AU778531B2 - Substituted 8-arylquinoline phosphodiesterase-4 inhibitors - Google Patents

Substituted 8-arylquinoline phosphodiesterase-4 inhibitors Download PDF

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AU778531B2
AU778531B2 AU23362/01A AU2336201A AU778531B2 AU 778531 B2 AU778531 B2 AU 778531B2 AU 23362/01 A AU23362/01 A AU 23362/01A AU 2336201 A AU2336201 A AU 2336201A AU 778531 B2 AU778531 B2 AU 778531B2
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c6alkyl
phenyl
aryl
methylsulfonyl
rule
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Denis Deschenes
Daniel Dube
Michel Gallant
Yves Girard
Patrick Lacombe
Dwight Macdonald
Anthony Mastracchio
Helene Perrier
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Merck Canada Inc
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Merck Frosst Canada and Co
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Description

WO 01/46151 PCT/CA00/01559 TITLE OF THE INVENTION SUBSTITUTED 8-ARYLQUINOLiNE PHOS-HOD'IESTERASE-4 IN"IBITORS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention is directed to compounds that are substituted 8arylquinolines. In particular, this invention is directed to substituted 8-arylquinolines which are phosphodiesterase-4 inhibitors wherein the aryl group at the 8-position contains a substituent substituted-alkenyl group.
RELATED BACKGROUND Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases are a family of enzymes that metabolize 5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 ("PDE4", also known as "PDE-IV"), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel antiasthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four -1- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly tie specific PrDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C.Burnouf et al., ("Burnouf'), Ann. Rep. In Med. Chem., 33:91-109(1998). B.Hughes et al., Br. J.Pharmacol., 118:1183-1191(1996); M.J.Perry et al., Cell Biochem.
Biophys., 29:113-132(1998); S.B.Christensen et al., J.Med. Chem., 41:821-835(1998); and Burouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M.D.Houslay et al., Adv. In Pharmacol., 44:225-342(1998) and D.Spina et al., Adv. In Pharmacol., 44:33- 89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
International Patent Publication W09422852 describes quinolines as PDE4 inhibitors.
A.H.Cook, et al., J.Chem. Soc., 413-417(1943) describes gammapyridylquinolines. Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al., J.Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J.Am. Chem. Soc., 114(17):6940- 6941(1992).
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Patent Nos.
5,679,712, 5,693,672 and 5,747,541describe substituted benzoylguanidine sodium channel blockers, U.S. Patent No. 5,736,297 describes ring systems useful as a photosensitive composition.
U.S. Patent Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 -2- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Patent No.
5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Patent No.
,5 1'27 A -r1- DTET7 +tii-+trs A4-4 Tla.n -ar4 1 drvt iv T Q IJ., 4 I JO LJlfi Lt±.r 11fL± «SJL O L LII AL L, i j IJbJLaL tl.a U UII J tl tl V ,a 'I VbJO. I .tA..
Patent No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Patent No. 5,780,478 describes PDE4 inhibitors that are tetrasubstituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Patent No.
5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
However, there remains a need for novel compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.
SUMMARY OF THE INVENTION The present invention is directed to novel substituted 8-arylquinolines that are PDE4 inhibitors, wherein the aryl group at the 8-position is substituted by a substituted-alkenyl group. This invention also provides a pharmaceutical composition which includes an effective amount of the novel substituted 8-arylquinoline and a pharmaceutically acceptable carrier. This invention further provides a method of treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic -3- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour g n, n AAA -o a IIG~c ~V.l Lautl D y UiC. awl1iniouatlarU 1 an cLi(&ICA-, tI V V amount of the novel substituted 8-aryiquinoline or a precursor compound which forms in vivo the novel substituted 8-aryiquinoline.
BRIEF DESCRIPTON OF THE DRAWINGS Fig. 1 is a chemical schematic drawing of the general structure of the compounds of the present invention.
Fig. 2 is a graph of Counts against 'Theta for an X-ray Powder Diffraction of the Form A polymorph of the benzenesulfonic acid salt of 641l-methyl- 1 -(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1 ,2,4-oxadiazol-5-yl]-2-14- (methylsulfonyl)phenyljethenyl]phenyl]quinoline.
Fig. 3 is a graph of Counts against 'Theta for an X-ray Powder Diffraction of the Form B polymorph of the benzenesulfonic acid salt of 6-I -methyl- I -(methylsulfonyl)ethyl]-8- [3-[(E)-2-[3-methyl- 1,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenylllphenyllquinoline.
Fig. 4 is a comparison of the X-ray Powder Diffractions of the Form A polymorph (bottom trace) and the Form B (upper trace) of the benzenesulfonic acid salt of 6-[1-methyl-1 -(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1I,2,4-oxadiazol-5yl]-2-[4-(methylsulfonyl)phenyl]ethenyllphenyljquinoline.
Fig. 5 is a graph of the distinguishing feature peaks of the X-ray Powder Diffraction of the Form A polymorph of the benzenesulfonic acid salt of 1 methyl-1-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl- 1,2,4-oxadiazol-5-yl]-2-[4- (methylsulfony])phenyllethenyljphenyllquinoline.
-4- SUBSTITUTE SHEET (RULE 26) .vco1sY Fig. 6 is a graph of the distinguishing feature peaks of the X-ray Powder Diffraction of the Form B poiymorph of the benzenesulfonic acid salt of 6-[1methyl-i -(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1I,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl)ethenyl~phenyl~quinoline.
DETAILED DESCRIPTON OF THE NVENTION A compound of this invention is represented by Formula S,
S
2
NX
S
3
(I)
or a pharmaceutically acceptable salt thereof, wherein SI, S2, and S3 are independently H, -OH, halogen, -CI-C6alkyl, -N02, -CN, or -Cl-C6alkoxy, wherein the alkcyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a H, OH, halogen, carbonyl, or -Cl-C6alkyl, -cYCloC3-C6alkyl, -C2-C~alkeny1, -C I-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C1 -C6alkylamino, -(Cj -C6alkyl)(C i-C6alkyI)anhino, -Ci -C6alkyl(oxy)C j-C~alkyI, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNH(CI -C6alkyI), -C(O)N(C0-C6alkyl)(C0-C6alkyl), -NH-SOn-(Ci -C6alkyl), -SOn-(CI -C6alkyl), -(Cj -C~alkyl)-O-C(CN)-dialkylamino, or -(Cl-C~alkyl)-SOn-(CI-C6alkyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -Ci -C~alkyl, -cyclOC3-C6alkyl, -C(O)(heterocyclOC3-C6alkyl), -C(O)-O-(CO-C~alkyI), -C(O)-aryloxy, -Ci -C6alkoxy, WO 01/46151 WO 01/615 1PCT/CAOO/01559 -(CO-C~alkyl)(CO-C6aIkyI)amino, cycloalkyloxy, acyl, acyloxy, -cYcloC3-C6alkyl, heterocycloC3-C6alkcyl, aryl, heteroaryl, carbonyl, carbainoyl, or -SOn-(C1 -C6alkyl); A is CHI. C-ester. or C-F4; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -CI-C6alkyl, heterocycloC 3 -6alkyI, -Cl-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(Ci -C6alkyl)-SOn-(C1-C6alkyl), -C(O)N(CQ-C6alkyl)(CO-C6alkyl), or -Cl-C6alkylacylamino group, wherein any of the groups is optionally substituted with substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alky], -NHi-cycloC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Cl-C6alkoxy, -Cl-C~alkyl, -cYclOC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyl);I one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optionally connected by a thio, oxy, or (Cl-C4alkyl) bridge to form a fused three ring system; R4 is an aryl, -Cl-C6alkyl, heteroaryl, -CN, carbonyl, carbamnoyl, -(Ci -C6alkyl)-SOn-(CL-C6alkyl), -CqO)N(CO-C6akyl)(CO-C6alkyl), or -C I-C~alkylacyl amino group, wherein any of the groups is optionally substituted with substituents, wherein each substituent is independently a carbonyl, -CN, halogen, -C(O)(CO-C6alkyl), -C(O)O(CO-C6alkyl), -Cl-C6alkyl, -SOn-(Cl-C6alkyl), -OH, C1-C6alkoxy, or -(CO-C6alkyl)(CO-C6allcyl)an-lino, group; n is independently 0, 1, or 2; and R2 or R3 may optionally be joined to R4 by a bond to form a ring.
In one aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein -6- SUBSTITUTE SHEET (RULE 26) Si1, S2, and S3 are independently H, -OH, halogen, -C I-C6alkyl, -N02, -CN, or -Ci-C6alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; Ri is a H, OH, halogen, carbonyl, or -Cl-C6alkyl, -cycloC3-C6alkyl, -C2-C6alkenyl, -Cl-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci -C6alkylamino, -(Ci -C6alkyl)(Ci -C6alkyl)amino, -CI -C6alkyl(oxy)C 1-C6alkyl, -C(O)N}I(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNII(heteroaryl), -SOnNH(C I-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), -NH-SOn-(Ci -C6alkyJ), -SOn-(Cl-C6alkyl), -(Ci-C6alkyl)-O-C(CN)-dialkylami no, or -(CI-C6aIkyl)-SOn-(C1-C6akyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -Ci -C6alkyl, -cYcloC3-C6alkyl, -C(O)(heterocyclOC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-aryloxy, -Cj -C6alkoxy, -(CO-C6alcyl)(Co- C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6aikyl, heterocycloC3- C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(Cl-C6alkyl); A is CH; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C1-C6alkyl, heterocYloC 3 6 alkyl, -Cl-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(Ci -C6alkyl)-SOn-(C I-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), or -Cl-C6alkylacylamino group, wherein any of the groups is optionally substituted with substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -CI-C6alkyl, -SOn-(CI-C6alkyl), -SOn-(arYl), -aryloxy, -heteroaryloxy, Ci -C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyI, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)anmino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C1-C6alkoxy, -C1-C6alkyl, -cyclOC3-C6alkyl, -ai-yloxy, -C(O)OH, -C(O)O(CI-C6alkyJ), halogen, -N02, -CN, -SOn-(CI-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyl); one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; -7- WO 01/46151 WO 01/615 1PCT/CAOO/0 1559 when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optionally connected by a thio, oxy, or (C I-C4alkyl) bridge to form a fused three ring system; and n is independently 0, 1, or 2.
Iii one embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, whcrein Si1, S2, and S3 are independently H, -OH, halogen, -Cl-C6alkyl, -N02, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; R1 is a -C1-C6Alyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, a-CN, -C(O)(hcterocycloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, hctcrocYcloC3-C6alcyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(Cl-C6alkyl), -(CO-C6alkYl)(CO-C6alkyl)am-ino; A is CH; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Cl-C6alkyl, hcterocyloC 3 6 alkyl,-Cl-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C
1 -C6alkyI)-SOn-(C j-C6alky]), -C(O)N(CO-C6alkyl)(CO-C6alkyl), or -Cl-C6alkylacylamino group, wherein any of the groups is optionally substituted with substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -0-aryl, -0-heteroaryl, Cl-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cyclOC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyI)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Ci -C6alkoxy, -Cl-C6alkyl, -cYcloC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(Cl-C~alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(CO-C6alkyI)(CO-C6alkyl); SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 one of R2 and R3 must be an aryl or Iheteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be system; n is independently 0, 1, or 2.
In anothcr embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyI, -N02, -CN, or -Cl-C~alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a -cYcloC3-C6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alcyl), -C(O)-O-(CG-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6a~kyl, heterocyclOC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, Or -SOn-(C I-C6alkyI); A is CH; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Cl-C6alkyl, heterocyloC 3 6 alkyl,-Cl-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(CI-C6aIkYl)-S~n-(C1-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyI), or -Cl-C6alkylacylamino group, wherein any of the groups is optionally substituted with substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -S~n-(CI-C6alcyl), -SOn-(aryl), -0-aryl, -0-heteroaryl, Cl-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NIH-cycloC3-C6alkyl, amino, -OH, or -(C0-C6alkYl)(C0-C6alkyI)axnino, -C(O)-N(Co-C6alkyl)(C0-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Cl-C6alkoxy, -Cl-C6alkyl, -cyclOC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -S~n-(C1-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyl); -9- SUBSTITUTE_ SHEET (RULE 26) one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optionally connected by a thio, oxy, Or (CL-C4alkyl) bridge to form a fused three ring system; and n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein Si1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl, -NO2, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; R1 is a -C2-C6alkenyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(C0-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3 -C6alkyl, heterocyclOC3-C6a~kyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(Cl-C6alkyl); A is CH; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci -C~alkyl, heterocylOC3- 6 alkyl,-C j-C~alkoxy, carbonyl, carbamoyl, -C(O)OH, -(Ci -C6alkyl)-S~n-(C jj-C~alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), or -CI-C6alkylacylamino group, wherein any of the groups is optionally substituted with substituients, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -SOn-(C1-C6alkyI), -SOn-(aryl), -0-aryl, -0-heteroaryl, Ci -C6alkoxy, N-oxide, -C(O)-heterocyclOC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amnino, -C(O)-N(C0-C6alkyl)(C0-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Cj -C6alkoxy, -Ci -C6alkyl, -cYcloC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(CI-C6alkyl), halogen, -NO2, -CN, -SOn-(CI-C6a]kyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyl); WO 01/46151 WO 0146151PCTICAOOO 1559 one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be -rinpl co nete byf 1 AfS~~ aJA* thi.i *oA-fl b L system; n is independently 0, 1, or 2.
In another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein Si1, S2, and S3 are independently H, -OHK halogen, -CI-C6alkyl, -N02, -CN, or -Cl-C~alkoxy, wherein said alkyl. and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a heteroaryl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocyclOC3- Cialkyl), -C(O)-O-(Co-C6alkyl), -C(O)-O-aryl, alkoxy, cycloallcyloxy, acyl, acyloxy, -cyclOC3-C6alkyl, heterocyclOC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamnoyl, or A is CH; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C l-C6alkyl, heterocyloC 3 6alkyl,-Cl1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, 1-C6alkyl)-SOn-(G l-C6alkyl), -C(O)N(CO-C~alkyl)(CQ-C6alkyl), or -Cl-C6alkylacylaflino group, wherein any of the groups is optionally substituted with substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -CI-C~alkyl, -SOn-(C1-C6alkYl), -SOn-(aryl), -aryloxy, -0-heteroaryl, CI-C~alkoxy, N-oxide, -C(O)-heterocyclOC3-C6alkyl, -NI{-cycloC3-C6alkyl, amino, -OHL or -(CO-C~alkyl)(CO-C6alkyI)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyI) substituent group, wherein each substituent group independently is optionally substituted with -OH, C l-C6alkoxy, -Cl-C~alkyl, -cyclOC3-C6alkyl, -aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(CO-C6a~kyl)(CO-C6alkyl); SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be upLiunaily cuieied by a tlwo, xy, of(%rjj Uju,_L viiaxaA n iir system; n is independently 0, 1, or 2.
In still another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein Si1, S2, and S3 are independently H, -OH, halogen, -C I-C~all, -N02, -CN, or -Cl-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a an -amino, -Cl-C6alkylamino, or
-(C
1 -C6alkyl)(C1-C6alkyl)amino group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6a~kyl, heterocyclOC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C I-C6alkyl); A is CH; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci -C6alkyl, heterocyloC 3 -6alkyl,-C l-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(Ci -C6alkyl)-SOn-(C j-C6alkyl), -C(O)N(CO-C~alky1)(CO-C6alkyl), or -Cl-C~alkylacylamino group, wherein any of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-C6alkoxy, N-oxide, -C(O)-heterocYcloC3-C6alkyl, -NI{-cYcloC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6a~kYl)amnino, -C(O)-N(CO-C6alkYl)(CO-C6alkYl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C 1-C6alkoxy, -CI1-C6alkyI, -cYclOC3-C6alkyl, -aryloxy, -C(O)OH, 12 SUBSTITUTE SHEET (RULE 26) MC015Y -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(CI-C6alkyl), or -C(O)-N(CO-C6alkyJ)(CO-C6alkyl); one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optional-ly connected by a thio, oxy, or (CI-C4alkyl) bridge to form a fused three ring system; n is independently 0, 1, or 2.
