) 3-Ethyl-2-(1-ethylpropyl)-6-1-(methylsulfo perature, water (250 mL) and ethyl acetate (250 mL) were nyl)phenyl)-1H-pyrazol-5-yl-2H-indazole added, the layers were separated, and the product was extracted with ethyl acetate (3x100 mL). The combined organic layers, were washed with water and brine, dried (so dium sulfate), and the volatiles were removed in vacuo to 10 afford 4.1 g (quantitative yield) of (2E)-3-(dimethylamino)- 1-(3-Ethyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-inda Zol-6-yl)prop-2-en-1-one, which was used without further purification. 15 Example 51 Synthesis of 6-1-3-(Benzyloxy)phenyl)-1H-pyra zol-5-yl)-3-ethyl-1H-indazole O S HC N 25 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol-5- yl)-1H-indazole (100 mg, 0.27 mmol), 3-bromopentane (70 mg, 0.46 mmol), potassium carbonate (45 mg, 0.33 mmol) and N,N-dimethylformamide (2 mL) were added to a 30 1-necked flask. The mixture was heated to 60° C. for 6 hours, / then slowly cooled to room temperature and stirred for a NN / further 48 hours. A further equivalent of 3-bromopentane (41 M N mg, 0.27 mmol) was then added, and the reaction was heated H N1 to 120° C. After cooling to room temperature, water and ethyl 35 acetate were added. The product was extracted once with ethyl acetate, and washed with water and brine. The com bined organics were dried, and filtered and concentrated. The reside was purified by column chromatography on silica gel (eluting using 50% ethyl acetate in hexanes for 10 minutes 40 and then a linear gradient to 100% ethyl acetate in hexanes at 20 minutes) to give 4.4 mg (3.7%) of 3-ethyl-2-(1-ethylpro pyl)-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)- 2H-indazole. LC/MS (EI) to 4.36 (Method C), m/z 437.1 45 (M"+1), H NMR (CDC1) & 0.6 (t, 3H), 1.4 (t, 2H), 1.8 (m, 2H), 1.9 (m, 2H), 3.0 (m, 6H), 4.0 (m. 1H), 6.5 (s, 1H), 7.0 (d. 1H), 7.1 (s, 1H), 7.5 (d. 2H), 7.7 (m. 1H), 7.8 (s, 1H), 7.8 (d. 2H). 13 mg (11%) of the corresponding isomer (3-ethyl-1- (1-ethylpropyl)-6-1-4-(methylsulfonyl)phenyl)-1H-pyra 50 (2E)-3-(dimethylamino)-1-(3-Ethyl-1-(2-(trimethylsi zol-5-yl)-1H-indazole) was also isolated. lyl)ethoxymethyl)-1H-indazol-6-yl)prop-2-en-1-one (256 The following compounds were synthesized in a similar mg, 0.685 mmol) and 3-benzyloxyphenylhydrazine hydro manner with different starting materials: chloride (270 mg, 1.1 mmol) were dissolved in ethanol (4 98) 3-ethyl-1-(1-ethylpropyl)-6-1-4-(methylsulfonyl)phe mL) in a 10 mL sealed tube. The mixture was subjected to 55 nyl)-1H-pyrazol-5-yl)-1H-indazole, LC/MS (EI) to 4.76 microwave radiation (300 watts, 160°C.) for 5 minutes. The (Method C), m/z. 437.1 (M"+1) solvent was removed and the residue was extracted with ethyl 100) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol acetate, then washed with water and brine. Removal of vola 5-yl)-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-indazole, tiles provided a tan solid, which was purified by column 60 LC/MS (EI) to 4.36 (Method C), m/z. 465.2 (M"+1) chromatography on silica gel, eluting with a 10-50% hexane/ ethyl acetate gradient over 10 minutes (flow rate 20 mL/min), 101) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol to give 160 mg (59%) of 6-1-3-(benzyloxy)phenyl)-1H 5-yl)-2-(tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole, pyrazol-5-yl)-3-ethyl-1H-indazole.' H NMR (CDC1) & 1.4 LC/MS (EI) to 4.3 (Method C), m/z. 465.2 (M"+1) (t,3H), 3.0 (q, 2H), 5.0 (s.2H), 6.6 (d. 1H), 6.8 (d. 1H), 6.9 (d. 65 102) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol 1H), 7.1 (m, 2H), 7.2 (t, 1H), 7.3, (m, 5H), 7.6 (d. 1H), 7.8 (m, 5-yl)-2-(2-pyrrolidin-1-ylethyl)-2H-indazole, LC/MS 1H), 9.7 (brs, 1H). (EI) to 4.11 (Method C), m/z 464.1 (M+1) US 7,723,348 B2 147 148 sodium tert-butoxide (19.7 mg, 0.21 mmol) and toluene (2.3 was thenwashed with dichloromethane, to afford 4.8g (77%) mL) was subjected to microwave irradiation (300 watts, 140° of 1-(2,6-difluoropyridin-3-yl)propan-1-one. C.) for 300 seconds in a 10 mL sealed tube. The solvent was removed and the crude product absorbed onto silica gel. The Example 57 residue was purified by column chromatography using as Synthesis of 3-Ethyl-6-fluoro-1-(tetrahydro-2H-py eluent 10% ethyl acetate in hexanes for 10 minutes, then a ran-4-yl)-1H-pyrazolo 3,4-bipyridine gradient to 50% ethyl acetate in hexanes at 20 minutes, then 50% for 5 minutes, then 100% at 35 minutes to provide 42 mg (70%) of 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyra 10 zol-5-yl)-1-pyrimidin-2-yl-1H-indazole. LC/MS (EI) to 3.82 (Method C), m/z. 445.1 (M+1), H NMR (CDC1) & 1.5 (t, 3H); 3.0 (s.3H); 3.1 (q, 2H); 6.6 (s, 1H); 7.1 (d. 2H); 7.6 (d. 2H); 7.7 (d. 1H); 7.8 (d. 1H); 7.9 (m, 2H); 8.7 (m, 3H). The following compound was synthesized in a similar 15 manner with different starting materials: 118) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol 5-yl)-1-pyridin-2-yl-1H-indazole, LC/MS (EI) to 5.37 (Method A), m/z. 444.2 (M+1) A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hy Example 56 drazinecarboxylate (3.8 g., 0.018 mol) and trifluoroacetic acid a) Synthesis of (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 25 90 minutes. The mixture was concentrated, and the residue 1-(2,6-difluoropyridin-3-yl)propan-2-ol was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin 3-yl)propan-1-one (2.34g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75°C. for 72 hours. After cooling to room temperature, the mixture was concentrated, OH 30 and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow N rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined 2 extracts were washed with saturated sodium bicarbonate and 35 then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6- fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipy 2,6-difluoropyridine (5.0 mL, 0.0551 mol) in tetrahydro ridine as a white solid. LC/MS (EI) to 3.5 (Method E), m/z. furan (55 mL) was slowly added to a 1-necked flask contain 250 (M+1). ing lithium diisopropylamide (31 mL, 1.8 M in tetrahydrofu The following compound was prepared in a similar fashion ran) at -78°C. The reaction was stirred at this temperature for 40 with different starting materials: 30 minutes and then propionaldehyde (3.96 mL, 0.0551 mol) 3-Ethyl-6-fluoro-1-isopropyl-1H-pyrazolo 3,4-bipyridine. was added. After stirring at this temperature for an additional 30 minutes, the reaction was quenched by the addition of a Example 58 saturated solution of ammonium chloride (20 mL). The prod 45 Synthesis of 3-Ethyl-1-(tetrahydro-2H-pyran-4-yl)- uct was extracted with diethylether, and purified by column 1H-pyrazolo 3,4-bipyridine-6-carbonitrile chromatography using as eluent 10% ethyl acetate in hexanes to provide 6.7 g (70%) of 1-(2,6-difluoropyridin-3-yl)pro pan-2-ol. 50 b) Synthesis of 1-(2,6-difluoropyridin-3-yl)propan-1-one 55 NC 60 A mixture of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4- yl)-1H-pyrazolo 3,4-bipyridine (2.92g, 0.0117 mol), sodium cyanide (3.9 g, 0.079 