In an embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein Si1, S2, and S3 are independently H, -OH, halogen, -C I-C6alkyl, -N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a -Cl-C6alkyl, -cycloC3-C6alkyl, -C2-C6alkenyl, -Cl-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci -C6alkylamino, -(Ci -C6alkyl)(C 1-C6alkyl)amino, -Ci -C6alkyl(oxy)C 1-C6alkyl, -C(O)NH(aryl), -C(O)NIH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNH(CI1-C6alkyl), -C(O)N(CO-C~aikyl)(CO-C6alkyl), -NI{-SOn-(C I-C6alkyl), -SOn-(C1 -C6alkyl), -carbamoyl, -(Ci1 -C~alkyl)-O-C(CN)-dialkylamino, or -(CjI -C6alkyl)-SOn-(C I1 C6aikyl) group, wherein any of the groups is optionally substituted with substituents; wherein each substituent is independently a halogen, -OH, -CN, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbarroyl, or -SOn-(C I -C6alkyl); A is CH; R2 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Ci -C6alkyl, -SOn-(C I-C6alkyl), -SOn-(aiyl), -aryloxy, -0-heteroaryl, Ci C6aikoxy, N-oxide. -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amnino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally 13 substituted with -OH, Cl-C6alkoxy, -Cj-C6a~kyI, -cycloC3-C6alkyl, -aryloxy, -C(O)OH, -C(O)O(Cl-C6alkyi), halogen, -N02, -CN, -SOn-(CI-C6a~kyl), or -C(O)-N(CO-C6alkyI)(CO-C6alkyl); R3 is a heteroaryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl~-C6alkyl, -SOn-(C1 -C6alkyI), -SOn-(aryl), -aryloxy, -0-heteroaryl, Ci -C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyI, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, CI-C6alkoxy, -Cl-C6alkyl, -cycloC3-C6alkyl, -aryloxy, -C(O)OH, -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(CI-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyJ); and n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceuti cally acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -C I-C6alkyl, -N02, -CN, or -CI-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a halogen, carbonyl, -Cl-C6alkyl, -cYcloC3-C6alkyl, -C2-C6alkenyl, -Cl-C6alkoxy, ary), heteroaryl, -CN, -heterocyclOC3-C6alkyl, -amino, -Ci -C~alkylamino, -(CI -C6alkyl)(C1 -C6alkyI)amino, -Ci -C6alkyl(oxy)ClI-C6alkyI, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNI{(heteroaryl), -SOnNH(C 1-C6alkyl), -C(O)N(CO-C6akyl)(CO-C6alkyl), -NK-SOn-(C I-C6alkyl), -SOn-(C 1-C6alkyl), -carbamoyl, -(CI -C~alky1)-O-C(CN)-dialkylamrino, or -(C1-C6alkYl)-SOn-(CL-C6alkyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C6aIkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alky), aryl, heteroaryl, carbonyl, carbarnoyl, or -SOn-(C I-C6alkyl); -14- MC015Y A is CH; R2 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -SOn-(C1-C6alkyl), -Sn-(aryl), -aryloxy, -0-heteroaryl, Cj- C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyI, amino, -OH, or -(CO-C6a~kYl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, CI-C6alkoxy, -CI-C6alkyI, -cycloC3-C6alkyl, -aryloxy, -C(O)OH, -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(CJ-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyI); R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alky1, -SOn-(CI-C6alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, Cj- C6alkoxy, N-oxide, -C(O)-heterocyclOC3-C6alkyl, -NH-cyclOC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Cl-C6alkoxy, -CI-C6alkyl, -cycloC3-C6alkyl, -aryloxy, -C(O)OH, -C(O)O(C1-C6alkyI), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(CQ-C6alkyl)(CO-C6alkyl); and n is independently 0, 1, or 2.
In still another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein S1, S2, and S3 are independently H, -OH, halogen, -Cl-C6alkyl, -N02, -CN, Or -Cl-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; .R1 is a halogen, carbonyl, -CI-C6alkyl, -cYcloC3-C6alkyl, -C2-C6alkenyl, -CI-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci -C6alkylamino, -(CI -C6alkyl)(CI1-C6alkyl)am-ino, -C1 -C6alkyl(oxy)CI1-C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNIH(aryl), -SOnNH(beteroaryl), eoo1 WO 01/46151 WO 01/615 1PCT/CAOO/01559 -SOnNI{(C 1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), -NII-SOn-(Ci -C6alkYl), -SOn-(CI -C6alkyl), -carbamoyl, I -C~al kyl)-O-C(CN)-di alkyl amino, or Srop,v.,hein any o grussc-tonl substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocYcloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cYcloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamnoyl, or -SOn-(CI-C6alkyl); A is CH; R2 is a carbonyl, optionally substituted with I substituent, wherein the substituent is an, aryl, heteroaryl, -C(O)OH, carbonyl, -Cl-C6alkyl, -0-aryl, -O-heteroaryl, 1-C6alkyI), -heterocycloC3-C6alkyl, -NH-cYcloC3-C6alkyl, amino, -OH, or -(CO-C6allyl)(CO-C6allcyl)amino, substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(C1-C6alkyl), -CI-C6alkyl, -cYcloC3-C6alkyl,*-O(aryl), -C(O)OH, -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(C I-C6alkyl), -cYcIoC3-C6alkyI or -C(O)-N(CO-C6alkyl)(Co-C6alkyl); R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, Ci- C6alkoxy, N-oxide, -C(O)-heterocYclOC3-C6akyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)am-ino, -C(O)-N(CO-C6alcYl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Cl-C6alkoxy, -Cl-C6alkyl, -cYclOC3-C6alkyl, -aryloxy, -C(O)OH, -C(O)O(Cl-C6a~kyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyl); and n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein Si1, S2, and S 3 are independently H, -OH, halogen, -C 1-C6alkyl, -NO2, -CN, or -CI-C6atkoxy, wherein said alkyl and alkoxy groups are optionally 16 SUBSTITUTE SHEET (RULE 26) MlC.OI1 substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a halogen, carbonyl, -Cl-C6alkyl, -cYcloC3-C6alkyl, C2C~aiU1y, -Cj -C6-31- xy, aiyi, heieroaryl, -CN, -heterocycIOC3-C6alkyl, -amino, -C1 -C6alkylamino, -(Ci -C6alkyl)(C i-C6alkyl)anuno, -CI -C6a~kyl(oxy)CI -C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNH(Cj -C6alkyl), -C(O)N(Co-C6alkyl)(CO-C6alkyl), -NH-SOn-(CI -C6alkyl), -SOn-(Cl~-C6alkyl), -carbamoyl, -(CI -C6alkyl)-O-C(CN)-dialcylamino, or -(Ci -C6alkyl)-SOn-(C1-C6alkyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(Ci-C6alkyl); A is CH; R2 is a carbamoyl, optionally substituted with 1-2 substituents, wherein each substituent is independently a carbonyl, -CN, -Cl-C6alkyl, -SOn-(Cl- C6alkyl), -0-aryl, -0-heteroaryl, -C(O)-heterocycloC3-C6alkyl, -NI{-cyclOC3-C6alkyl, amino, -OH, Or -C1 -C6alkyl (amino) substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(CI-C6alkyl), -O(aryl), -COOH, -COO(Cjl-C6alkyl), halogen, -N02, -CN, or -C(O)-N(CO-C6alkyI)(CO-C6alkyl); R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -SOn-(CI-C6alkyl), -SOn-(aiyl), -aryloxy, -0-heteroaryl, Cj- C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NHi-cycloC3-C6alky], amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Ci-C6alkoxy, -Cl-C6alkyl, -cycloC3-C6a~kyl, -aryloxy, -C(O)OH, -C(O)O(C1-C6alkyI), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(CO-C6alkyl)(CO-C6alkyl); and n is independently 0, 1, or 2.
-17- .M 1IY In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein S1, S2, and S3 are independently H, -OH, halogen, -CI-C6alkyl, -N02, CN, or-- "-ixy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a halogen, carbonyl, -CI-C6alkyl, -cYClOC3-C6alkyl, -C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocyclOC3-C~alkyl, -amino, -C1 -C6alkylamino, -(Cj -C6alkyl)(CI -C6alkyl)amnino, -Cj -C6allcyl(oxy)Cj1-C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNIH(heteroaryl), -SOnNIH(CI1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C~alkyl), -NIH-SOn-(C 1-C6alkyl), -SOn-(CI1-C6alkyl), -carbamoyl, -(C 1 -C6alkyl)-O-C(CN)-dialkylamino, or -(CjI-C6aIcYl)-SOn-(C1-C6alkyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C~alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alcY], aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl); A is CH; R2 and R3 are each independently an aryl, optionally substituted, connected to each other by a thi o, ox y, or (C I-C4alkyl) bri dge to form a fused three ring system; and n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention is represented by Formula (ii) or a pharmaceutically acceptable salt thereof, wherein SI, S2, and S3 are independently H, -OH, halogen, -Cl-C6alkyl, -N02, -CN, or -CI-C6alkoxy; RI is a halogen, carbonyl, -Cl.-C6alkyl, -cycloC3-C6alkyl, -C2-C6alkenyl, -C1 -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3 -C6alkyl, -amino, -Ci -C6alkylamino, -(CI -C6alkyl)(Cj1-C6alkyl)axnino, -C1 -C6alkyl(oxy)Cj1-C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNIH(Cj1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C~alkyl), -NH-SOn-(CI1-C6alkyl), -18- LO L 06 WO 01/46151 WO 0146151PCT/CAOO/01559 -SOn-(C 1-C6alkyl), -carbamoyl, l-C6alkyl)-O-C(CN)-dialkylailo, or -(C1-C6alkYl)-SOn-(C1-C6alkYl) group, wherein any of the groups is optionally Subusdututrld wiUI 1-5 suUbUsiWnis wherein each substituent is independently a halogen, -CN, -C(O)(heterocYcloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -CYClOC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(Cl-C6alkyl); A is CH; R2 is a -(C1-C6alkyI)-S~n-(Cl-C6alkyl), optionally substituted with substituents, wherein each substituent is independently a halogen, -N02, -COOH, carbonyl, -CN, -CI-C~a~kyl, -SOn-(C1-C6alkyl), -0-aryl, -0-heteroaryl, -C(O)-heterocycloC3-C6aIkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -CI-C6alkyl(amino) substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(C1-C6alkyl), -O(aryl), -COOH, -COO(C 1-C6alkyl), halogen, -NO2, -CN, or -C(O)-N(CO-C6alkyl)(Co-C6alkyl); R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OK, carbonyl, -CN, -Cl-C~alcyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, Ci- C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cyclOC3-C6alkyl, amino, -OH, or -(CO-C~alky1)(CO-C6a~kyl)amino, -C(O)-N(CO-C~a~ky1)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C 1-C6alkoxy, -Cl-C6alkyl, -cycloC3-C6alcyl, -aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), Or -C(O)-N(CO-C6alkyl)(CO-C6akyl); and n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein Si1, S2, and S3 are independently H, -OH, halogen, -C I-C6alkyI, -N02, -CN, or -CI-C6allcoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; 19 SUBSTI TUTE SHEET (RULE 26) RI is a halogen, carbonyl, -Cl-C6alkyl, -CYCIOC3-C6alkyl, -C2-C6alkenyl, -CI-G6akoxy, aryl, heteroaryl, -CN, -heterocycJoC3-C6a~kyI, -amino, -C(O)NH(ary)), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -S~nNli(CI-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C 6 alkyl), -NH-SOn-(Cj -C6alkyI), -S~n-(C1-C6alkyl), -carbamoyl, 1-C6alkyl)-O-C(CN)-dialkylamrino, or 1-C6atkyl)-S~n-(CI-C6alcyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(C0-C6alkyl), -C(O)-O-ary], alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocYcloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl. or -S~n-(Ci -C6alkyI); A is CH; R2 is a -C(O)N-(CO-C6adkyI)(CO-C 6 alkyl), optionally substituted with substituents, wherein each substituent is independently a halogen, -N02, -COOH, carbonyl, -CN, -Cl-C6alkyl, -S~n-(Cl-C6alkyl), aryloxy, -heteroaryloxy, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-Calkyl, amnino, -OH, or -Cl-C6alkyl(amino) substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(C I-C6alkyI), -O(aryl), -COOH, -COO(CI-C6alkyl), halogen, -N02, -CN, or -C(O)-N(CO-C6alkyl)(CO-C6alkyl); R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbony), -CN, -CI-C6alkyl, -S~n-(Cl-C6alkyI), -SOn-(ary]), -aryloxy, -0-heteroaryl, Cj- C6alkoxy, N-oxide, -C(O)-heterocyclOC3-C~alkyl, -NI--cyclOC3-C6alkyI, amino, -OH, Or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alky)(C0-C 6 alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C1-C6alkoxy, -Cl-C6alkyl, -cYclOC3-C~alkyl, -aryloxy, -C(O)OH, -C(O)O(CI-C6alkyJ), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(Co-C6alkyl)(CO-C6alkyl); and n is independently 0, 1, or 2.
20- -01
V
N1 CO! In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein S 1, S2, and S3 are independently H, -OH, halogen, -C1 -C6alkyl, jtWJIavI i aialyi d d1iKoAy groups are opuonanly substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; RI is a halogen, carbonyl, -Cl-C6alkyl, -cYcloC3-C6alkyl, -C2-C~alkenyl, -Ci-C6alloxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci -C~alkylanhino, 1 -C6alkyl)(C1 -C6aIkyl)amino, -C1 -C6alkyl(oxy)Cl1-C6alkyl, -C(O)NIH(aryl), -C(O)NI{(heteroaryl), -SONH(arl), -SOnNH(heteroaryl), -SOnNH(C 1-C6all), -C(O)N(CO-C6alkyl)(CO-C6alkyl), -NH-SOn-(Ci -C6alkyl), -SOn-(C l-C6alkYl), -carbamoyl, -(Ci -C6alkyl)-O-C(CN)-dialkylamino, or -(Cl-C6alkyl)-SOn-(Cl-C6alkyl) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocYCloC3-C6alkyI, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1 -C6alkyl); A is CH; R2 is-CN; R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Ci -C6allcyl, -SOn-(C 1-C6alkyl), -SOn-(aryl), -aryloxy, -O-heteroaryl, C1- C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH. or -(CO-C~alkyl)(CO-C6alkyl)amino, -C(O)-N(CQ-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, CI-C6alkoxy, -Cl-C6alkyl, -cycloC3-C6alkYl, -aryloxY, -C(O)OH, -C(O)O(CI -C6alkyl), halogen, -N02, -CN, -SOn-(CI -C6alkyl), or -C(O)-N(CO-C6alkyl)(Co -C6alkyl); and n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein -21- WO 01/46151 WO 0146151PCT/CAOO/01559 Si1, S2, and S3 are independently H, -01HL halogen, -Cl-C6alkyl, -N02, -CN, or -Cl-C6alkoxy, wherein said alkyl and alkoxy groups are optionally or OH; RI is -C1-C6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -Cl-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-aryloxy, -C1-C6alkoxy, -(CO-C6alkyl)(CO-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cYcloC3-C6alkyl, heterocyclOC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyI); A is CH, R2 and R3 each independently is an aryl or heteroaryl, wherein each is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(Cl-C~alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, Cl-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cyclOC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)anhino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, Cl-C~alkoxy, -C1-C6alkyl, -cyclOC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(Cj-C6alkyl), or -G(O)-N(GO-C6alkYI)(CO-C6alkYl); R2 and R3 may be optionally connected by a thio, oxy, or (CGI-C4alkyl) bridge to form a fused three ring system; and n is independently 0, 1, or 2; In yet another embodiment of this aspect, a compound of this invention is represented by Formula or a pharmaceutically acceptable salt thereof, wherein S1, S2, and S3 are each H; RI is -Cl-C6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -CI-C6alkyl, -cyclOC3-C6a~kyI, -C(O)(heterocycloC3-C6alkyJ), -C(O)-O-(CO-C6alkyl), 22 SUBSTIT-1UT1E SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 -C(O)-aryloxy, -Cl-C6alkoxy, -(CO-C6alkyl)(CO-C6alkyl)amiflo, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamnoyi, or-SOn-(Ci-C6aiy) A is CH, R2 and R3 each independently is an aryl or heteroaryl, wherein each is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -SOn-(C i-C6alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, Ci -C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(CO-C6alkyl)(CO-C6alkyl)amlflo, -C(O)-N(CQ-C~alkyl)(CO-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C I -C6alkoxy, -C I -C6alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or -C6alkYl)(CO-C6alkYl); R2 and R3 may be optionally connected by a thio, oxy, or (Cl-C4alkyl) bridge to form a fused three ring system; and n is independently 0, 1, or 2; As used herein, "alkyl' as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. '"Akenyl", "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond.
The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems.
Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- 23 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 tetrahydronaphalene and the like. Similarly, "cycloalkenyl" means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocyc, s, as -well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
The term "cycloalkyloxy" unless specifically stated otherwise includes a cycloalkyl group connected to the oxy connecting atom.
The term "alkoxy" unless specifically stated otherwise includes an alkyl group connected to the oxy connecting atom.
The term "aryl" unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.
The term "aryloxy" unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl, connected through the oxy connecting atom to the connecting site.
Ther term "Co-C6alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent or a direct bond depending on whether the alkyl is a terminus or a bridging moiety.
The term "hetero" unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a is a five membered ring containing from 5 to no carbon atoms.
Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.
The term "heteroaryloxy" unless specifically stated otherwise describes a heteroaryl group connected through an oxy connecting atom to the connecting site.
Examples of heteroaryl(Ci-6)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, -24- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, Priid 11wrlJ ictyli, pyranlmeyll, quini1olinylmety, iS y quinoliiyiiiieihy and quinoxalinylmethyl.
Examples of heterocycloC3.yalkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
Examples of aryl(C 1 -)alkyl include, for example, phenyl(C 1 6 )alkyl, and naphthyl(C 1 .6)alkyl.
Examples of heterocycloC 3 -7alkylcarbonyl(Ci.6)alkyl include, for example, azetidinyl carbonyl(CI.
6 )alkyl, pyrrolidinyl carbonyl(Cj.)alkyl, piperidinyl carbonyl(C 1 6 )alkyl, piperazinyl carbonyl(CI-)alkyl, morpholinyl carbonyl(CI-)alkyl, and thiomorpholinyl carbonyl(C 1 6 )alkyl.
The term "amine" unless specifically stated otherwise includes primary, secondary and tertiary amines.
Unless otherwise stated, the term "carbamoyl" is used to include -NHC(O)OC1-C4alkyl, and -OC(O)NHCl-C4alkyl.
The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, the substitution can be made at any of the groups. For example, substituted aryl(C-s)alkyl includes substitution on the aryl group as well as substitution on the alkyl group.
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.
Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereosomners of Forula I and pharmacutically acceptable salts thereof. Further, 1 V uL n. m. Ia UItLiy a ~iC LLauiJ. ,aiL Uj1 I-Ui. 1'UILL mixtures of stereoisomers as well as isolated specific stereoisomers are also included.
During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, Nethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal antiinflammatory drugs ("NSAID"), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
Dosage levels from about 0.001mg/kg to about 140mg/kg of body weight per day are useful in the treatment of conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, -27- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokinemediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory mpairment, mrnnnpolr depression, acute ard chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues which are responsive to PDE4 inhibition, or alternatively about 0.05mg to about 7g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01mg to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 2.5g per patient per day. Further, it is understood that the PDE4 inhibiting compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.01mg to about 1000mg of the active ingredient, typically 0.01mg, 0.05mg, 0.25mg, 1mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration -28- SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as ar 1l." n a SO!Litinfl nc a Sci flP,,Crd.f n no -q e u-I; c i r A-j1-~A q4. f~uAL as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula 1, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, dilucnts, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers 29 SUBSTITUTE0 SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0. mg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about 0.lmg to about 500mg of the active ingredient.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is nrepnard by mvixin hydrophilic material and water, together with about wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives. (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
The compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, -31- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia. muscle wasting, depression, memory impairment, mnopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cCAMP levels by the administration of an effective amount of the compounds of this invention. The term "mammals" includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle.
Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.
Further, as described above, the compound of this invention can be utilized in combination with other therapeutic compounds: In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) H1 (histamine) receptor antagonists and ix) beta 2 adrenoceptor agonist.
In another aspect, it was found that the compound of this invention can be formed as a metabolite in the mammalian system. For example, Example 19, 1-methyl-1 -(methylsulfonyl)ethyl]-8-quinolinyl phenyl)-1-[4- (mcthylsulfonyl)phenyl]ethenyl ,2,4-oxadiazol-3-yl)methanol: -32- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 t3U 1 0 which is a PDE4 inhibitor is formed ii vivo as a metabolite when Example 14:
H
3 O -CH 'S-CH3
CH
3 CH3
NO
S
H
3 C" is administered. Accordingly, the present invention includes prodrugs that form PDE4 inhibitors in vivo as a metabolite after administering such prodrugs to a mammal. Further, this invention includes a method of treatment by a step of administering a prodrug to form in vivo an effective amount of a PDE4 inhibitor described by Formula I.
-33- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 The abbreviations used herein have the following tabulated meanings.
Abbreviations not tabulated below have their meanings as commonly used unless Ac acetyl Bn =benzyl CAWvI cyclic DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene DIB3AL =diisobutylaluminum hydride DMAP =4-(dimethylarnino)pyridine DMIF =NN-dimethylformrnide Et3N =triethylamine GST glutathione transferase HM4DS hexamethyldisilazide LDA lithium diisopropylamide m-CPBA =metachloroperbenzoic acid IMP monoperoxyphthalic: acid MIPPM =monoperoxyphthalic acid, magnesium salt 6H20 Ms =methanesulfonyl mesyl SO2Me MsO methanesulfonate mesylate NSAID =non-steroidal anti-inflammatory drug o-Tol =ortho-tolyl OXONE® 2KIHSO5-KHSO4*K2S04 PCC pyridinium chlorochromate PDC =pyridinium, dichromate PDE phosphodiesterase Ph pheny] Phe =benzenediyl PNM =Para-methoxybenzy] -34- SUBSTITU TE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 Pye =pyridinediyl r.t. =room temperature Rac. =racemc SAM =arninosulfonyl or sulfonamide or SO2NI-2 SEM =2-(trimethylsilyl)ethoxymethoxy SPA =scintillation proximi ty assay TBAF =tetra-n-butylammonium fluoride Th or 3-thienyl TFA trifluoroacetic acid TFAA =trifluoroacetic acid anhydride THE tetrahydrofuran Thi =thiophenediyl TLC thin layer chromatography TMS-CN =trimethylsilyl cyanide TMSI trimethylsilyl iodide Tz I 1H (or 21{)-tetrazol-5 -yl CAN cenic ammonium nitrate =allyl ALKYL GROUP ABBREVIATIONS me Methyl Et ethyl n-Pr normal propyl i-Pr isopropyl n-Bu normal butyl i-Bu isobutyl s-Bu secondary butyl t-Bu tertiary butyl c-Pr cyclopropyl 35 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 c-Bu cyclobutyl c-Pen cyclopentyl c-Hex cyciohexyl ASSAYS DEMONSTRATING BIOLOGICAL ACTIVITY LPS AND FMLP-INDUCED TNF-ca AND LTB4 ASSAYS IN HUMAN WHOLE BLOOD Whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE4selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-a and LTB4. Upon stimulation with LPS, activated monocytes express and secrete TNF-x up to 8 hours and plasma levels remain stable for 24 hours.
Published studies have shown that inhibition of TNF-a by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity occurs at the transcriptional level. LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE4-selective inhibitors. As there is little LTB4 produced during a 24 hour LPS stimulation of whole blood, an additional LPS stimulation followed by fMLP challenge of human whole blood is necessary for LTB4 synthesis by activated neutrophils. Thus, by using the same blood sample, it is possible to evaluate the potency of a compound on two surrogate markers of PDE4 activity in the whole blood by the following procedure.
Fresh blood was collected in heparinized tubes by venipuncture from healthy human volunteers (male and female). These subjects had no apparent inflammatory conditions and had not taken any NSAIDs for at least 4 days prior to blood collection. 500/L aliquots of blood were pre-incubated with either 2CtL of vehicle (DMSO) or 2AL of test compound at varying concentrations for 15 minutes at 37 0 C. This was followed by the addition of either 10plL vehicle (PBS) as blanks or LPS (1/g/mL final concentration, #L-2630 (Sigma Chemical Co., St. Louis, MO) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours of incubation at 37 0 C, another 10/pL of PBS (blank) or 10.L of LPS (1/g/mL -36- SUBST!TUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 final concentration) was added to blood and incubated for 30 minutes at 37 0 C. The blood was then challenged with either 10p.L of PBS (blank) or 10/L of fMLP (1/iM f nn1 rg~nnpptntr.nt~on 1 fI M. n. TC1 A Tn C'N' I n concentration, -350 (Sig diluted in 1% v SA (in BS)) for minutes at 37 0 C. The blood samples were centrifuged at 1500xg for 10 minutes at 4 0 C to obtain plasma. A 50ItL aliquot of plasma was mixed with 200/L methanol for protein precipitation and centrifuged as above. The supernatant was assayed for LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's procedure. TNF-a( was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NJ) according to manufacturer's procedure. The IC50 values of Examples 1-42 generally ranged from 0.04pM to 8.7 I1M. ANTI-ALLERGIC ACTIVITY IN VIVO Compounds of the invention have been tested for effects on an IgEmediated allergic pulmonary inflammation induced by inhalation of antigen by sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in combinations with aluminum hydroxide and pertussis vaccine. Booster doses of antigen were given two and four weeks later. At six weeks, animals were challenged with aerosolized ovalbumin while under cover of an intraperitoneally administered anti-histamine agent (mepyramine). After a further 48h, bronchial alveolar lavages (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted. The lungs were also removed for histological examination for inflammatory damage. Administration of compounds of the Examples (0.001-10mg/kg i.p. or up to three times during the 48h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples.
-37- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 SPA BASED PDE ACTIVITY ASSAY PROTOCOL Compounds which inhibit the hydrolysis of cAMP to AMP by the y Se-fC LA.lA- YeAII phsphkOditsrsIU were scOeened in. a 96 eV plate format as follows: In a 96 well-plate at 30 0 C was added the test compound (dissolved in 2JIL DMSO), 188mL of substrate buffer containing [2,8-3H] adenosine phosphate (cAMP, 100nM to 50MM), 10mM MgCI2, 1mM EDTA, 50mM Tris, pH The reaction was initiated by the addition of 10mL of human recombinant PDE4 (the amount was controlled so that -10% product was formed in 10min.). The reaction was stopped after 10min. by the addition of 1mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, NJ). The product AMP generated was quantified on a Wallac Microbeta® 96-well plate counter (EG&G Wallac Co., Gaithersburg, MD). The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted. Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multiple binding sites equation from a ten point titration.
The IC50 values of Examples 1-42 were determined with 100nM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase Na (met-248) produced from a baculovirus/Sf-9 expression system. The IC50 values of Examples 1-42 generally ranged from 0.14nM to 10.24nM, although one example had an IC50 value of 109nM.
The examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied.
Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperature that is, at a temperature in the range of 18-25 0 C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600- 4000pascals: 4.5-30mm. Hg) with a bath temperature of up to 60 0 C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are -38- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 given for illustration only. Melting points are uncorrected and indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials wilh different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. Yields are given for illustration only. When given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, "Ar" signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Methods of Synthesis Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula I except where defined otherwise.
SCHEME 1 Ketone Synthesis -39- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/0 1559 ArX
IV
1. base or organolithium 2. A X Ar 1 Y IjAr- E-Ar1-4
L
base or organolithium 2. E or A 13. base or organolithium 4. A or E
OH
A Ar SMe OH0 Arr VI S02MeSMe VIN~ VII Ar AaSO 2 Me Wherein X=halogen, H Y=halogen, H A=4-(methylthio)benzaldehyde E--electrophile Ar--aryl or heteroaryl Referrng to Scheme 1 above, and Scheme 1 Table below, the alcohol intermediate 11 may be prepared by the reaction of an aryl or heteroaryl metallic species 1ll such as an organomagnesium halide with 4-(methylthio)benzaldehyde (A) in an organic solvent such as THF. The alcohol intermediate HI may also be prepared 40 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 by treatment an aryl or heteroaryl hydride or bromide IV with a base or an organometallic such as n-butyllithium in an organic solvent such as THF, followed by 4-(methylthio)benzaldehyde. Alternatively the alcohol intermediate II may also be prepared by the following chemical transformations: 1) Treatment of an aryl or heteroaryl dihydride, halide-hydride or dihalide V with a base or an organometallic such as n-butyllithium in an organic solvent such as THF, followed by an electrophile such as acetone or 4-(methylthio)benzaldehyde; 2) Subsequent treatment with a base or an organometallic such as n-butyllithium in an organic solvent such as THF, followed by an electrophile such as acetone or 4-(methylthio)benzaldehyde, where the first or the second transformation must use 4-(methylthio)benzaldehyde as the electrophile. The sulfone-alcohol VI may be prepared by the oxidation of the sulfidealcohol I with an oxidizing agent such as oxone in a solvent such as a mixture of The ketones VII and VIII may be prepared by the oxidation of the alcohols II and VI, respectively, with an oxidizing agent such as MnO 2 in a solvent such as CH 2 C2. The sulfone-kctone VIII may also be prepared by the oxidation of the sulfide-ketone VII with an oxidizing agent such as oxone in a solvent such as a mixture of THF/MeOH/H0O.
SCHEME 1 TABLE: Ketones -41- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559
O
Ar% SOnMe VII (n=0) VIII (n=2) Ar n Ketone Ar n Ketone F CH2 K1 HC CH2 2 K7
H
3
C
CH, 0 K2 C 2 K8 C H
H
2 CH 2 K3 Me 2 S 2 K9 CH2 0 K4
_CH
2 2 N 2 K5 N
H
3 C CH IH 2 a 2 K6 H3 N 2 K11
H
3 C NHOCH3 Ketone K1 (4-Fluorophenyl)[4-(methylsulfonyl)]phenyl ketone Ketone K1 was prepared by the following procedure.