mol), tetra-N-butylammonium bromide A mixture of 1-(2,6-difluoropyridin-3-yl)propan-2-ol (6.3 (7.6 g., 0.023 mol) and dimethylsulfoxide (60 mL) was heated g, 0.036 mol) pyridinium chlorochromate (27.1 g, 0.126 mol) 65 at 150° C. for 2 hours. After cooling, the product was and chloroform (320 mL) was stirred at room temperature for extracted using ethyl acetate (300 mL). The extract was 16 hours. The mixture was filtered through silica gel, which washed with water (5x50 mL) and brine (50 mL), and then US 7,723,348 B2 149 150 concentrated to provide the crude product as a brown solid, Example 60 which was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient over 15 min 116) 3-ethyl-6-1-(4-methylsulfonyl)phenyl)-1H utes (flow rate 20 mL/min) to afford 2.22 g (73.9%) of pyrazol-5-yl)-1 (tetrahydro-2H-pyran)-1H-indazole 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-b 5 pyridine-6-carbonitrile as an off-white solid, which was used without further purification. LC/MS (EI) to 3.57 (Method E), m/z 257.2 (M+1). The following compound was prepared in a similar fashion with different starting materials: 10 3-Ethyl-1-isopropyl-1H-pyrazolo 3,4-bipyridine-6-carboni trile. / Example 59 15 Y. / Synthesis of 1-3-Ethyl-1-(tetrahydro-2H-pyran-4- yl)-1H-pyrazolo3.4bpyridin-6-yl)ethanone l 25 ^ 21 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol-5- 30 yl)-1H-indazole (0.18 g. 0.49 mmol) in N,N-dimethylforma Y. s mide (6 mL) was added to a mixture of sodium hydride (29 mg, 60% in mineral oil, 0.74 mmol) and N,N-dimethylfor mamide (6 mL) under an atmosphere of argon, and the result 35 ing mixture was stirred for 30 minutes. 4-iodotetrahydro-2H pyran (0.16 g., 0.74 mmol) in N,N-dimethylformamide (6 mL) was then added and the reaction was heated at 60°C. for 50 hours. After cooling, the reaction mixture was concen trated and the residue diluted with waterfacetonitrile (40 mL) 40 and filtered (0.45um). The product was purified by prepara tive HPLC using a gradient of 20-80% acetonitrile:water Methyltriphenylphosphonium bromide (4.64 g., 0.0130 (with 0.1% formic acid and a flow rate of 45 mL/minto afford mol) and lithium iodide (0.48g, 0.0036 mot) were mixed in 10 mg (4.6%) of 3-ethyl-6-1-4-methylsulfonyl)phenyl tetrahydrofuran (70 mL) in a 3-necked flask under an atmo 45 1H-pyrazol-5-yl)-1 (tetrahydro-2H-pyran)-1H-indazole as a sphere of nitrogen. The flask was wrapped in aluminum foil to yellow solid. LC/MS (EI) to 4.54 (Method A), m/z 451.2 exclude light, and chilled to 0°C. n-Butyllithium (5.8 mL, 2.5 (M"+1). "H NMR (CDC1) & 1.4 (t,3H); 1.9 (d. 2H); 2.4 (m, M in hexanes, 0.014 mol) was then added and the resulting mixture stirred for 30 minutes. A solution of 3-ethyl-1-(tet 2H);3.0 (m. 1H); 3.1 (s.3H); 3.6 (m,3H); 4.1 (d. 2H); 4.5 (m, rahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipyridine-6-car 1H); 6.6 (s, 1H); 6.9 (d. 1H): 7.2-7.3 (m,3H): 7.5-7.7 (m,2H): bonitrile (1.85 g, 7.22 mmol) in tetrahydrofuran (19.8 mL) 50 7.8-7.9 (m, 2H). was then added and the reaction stirred at 50° C. for 90 The following compounds were made using a similar pro minutes. After cooling to room temperature, the product was cedure using different starting materials: extracted using dichloromethane (250 mL). The extract was 117) 1-(difluoromethyl)-3-ethyl-6-1-4-(methylsulfonyl) washed brine and concentrated to afford the crude product as 55 phenyl)-1H-pyrazol-5-yl)-1H-indazole, LC/MS (EI) to a semi-solid, which was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient over 4.21 (Method A), m/z. 417.1 (M"+1) 10 minutes (flow rate 20 mL/min). Concentration of the 119) 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-ethyl-6-1- organics afforded 1.39 g (70.4%) of 1-3-Ethyl-1-(tetrahy 4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)-1H-inda dro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipyridine-6-yletha zole, LC/MS (EI) to 5.19 (Method A), m/z. 491.1 (M"+1) none as a colorless oil. LC/MS (EI) to 3.72 (Method E), m/z. 60 120) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol 274.1 (M"+1). All reagents were stored in a desiccator prior to 5-yl)-1-(tetrahydrofuran-3-yl)-1H-indazole, LC/MS (EI) SC. to 4.02 (Method A), m/z 437.2 (M"+1) The following compound was prepared in a similar fashion 121) Tert-butyl 3-(3-ethyl-6-1-4-(methylsulfonyl)phenyl with different starting materials: 65 1H-pyrazol-5-yl)-1H-indazol-1-yl)pyrrolidine-1-car 1-(3-Ethyl-1-isopropyl-1H-pyrazolo 3,4-bipyridine-6-yl) boxylate, LC/MS (EI) to 4.97 (Method B), m/z 436.2 (M"+ ethanone. 1). US 7,723,348 B2 151 152 Example 61 A mixture of potassium tert-butoxide (0.144g, 1.28 mmol) and iodoethane (0.20g, 1.28 mmol) in THF (1 mL) was added 112) 1-Cyclopropyl-3-ethyl-6-1-4-(methylsulfo to a solution of 3-ethyl-1H-indazole-6-carboxylic acid meth nyl)phenyl)-1H-pyrazol-5-yl)-1H-indazole oxy-methyl-amide (0.20g, 0.86 mmol) in THF (3 mL) and the resulting mixture stirred at room temperature for 16 hours. Ethyl acetate (30 mL) was then added and the product was CH extracted with 0.5 NHCl (10 mL). The aqueous layer was then re-extracted with ethyl acetate (30 mL). The organics 10 were combined, dried, filtered and concentrated to afford 250 mg of 1,3-diethyl-1H-indazole-6-carboxylic acid methoxy methyl-amide that was used without further purification. The following compounds were made using a similar pro cedure using different starting materials: 15 3-ethyl-1-(2-methoxyethyl)-1H-indazole-6-carboxylic acid methoxy-methyl-amide, 3-ethyl-1-isopropyl-1H-indazole-6-carboxylic acid meth oxy-methyl-amide, 1-cyclopropylmethyl-3-ethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide, 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol-5- 1-cyclopentyl-1H-indazole-6-carboxylic acid methoxy-me yl)-1H-indazole (20 mg, 0.054 mmol), cyclopropylboronic thyl-amide. acid (14 mg., 0.16 mmol), cupric acetate (20 mg, 0.11 mmol), 25 triethylamine (0.038 mL, 0.27 mmol), pyridine (0.035 mL, 0.44 mmol), and tetrahydrofuran (2.0 mL) were added to a 10 Example 63 mL sealed tube. The mixture was subjected to microwave radiation (300 watts, 140°C.) for 10 minutes. The solvent was Synthesis of removed and the residue was extracted with ethyl acetate (10 30 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone mL). The ex-tract was washed with saturated sodium bicar bonate solution (2x50 mL). Concentration afforded 22 mg (40%) of 1-cyclopropyl-3-ethyl-6-1-4-(methylsulfonyl) phenyl)-1H-pyrazol-5-yl)-1H-indazole. LC/MS (EI) to 4.15 (Method A), m/z 407.1 (M"+1). H NMR (CDC1) & 1.1 (m, 35 4H); 1.4 (t,3H); 2.9 (m, 2H); 3.1 (s.3H); 3.5 (m, 1H): 6.5 (s, 1H); 6.9 (d. 1H); 7.4 (s, 1H): 7.5 (d. 1H): 7.6 (d. 2H); 7.8 (s, 1H); 7.9 (d. 2H). The following compounds were made using a similar pro cedure using different starting materials: 40 106) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol 5-yl)-1-pyridin-3-yl-1H-indazole, LC/MS (EI) to 3.92 (Method C), m/z 444.2 (M"+1) 111) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol 1,3-Diethyl-1H-indazole-6-carboxylic acid methoxy-me 5-yl)-1-pyrimidin-5-yl 1H-indazole, LC/MS (EI) to 3.41 45 thyl-amide (0.22 g, 0.86 mmol) was dissolved in tetrahydro (Method C), m/z. 445.1 (M-1) furan (8 mL) and cooled to -70° C. Methylmagnesium chlo 118) 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol ride (2 mL, 3M in tetrahydrofuran, 0.06 mol) was added 5-yl)-1-pyridin-2-yl-1H-indazole, LC/MS (EI) to 5.37 dropwise and the resulting mixture was stirred for 30 minutes (Method A), m/z. 444.2 (M+1). 