Step 1: (4-Fluorophenyl)[4-methylthio)phenyl]ketone To a -78 0 C solution of 4-(methylthio)benzaldehyde (2.5g, 16.4mmol) in THF (100ml) was added 4-fluorophenylmagnesium bromide (1.OM in THP, 19.7m, 19.7mmol) dropwise. The resulting solution was stirred at -78 0 C for 3h., and quenched with a saturated aqueous solution of MINH 4 C1. The mixture was then diluted with EtOAc and HCI 10%, extracted and washed (NaHCO 3 brine). The organic phase was dried over MgSO 4 and concentrated. The residue was then treated with MnO 2 (28.6g, 330mmol) in CH 2
C
2 (150ml) and the reaction was stirred at r.t.
-42- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 overnight. The mixture was filtered through a plug of silica (EtOAc) to yield 2.6g of the (4-Fluorophenyl)[4-methylthio)phenyl]ketone compound Step 2: (4-wFiuoropheny1) [4-(methylsulfonyl)pheny1] ketone To a solution of the sulfide in other words, the (4-Fluorophenyl)[4methylthio)phenyllketone from the present step 1 (2.0g, 8. 1imol) in THFJMeOHJH 2 O (80/40/40 ml) was added oxone (7.5g, 12.2mmol). The mixture was stirred at r.t. for 4h, quenched with NaHCO 3 and diluted with EtOAc. The organic phase was washed with NaHCO 3 brine, dried over Na 2
SO
4 filtered and concentrated. Crystallization (CH 2 Cl 2 IHexanes) yielded (4-Fluorophenyl)[4- (methylsulfonyl)phenyllketone, the K1 ketone compound, as a white solid.
Ketone K(2 (1 -Methyl- 1H-imridazol-2-yl)[4-methylthio)phenyllketone Ketone K(2 was prepared by the following procedure.
Step 1: (1 -Methyl- IH-imidazol-2-yl) [4-(methylthio)phenyll methanol To a solution of N-methylimidazole (10.0g, l22mmol) in 500mL THF at -78*C was added n-butyllithium (2.5M in hexanes, 48.7m], 1 l8mmol) dropwise and the resulting solution was stirred at -78 0 C for 30mmn. 4-(Methylthio)benzaldehyde (14.73nil, I10mmol) was then added at -78'C and the mixture was stirred until completion by TLC, and quenched with NI{ 4 C1 (sat). The mixture was then diluted with EtOAc, extracted and washed (NaHCO 3 brine). The organic phase was dried over MgSO 4 filtered and concentrated. Crystalisation (EtOAc/Hexanes) yielded (1 -Methyl-lH-irnidazol-2-yl)[4-(methylthio)phenyllmethanol.
Step 2: (1-Methyl-1H-imidazol-2-yl)[4-(niethylthio)phenyllketone To a solution of the alcohol from the present step 1 (25.7g, 11 Immol) in EtOAc (2S0nml) and C11 2
C
2 (250m1) was added MnO 2 (140g, 1.66mo1) and the 43 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 reaction was stirred at r.t. overnight. The mixture was filtered through a plug of silica (EtOAc) to yield ketone 1(2.
Ketone K(3 (4-Methylsulfonyl)(phenyl)ketone Ketone K(3 was prepared by the following procedure.
Step 1: (4-Methylthio)(phenyl)methanol To a solution of 4-(methylthio)benzaldehyde (1 .0g, 6.5mmol) in THF (2OmQ) at 0 0 C was added phenylmagnesiumn chloride (2M, THFP, 3.5mL, 7.Ommol).
After 0.5h at the mixture was neutralised with saturated NH4C1 solution, diluted with water and extracted with Et2O. The organic extracts were washed (1120), (brine), dried (MgSO4), filtered and concentrated. Purification by stirring vigorously in hexane/Et2O and filtration yielded (4-Methylthio)(phenyl)methanol as a white solid.
Step 2: (4-Methylthio)(phenyl)ketone (4-Methylthio)(phenyl)ketone was obtained by treating the (4- Methylthio)(phenyl)methanol from the present step 1 with MnO2 as in step 2 of the procedure for K4 below.
Step 3: (4-Methylsulfonyl)(phenyl)ketone To a solution of (4-Methylthio)(phenyl)ketone from the present step 2 (0.98g, 4.3mmol) in CHC13 (lOmL) at 0 0 C was added mCPBA (m-chloroperbenzoic acid) (1.7g, l0mmol). After 0.5h at Ca(OH)2 (1.7g, 23mmol) was added to the mixture which was stirred for lh. Filtration on Celite®) and concentration yielded ketone K(3 as a white solid.
Ketone K4 (1 ,3-Thiazol-2-yl)[4-(methylthio)phenyl]ketone Ketone K4 was prepared by the following proeedure.
-44- SUBST ITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 Step 1: (1 ,3-Thiazol-2-yl)[4-(methylthio)phenyllmethanol To a 78C( solution of thiazole (5.0g, 58.7mmol) in TFHF (250m1) was added n-butyliithium. (2.5M in hexanes, 23.5mi, 58.7mmol) dropwise and the resulting solution was stirred at -78 0 C for 10min. 4-(Methylthio)benzaldehyde (7.lIml, 53.4mmol) was then added at -78'C. The resulting mixture was stirred until completion, and quenched with a saturated aqueous solution of Nl{4Cl. The mixture was then diluted with EtOAc and HCl 10%, extracted and washed (NaHICO 3 (sat.), brine). The organic phase was dried over MgSO 4 and concentrated. The residue was then purified by flash chromatography (80% CH 2
CI
2 20% EtOAc) to yield (1,3- Thiazol-2-yl) [4-(methylthio)phenyl] methanol.
Step 2: (1 ,3-Thiazol-2-yl)[4-(methylthio)phenyllketone To a solution of the (1 ,3-Thiazol-2-yl)[4-(methylthio)phenyllmethano from the present step 1 (10.0g, 42.lmmol) in EtOAc (250m]) was added NMnO 2 843mmo1) and the reaction was stirred at 25 0 C overnight. The mixture was filtered through a plug of silica (EtOAc) to form the K(4 ketone compound.
Ketone (1 ,3-Thiazol-2-yl)[4-(methylsulfonyl)phenyl]ketone Ketone K(5 was prepared by the following procedure. To a solution of K(4 (1,3-Thiazol-2-yl)[4-(methylthio)phenyljketone (8.2g, 34.7mmol) in THF/MeOII/1 2 0 (350/175/175 nil) was added oxone (42.6g, 69.4mmol). The reaction was stirred at 25*C for 3h and quenched with a saturated aqueous solution of NaHCO 3 The resulting mixture was then diluted with EtOAc, extracted and washed (NaHCO 3 brine). The organic phase was dried over MgSO4 and concentrated.
The residue was then purified by crystallization (EtOAc/Hexanes) to yield of (1,3- Thiazol-2-yl)[4-(methylsulfonyl)phenylllketone.
Ketone K(6 -Hydroxy- 1-Methylethyl)- 1 ,3-thi azol-2-yl] [4-(methyl sulfon yl)phenyl] ketone 45 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/0I 559 Ketone K6 was prepared by the following procedure.
Step 1: -Hyciroxy- 1-Methylethyl)-1 ,3-thiazol-2-yl] [4hyl.flA -*No ph en 11- StlA To a -78'C solution of thiazole (1.0g, 12.Ommol) in THF (lO0mi) was added n-butyllithium (2.3M in hexanes, 5.3rn1, 12.3mmol) dropwise and the resulting solution was stirred at -78 0 C for 10min. 4-(Methylthio)benzaldehyde (7.linl, 53.4mmol) was then added at -78 0 C. The resulting mixture was stirred at r.t. and cooled at -78'C. Then n-butyllithium (2.3M in hexanes, 5.3m1, 12.3mmol) was added dropwise and the resulting solution was stirred at 25 0 C for 10min and quenched with acetone The mixture was then diluted with EtOAc and HCl extracted and washed (NaHICO 3 brine). The organic phase was dried over MgSO4 and concentrated. The residue was then treated with MnO2 (20.4g, 23Smrnol) in CH 2 C1 2 (250m1) and the reaction was stirred at r.t. overnight. The resulting mixture w as then filtered through a plug of silica (EtOAc). Flash chromatography (90%CH 2 C1 2 /10%EtOAc) yielded [5-(1-Hydroxy-1-Methylethyl)-1 ,3-thiazol-2-yl] [4- (methylthio)phenyljketone.
Step 2: [5-(I-Hydroxy-1-Methylethyl)-1 ,3-thiazol-2-yl][14- (methylsulfonyl)phenyl] ketone To a solution of the sulfide that is, [5.-(1-Hydroxy-1-Methylethyl)- 1 ,3-thiazol-2-yl] [4-(methylthio)phenyl]ketone from present step 1 (1.7g, 5. 8mmol) in THFIMeOHJH 2 O (100/50/50 ml) was added oxone (7.1g, 11.5mmol). The reaction was stirred at 25'C for 3h and quenched with a saturated'aqueous solution of NaHCO 3 The mixture was then diluted with EtOAc, extracted and washed (NaHCO 3 brine). The organic phase was dried over MgS04 and concentrated. The residue was then purified by crystallization (EtOAc/Hexanes) to yield ketone K6.
Ketone K7 (6-Methyl-3-pyridinyl)[4-(methylsulfony)pheny]ketone Ketone K(7 was prepared by the following procedure.
Step 1: (6-Methyl-3-pyridinyl)[4-(methylthio)phenyllmethalo -46 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 To solution of 3-bromo-6-methylpyridine (760mg, leq) in THF (2OmL) at -78 0 C, was added slowly n-butyllithium in hexane (1.1 eq). The solution xas- hen d wasthe sti-ed3n'.n. -(hicnztyl~cnaideLyae kIonag, 3±.1eq -was then s'ovwiy added. The solution was warmed to rt. NH 4 Cl (sat.) was added, then water and EtOAc. The organic phase was separated, dried over MgSO 4 and concentrated. The (6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol was obtained by precipitation with ether/hexane and was used without further purification for the next step.
Step 2: (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyllmethanol Following the procedure of step 2 of ketone 1(1 above but substituting the sulfide (6-Meth yl-3-pyridinyl)[4-(methyl thio)phenyl] methanol from the present step 1 for (4-fluorophenyl)[4-(methylthio)phenyl]ketone as the starting material, (6- Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyllmethanoI was obtained.
Step 3: (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyllketone Following the procedure of step 2 of ketone K(2 above but substituting the (6-Methyl-3-pyridinyl)[14-(methylsulfonyl)phenyllmethanol from the present step 2 for (1-methyl- 1H-iinidazol-2-yl)[4-(methylthio)phenyllmethanol as the starting material, ketone K7 was obtained.
Ketone K(8 (5-Methyl-2-pyridinyl)114-(methylsulfonyl)phenyl]ketone Ketone K(8 was prepared by following the procedure described for ketone K(7 but substituting 2-bromo-5-methylpyridine for 3-bromo-6-methylpyridine.
Ketone K(9 Bis-[(4-methylsulfonyl)phenyl]ketone Ketone K(9 was prepared by following the procedure described for ketone K7 but substituting 4-broniothioanisole for 3-bromo-6-methylpyridine and using twice the amount of Oxone in the sulfide-oxidation step.
Ketone -47 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 (2-Pyridinyl)[4-(methylsulfonyl)phenyllketone Ketone K1O was prepared by following the procedure described for ketone K7 but substituting 2-bromopyridine for 3-bromo-6-methylpyridine.
Ketone K11 [5-(1-Hydroxy-1-methylethyl)-2-pyridiflyll [4-(methylsulfonyl)phenyllketone Ketone K11 was prepared by the following procedure.
Step 1: [5-(l-Hydroxy- 1-methylethyl)-2-pyridinyl] [4- (methylthio)phenyljlmethanol To a suspension of 2,5-dibromopyridine (5.12g, leq) in ether at -78 0
C,
was added n-butyllithium in hexane (1.O5eq) slowly. The resulting yellow-orange precipitate was strirred 30min. Then acetone (1 .54in1, 1 .O5eq) was added. The solution was kept at -78 0 C for another 30min. n-Butyllithium in hexane leq) was slowly syringed to the resulting orange suspension. The suspension was then stirred lb at -78'C. Following this, 4-(methylthio)benzaldehyde (2.85 ml, 1.1 eq.) was added. The resulting suspension was warmed to -35*C and quenched with a solution of N114CI Water and EtOAc were added and the organic layer dried over MgSO 4 evaporated and purified by flash chromatography (EtOAc) to give Hydroxy-1 -methylethyl)-2-pyridinyl] [4-(methylthio)phenyl]methanol.
Step 2: f5-( 1-Iydroxy-1-mcthylethyl)-2-pyridinyll[4- (methylsulfonyl)phenyllmethanol Following the procedure described above for step 2 of ketone K1 but substituting the sulfide that is, [5-(1-Hydroxy-1-methylethl)-2-pyridinyl][4- (methylthio)phenyl] methanol from the present step 1 for (4-fluorophenyl)[4- (methylthio)phenyl]ketone as the starting material, [5-(l-Hydroxy-1-methylethyl)-2pyridinyl] [4-(methylsulfonyl)phenyllmethanol was obtained.
Step 3: 1-Hydroxy-1-methylethyl)-2-pyridinyl] [4- (methylsulfonyl)phenyl]ketone Following the procedure described above for step 2 for ketone 1K2 but substituting the [5-(1-Hydroxy-1 -methylethyl)-2-pyridinyl] 14- (methylsulfonyl)phenyllmethanol from the present step 2 for (1-methyl-1H-imidazol- -48 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAGO/01559 2-yl) 4-(methylthio)phenyl) methanol as the starting material, ketone K11 was obtained.
The boronate compounds utilized to prepare the compounds of this invention can be made according to Scheme 2 shown below: SCHEME 2 Boronate Synthesis Br q P Ph 3
BC
xi Ar 04 'SOnMe ViI or Vill Br NZ -Ar MeOnS IX 49 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 Ketone (VII or Vill) Ar n Boronate, (XII) H0N
H
2 C ,,S 0 B2 2 B3 2 B4 K8I
H
H
2 C N
H
3 C
OH
K1 H 2 C N H The aryl bromides IX and X may be prepared by treatment of the benzyl phosphonium bromide XI with a base such as t-BuOK or LiLMDS in an organic solvent such as THE, followed by the addition of the ketone VII or VIII to the reaction mixture. The sulfide in IX may be converted to the sulfone X by treatment with oxone in a solvent such as a mixture of TI-IFJMeOHIH 2 O. The boronate ester XII can be prepared by heating the aryl bromide X with pinacol diborane in thc presence of a base such as KOAc and a catalyst such as PdCI 2 (dppf) in a solvent such as DMF.
Boronate B1 Pinacol 3- 1-methyl-1H-imidazol-2-y)-2-[4- (methylsulfonyl)phenyllethenyl phenylboronate Boronate BI was prepared by the following procedure.
Step 1: (E/Z)-2-(3-Bromophenyl)-l1-(1-methyl-1H-imidazol-2-yl)- 1-[4- (methylthio)phenyl]ethene 50 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 To a solution of (3-bromobenzyl)(triphenyl)phosphonium bromide (10.2g, 19.9mmol) in THF (200mQ) and CH 3 CN (5OrmL) at 25 0 C was added t-BuOK %.0M VIIT 1. rnL,9 19.7ll."c,) dropVWi~i the ieUit Ue ullf was stirred at r.t. for 20min. To this resulting ylide was then added at 251C the ketone K2 (4.4g, 18.9mmol). The resulting mixture was stirred at 60'C for 2 days and quenched with NH 4 CI (sat). The mixture was then diluted with EtOAc. The organic phase was washed with NaHCO 3 brine, dried over MgSQ 4 filtered and concentrated, and used directly in the next present step 2.