50 at -70° C. After warming to room temperature, the mixture was stirred for a further 3 minutes, then quenched by the Example 62 addition of a chilled Saturated Solution of ammonium chlo Synthesis of 1,3-Diethyl-1H-indazole-6-carboxylic ride. Ethyl acetate (150 mL) and water (40 mL) were then acid methoxy-methyl-amide added and the product was extracted. The aqueous layer was 55 re-extracted with ethyl acetate (75 mL). The organic layers were combined, dried, filtered, and concentrated to afford 200 mg of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone. The following compounds were made using a similar pro 60 cedure using different starting materials: O 1. 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-ethanone, 1-(3-ethyl-1H-indazol-6-yl)-ethanone, (N NN 1-1-(cyclopropylmethyl)-3-ethyl-1H-indazol-6-yl-etha - / none, 65 1-(3-ethyl-1-(2-methoxyethyl)-1H-indazol-6-yl)-ethanone, 1-(3-ethyl-1-isopropyl-1H-indazol-6-yl)-ethanone. US 7,723,348 B2 153 154 Example 64 dropwise to a solution of methyl 4-5-(1-cyclopropyl-3- ethyl-1H-indazol-6-yl)-1H-pyrazol-1-ylbenzoate (36 mg, Synthesis of (2E)-1-(1,3-diethyl-1H-indazol-6-yl)-3- 0.093 mmol) in tetrahydrofuran (4 mL) under an atmosphere (dimethylamino)prop-2-en-1-one ofargon at -78°C. The reaction was allowed to warm to room temperature with stirring over 1 hour. A further charge of methylmagnesium chloride (1.2 mL, 3M in tetrahydrofuran, 4 mmol) was added and the reaction was stirred for a further / 30 minutes. The reaction was cooled to 0°C. and a saturated 10 solution of ammonium chloride was slowly added. The mix Y N NS ture was then added to water, and the product was extracted twice with ethyl acetate. The organic layers were combined, O dried, and concentrated. The residue was purified on silica gel 1,1-dimethoxy-N,N-dimethylmethanamine (0.891 g, using a 20-50% ethyl acetate/hexane gradient to afford 12.9 0.0075 mol) was added to a solution of 1-(1,3-Diethyl-1H 15 mg (36%) of 2-4-5-(1-cyclopropyl-3-ethyl-1H-indazol-6- indazol-6-yl)-ethanone (0.187 mg, 8.64 mmol) in N,N-dim yl)-1H-pyrazol-1-yl)phenylpropan-2-ol. LC/MS (EI) to ethylformamide (8 mL), and the resulting mixture was shaken at 120° C. for 16 hours. 1,1-dimethoxy-N,N-dimethylmetha 4.30 (Method A), m/z,387.2 (M"+1). namine (0.618 g., 0.0052 mol) was added, and the reaction was refluxed at 140°C. for a further 16 hours. The solvent was Example 66 removed in vacuo, and the residue extracted with ethylacetate (30 mL) and water (10 mL). The aqueous layer was re-ex 173) 3-5-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H tracted with ethyl acetate (30 mL). The organic layers were pyrazolo 3,4-bipyridin-6-yl)-1H-pyrazol-1- combined, dried, filtered and concentrated. The resulting yl)phenol crude product was purified by Silica-gel chromatography, 25 using an eluent gradient of 0.25-0.5% methanol in dichlo romethane (mobile phase contained 0.5% ammonium hydroxide solution) to afford 35 mg of (2E)-1-(1,3-diethyl CH 1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one. The following compounds were made using a similar pro 30 cedure using different starting materials: (2E)-1-1-(cyclopropylmethyl)-3-ethyl-1H-indazol-6-yl)-3- (dimethylamino)prop-2-en-1-one, (2E)-3-(dimethylamino)-1-(3-ethyl-1-isopropyl-1H-inda Zol-6-yl)-3-(dimethylamino)prop-2-en-1-one, 35 / (2E)-3-(dimethylamino)-1-(3-ethyl-1-(2-methoxyethyl)- NN N 1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one, (2E)-1-1-(cyclopentyl)-3-ethyl-1H-indazol-6-yl)-3-(dim ethylamino)prop-2-en-1-one, (2E)-3-(dimethylamino)-1-(3-ethyl-1-isopropyl-1H 40 pyrazaol3,4-b-pyridin-6-yl)-prop-2-en-1-one, OH (2E)-3-(dimethylamino)-1-3-ethyl-1-(tetrahydro-2H-py ran-4-yl)-1H-pyrazaol3,4-b-pyridin-6-yl-prop-2-en-1- 6-1-4-(benzyloxy)phenyl)-1H-pyrazol-5-yl)-3-ethyl-1- OC. (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipyridine 45 (290 mg. 0.60 mmol) and ethanol (30 mL) were added to a Example 65 Parr bottle. 10% Pd/C (150 mg, 0.14 mmol) was added, and 129) 2-4-5-(1-cyclopropyl-3-ethyl-1H-indazol-6- the mixture was shaken under an atmosphere of hydrogen (45 yl)-1H-pyrazol-1-yl)phenylpropan-2-ol psi) for 4 hours. The reaction was degassed under reduced 50 pressure, flushed with argon for 5 minutes, filtered through Celite and concentrated to yield 0.23g 3'-5-3-ethyl-1-(tet rahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipyridin-6-yl)- 1H-pyrazol-1-yl)phenol as an oil. LC/MS (EI) to 2.87 (Method E), m/z 390.2 (M+1). "H NMR (CDC1) & 1.4 (t, 55 3H); 1.7 (m, 2H); 2.2 (m, 2H);3.0 (q,2H); 3.5 (t, 2H); 4.0 (m, 2H); 4.5 (m. 1H); 6.7-6.9 (m,3H); 7.0 (s, 1H); 7.2 (m. 1H); 7.3 (d. 2H); 7.7 (s, 1H); 8.0 (m. 1H). The following compound was prepared using a similar 60 procedure with different starting materials: 138) 3-5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H CH pyrazol-1-yl)phenol, LC/MS (EI) to 2.7 (Method E), m/z. 345.2 (M"+1) OH 65 143) 4-5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H Methylmagnesium chloride (0.09 mL, 3M in tetrahydro pyrazol-1-yl)phenol, LC/MS (EI) to 2.83 (Method E), m/z. furan, 0.3 mmol) in tetrahydrofuran (0.09 mL) was added 345.2 (M"+1) US 7,723,348 B2 157 158 wise to a solution of methyl 4-5-(1-cyclopropyl-3-ethyl-1H 0.1 nM to 10,000 nM and then plotting drug concentration indazol-6-yl)-1H-pyrazol-1-ylbenzoate (36 mg, 0.093 versus H-adenosine concentration. Prism R may be used to mmol) in tetrahydrofuran (5 mL) under an atmosphere of estimate pCso values. argon at -78°C. The reaction was allowed to warm to room Compounds of the invention show activity in the range of temperature over a period of 1 hour. The mixture was then 5 10 nMV-5000 nM IC50 in the assay. chilled to -40° C. and methanol (4 mL) was slowly added. Again, the reaction was allowed to warm slowly to room Example 71 temperature, then it was poured into a mixture of ethylacetate and water. The product was extracted (3x ethyl acetate), and Passive Avoidance in Rats, an In Vivo Test for the combined organics were dried and concentrated. The 10 Learning and Memory residue was purified by silica gel column chromatography using 50% ethyl acetate in hexanes as the eluent to afford 22.6 The test may be performed as previously described Zhang, mg (68%) of 4-5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)- H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and 1H-pyrazol-1-yl)phenyl)methanol. LC/MS (EI) to 3.19 O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198 (Method A), m/z. 359.2 (M"+1). H NMR (CDC1) & 1.0 (m, 15 204). The apparatus (Model