Step 2: (E)-2-(3-Bromophenyl)-1-( I-methyl-1H-imidazol-2-yl)-1-[4- (methylsulfonyl)phenyllethene To a solution of the crude sulfide that is, (EIZ)-2-(3-Bromophenyl)- 1 -(1-methyl- 1H-imuidazol-2-yl)-1-[4-(methylthio)phenyl]ethene from present step 1 (18.9mmol) in TH-F/MeOLII 2 O (200/100/100 mld) was added oxone (23.2g, 37.8mmol). The mixture was stirred at r.t. for 4h, quenched with NaHCQ 3 (sat), and diluted with EtOAc. The organic phase was washed with NaHCO 3 brine, dried over Na 2
SO
4 filtered and concentrated. Flash chromatography (95%EtOAc/5% Et 3
N)
yielded (E)-2-(3-Bromophenyl)- 1-(1-methyl-1H-imidazol-2-yl)- 1-[4- (methylsulfonyl)phenyl]ethene (single isomer) as a foam.
Step 3: Pinacol 3- 1-methyl-1H-inmidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl lphenylboronate A suspension of the bromidde that is, (E)-2-(3-Bromophenyl)-1-(1methyl- I H-imidazol-2-yl)- 1 -[4-(methylsulfonyl)phenyl]ethene from present step 2 4.8rmmol), pinacol diborane (1.5g 5.8mmol), KOAc (1.65g; 16.8mmnol) and PdCl 2 (dppf) (0.2g; 0.24mxnol) in 5OmL of DMIF was stirred at 90'C for 4h. The resulting mixture was cooled to diluted with EtOAc, washed with H 2 0 brine, dried over Na 2
SO
4 filtered and concentrated. Flash chromatography (95%EtOAc/5% Et 3 N) yielded boronate B1 as a foam.
Boronate B2 Pinacol 3- ,3-thiazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl }phenylboronate -51- SUBST ITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 Boronate B2 was prepared by the following procedure.
Step 1: (E/Z)-2-(3-BromophenylD-1-( 1,3-thiazol-2-yl)-1- [4- (methylthio)phenyliettlene To a solution of (3-bromobenzy1)(triphenyl)phosphonium bromide (44.5g, 86.9mmol) in TIF (500~mL) and DME (200miL) at 0 0 C was added LiHIVIS (1.OM in TDiF, 86.9mL, 86.9mmol) dropwise and the resulting red solution was stirred at r.t. for 20min. To the resulting ylide was then added at 0 0 C the ketone K4 (I18.6g, 79.Ommol). The mixture was stirred until completion by TLC, and quenched with a NII4Cl (sat). The mixture was then diluted with EtOAc. The organic phase was washed with NaHCO3 brine, dried over MgSO4, filtered and concentrated.
Flash chromatography (CH2CI2) yielded (EIZ)-2-(3-Bromophenyl)-1 ,3-thiazol-2yl).-1-[4-(methylthio)phenyl]ethene (1.5 to 1 mixture of isomers).
Step 2: (F/Z)-2-(3-Bromophenyl)-1-(1 ,3-thiazol-2-yl)-1-t4- (methylsulfonyl)phenyl]ethene To a solution of the sulfide that is, (E/Z)-2-(3-Bromophenyl)-l-(1,3thiazol-2-yl)- 1-[4-(methylthio)phenyllethene from present step 1 (24.8g, 63.9mmol) in THFJMeOI{1H20 (600/300/300 nil) was added Oxone (78.5g, 1 28mmol). The resulting reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched with a NaH{C03 (sat), and diluted with EtOAc. The organic phase was washed with NaI9CO3 brine, dried over Na2S 04, filtered and concentrated to yield (E/Z)-2-(3-Bromophenyl)-1-(1 ,3-thiazol-2-yl)-1-[4- (methylsulfonyl)phenyl]ethene (3 to 2 mixture of -isomers).
Step 3: Pinacol 1,3-thiazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl) phenylboron ate A suspension of the bromide (E/Z)-2-(3-Bromophenyl)-1-(1 ,3-thiazol- 2-yl)-1-[4-(methylsulfonyl)phenyllethene from present step 2 (1 5.0g, 35.7mmol), pinacol diborane (10.9g, 42.8mxnol), KOAc (12.3g, l25mmol) and PdCI2(dppf) (1.46g, 1.7Smmol) in 350mL of DMF was stirred at 90'C for 4h. The resulting mixture was cooled to diluted with EtOAc, washed with H20 brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (TollAcetone, 9/1) yielded boronate R2 (3 to 1 mixture of isomers) as a foam.
52 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 Boronate B3 Pinacol 3- {(E)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl Iphenylboronate Boronate B3 was prepared by the following procedure.
Step 1: (E)-2-(3-Bromophenyl)-1-(5-methyl-2-pyridiflyl)-l (methylsulfonyl)phenyllethylene Following the procedure described for step 1 for boronate B1 but substituting the ketone K8 for ketone K2 as the starting material, Bromophenyl)-1 -(5-methyl-2-pyridinyl)-1-[4-(methylsulfoniy)phelyl]ethylefle was obtained after separation of the isomers by flash chromatography.
Step 2: Pin acol (E)-2-(5-methyl-2-pyridinyl)-2- [4- (methylsulfonyl)phenyllethenyl }phenylboronate Following the procedure described for step 3 for boronate B1 but substituting the bromide (E)-2-(3-Bromophenyl)- I-(5-methyl-2-pyridinyl)-l-[4- (methylsulfonyl)phenyllethylene from present step 1 for (E)-2-(3-Bromophenyl)-1-(1methyl-1H-imnidazol-2-yl)- 1-[4-(methylsulfonyl)phenyl]ethene as the starting material, boronate B3 was obtained.
Boronate B4 Pinacol 3- {(E)-2-(5-(1-hydroxy-1-methylethyl)-2-pyridinyl)-2-[4- (methylsulfonyl)phenyljethenyl }phenylboronate Boronate B4 was prepared by the following procedure.
Step 1: (E)-2-(3-Bromophenyl)-1 I-hydroxy-1 -methylethyl)-2pyridinyl]-1 -[4-(methylsulfonyl)phenyl]ethcnc Following the procedure described for step I for boronate BI but substituting the ketone KII for ketone K2 as the starting material, Bromophenyl)-1 -hydroxy-1 -methylethyl)-2-pyridinyl]-1 (methylsulfonyl)phenyl]ethene was obtained after separation of the isomers by flash chromatography.
53 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 Step 2: Pinacol 3- -hydroxy-l1-methylethyl)-2-pyridinyl)- 2 [4-(methylsulfonyl)phenyllethenyl I}phenylboronate -Ib 1-Ue A J -J LJI UUIt l U substituting the bromide (E)-2-(3-Bromophenyl)- 1-[5-(1-hydroxy-1 -methylethyl)-2pyridinyl] -1-[4-(methylsulfonyl)phenyl]ethene from present step 1 for Bromophenyl)-1 -(1-methyl-1H-irnidazol-2-yl)-l1-[4-(methylsulfonyl)phenyllethene as the starting material, boronate B4 was obtained.
The aryl bromide compounds utilized to prepare the compounds of this invention can be made according to Schemes 3 and 4 shown below: SCHEME 3 Oxadiazole Synthesis p-MeOPhOH ClK,.CN o. p-M9OPhO.,CN ,H Me 2 SC C2 NH xv N R RR
NH
2 Me 2 b-N R Oxadiazole (XVI) Me oxi p-MeOPhOCH 2 0X2 Referring to Scheme 3 above, the nitrile intermediate XlIa may be prepared by the alkylation of 4-methoxyphenol with chioroacetonitrile in the presence of a base such as potassium carbonate in a solvent such as acetone. The amide-oxime XIV may be prepared by treatment of the nitrile XIII with hydroxyl amine in a -54 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CADO/01559 solvent such as methanol in the presence of a base such as sodium acetate. Formation of the oxadizole XVI may be achieved by activation of the arylacetic acid XV with car n y liiinirgip in P enhiant vr,, 4 i TD4fP t K. A; .C oxime XJV and subsequent heating of the reaction mixture.
SCHEME 4 Aryl Bromide Synthesis M0 2 S rC2 Br XV 6~CHO
O
XVII MeQ Br 2S C02
H
Br
CONR
1 R 2 Me0 2 S Z Ix Br
~%N.CH,
MeO 2 S a-N XVII1c XVII1a (ABi) XVII1b Ri R 2Aryl Bromide (XVII1b) H i-Pr H H H t-Bu AB2 AB3 AB4 Referring to Scheme 4 above, condensation of the aldehyde XVII by heating with the arylacetic acid XV in the presence of a base such as piperidine in a solvent such as toluene produces the unsaturated acid XVII1a. Formation of the acid chloride of XVIIIa in situ by treatment with thionyl chloride and a base such as triethylainine in a solvent such as toluene, is followed by the addition of an amine to the reaction mixture to yield the amide XVIIb. The oxadiazole-ethene XVI11c may 55 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 be formed by heating OX1 with XVII in the presence of a base such as piperidine in a solvent such as toluene.
Scheme 4 appendix Aryl Bromide Synthesis r Br r CO2H COMe MeO 2 S MeO 2 S MeO OH XVIIa (AB1) XVIIId XVllle Br MeOzS NMe 2 XVIIIf (AB6) Referring to Scheme 4 appendix above, treatment of the acid XVIIIa with diazomethane in a solvent such as THF produces the methyl ester XVIIId.
Reduction of the ester XVIIId using DIBAL-H in a solvent such as THF gives the allylic alcohol XVIIIe. Conversion of the alcohol group in XVIIIe to a leaving group such as a mesylate using reagents such as methanesulfonyl chloride and triethylamine in a solvent such as THF, followed by displacement with a nucleophile such as dimethylamine in a solvent such as DMF produces the compound XVIIIf.
-56- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 Aryl Brom-ide ABI (E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid Aryl Bromide ABi was prepared by the following procedure. To a solution of 3-bromobenzaldehyde (12.9g, 7Ommol) in toluene (lOOmL) was added 4- (methylsulfonyl)phenylacetic acid (15g. 7Ommol) and piperidine (2mL). After overnight refluxing, the mixture was cooled down to r.t. To the slurry thus formed, toluene was added (10 mL) Filtration gave (E)-3-(3-Bromophenyl)-2-[4- (methylsulfonyl)phenyl]-2-propenoic acid as a white solid.
Aryl Bromide AB2 (E)-N-Isopropyl-3-(3-bromophenyl)-2-14-(methylsulfonyl)phenyll-2-propenamide Aryl Bromide AB2 was prepared by the following procedure. To a solution of ABi (24.9g, 65mmol) in toluene (250mL) was added thionyl chloride (14.3mL, l96mmol) and triethylamine (34mL, 24Srnmol). After stirring at r.t. for isopropyl amine (28mL, 327mmo1) was added. After a further 2h at the mixture was cooled to OTC and was neutralised with saturated N14 4 CI solution, then extracted with EtOAc. The organic extracts were washed (H120, brine), dried (MgSO 4 filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 1: 1 to pure EtOAc) yielded (E)-N-Isopropyl-3-(3-bromophenyl)-2-[4- (methylsulfonyl)phenyl]-2-propenamide.
Aryl Bromide AB3 -3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenylI-2-propenamide .Aryl Bromide AB3 was prepared by following the procedure described for aryl bromide AB2 but substituting ammonium hydroxide for isopropyl amine as the starting material.
57 SUBSTI TUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 Aryl Bromide AB4 (E--tBtl--3Boohnl--4-mtysloy~hnl--rpnmd Aryl Bromide AB4 was prepared by following the procedure described for aryl bromide AB2 but substituting t-butyl amine for isopropyl amine as the starting material.
Aryl Bromide ABS 1-(3-Bromophenyl)-2-(3-rnethyl-1 ,2,4-oxadiazol-5 (methylsulfonyl)phenyllcthenc Aryl Bromide ABS was prepared by the following procedure.
Step 1 (Scheme 3, Oxadiazole OXI): (3-Methyl-l,2,4-oxadiazol-5-yl) [4-(methylsulfonyl)phenyljmethane To a solution of L-(methylsulfonyl)phenylacetic acid (15g, 70mniol) in DMF (300mb) at was added carbonyldiimidazole (12.5g, 77nol). After 0.5h at acetamide oxime (5.7g, 77rnmol) was added. After stirring the resulting mixture overnight at the mixture was heated to 1200(C for 6h. After cooling to the mixture was quenched with H 2 0, and extracted with EtOAc. The organic extracts were washed (1H20, brine), dried (MgSO 4 filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 1: 1) yielded (3-Methyl-i ,2,4-oxadiazol-5-yl) [4- (methylsulfonyl)phenyl] methane.
Step 2 (Scheme (E)-1-(3-Bromnophenyl)-2-(3-methyl-1 ,2,4oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyljethene To a solution of 3-bromobenzaldehyde (2.2g, 11 .9mmol) in toluene was added the product from step 1 (OXi) (3.0g, 11.9mimol) and piperidine (0.4mb). After overnight refluxing, the mixture was cooled down to r.t. To the resulting slurry, MeGH (30mQ) was added. After further refluxing then cooling to 00(2, filtration gave (E)-1-(3-Bromophenyl)-2-(3-methyl-1 ,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyllethene as a white solid.
-58 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 The Bromoquinolines utilized to prepare the compounds of this invention can be made according to Scheme 5 shown below: Preparation of Bromoquinolines
CH
3 BEy r IR R Br Br Br XIX XXa XXb N) H 3 C CH 3 Br XXc Referring to Scheme 5 above and the Scheme 5 table below, treatment of the bromomethyl compound XIX with a nucleophile such as sodium methanesulfinate or potassium cyanide in a solvent such as DMF or a mixture of DMF and water can be used to produce the compounds XXa. The compound XXb may be prepared by treatment of XXa with a base such as potassium t-butoxide (1.1 equivalents) in a solvent such as THF followed by the addition of the resulting mixture into a solution of methyl iodide in a solvent such as THF. The compound XXc may be prepared by treatment of XXb with a base such as potassium t-butoxide (1.1 equivalents) in a solvent such as THF followed by the addition of the resulting mixture into a solution of methyl iodide in a solvent such as THF. The compound XXc (where R' CN) may also be prepared by treatment of XXa with a base such as potassium t-butoxide (2.2 equivalents) and methyl iodide in a solvent such as THF.
-59- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 The compound XXc (where R1 SO 2 M~e) may also be prepared by treatment of XXa with a base such as potassium t-butoxide (1.3 equivalents) and methyl iodide (1.6 equivalents) in a solvent such as THF, followed by an additional amount of methyl iodide (1.6 equivalents) and an additional amount of the same base (1.0 equivalents).
Scheme 5 Table Bromoquiniolines R 2 R 3 Br i R 2 R 3 Bromoquinoline (XX)
SO
2 Me H H 01
SO
2 Me Me H 02
SO
2 Me Me Me 03 CN H H Q4 ON Me Me Bromoquinoline Q1 6-(methylsulfonyl)methyl- 8-bromoquinoline Bromoquinoline Q1 was prepared by the following procedure. DNiF (500mL) was added to 6-bromomethyl-8-bromoquinoline (60g, 200mrmoI) (described in International Patent Publication WO 94/22852) and sodium methanesulfinate 60 SUBSTIT-1UTE SHEET (RULE 26) WO 01/46151 WO~l/6151PCT/CAGO/O 1559 (27.6g, 27Ommol). After stirring overnight at the mixture was quenched with
H
2 0 (2000niL), stirred for one hour, isolated by filtration and washed with Et 2 O to Bromoquinoline Q2 1 -(methylsulfonyl)ethyl]-8-bromoquinoline Bromoquinoline Q2 was prepared by the following procedure. To a solution of bromoquinoline Q1 (16.1g, 54mmol) in TBHF (500mL) at -78'C, was added potassium t-butoxide (59mL, iN in 'VHF). After 0.5h at -78 0 C, the resulting mixture was stirred at 0 0 C for 45min and then transferred by canula dropwise into a solution of Mel (16.7mL, 268.3mmol) in THF (i6OinL). After stirring overnight at the mixture was neutralised with saturated NH 4 Cl solution and extracted with EtOAc. The organic extracts were washed (1120), (brine), dried WMgON, filtered and concentrated. Stirring in ether, followed by isolation by filtration gave 6-[1- (methylsulfonyl)ethyl]-8-bromoquinoline.
Bromoquinoline Q3 1-methyl-i -(methylsulfonyi)ethyl]-8-bromoquinoline -Bromoquinoline Q3 was prepared by the following procedure. To a solution of bromoquinoline Q2 (15.7g, 50mmol) in THF (500mL) at -78'C, was added potassium t-butoxide (55mL, IN in TI-IF). After stirring 0.5h at -78 0 C, the resulting mixture was stirred at O'C for 45min and then transfered dropwise into a solution of Mel (i5.6mL, 250mmol) in TE (4OmL) at 0 0 C. After stirring overnight at the mixture was neutralised with saturated NH 4 LCI solution, and extracted with EtOAc. The organic extracts were washed (1-120, brine), dried (MgSO 4 filtered and concentrated. Stirring in ether, followed by isolation by filtration gave 6-[1-methyl-1- (methylsulfonyl)ethyl]-8-bromoquinoline.
Bromoquinoline Q4 6-cyanomethyl-8-bromoquinoline 61 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 Bromoquinoline Q4 was prepared by the following procedure. DMIF (lOmL) and H120 (5mL) were added to 6-bromomethyl-8-bromoquinoline (3g, A ~JIULCI LI L I uL)IILaau0jl V %J 79-fl.IOJ4,J dJIU p1JUUZW cyanide (1.6g, 25mmol). After heating at 100 0 )C for 1 hour, the resulting mixture was quenched with 1120 (lO0nmL) and extracted with EtOAc. The organic extracts wcre washed (1120, brine), dried (MgSO 4 filtered and concentrated. Purification by flash chromatography (Hex:Et0Ac, 3: 1) yielded 6-cyanomethyl-8-bromoquinoline.
Bromoquinoline 1-methyl- l-cyanoethyl]-8-bromoquinoline Bromoquinoline Q5 was prepared by the following procedure. To a solution of bromoquinoline Q4 (3g, 12.lmrnol) in THF (lOOmL) at -78CG, was added Mel (1 .7mL, 27mmol) followed by potassium t-butoxide (27mL, 27mxnol). After 2h at -78'C, the mixture was warmed to 0 0 C and was neutralised with saturated NH 4
LO
solution then extracted with EtOAc. The organic extracts were washed (H120, brine), dried (MgSO 4 filtered and concentrated. Purification by flash chromatography (Hex :EtOAc, 3:1) yielded 1-methyl- 1-cyanoethyl]-8-bromoquinoline.
The Benzyl Phosphorus Reagents utilized to prepare the compounds of this invention can be made according to Scheme 6 shown below: SCHEME 6 Preparation of Benzyl Phosphorus Reagents 62 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559
H
3 C CH
R
1 Br
XX
B(OH)
2
GOH
H
3
C
-Qr 1 C H 3 3 C CH 3 sOH X XXIII (X Br) XXIV (X OS02Me) HC H 3
I
R
2
XXV
R' R Benz. Phos. Reag.(XXV) H CH 2 P(Ph) 3 +Br P1 H CH 2 P(O)(OEt) 2 P2 CN CH 2 P(O)(OEt) 2 P3 The arylquinolines of the formula XXII may be prepared by coupling bromoquinoline XX with the boronic acid XXI by heating in the presence of a catalyst such as Pd(PPh 3 4 and a base such as sodium carbonate (aqueous) in a solvent such as a DME. The alcohol XXII may be converted to the bromide XXIII by treatment with HBr (aq) in a solvent such as acetic acid. The alcohol XXII may be converted to the methyl sulfonate ester XXIV by methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane. The benzyl phosphorous reagents XXV may be prepared either by heating XXIII in the presence of PPh 3 in a solvent such as acetonitrile or by treating XXIII or XXIV with diethylphosphite and a base such as potassium t-butoxide in a solvent such as THF.
-63- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 Benzylphosphonium Bromide P1 [3-(6-Isopropyl-8--quinolinyl)benzyl](triphenyl)phosphonium Bromide Benzylphosphonium Bromide P1 was prepared by the following procedure.
Step 1: 6-Isopropyl-8-[3-(hydroxymnethyl)phenyl]quinoline A mixture of 6-isopropyl-8-Bromoquinoline (11.l1g, 44.4mmol) (described in International Patent Publication WO 94/22852), 3- (hydroxyniethyl)phenylboronic acid (8.70g. 57 .2mmnol), Na 2
CO
3 (2M, 7lmL, l42mmol) and Pd(PPh 3 4 (2.5 1mg, 2.l7mmol) in 28OmL of DIVE was stirred at for 5h. The resulting mixture was cooled to diluted with EtOAc, washed with brine, dried over Na 2
SO
4 filtered and concentrated. Flash chromatography (Hex/EtOAc, 111) and stirring in CH 2 Cl~fhexane yielded 6-Isopropyl-8-[3- (hydroxymethyl)phenyllquinoline as a white solid.
.Step 2: 6-Isopropyl-8-[3-(bromomethyl)phenyllquinolinc A suspension of the hydroxymethyl product compound from present step 1 (7.40g, 26.7mmol) in AcOH (5OmL) and HBr (50mL, 48% aq) was stirred for 12h at 100TC. The mixture was cooled to poured into NaOH (2N) in ice, the pH was adjusted to 8 and the mixture was diluted with ether. The organic phase was washed with brine, dried over MgSO 4 filtered and concentrated to yield 6-Isopropyl- 8-[3-(bromomethyl)phenyllquinoline as a yellow solid.
Step 3: [3-(6-Isopropyl-8-quinolinyl)benzyl](triphenyl)phosphonium Bromide To a solution of the bromomethyl product compound from present step 2 (3.807g, 11.l1mmol) in 4OmiL of CH 3 CN was added triphenylphosphine (3.22g, 12.3mmol). The mixture was stirred at 60 0 C for 12h, cooled to diluted with ether, filtered, and washed with ether to yield [3-(6-Isopropyl-8quinolinyl)benzyl] (triphenyl)phosphonium Bromide.
Benzylphosphonate P2 Diethyl 3-(6-isopropyl-8-quinolinyl)benzylphosphonate 64- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 Benzylphosphonate P2 was prepared by the following procedure. The bromomethyl compound from from step 2 above of the synthesis of P1 (I1.34g, leq) ,vsuissolved -i-i irwMM Dicihyiphosphiie (3.87mil, i.05eq) was added and the solution was cooled down to 0 0 C. Next, t-BuOK (3.87mL, 1N in THF) was added slowly. The reaction was stirred 2h and the quenched by addition of NII 4 Cl(sat), water and EtOAc. The organic phase was separated and washed with brine, dried Over MgSO 4 and concentrated. Purification by flash chromatography on silica gel (hexane:EtOAc, 1/9) gave Diethyl 3-(6-isopropyl-8--quinolinyl)benzylphosphonate as a clear oil.
Benzylphosphonate P3 Diethyl 3-[6-(l-.cyano-l -mcthylethyl)-8-quinolinyllbenzylphosphonate Benzylphosphonate P3 was prepared by the following procedure.
Step 1: 6-(1-Cyano-1-methylethyl)-8-[3- (hydroxymethyl)pbenyl]quinoline Following step 1 described above of the procedure for Jlenzylphosphonium Bromide P1, but substituting the bromoquinoline Q5 for 6isopropyl-8-bromoquinoline as the starting material, 6-(1 -Cyano-1 -methylethyl)-8-[3- (hydroxymethyl)phenyllquinoline was obtained.
Step 2: 1-Cyano-1 -methylethyl)-8-quinolinyl]benzyl methanesutfonate To a solution of the alcohol 6-(1-Cyano-1-methylethyl)-8-[3- (hydroxymethyl)phenyl]quinoline from present step I (5.15g, l7nimol) in CH 2 C1 2 (l5OmL) at -78 0 C was added Et 3 N (3.6mL, 26mmoI) and methanesulfonyl chloride ("MsCl") (1.6mL, 2lminol). After 0.5h at the mixture was neutralised with saturated NICI solution, diluted with water and extracted with ether. The organic extracts were washed (H 2 0, brine), dried WgON, filtered and concentrated to yield 1-Cyano-] -methylethyl)-8-quinolinyllbenzyI methanesulfonate as a white foam.
Step 3: Diethyl 3-[6-(1-cyaino-1-methylethyl)-8quinolinyllbenzylphosphonate SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 To a solution of diethyiphosphite (2.5mL, l~mmol) in THF (1lOQL at -78'C was added potassium t-butoxide (IM, TUF, l6mL, l6mmol) and the mesylate comoud 3[6(1Cy.,o I -Y1 -1~niuIyiJ--jiuilIenzyi methanesuifonate from present step 2 1g, 13.5mrnol). After 0.5h at -78'C and 12h at the resulting mixture was neutralised with saturated NH 4 CI solution, diluted with water and extracted with ether. The organic extracts were washed (1120, brine), dried (MgSO 4 filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 1:4 to 1: 10) yielded Diethyl -cyano- 1-methylethyl)-8-qui nolinyllbenzylphosphonate as an oil.
SCHEME 7 Benzyphosphorous Reagent Ketone Coupling HC
CH
3
N
Re- Benz. Phos. Reag.
(XXV)
ViI
ON-
H-
3 C OH 3
RI
N
Me
XXVI
Vill Example (1) Compounds corresponding to the formula I may be prepared using the reaction pathways outlined in Scheme 7 above. The compound XXVI may be -66 SUBST!TUTE SHEET (RULE 26%) WO 01/46151 WO 01/615 1PCT/CAOO/01559 obtained by adding a solution of the ketone VUI in a solvent such as TBF to a mixture of the benzylphosphorous reagent XXV and a base such as potassium t-butoxide in a solvent sucih as TTFF The com-u1nC crespOnding+ tl,. "-MA'la T m.a- U1%cn LAI prepared by treating XXVI with oxone in a mixture of solvents such as THFfMeOH~water. Alternatively the compounds of formula I may be prepared by reacting the ketone vm with XXV in the presence of a base such as potassium tbutoxide in a solvent such as THF.
Referring to Scheme 7 above and Table 1 below, the coupling of the ketones with the benzyl phosphorous reagents resulted in the tabulated Examples.
Tablel Benz. Phos. Reag. Ketone Example P2 K3 1 P2 K3 2 P1 K5 3 P1 K2 4 P2 K1 P2 K1 6 P2 KG 7 P3 KG 8 P3 K2 9 P2 Commercial P2 K7 31 P2 K7 32 P2 K8 33 P2 KS 34 P2 K9 P3 K8 36 P3 K8 37 -67 SUBSTITUTE SHEET (RULE 26)1 WO 01/46151 WO 01/6 151PCT/CAOO/01559 Tablel Rcan, Phos. R~ag. IfKetrone mm P3 K9 38 P3 K10 39 SCHEME 8 Aryl Bromidde Bromoquinoline Coupling
H
3
J
BrB- MeO 2 Sc MeO 2
S
1- 3 C 2 Bramoquinoline INI
H
(XX)
MeO 2 S
R
Aryl Bromide
(XVIII)
Boronate (used in situ) Example (1) Referring to Scheme 8, compounds corresponding to the formula I may be prepared by in situ conversion of the aryl bromide XVII to the corresponding boronate ester by heating with diboron pinacol ester, a catalyst such as 1,1Fbis(diphenylphosphino)-ferrocenejdichloropalladium(Il) and a base such as potassium acetate in a solvent such as DMF, followed by the addition of the bromoquinoline XX, an additional amount of the same catalyst, an additional amount of a base such as sodium carbonate (aqueous) and an additional period of heating.
Referring to Scheme 8 above, Table 2 and Table 2 appendix below, the coupling of the Aryl Bromide with the Bromoquinoline resulted in the tabulated Examples.
-68- SUB3STITU,',TE SHEE T (RULE 26) WO 01/46151 WO 0146151PCTCAOOO 1559 Table 2 Aryl ooun:n xm~ 03 14 Q3 AB2 Q5 16 AB2 Q5 17 AB2 Q3 ABi Q5 21 Q5 22 AB3 Q5 23 AB4 05 24 ABi WO094/22852 WO 94/22852 26 Compounds of this invention can be prepared by following Scheme 9 shown below.
69 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 SCHEME 9 B(OH~q
XXVI
XXVI
N
C0 2
H
MeO 2 S Me( XVI (Example 18) R 2= H (Example 19)
N
I NR 2 R 3 DS 0
XXVIII
Example (1) NR 2R3 ND' Example 27 NH-<1 Example 28 NH (CIH3
CH
3 Example 29 Scheme 9 outlines the preparation of compounds of formnula I where the aldehyde XXVII may be prepared by heating the bromoquinoline XX, 3formylbenzeneboronic acid, a catalyst such as Pd(PPh 3 4 and a base such as sodium 70 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 carbonate (aqueous) in a solvent such as DME. The aldehyde XXVII may be converted to Example 18 by heating with XVI in the presence of a base such as pipeidinie in a suivent such as iuluie. Example 19 may be obtained by treatment of Example 18 with cerric ammonium nitrate in a mixture of solvents such as acetonitrile/water. Alternatively the aldehyde XXVII may be converted to the unsaturated acid XXVIII by heating with XV and a base such as piperidine in a solvent such as toluene. The acid XXVIII may then be converted to the amide I (Example 27, 28 and 29) by treatment with a coupling system such as EDCI, HOBt, and an amine in a solvent such as DIF.
Compounds of this invention can be prepared by coupling Bromoquinoline compounds with Boronate compounds according to Scheme below.
SCHEME Bromoquinoline-Boronate Coupling H3 C H3
R
fYY'" ri R OB.0 1 Br Br Aj 'Ar MeO 2 S MeO 2
S
Bromoquinoline (XX) Boronate Example (I)
(XII)
Scheme 10 describes how compounds of formula I may be obtained by coupling the bromoquinoline XX with the boronate ester XII in the presence of a catalyst such as Pd(OAc) 2 PPh 3 and a base such as sodium carbonate (aqueous) in a solvent such as n-propanol. Referring to Table 3, the coupling of the Bromoquinoline with Boronate resulted in the tabulated Examples.
-71- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 Table 3 Q2 B2 Q3 B2 11 02 B1 12 03 B1 13 03 B3 03 B3 41 Q3 B4 42 EXAMPLES 1 and 2 6-isopropyl-8-(3-{ (ZIE)-2-[4-(methylsulfonyl)phenyl]-2phenylethenyl }phenyl)quinoline
CH
3
CH
3
N
H
3 C, Example 1 72 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 Example 2 Examples 1 and 2 were prepared by the following procedure. To a mixture of benzylphosphonate P2 (330mg, 0.83mmol) and ketone K3 (200mg, 0.77mmol) in THF (6mL) at r.t. was added potassium t-butoxide (1M, THF, 0.83mL, 0.83mmol). After lh at the mixture was diluted with water and extracted with Et 2 O. The organic extracts were washed (H20), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 7:3) produced Examples 1 and 2 as white foams with one product being less polar than the other product. Example 1 was the less polar Z-isomer and Example 2 was the more polar E-isomer.