E10-16SC, Coulbourn Instru 4H); 1.2 (t,3H); 2.5 (m, 1H); 2.8 (m, 2H); 3.2 (m. 1H); 4.5 (s, ments, Allentown, Pa.) consisted of a two-compartment 2H); 6.5 (s, 1H); 6.9 (t, 1H); 7.0–7.2 (m, 5H); 7.5 (d. 1H); 7.6 chamber with an illuminated compartment connected to a (s, 1H). darkened compartment by a guillotine door. The floor of the darkened compartment consisted of stainless steel rods Example 70 through which an electric foot-shock may be delivered from a constant current source. All experimental groups may be In Vitro Measurement of Type 4 Phosphodiesterase first habituated to the apparatus the day before the start of the experiment. During the training, the rat (Male Spraque-Daw Enzyme Preparation: ley (Harlan) weighing 250 to 350 g) may be placed in the 25 illuminated compartment facing away from the closed guil Human PDE4 was obtained from baculovirus-infected Sf9 lotine door for 1 minute before the door was raised. The cells that expressed the recombinant enzyme. The cDNA latency for entering the darkened compartment may be encoding hPDE-4D6 was subcloned into a baculovirus vec recorded. After the rat enters the darkened compartment, the tor. Insect cells (Sf9) were infected with the baculovirus and door may be closed and a 0.5 mA electric shock was admin cells were cultured until protein was expressed. The baculovi 30 istered for 3 seconds. Twenty-four hours later, the rat may be rus-infected cells were lysed and the lysate was used as Source administered 0.1 mg/kg of the test compound or saline, 30 of hPDE-4D6 enzyme. The enzyme was partially purified minutes prior to the injection of saline or test compound using a DEAE ion exchange chromatography. This procedure (dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 minutes can be repeated using cDNA encoding other PDE-4 enzymes. before the retention test starts. The rat may be again placed in 35 the illuminated compartment with the guillotine door open. Assay: The latency for entering the darkened compartment may be Type 4 phosphodiesterases convert cyclic adenosine recorded for up to 180 seconds, at which time the trial was monophosphate (cAMP) to 5'-adenosine monophosphate (5'- terminated. AMP). Nucleotidase converts 5'-AMP to adenosine. There All data may be analyzed by analyses of variance fore the combined activity of PDE4 and nucleotidase converts 40 (ANOVA); individual comparisons were made using Kew cAMP to adenosine. Adenosine is readily separated from man-Keuls tests. Naive rats required less than 30 seconds, on cAMP by neutral alumina columns. Phosphodiesterase average, to cross from the illuminated compartment to the inhibitors block the conversion of cAMP to adenosine in this darkened compartment. assay; consequently, PDE4 inhibitors cause a decrease in adenosine. 45 Example 72 Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 ul of inhibitors and incubated Radial Arm Maze Task in Rats, an In Vivo Test for for 12 minat room temperature. Final concentrations of assay Learning and Memory components were: 0.4 ug enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl, 3 uM cAMP 0.002 U 5'-nucleotidase, and 50 The test may be performed as previously described Zhang, 3x10 cpm of 3H]cAMP. The reaction was stopped by add H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and ing 100 ul of boiling 5 mM HC1. An aliquot of 75 ul of —O'Donnell, J. M., Neuropsychopharmacology, 2000, 23. reaction mixture was transferred from each well to alumina 198-204.). Five days after initial housing, rats (male Spraque columns (Multiplate; Millipore). Labeled adenosine was Dawley (Harlan) weighing 250 to 350 g) may be placed in the eluted into an OptiPlate by spinning at 2000 rpm for 2 min: 55 eight-arm radial maze (each arm was 60x10x12 cm high; the 150 ul per well of scintillation fluid was added to the Opti maze was elevated 70 cm above the floor) for acclimation for Plate. The plate was sealed, shaken for about 30 min, and cpm two days. Rats may be then placed individually in the center of Hadenosine was determined using a Packard Topcount of the maze for 5 minutes with food pellets placed close to the 96 counter. food wells, and then, the next day, in the wells at the end of the All test compounds were, dissolved in 100% DMSO and 60 arms; 2 sessions a day may be conducted. Next, four ran diluted into the assay such that the final concentration of domly selected arms may be then baited with one pellet of DMSO is 0.1%. DMSO does not affect enzyme activity at this food each. The rat may be restricted to the centerplatform (26 concentration. A decrease in adenosine concentration is cm in diameter) for 15 seconds and then allowed to move indicative of inhibition of PDE activity. This procedure may freely throughout the maze until it collected all pellets of food be used to screen compounds of the present invention for their 65 or 10 minutes passed, whichever came first. Four parameters ability to inhibit PDE4: plCso values may be determined by may be recorded: 1) working memory errors, i.e., entries into screening 6 to 12 concentrations of compound ranging from baited arms that had already been visited during the same US 7,723,348 B2 159 160 trial; 2) reference memory errors, i.e., entries into unbaited arms; 3) total arm entries; and 4) the test duration (seconds), -continued i.e., the time spent in the collection of all the pellets in the maze. If the working memory error is Zero and the average reference memory error is less than one in five successive trials, the rats may begin the drug tests. The test compound or saline may be injected 15 minutes prior to vehicle or test agent, which may be given 45 minutes before the test. Experi ments are performed in a lighted room, which contained 10 several extra-maze visual cues. All data may be analyzed by analyses of variance (ANOVA); individual comparisons were made using Kew man-Keuls tests. wherein 15 X is CH or N: The preceding examples can be repeated with similar Suc L is a single bond; C-C straight chain or branched alky cess by Substituting the generically or specifically described lene, wherein a CH2 group is optionally replaced by O. reactants and/or operating conditions of this invention for NH, NR", or S, which is unsubstituted or substituted one those used in the preceding examples. or more times by Oxo, halogen, hydroxy, cyano or com While the invention has been illustrated with respect to the binations thereof: (CH2)CONH; (CH), OCONH; production and of particular compounds, it is apparent that (CH),CON(C-alkyl); (CH),NHCO; (CH), CONHSO; (CH), SONH; (CH),SO; or (CH), variations and modifications of the invention can be made CO: without departing from the spirit or scope of the invention. n is 0 to 3: Upon further study of the specification, further aspects, 25 R is H, objects and advantages of this invention will become apparent alkyl having 1 to 8 carbon atoms, which is unsubstituted to those skilled in the art. or Substituted one or more times by halogen, Oxo, or combinations thereof