Example 1: NMR 'H (400MHz, Acetone-d 6 a 8.79 1H), 8.28 (q, IH), 7.94 2H), 7.73 IH), 7.6-7.1 14H), 3.14 1H), 2.97 3H), 1.34 (d, 6H).
Example 2: NMR 'H (400MHz, Acetone-d6) a 8.78 1H), 8.25 (q, IH), 7.89 2H), 7.71 1H), 7.6 3H), 7.45 3H), 7.39-7.2 8H), 3.11 (m, 4H), 1.34 6H).
-73- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 EXAMPLE 3 6-isopropyl-8-{ 3-[(EIZ)-2-[4-(methylsulfonyl)phenyl]-2-( 1,3-thiazol-2yl)ethenyl~jphenyl }quinoline
CH
3
CH
3
N
S-N
6 Example 3 was prepared by the following procedure. To a suspension of the benzylphosphonium bromide P1 (320mg, 0.53 1mmo1) in 2.5mL THF at -78'C was added t-BuOK (1.OM in THE, 0.55rnL, 0.5 Smrol) dropwise and the resulting red solution was stirred 30mmi at 0 0 C To this ylide at -78'C was then added ketone (122mg, 0.455mmo1) in 2mL of THE dropwise. The mixture was warmed to then stired for lh, quenched with a NH 4 Cl (sat.) and diluted with EtOAc. The organic phase was washed with brine, dried over Na 2
SO
4 filtered and concentrated. Flash chromatography (Silica cartridge, HexIEtOAc 10 to 100% in 20min) yielded Example 3 (1.5 to 1 mixture of isomers).
NMR 1 H (500MUi~z in acetone-d 6 a 8.79-8.78 (mn, 111), 8.26-8.23 (mn, 1H1), 8.01-7.92 (in, 3H), 7.84 0.41, minor), 7.78 0.611, major), 7.73-7.47 (mn, 7.43 (dd, 1H1), 7.34 0.6H, major), 7.27 0.41, minor), 7.18 0.6H, major), 7.09 (di, 0.411, minor), 3.12 (in, IM1, 3. 11 1.8K1 major), 2.99 1.2H, minor), 1.36-1.33 (in, 6H1).
74 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 MIS 1) 511.
EXAMPLE 4 6-isopropyl-8-(3- I (E)-2-(1-methyl- 1 H-imnidazol-2-y)-2-14- (methylsulfonyl)phenyljethenyl I}phenyl)quinoline
H
3
C
Example 4 was prepared by the following procedure.
Step 1: 6-isopropyl-8-(3- {(E)-2-(1-methyl- 1H--imiidazol-2-yl)-2-[4- (methylthio)phenyllethenyl }phenyl)quinoline Following the procedure for Example 3 but substituting the ketone K(2 for K5 as the starting material, 6-isopropyl-8-(3-{(E)-2-(1-methyl-1H-iniidazol-2-y)- 2-[4-(methylthio)phenyl]ethenyl lphenyl)quinoline was obtained.
Step 2: 6-isopropyl {(E)-2-(1-methyl-LH-i midazol-2-yI)-2-[4- (methylsutfonyl)phenyllethenyl I phenyl)quinoline Following the procedure used for the preparation of the boronate B1 (step 2 of Scheme 2) but substituting the sulfide obtained in the present step I for 75 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 (EIZ)-2-(3-Bromophenyl)-1-(1-methyl-IH-imi dazol-2-yl)-I (methylthio)phenyl]ethene as the starting material, Example 4 was obtained.
NMvR 'H (500 Mgh in acetone-Q4 a 8.77 (dci, 1M), 8.24 (dd, 1H), 7.88 7.7 1(d, 111), 7.59 111), 7.53 21-1), 7.48 7.41 (dd, IH), 7.28 (t, 111), 7.23 114), 7.15 111), 7.07 111), 6.95 111), 3.51 311), 3.10 (in, 1H1), 2.99 311), 1.32 (di, 611).
MS: 509.4 EXAMPLES 5 and 6 6-isopropyl-8-(3-{ (ZIE)-2-(4-fluorophenyl)-2-[4- (methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
CH
3
CH
3
NJ
S
Example 76 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559
CH
3 Example 6 Examples 5 and 6 were prepared by the following procedure.
Following the procedure for Example 1 but substituting the ketone KI for K3 as the starting material, and purification by flash chromatography %EtOAc/SO%Hexanes) yielded Examples 5 and 6.
NMIR 'H (500M1{z in acetone-d6) Example 5: Major isomer- a 8.78 (dd, 11H), 8.25 (dd, 1H1), 7.93 211), 7.72 111), 7.55-7.40 (in, 6H1), 7.35 (mn, 211), 7.25 111), 7.23 111), 7.11 2H), 7.05 1H), 3.12 (in, 111), 2.96 311), 1.34 611).
NMiR 'H (500Mhz in acetone-d 6 Example 6: Minor isomer: a 8.78 (dd, 1H), 8.35 (dd, 111), 7.93 211), 7.72 1H1), 7.65-7.55 (in, 311), 7.45 (dd, 111), 7.35-7.15 (in, 9H), 3.12 (in, 4H4), 1.34 614).
77 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 EXAMPLE 7 (E/Z)-2-[3-(6-isopropyl-8-quinolinyl)phenyl]- 1-[4- (methylsulfonyl)phenylllethenyl }-1,3-thiiazol-5-yl)-2-propanol
H
3 C
H
OH3
-OH
N
OH
3 N~ S 3 Example 7 was prepared by following the procedure for Example 1 but substituting the ketone K6 for K3 as the starting material. Purification by flash chromatography (100%EtOAc) yielded Example 7 as a mixture of isomers.
NMvIR (400MIHz in acetone-d6) L9 8.80 (in, 111), 8.30 (mn, IM1, 8.05 (d(major), 1.44H), 7.93 (d(rninor), 0.5 5H), 7.85 (s(major), 0.72M), 7.77 (s,(minor), 0.28H), 7.75-7.45 (mn, 7H1) 7.35 (t(minor), 0.28H), 7.28 (t,(major), 0.72H), 7.21 (drminor), 0.28H1), 7.10 (d(major), 0.7211, 4.7 (mn, 1H), 3.15 (in, 111), 3.15 (s(ininor), 0.84), 2.99 (s(major), 2.161-1), 1.60 (in, 611), 1.35 (in, 611).
MS 569.6 78 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMEPLE 8 I-hydroxy-1-methylethyl)-1 ,3-thiazol-2-yl]-2-[4- (niethylsulfonyl)phenyl]ethenyl }phenyl)-6-quinolinyl]-2-methylpropanenitrile
H
3 C
A/N
SCH
3 OH 3
H
N
Example 8 was prepared by following the procedure for Example 1 but substituting the ketone K6 for K3 and the benzyl phosponate P3 for P2 as the starting materials. Purification by flash chromatography (20%CH 2
CI
2 /80%EtOAc) yielded Example 8 as a mixture of isomers.
NMR 'H (400MIHz in acetone-d 6 a 8.92 (mn, 111), 8.45 (in, 1IM, 8.10 (mn, 1W), 8.05 (mn, 1W), 7.93 (in, 1IM, 7.85 (in, 2M, 7.77-7.55 (mn, Xli), 7.40 (t(minor), 0.43H), 7.28 (t,(major), 0.57H), 7.21 (d(minor), 0.43H), 7.10(d(major), 0.57H), 4.67 (s,(inajor), 0.57H1), 4.63 (s(minor), 0.43H), 3.15 (s(minor), 1.3H), 2.99 (s(major), 1.7W), 1.90 (in, 6H), 1.65 (s,(major), 3.4W), 1.45 (s(niinor), 2.611).
MS 594.6 79 SUBSTITUTE SHEET (RULE 26) WO 01146151 WOO1/6151PCT/CAGO/01559 EXAMPLE 9 2-methyl-2-[8-(3- (E)-2-(1-mcthyl-1H-irnidazol-2-yl)-2-[4- (methylsulfonyl)phenyljethenyl }phenyl)-6-quinoliny1]propanenitile
H
3 C CH 3
ZN
N
H
3 0: H1 3
C
Example 9 was prepared by the following procedure.
Step 1: 2-methyl-2-[8-(3-{ (E)-2-(1-methyl-1H-imidazol-2-yl)-2-[4- (methylthio)phenyl]ethenyl }phenyl)-6-quinolinyl]propanenitrile was prepared by following the procedure for Example I but substituting the ketone K2 for K(3 and the benzyl phosphonate P3 for P2 as the starting materials.
Step 2: 2-methyl-2-1i8-(3- {(E)-2-(1-methyl- 1I--imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl Iphenyl)-6-quinolinyllpropanenitrile, Example 9, was prepared by following the procedure used for the preparation of the boronate B1 (step 2 of Scheme 2) but substituting the sulfide obtained in present step 1 for Bromophenyl)-1-( 1-methyl-1H-imidazol-2-yl)-1 44-(methylthio)phenyl]ethene as the starting material. Example 9 was obtained after purification by flash chromatography (97 %EtOAc/3 %Et 3
N).
80 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 NIVR 'H (400 ~h in acetone-d 6 a 8.92 (dd, 111), 8.45 (dd, IM1, 8.10 1H), 7.93 2ff), 7.76 1H), 7.60-7.50 (in, 511), 7.38 111), 7.35 1H1), 7.19 (in, 111), 7.10 (in, 111), 6.95 (mn, 1H), 3.55 31-1), 3.00 3H1), 1.85 611).
MS 533.3 EXAMPLE 1-(methylsulfonyl)ethyll-8- {3-[(E)-2-[4--(methylsulfonyl)phenyl]-2-( 1,3-thiazol-2yl)ethenyl]phenyl }quinoline 0
H
3
C
Example 10 was prepared by the following procedure. A mixture of bromoquinoline Q2 (105mg, 0.33mmol), boronate B2 (236mg, 0.5 immol), Na 2
CO
3 (2M, 0.65mb, 1 .3mmol), Pd(OAC) 2 (6.3mg, 0.O28nimol) and PPh1 3 (28mg, 0. 1 iimol) in 4mL of n-propanol was stirred at 90'C for 2h. The mixture was cooled to diluted with EtOAc, washed with brine, dried over Na 2
SO
4 filtered and concentrated. Flash chromatography (TollAcetone; 4/1) and stirring in Hexane/EtOAc yielded Example 10 (single isomer) as a white solid.
-81- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/46151PC T/CAOO/O 1559 NMR 'H (400MIHz, Acetone-dl 6 a 8.89 (dd, IH), 8.39 (dd, 111), 8.07 1H1), 8.03 2HM, 7.94 1H1), 7.86 1H), 7.71-7.68 (mn, 311) 7.62-7.60 (in, 2H), 7.55 (dd, 111), 7.45 1I1 7.34 111, 7.18 1IM, 4.67 IM1, 3.04 311), 2.86 3H) 1.88 (s,3H) MS 1)576.
EXAA1PLE 11 6-fl -methyl-i -(methylsulfonyl)ethyl]-8-{ 3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(l ,3thiazol-2-yl)ethenyl]phenyl }quinoline Example I11 was prepared by following the procedure described in Example 10 but substituting bromoquinoline Q3 for Q2 and using boronate B2. Flash chromatography (Tol/Acetone; 9/1) and stirring in EtOAc/Hex. yielded Example 11 (single isomer) as a white solid.
82 SUBSTI1 TUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 NMR 'H (400M4Hz, Acetone-d 6 19 8.90 (dd, 1H1), 8.41 (dd, 11H), 8.23 1H), 8.02-7.99 3H1), 7.95 11-1), 7.86 111), 7.70 2H1), 7.60-7.54 (in, 4H1), 7.32 1H1), 7.13 111), 3.00 31H), 2.69 3H1), 1.96 6H) MS 523.
EXAMPLE 12 8-(3-f (Z)-2-(1-methyl-1H-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyllethenyl )phenyl)-6-[1-(methylsulfonyl)ethyllquinoline 0 O CH 3
S
CH
3
N
N N..CH3 Example 12 was prepared following the procedure described in Example 10 using the bromoquinoline Q2 but substituting the boronate BI for boronate B2. Flash chromatography (95%CH 2 Cl 2 /5%EtOH-) yielded the Example 12 compound.
NM~R 'H (400MHz in acetone-d 6 a 8.92 (dd, 111), 8.45 (dd, 111), 8.10 1H1), 7.93 (di, 211), 7.76-7.65 (in, 4H1), 7.59 (dd, 1M1, 7.39 111), 7.26 111), 7.18 111, 7.05 (mn, 2H), 4.70 11H), 3.40 31-1), 3.13 3M1, 2.93 311), 1.87 31H).
MS 572.4 83 SUBSTIITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 EXAMPLE 13 -methyl-1H-imidazol-2-yl)-2-[4- (metliylsulfonyl)phenyljethenyl }phenyl)-6-[1 -methyl-i- (methylsulfonyl)ethyllquinoline 0 Q' CH 3 OH 3
OH
3
N
Example 13 was prepared following the procedure described in Example 10 but substituting the bromnoquinoline Q3 for Q2 and substituting the boronate B1 for boronate B2. Flash chromatography (95%EtOAcI5% Et 3 N) produced Example 13 (single isomer) as a foam.
NM 1H (400Mflz in acetone-4l) a 8.92 (dd, 111), 8.45 (dd, 1H1), 8.37 111), 8.05 111), 7.93 211), 7.76 111), 7.69 211), 7.65 111), 7.59 (dd, 1H1), 7.38 11H), 7.31 111, 7.18 111), 7.05 (in, 211), 3.40 3H1), 3.13 3H1), 2.70 311, 1.95 611).
MS 586.2 84 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLES 14 and 1-methyl-i -(methylsulfonyl)ethyl)-8-(3-{ (E/Z)-2-(3-methyl- 1,2,4-oxadiazol-5-yl)- 2-14-(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline Example 14 Example SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAGO/01559 Examples 14 and 15 were prepared by the following procedure. A solution of the aryl bromide AB5 (249mg, 0.57mmol), diboron pinacol ester (167mg, 0.66mmol), [1,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(L) (12mg, 0.0 l5mmoI) and potassium acetate (176mg, 1.8mmol) in DMEF (Nfl- Dimethylformamide) (l0mL) was degassed and stirred at 80'C for 3h. To that resulting mixture at 25*C was then added the bromoquinoline Q3 (150mg, 0.46mmol), -bis(diphenylphosphino)-ferrocene]dichloropalladium(lI) (12mg, 0.0 l5mmol) and sodium carbonate (O.6mL, 2MW. After degassing, the mixture was heated at 80'C overnight. The mixture was then cooled to r.t. quenched with H 2 0, and extracted with EtOAc. The organic extracts were washed (H 2 0, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (hexane:EtOAc:Et3N, 22:68: 10 then hexane:EtOAc, 3: 1) yielded both isomers (Example 14 and Example NMR 'H4 (500MIHz, Acetone-4) Major(E) isomer (Example 14): a 8.91 (dd, 111), 8.42 (dd, 111), 8.25 111), 8.12 IM1, 8.02 11H), 8.00 21-1), 7.70 (in, 311), 7.64 111), 7.55 (dd, 11H), 7.38 11M, 7.23 111), 3.03 311, 2.69 311), 2.33 3H 1.96 6H1).
MS 588.2 Minor(Z) isomer (Example 15): a 8.92 (dd, 111), 8.45 (dd, 111), 8.29 111), 8.07 111), 7.99 211), 7.88 111), 7.75 (in, 3H1), 7.62 111, 7.58 (q, 111), 7.48 111), 7.24 1M1 3.16 311), 2.70 3H4), 2.38 3H), 2.00 6H).