wherein optionally one or more —CH2CH2— groups are replaced in each case by We claim: 30 —CH=CH or —C=C groups, cycloalkyl having 3 to 8 carbon atoms, which is unsub 1. A method for treating memory impairment in a patient stituted or substituted one or more times by halogen, comprising administering to said patient an effective amount oxo, alkyl, or combinations thereof, of a compound according to Formulas III, VI, IX or X: aryl having 6 to 14 carbon atoms, which is unsubstituted 35 or Substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, III alkylamino, dialkylamino, CO N(R'), —SO, N(R'), hydroxyalkyl, hydroxyalkoxy, 40 alkoxyalkoxy, alkoxyalkoxyalkyl, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyl Sulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, phenyl, halogenated phenyl, phenoxy, benzyloxy, acyloxy, acylamido, furanyl which is unsubstituted or 45 Substituted by halogen, C-alkyl, C-alkoxy, Cis alkoxycarbonyl, and/or benzyl, pyrrolyl which is VI unsubstituted or substituted by halogen, C-alkyl, C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, pyrazolyl which is unsubstituted or substituted by 50 halogen, Ca-alkyl, C-alkoxy, C2-s-alkoxycarbo nyl, and/or benzyl, isoxazolyl which is unsubstituted or Substituted by halogen, C-alkyl, C-alkoxy, Cs-alkoxycarbonyl, and/or benzyl, imidazolyl which is unsubstituted or substituted by halogen, 55 C-alkyl, C-alkoxy, C2-s-alkoxycarbonyl, and/or benzyl, pyridinyl which is unsubstituted or substi IX tuted by halogen, Ca-alkyl, C-alkoxy, C2-s- alkoxycarbonyl, and/or benzyl, pyrimidinyl which is unsubstituted or Substituted by halogen, C-alkyl, 60 C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, morpholinyl which is unsubstituted or substituted by C-alkyl, C-s-alkoxycarbonyl, and/or benzyl, pip eradinyl which is unsubstituted or substituted by C alkyl, C-s-alkoxycarbonyl, and/or benzyl, piperazi 65 nyl which is unsubstituted or substituted by C alkyl, C-s-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted or substituted by C-alkyl, US 7,723,348 B2 161 162 Cs-alkoxycarbonyl, and/or benzyl, alkylsulphonim alkoxycarbonyl ( C(=O)C)-alkyl) having 2 to 6 car ide, arylsulphonimide wherein the aryl portion is bon atoms; optionally Substituted by halogen, C-alkyl, C CO NRR'?: alkoxy, or combinations thereof, cycloalkyl having 3 to 4 carbon atoms, which is unsub heterocyclic group, which is Saturated, partially Satu stituted or Substituted one or more times by halogen, rated or fully unsaturated, having 5 to 10 ring atoms in oxo, alkyl, or combinations thereof, which at least 1 ring atom is an N, O or Satom, which cycloalkylalkyl having 4 to 16 carbon atoms, which is is unsubstituted or substituted one or more times by unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogen, oxo, alkyl or combinations thereof, halogenated alkoxy, nitro, methylenedioxy, ethylene 10 aryl having 6 to 14 carbon atoms, which is unsubstituted dioxy, amino, alkylamino, dialkylamino, hydroxy or Substituted one or more times by halogen, CF alkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxy OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, carbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, ethylenedioxy, amino, alkylamino, dialkylamino, arylsulfinyl, arylsulfonyl, phenyl, halogenated phe hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, nyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, 15 alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfo arylsulphonimide, aryl, oxo, acylamido, or combina nyl, phenoxy, acylamido, and acyloxy, or combina tions thereof, tions thereof, arylalkyl having 7 to 16 carbon atoms, which is unsub arylalkyl having 7 to 16 carbon atoms, which is unsub stituted or Substituted one or more times by halogen, stituted or Substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, haloge CF. OCF, alkyl, hydroxy, alkoxy, nitro, methylene nated alkoxy, nitro, methylenedioxy, ethylenedioxy, dioxy, ethylenedioxy, amino, alkylamino, dialky amino, alkylamino, dialkylamino, hydroxyalkyl, lamino, hydroxyalkyl, hydroxyalkoxy, carboxy, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, nyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfi alkylsulfonyl, phenoxy, acylamido, and acyloxy, or nyl, arylsulfonyl, phenyl, halogenated phenyl, phe 25 combinations thereof, noXy, acyloxy, acylamido, tetrazolyl, a heterocyclic group, which is saturated, partially satu alkylsulphonimide, arylsulphonimide, or combina rated or fully unsaturated, having 5 to 10 ring atoms in tions thereof and/or substituted in the alkyl portion by which at least 1 ring atom is an N, O or Satom, which halogen, Oxo, cyano, or combinations thereof, is unsubstituted or substituted one or more times by a heterocyclic-alkyl group, which is saturated, partially 30 halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, saturated or fully unsaturated, having 5 to 10 ring halogenated alkyl, nitro, oxo, amino, alkylamino, atoms in which at least 1 ring atom is an N, O or S dialkylamino, or combinations thereof, or atom, which is unsubstituted or substituted one or a heterocyclic-alkyl group, which is saturated, partially more times in the heterocyclic portion by halogen, saturated or fully unsaturated, having 5 to 10 ring alkyl, hydroxy, alkoxy, halogenated alkyl, haloge 35 atoms in which at least 1 ring atom is an N, O or S nated alkoxy, nitro, methylenedioxy, ethylenedioxy, atom, which is unsubstituted or substituted one or amino, alkylamino, dialkylamino, hydroxyalkyl, more times in the heterocyclic portion by halogen, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo aryl, alkyl, alkoxy, cyano, nyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfi halogenated alkyl, nitro, oxo, amino, alkylamino, nyl, arylsulfonyl, phenyl, halogenated phenyl, phe 40 dialkylamino, carboxy or combinations thereof and/ noxy, acyloxy, tetrazolyl, alkylsulphonimide, or Substituted in the alkyl portion by halogen, OXo, arylsulphonimide, aryl, oxo, or combinations thereof cyano, or combinations thereof; and/or Substituted in the alkyl portion by halogen, R’ is H, halogen, or alkyl having 1 to 6 carbon atoms oXo, cyano, or combinations thereof, wherein optionally one or more —CH2CH2— groups cycloalkylalkyl having 4 to 16 carbon atoms, which is 45 are replaced in each case by —CH=CH or unsubstituted or substituted one or more times by —C=C-groups and wherein the alkyl is unsubstituted halogen, Oxo, alkyl or combinations thereof, or or Substituted one or more times by halogen; alkoxyalkyl having 3 to 8 carbon atoms; R is H, halogen, alkyl having 1 to 6 carbonatoms wherein optionally one or more —CH2CH2— groups are R is H, 50 replaced in each case by —CH=CH or C=C alkyl having 1 to 6 carbonatoms, which is unsubstituted groups and wherein the alkyl is unsubstituted or Substi or Substituted one or more times by halogen, oxo, or tuted one or more times by halogen or hydroxyl, car combinations thereof wherein optionally one or more boxy, alkoxycarbonyl having 2 to 6 carbon atoms, —CH2CH2— groups are replaced in each case by —CO-alkyl having 2 to 6 carbon atoms, or phenyl: —CH=CH or —C=C groups, or 55 R" is H, alkoxycarbonyl ( C(=O)C)-alkyl) having 2 to 6 car alkyl having 1 to 8 carbon atoms, which is unsubstituted bon atoms; or Substituted one or more times by halogen, oxo or R is H, combinations thereof wherein optionally one or more alkyl having 1 to 6 carbonatoms, which is unsubstituted 60 —CH2CH2— groups are replaced in each case by or Substituted one or more times by halogen, OXo, —CH=CH or —C=C groups, or hydroxy or combinations thereof wherein optionally alkoxy having 2 to 8 carbon atoms, which is unsubsti one or more —CH2CH2— groups are replaced in tuted or Substituted one or more times by halogen; each case by —CH=CH- or —C=C- groups, R'' is H, alkoxyalkyl having 2 to 6 carbon atoms which is unsub 65 alkyl having 1 to 6 carbonatoms, which is unsubstituted stituted or Substituted one or more times by halogen, or Substituted one or more times by halogen, Oxo, or oXo, or combinations thereof; combinations thereof wherein optionally one or more US 7,723,348 B2 163 164 —CH2CH2— groups are replaced in each case by 8. A method according to claim 1, wherein R is ethyl, aryl —CH=CH or —C=C groups, or which is substituted or unsubstituted or heteroaryl which is a heterocyclic-alkyl group, which is saturated, partially Substituted or unsubstituted, and L is a single bond. saturated or fully unsaturated, having 5 to 10 ring 9. A method according to claim 1, wherein X is CH and L atoms in which at least 1 ring atom is an N, O or S is a single bond. atom, which is unsubstituted or substituted one or 10. A method according to claim 1, wherein R is ethyl, aryl more times in the heterocyclic portion by halogen, which is substituted or unsubstituted or heteroaryl which is aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, substituted or unsubstituted, L is a single bond, and X is CH. oxo, amino, alkylamino, dialkylamino, carboxy or 11. A method according to claim 1, wherein R is aryl combinations thereof and/or substituted in the alkyl 10 substituted at least once by SO. N(R'), alkoxyalkoxy, portion by halogen, Oxo, cyano, or combinations alkoxyalkoxyalkyl or benzyloxy. thereof 12. A method according to claim 1, wherein said com R’ is H, pound is of Formula III or VI, and R is alkyl having 1 to 6 alkyl having 1 to 6 carbonatoms, which is unsubstituted carbon atoms which is substituted at least once by hydroxy: or Substituted one or more times by halogen, oxo, or 15 alkoxyalkyl having 2 to 6 carbon atoms which is unsubsti combinations thereof wherein optionally one or more tuted or Substituted one or more times by halogen, oxo, or —CH2CH2— groups are replaced in each case by combinations thereof; alkoxycarbonyl having 2 to 6 carbon —CH=CH or —C=C groups, atoms; or – CO NR'R''. cycloalkyl having 3 to 8 carbon atoms, which is unsub 13. A method according to claim 1, wherein said com stituted or Substituted one or more times by halogen, pound is of Formula III, X is CH, and L is a single bond. oxo, alkyl, or combinations thereof, or 14. A method according to claim 1, wherein R is aryl a heterocyclic-alkyl group, which is saturated, partially having 6 to 14 carbon atoms which is unsubstituted or sub saturated or fully unsaturated, having 5 to 10 ring stituted with one or more halogen, cyano, nitro, amino, alkyl, atoms in which at least 1 ring atom is an N, O or S alkoxy or carboxy. atom, which is unsubstituted or substituted one or 25 15. A method according to claim 1, wherein R is cyclo more times in the heterocyclic portion by halogen, hexyl, cyclopentyl, ethyl, CH(CH), n-propyl. n-butyl, or aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, t-butyl. oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl 16. A method according to claim 1, wherein R is thiazolyl, 30 pyridyl or benzothiazolyl, which in each case is substituted or portion by halogen, Oxo, cyano, or combinations unsubstituted. thereof 17. A method according to claim 1, wherein R is benzyl, or a pharmaceutically acceptable salt thereof. methylbenzyl, tert-butylbenzyl, methoxybenzyl, dimethoxy 2. A method according to claim 1, wherein L is (CH), benzyl, carboxybenzyl, fluorobenzyl, difluorobenzyl, trifluo OCONH. 35 romethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, 3. A method according to claim 1, wherein R is aryl having nitrobenzyl, methoxycarbonylbenzyl, or phenethyl, which in 6 to 14 carbon atoms which is substituted by at least one substituent selected from —CO N(R'), aminosulfonyl, each case is Substituted or unsubstituted. furanyl which is unsubstituted or substituted by halogen, 18. A method according to claim 1, wherein R is a hetero C-alkyl, C-alkoxy, Cis-alkoxycarbonyl and/or benzyl, cyclic-alkyl group, which is saturated, partially saturated or 40 fully unsaturated, having 5 to 10 ring atoms in which at least pyrrolyl which is unsubstituted or substituted by halogen, 1 ring atom is an N, O or S atom, and which is optionally C-alkyl, C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, substituted one or more times in the heterocyclic portion by pyrazolyl which is substituted by halogen, C-alkyl, C halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, haloge alkoxy, C-s-alkoxycarbonyl, and/or benzyl, isoxazolyl nated alkoxy, nitro, amino, alkylamino, dialkylamino, which is unsubstituted or substituted by halogen, C-alkyl, C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, imidazolyl 45 hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, or combina which is Substituted by halogen, C-alkyl, C-alkoxy, tions thereofand/or optionally substituted in the alkyl portion Cs-alkoxycarbonyl, and/or benzyl, pyridinyl which is sub by halogen, oxo, cyano, or combinations thereof. stituted by halogen, C-alkyl, C-alkoxy, Cis-alkoxycar 19. A method according to claim 1, wherein when R is a bonyl, and/or benzyl, pyrimidinyl which is unsubstituted or ring Substituent it is alkyl having 1 to 3 carbon atoms, and Substituted by halogen, C-alkyl, C-alkoxy, Cis-alkoxy 50 when R is part of the -CORR'' group it is H. carbonyl, and/or benzyl, morpholinyl which is substituted by 20. A method according to claim 1, wherein said com C -alkyl, C-s-alkoxycarbonyl, and/or benzyl, piperadinyl pound is of Formula III or VI, and R is cyclopropyl. which is substituted by C-alkyl, C-s-alkoxycarbonyl, and/ 21. A method according to claim 1, wherein R7 and Rare or benzyl, piperazinyl which is substituted by C-alkyl, each H. Cs-alkoxycarbonyl, and/or benzyl, tetrazolyl which is 55 22. A method according to claim 1, wherein R7 is H, and R' unsubstituted or substituted by C -alkyl, C-s-alkoxycar is H, CH, CH5, CFs, hydroxymethyl, 2-(2-hydroxy)pro bonyl, and/or benzyl, or arylsulphonimide wherein the aryl pyl), carboxy, ethoxycarbonyl, CHCO, or phenyl. portion is Substituted by halogen or C-alkoxy. 23. A method according to claim 1, wherein said com 4. A method according to claim 1, wherein said compound 60 pound is of Formula VII or VIII, and R is F. is of Formula IX. 24. A method according to claim 1, wherein R' is H or 5. A method according to claim 1, wherein said compound alkyl having 1 to 4 carbon atoms. is of Formula III. 25. A method according to claim 1, wherein said com 6. A method according to claim 1, wherein said compound pound is of Formula IX or X, and R'' is methyl, ethyl, ethyl is of Formula VI. 65 propyl, tetrahydro-2H-pyranylmethyl, or pyrrolidinylethyl. 7. A method according to claim 1, wherein said compound 26. A method according to claim 1, wherein R' is methyl, is of Formula X. ethyl, ethylpropyl, or furylmethyl. US 7,723,348 B2 169 170 clic group, and R is aryl, arylalkyl, or heteroaryl, which in 59. A method according to claim 38, wherein said com each case is substituted or unsubstituted. pound is 3-ethyl1-isopropyl-6-1-4-(methylsulfonyl)phe 46. A method according to claim 1, wherein said com nyl)-1H-pyrazol-5-yl)-1H-pyrazolo 3,4-bipyridine, or a pound is of Formula III or Formula VI: R is CHCH: R is pharmaceutically acceptable salt thereof. tetrahydropyranyl, or pyrimidinyl; R is aryl, arylalkyl, or 5 60. A method according to claim 38, wherein said com heteroaryl, which in each case is substituted or unsubstituted; pound is 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyra and L is a single bond. zol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-b 47. A method according to claim 46, wherein R is phenyl, pyridine, or a pharmaceutically acceptable salt thereof. benzyl, pyridinyl, pyrimidinyl, pyrazolyl, or pyrrolyl, which 61. A method for achieving PDE4 inhibition in a patient in each case is Substituted or unsubstituted. 10 comprising administering to said patient an effective amount 48. A method according to claim 1, wherein said com of a compound according to Formulas III, VI, IX or X: pound is of Formula IX or Formula X, and R'' is alkyl having 1 to 6 carbon atoms, tetrahydro-2H-pyranylmethyl or pyrro lidinylethyl. III 49. A method according to claim 1, wherein said com 15 pound is of Formula IX or Formula X: R is CHCH: R'' is methyl, tetrahydro-2H-pyranylmethyl or pyrrolidinylethyl: R is phenyl which in each case is substituted or unsubsti tuted; and L is a single bond. 50. A method according to claim 10, wherein R is alkyl having 1 to 3 carbon atoms; R is alkyl having 1 to 6 carbon atoms, or a heterocyclic group; and R is aryl, alkyl, or het eroaryl group, which in each case is Substituted or unsubsti VI tuted. 51. A method according to claim 50, wherein R is 25 CHCH; R is isopropyl, tetrahydropyranyl, or pyrimidinyl: andR is phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, or pyrrolyl, which in each case is substituted or unsubstituted. 52. A method according to claim 51, wherein R is phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, or pyrrolyl, which 30 in each case is Substituted or unsubstituted by alkyl, alkoxy, halogenated alkoxy, carboxy, acetyl, cyano, halogen, —CO N(R'), aminosulfonyl, alkylsulfonyl, tetrazolyl, alkoxyalkoxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, or hydroxy. 35 53. A method according to claim 1, selected from: 3-ethyl-1-isopropyl-6-1-4-(methylsulfonyl)phenyl 1H-pyrazol-5-yl)-1H-indazole, 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol-5- yl)-1-pyrimidin-2-yl-1H-indazole, 40 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyrazol-5- yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-b pyridine, 3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1-(tetrahy dro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipyridine, and 45 pharmaceutically acceptable salts thereof. 54. A method according to claim 53, wherein said com pound is 3-ethyl1-isopropyl-6-1-4-(methylsulfonyl)phe nyl)-1H-pyrazol-5-yl)-1H-indazole, or a pharmaceutically 50 acceptable salt thereof. 55. A method according to claim 53, wherein said com pound is 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyra wherein Zol-5-yl)-1-pyrimidin-2-yl-1H-indazole, or a pharmaceuti X is CH or N: cally acceptable salt thereof. 55 L is a single bond; C-C straight chain or branched alky 56. A method according to claim 53, wherein said com lene, wherein a CH group is optionally replaced by O. pound is 3-ethyl-6-1-4-(methylsulfonyl)phenyl)-1H-pyra NH, NR", or S, which is unsubstituted or substituted one zol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-b or more times by Oxo, halogen, hydroxy, cyano or com pyridine, or a pharmaceutically acceptable salt thereof. binations thereof: (CH2)CONH; (CH), OCONH; 57. A method according to claim 53, wherein said com 60 (CH),CON(C-alkyl); (CH),NHCO; (CH), pound is 3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1- CONHSO; (CH), SONH; (CH),SO; or (CH), (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo 3,4-bipyridine, or CO: a pharmaceutically acceptable salt thereof. n is 0 to 3: 58. A method according to claim 38, wherein said com R is H, pound is 3-ethyl1-isopropyl-6-1-4-(methylsulfonyl)phe 65 alkyl having 1 to 8 carbon atoms, which is unsubstituted nyl)-1H-pyrazol-5-yl)-1H-indazole, or a pharmaceutically or Substituted one or more times by halogen, Oxo, or acceptable salt thereof. combinations thereof wherein optionally one or more US 7,723,348 B2 171 172 —CH2CH2— groups are replaced in each case by tions thereof and/or substituted in the alkyl portion by —CH=CH or —C=C groups, halogen, oxo, cyano, or combinations thereof, cycloalkyl having 3 to 8 carbon atoms, which is unsub a heterocyclic-alkyl group, which is saturated, partially stituted or Substituted one or more times by halogen, saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S oxo, alkyl, or combinations thereof, atom, which is unsubstituted or substituted one or aryl having 6 to 14 carbon atoms, which is unsubstituted more times in the heterocyclic portion by halogen, or Substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkyl, hydroxy, alkoxy, halogenated alkyl, haloge alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, nated alkoxy, nitro, methylenedioxy, ethylenedioxy, alkylamino, dialkylamino, CO N(R'), 10 amino, alkylamino, dialkylamino, hydroxyalkyl, —SO. N(R'), hydroxyalkyl, hydroxyalkoxy, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo alkoxyalkoxy, alkoxyalkoxyalkyl, carboxy, cyano, nyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfi acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkyl nyl, arylsulfonyl, phenyl, halogenated phenyl, phe Sulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, noxy, acyloxy, tetrazolyl, alkylsulphonimide, 15 arylsulphonimide, aryl, oxo, or combinations thereof phenyl, halogenated phenyl, phenoxy, benzyloxy, and/or Substituted in the alkyl portion by halogen, acyloxy, acylamido, furanyl which is unsubstituted or oXo, cyano, or combinations thereof, Substituted by halogen, C-alkyl, C-alkoxy, Cis cycloalkylalkyl having 4 to 16 carbon atoms, which is alkoxycarbonyl, and/or benzyl, pyrrolyl which is unsubstituted or substituted one or more times by unsubstituted or Substituted by halogen, C-alkyl, halogen, oxo, alkyl or combinations thereof, or C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, alkoxyalkyl having 3 to 8 carbon atoms; pyrazolyl which is unsubstituted or substituted by halogen, Ca-alkyl, C-alkoxy, C2-s-alkoxycarbo R is H, nyl, and/or benzyl, isoxazolyl which is unsubstituted alkyl having 1 to 6 carbonatoms, which is unsubstituted or Substituted by halogen, C-alkyl, C-alkoxy, or Substituted one or more times by halogen, Oxo, or 25 combinations thereof wherein optionally one or more Cs-alkoxycarbonyl, and/or benzyl, imidazolyl —CH2CH2— groups are replaced in each case by which is unsubstituted or substituted by halogen, —CH=CH or —C=C groups, or Ca-alkyl, C-alkoxy, C2-s-alkoxycarbonyl, and/or alkoxycarbonyl ( C(=O)C)-alkyl) having 2 to 6 car benzyl, pyridinyl which is unsubstituted or substi tuted by halogen, Ca-alkyl, Ca-alkoxy, C2-s- bon atoms; alkoxycarbonyl, and/or benzyl, pyrimidinyl which is 30 R is H, unsubstituted or substituted by halogen, C-alkyl, alkyl having 1 to 6 carbonatoms, which is unsubstituted C-alkoxy, C-s-alkoxycarbonyl, and/or benzyl, or substituted one or more times by halogen, oxo, morpholinyl which is unsubstituted or substituted by hydroxy or combinations thereof wherein optionally C-alkyl, C-s-alkoxycarbonyl, and/or benzyl, pip one or more —CH2CH2— groups are replaced in 35 each case by —CH=CH- or —C=C- groups, eradinyl which is unsubstituted or substituted by C alkoxyalkyl having 2 to 6 carbon atoms which is unsub alkyl, C-s-alkoxycarbonyl, and/or benzyl, piperazi stituted or Substituted one or more times by halogen, nyl which is unsubstituted or substituted by C oXo, or combinations thereof; alkyl, C-s-alkoxycarbonyl, and/or benzyl, tetrazolyl alkoxycarbonyl ( C(=O)C)-alkyl) having 2 to 6 car which is unsubstituted or substituted by C-alkyl, 40 bon atoms; Cs-alkoxycarbonyl, and/or benzyl, alkylsulphonim CO NRR'?: ide, arylsulphonimide wherein the aryl portion is cycloalkyl having 3 to 4 carbon atoms, which is unsub optionally substituted by halogen, C-alkyl, C stituted or Substituted one or more times by halogen, alkoxy, or combinations thereof, oxo, alkyl, or combinations thereof, heterocyclic group, which is Saturated, partially Satu 45 cycloalkylalkyl having 4 to 16 carbon atoms, which is rated or fully unsaturated, having 5 to 10 ring atoms in unsubstituted or substituted one or more times by which at least 1 ring atom is an N, O or Satom, which halogen, oxo, alkyl or combinations thereof, is unsubstituted or substituted one or more times by aryl having 6 to 14 carbon atoms, which is unsubstituted halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, or substituted one or more times by halogen, CF halogenated alkoxy, nitro, methylenedioxy, ethylene 50 OCF, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, dioxy, amino, alkylamino, dialkylamino, hydroxy ethylenedioxy, amino, alkylamino, dialkylamino, alkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxy hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, carbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfo arylsulfinyl, arylsulfonyl, phenyl, halogenated phe nyl, phenoxy, acylamido, and acyloxy, or combina nyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, 55 tions thereof, arylsulphonimide, aryl, oxo, acylamido, or combina arylalkyl having 7 to 16 carbon atoms, which is unsub tions thereof, stituted or Substituted one or more times by halogen, arylalkyl having 7 to 16 carbon atoms, which is unsub CF. OCF, alkyl, hydroxy, alkoxy, nitro, methylene stituted or Substituted one or more times by halogen, dioxy, ethylenedioxy, amino, alkylamino, dialky alkyl, hydroxy, alkoxy, halogenated alkyl, haloge 60 lamino, hydroxyalkyl, hydroxyalkoxy, carboxy, nated alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylsulfonyl, phenoxy, acylamido, and acyloxy, or hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbo combinations thereof, nyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfi a heterocyclic group, which is saturated, partially satu nyl, arylsulfonyl, phenyl, halogenated phenyl, phe 65 rated or fully unsaturated, having 5 to 10 ring atoms in noXy, acyloxy, acylamido, tetrazolyl, which at least 1 ring atom is an N, O or Satom, which alkylsulphonimide, arylsulphonimide, or combina is unsubstituted or substituted one or more times by US 7,723,348 B2 173 174 halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, combinations thereof wherein optionally one or more halogenated alkyl, nitro, oxo, amino, alkylamino, —CH2CH2— groups are replaced in each case by dialkylamino, or combinations thereof, or —CH=CH or —C=C groups, or a heterocyclic-alkyl group, which is saturated, partially a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or 10 oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl combinations thereof and/or substituted in the alkyl portion by halogen, Oxo, cyano, or combinations portion by halogen, Oxo, cyano, or combinations thereof thereof R’ is H, halogen, or alkyl having 1 to 6 carbon atoms R" is H, wherein optionally one or more —CH2CH2— groups 15 are replaced in each case by —CH=CH or alkyl having 1 to 6 carbonatoms, which is unsubstituted —C=C-groups and wherein the alkyl is unsubstituted or Substituted one or more times by halogen, Oxo, or or Substituted one or more times by halogen; combinations thereof wherein optionally one or more R is H. halogen, alkyl having 1 to 6 carbonatoms wherein —CH2CH2— groups are replaced in each case by optionally one or more —CH2CH2— groups are —CH=CH or —C=C groups, replaced in each case by —CH=CH or C=C cycloalkyl having 3 to 8 carbon atoms, which is unsub groups and wherein the alkyl is unsubstituted or Substi stituted or Substituted one or more times by halogen, tuted one or more times by halogen or hydroxyl, car oxo, alkyl, or combinations thereof, or boxy, alkoxycarbonyl having 2 to 6 carbon atoms, a heterocyclic-alkyl group, which is saturated, partially —CO-alkyl having 2 to 6 carbon atoms, or phenyl: 25 saturated or fully unsaturated, having 5 to 10 ring R is H, atoms in which at least 1 ring atom is an N, O or S alkyl having 1 to 8 carbon atoms, which is unsubstituted atom, which is unsubstituted or substituted one or or Substituted one or more times by halogen, oxo or more times in the heterocyclic portion by halogen, combinations thereof wherein optionally one or more aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, —CH2CH2— groups are replaced in each case by 30 oxo, amino, alkylamino, dialkylamino, carboxy or —CH=CH or —C=C groups, or combinations thereof and/or substituted in the alkyl alkoxy having 2 to 8 carbon atoms, which is unsubsti portion by halogen, Oxo, cyano, or combinations tuted or Substituted one or more times by halogen; thereof R'' is H, or a pharmaceutically acceptable salt thereof. alkyl having 1 to 6 carbonatoms, which is unsubstituted 35 or Substituted one or more times by halogen, oxo, or k k k k k