MS 588.2 Alternatively, Example 14 can be made by the following procedure: 86 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAGO/01559 glycerol Br S3Na NH1 2 qBr N0 2
AIBN
NBS
Br N
CH
3
SO
2 Na Br Mel t-BuONa Pd/C piperidie 1. EDC/HOBt
NOH
2 W02S,1
OH
Example 14 IPhSO 2
OH
Benzenesulfonic acid salt 87 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 Step 1. Skraup Reaction glycerol m-NO 2 PhSO 3 Na MsOH Br N
NH
2 Br To methanesulfonic acid (8-10 equiv) at 20 0 C was added sodium mnitrobenzenesulfonate (0.6-0.8 equiv), followed by iron sulfate heptahydrate (0.01- 0.05 equiv). To the resulting mixture was added 2-bromo-4-methylaniline (1 equiv).
Glycerol (2-3 equiv) was added and the resulting slution was heated at 120-140 0 C and aged until the reaction was complete.
The mixture was cooled to 70-90°C and diluted with water. The solution was then cooled to about 20°C, and neutralized with aqueous NaOH and sodium bicarbonate. MTBE (methyl t-butyl ether) was added and the mixture was filtered and the phases were separated (the product was in the MTBE layer).
Step 2. Bromination AIBN Br N BS
(N
Br Br -88- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 The MTBE solution from step 1 was solvent switched to chlorobenzene. After filtered through Silica gel and partially concentrated, Nbromosuccinimide (NS, 0.6-0.8 equiv) and 2,2'-azo'iisoiUbuLyliUriIe (AIBN, 0.01- 0.1 equiv) were added. The degassed mixture was heated at 55-85 0 C. The resulting mixture was diluted with cyclohexane. Additional NBS (0.3-0.5 equiv) and AIBN (0.01-0.05 equiv) were added. The degassed mixture was heated at about 55-85°C until reaction completed. The mixture was cooled at 10-40 0 C and diluted with cyclohexane and aged. The solid was isolated by filtration.
Step 3. Sulfone Formation Br SO 2 Me
CH
3
SO
2 Na Br Br To a solution of bromomethyl-bromoquinoline (product from previous step, 1 equiv) in DMF was added powdered sodium methanesulfinate (1.0-1.5 equiv) at 10-60 OC. The mixture was heated at about 50-70 0 C for 30min. The mixture was diluted with water while maintaining temp at about 50-70 °C with vigorous stirring, then cooled to about 10-20°C and aged. The mixture was filtered and the solid washed sequentially with 1:4 DMF/water and then water and dried.
Step 4. Methylation
H
S SO2CH3 Na OtBu OC NaOtu 2CH 3 Mel, DMF Mel, DMP -8r Br -89- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 A solution of the sulfone (product from the previous step, 1 equiv) in DMF was cooled to about -10 to 0°C. Sodium t-butoxide equiv) was added A solution of me,,.thyl ididDF solution equiv o el) %was added slowly Wile maintaining temperature at about -10 to O0C.
A second portion of solid sodium t-butoxide equiv) was added, followed by methyl iodide/DMF solution equiv) was added while maintaining the temperature at -5 to 10 OC (Additional base and Mel may be added if the reaction was not completed). The reaction was quenched by adition of water and the product crystallized, which was isolated and dried.
Step 5. Suzuki Coupling so 2 CHs (X OH) 2 S 3
S
0 2 CH Pd/C Br "CHO K 2 C0 3
/DMF
C
HO
To a solution of the sulfone from the previous step (1 equiv) was added Pd/C (5 or 10 0.005-0.1 equiv), potassium carbonate (2-3 equiv), and 3-formyl phenylboronic acid (1-2 equiv). The degassed reaction mixture was heated at 120 0 C until the reaction was complete. The mixture was filtered and the filtrate was diluted with water. The product crystallized and was isolated by filtration and dried.
Step 6. Oxadiazole OH 1. EDC/HOBt H01I- MeO 2 S 2. MeO 2
S
H
2
N
90 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 To the mixture of hydroxy benzotriazole ("HOBt") hydrate (1-1.5 equiv), 4-methylsulfonylphenylacetic acid (1 equiv) in acetonitrile was added EDC hydrochioride (i-i.5 equiv). The slurry was aged at about 20-30C for Other N-OH compounds, such as N-hydroxyphthalimide, 2hydroxypyridine N-oxide, N-hydroxysuccinimide, can also be used to replace HOBt.
Other carbodiimides, such as dicyclohexylcarbodiimide and diisopropylcarbodiimide can be used to replace EDC hydrochloride (ethyl dimethylaminopropylcarbodiimide hydrochloride).
To the slurry was added acetamide oxime (1-1.5 equiv). The resulting mixture was then heated at reflux until the reaction was complete. The resulting solution was concentrated and diluted with ethyl acetate. To the resulting mixture was washed with aqueous sodium bicarbonate. The solution was solvent switched to 2-propanol and product crystallized upon cooling, which was isolated and dried.
Step 7. Condensation to form Example 14 so 2 tMve
N
a SO 2 Me N piperidine N MeO 2
S
CHO
N
MeO 2
S
To a slurry of the aldehyde from step 5 above (1 equiv) in 2-propanol was added the oxadiazole from step 6 above (1-1.5 equiv), followed by piperidine (0.2-1.5 equiv).
In place of 2-propanol, other solvents such as, for example, DMF, acetonitrile, 1-propanol, toluene, esters, and other alcohols. Piperidine serves as a basic initiator. In place of piperidine, other amine bases, especially secondary amines, can be used.
-91- SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 The resulting mixture was heated at retlux over molecular sieves until reaction completed. After cooling, the product was isolated by filtration and dried.
EXAMPLES 16 and 17 3-[6-(1-cyano- 1-methylethyl)-8-quinolinyl]phenyl -N-isopropyl-2-[4- (methylsulfonyl)phenyl]-2-propenam-ide H1 3 0
CH
3
.~N
N
JN
H
N<CH
3 0 0
OCH
3 Example 16 H OH 3
-N
OH
3 92 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAGO/01559 Example 17 Examples 16 and 17 were prepared following the procedure described previously for Examples 14 and 15 but substituting the aryl bromide AB2 for ABS and the bromoquinoline Q5 for Q3 as the starting materials. Examples 16 and 17 were obtained as a 4:1 mixture.
NMvR 'H (500 MIHz, Acetone-d 6 Major(E) isomer (Example 16): a 8.89 (dci, 111'), 8.43 (dci, 111), 8.09 1M1, 7.90 (di, 211), 7.81 1H1), 7.68 1IM, 7.57 (in, 41H), 7.45 111), 7.29 111), 7.04 (di, 1 6.71 (bd, 111), 4.13 (in, 111 2.92 311), 1. 87 611), 1. 12 61H).
MS 538.3 Minor(Z) isomer (Example 17): L9 8.93 (dd, 1M1, 8.48 (dd, 111, 8.14 1M1, 7.94 (in, 7.85 2H1), 7.70 (dci, 21-1), 7.59 111, 7.50 (in, 2 7.28 1H1), 4.15 (mn, 111) 3.13 3H), 1.91 611, 1.04 611).
MS 538.3 EXAMPLE 18 j3-[(4-methoxyphenoxy)methyl]-1 ,2,4-oxadiazol-5-yl I-2-[4- (methylsulfonyl)phenyl]ethcnyl }phenyl)-6-[1-methyl- 1- (inethylsulfonyl)ethyllquinoline 93 SUJBSTITUT E SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 0 3
H
3
C"
Example 18 was prepared by the following procedure.
Step 1 (Scheme (4-methoxyphenoxy)acetonitrile A mixture of 4-methoxyphenol (10g, 8Ommol), chioroacetonitrile (7.OmL, 11 mmol) and KC0 3 (26g, l88mmoI) in acetone (150 rnL) was stirred at r.t. for 18Sh. The mixture was filtered, concentrated and purified by flash chromatography (lHex:EtOAc, 4: 1) to yield (4-methoxyphenoxy)acetonitri le as a clcar oil.
Step 2 (Scheme (4-methoxyphenoxy)acetamide oxiine A mixture of the (4-methoxyphenoxy)acetonitrile product (5.0g, 3l1mmol) from step 1, hydroxylamidne hydrochloride (4.3g, 62mmol) and sodium acetate (5.1g, 62mmol) in MeOH (lO0m]L) was stirred at r.t. for 2h. The resulting mixture was filtered on Celite®, concentrated, stirred in CHCI 3 for i~h and filtered. The resulting solution was concentrated to yield (4-methoxyphenoxy)acetamide oxime as a gum.
94 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 Step 3 (Scheme 3, Oxadiazole 0X2): 3-1(4-methoxyphenoxy)methyll- 5-[4-(methylsulfonyl)benzyl]- I,2,4-oxadiazole 3.-[(4-methoxyphenoxy)meithyij-5-[4-(methylsuifoflyi)belzy1j-l,2,4oxadiazole was prepared following the procedure as described in Scheme 3 for step I (OX1) but substituting the (4-methoxyphenoxy)acetamide oxime from step 2 above for acetamnide oxime and heating the reaction at 90'C for 6h. Purification by flash chromatography (Hex :EtOAc, 3:2 to 1:4) yielded the desired material as a pale brown solid.
Step 4: 1-methyl-i -(methylsulfonyl)ethyl] -8quinolinyl )benzaldehyde To bromoquinoline Q3 (10.1g, 30.9mmol) 3-formylbenzeneboronic acid (5.8g, 38.7mmol), tetrakis(triphenylphosphine)-palladium (2.1ig 1 .86mmol) and sodium carbonate (39mL, 2M was added DME (330mL). After degassing, the mixture was heated at 80 0 C overnight. After cooling to r.t. the resulting mixture was quenched with 1120, and extracted with EtOAc. The organic extracts were washed
(H
2 0, brine), dried (MgSO 4 filtered and concentrated. Stirrng in ether, followed by isolation by filtration gave 3- {6-Il-methyl-1-(methylsulfonyl)ethyl]-8quinolinyl I benzaldehyde.
Step 5: {3-[(4-methoxyphenoxy)methyl] -1 ,2,4-oxadiazol- 5-yl }-2-[4-(methylsulfonyl)phenyl]ethenyl }phenyl)-6-[1-methyl- 1- (methylsulfonyl)ethyllquinoline A mixture of the product from present step 4 (150mg, 0.42mmoI), the oxadiazole 0X2 from present step 3 above (175mg, 0.47mmoI) and piperidine lmL, 1.Ommol) in toluene (0.6mL) was heated at 120 0 C for 3h. The mixture was purified by flash chromatography (IHex:EtOAc, 3:2 to 1:4) to yield Example 18 as a foam.
NMR~ 111 (400IIz, Acetone-tI 6 a 8.90 111), 8.42 1H1), 8.24 (d, 8.20 IM, 8.02 (in, 3M1, 7.75-7.66 (in, 411'), 7.55 111), 7.39 111), 7.25 (d, 95 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 1H1), 7.00 2H1), 6.87 2H1), 5.17 2H1), 3.73 3H1), 3.03 31H), 2.80 311), 1.96 611).
EXAMPLE 19 1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinylI phenyl)-1-[4- (methylsulfonyl)phenyllethenyl 1-1 ,2,4-oxadiazol-3-yl)methanol
H
3 C 9% 0 N
CH
3 0 O\ N
N'
H1 3 C it OH 0 Example 19 was prepared by the following procedure. To a solution of the Example 18 compound (250mg, .35mmol) in acetonitri le: water 8 mL) was added CAN (330mg, 0.62mmol) in two portions at r.t. After 3h at the mixture was diluted with saturated NaHICO 3 solution, diluted with water and extracted with EtOAc. The organic extracts were washed (1120), (brine), dried (MgSO 4 filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 3:7) yielded 6-[l -methyl- I -(methylsulfonyl)ethyl]-8quinolinyl Iphenyl)- I-[4-(methylsulfonyl)phenyl]ethenyI 1-1 ,2,4-oxadiazol-3yl)methanol as a pale yellow foam.
96- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 NMR '1H (400MG-z, Acetone-d 6 a 8.90 1H), 8.42 1H1), 8.25 (d, 1H), 8.15 111, 8.02 (in, 3H), 7.73-7.65 (in, 411, 7.55 111, 7.38 111), 7.23 (d, 111), 4.67 (mn, 3H), 3.04 311), 2.82 3H), 1.96 6H1).
EXAMPLE (E)-N-isopropyl-3-(3-{ 1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl }phenyl)-2- [4-(methylsulfonyl)phenyl]-2-propenamide 11 3 C 0 N
CH
3
NN
H3C"H1C 0 Example 20 was prepared by following the procedure described above for Examples 14 and 15 but substituting the aryl bromide AR2 for AB5, and using the bromoquinoline Q3, as the starting materials.
NMR 1H (300M4Hz, Acetone-d 6 L9 8.89 (dd, 111), 8.41 (dd, 111, 8.22 111), 7.99 111), 7.88 211), 7.67 1H), 7.53 (in, 411), 7.43 1H1), 7.28 (t, 111), 7.05 111), 6.71 (bd, 1117), 4.14 (in, 1H) 2.9 311), 1.95 6H1), 1.13 611).
MS(M+1): 591.3 97 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 EXAMPLE 21 {3-[6-(1-cyano- 1-methylethyl)-8-quinolinyllphenyl) -2-14- (methylsulfonyl)phenyl]-2-propenoic acid 11 3 C CH,
N
OH
H3C 1 Example 21 was prepared by following the procedure described above for Examples 14 and 15 but substituting the aryl bromide ABI for AB5 and the bromoquinoline Q5 for Q3 as the starting materials.
NMR'4 'H1 (500M~z, Methanol) a 8.8 (dd, 1H), 8.38 (dd, 1H), 8.04 (d, 2H), 7.88 211, 7.66 111), 7.55 (in, 4H1), 7.36 114), 7.29 111), 7.18 111), 2.93 31H), 1.88 61H).
MS (M-C0 2 451.4 (negative ion).
98 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 E XAMPLE 22 2-methyl-2-18-(3-{ (E)-2-(3-methyl- 1,2,4-oxadiazol-5-yl)-2-14- (methylsulfonyl)phenyl]ethenyl I phenyl)-6-quinolinyllpropanenitrile Example 22 was prepared by following the procedure described for Examples 14 and 15 using the aryl bromide ABS and substituting the bromoquinoline for Q3 as the starting materials.
NMvR 'H (500 MHz, Acctone-d 6 a 8.90 (dd, 1H), 8.43 (dd, 1H1), 8.1 211), 8.01 2M1, 7.83 111), 7.71 311), 7.66 111, 7.56 111, 7.55 (dd, 1H), 7.38 111), 7.22 111), 3.03 3H), 2.33 3H 1.87 611) MS 535.2 99 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 EXAMPLE 23 (E)-3-({3-[6-(1-cyano-1-methylethyl)-8-quinolinyl~phenyl)}-2-[4- (methyisuifonyi)phenylJ-2-propenamide
H
3 C CH,
NN
NH
2 0\ 0
-S
H
3 C k Example 23 was prepared by following the procedure described above for Examples 14 and 15 but substituting the aryl bromide AB3 for AB5 and the bromnoquinoline Q5 for Q3 as the starting materials, the title compound was obtained.
NMR 'H (500NMz, Acetone-d 6 a 8.89 (dd, 8.43 (dci, 1H), 8.08 (ci, 1H1), 7.93 (di, 2H), 7.8 (di, 2H), 7.6 (in, 41H), 7.48 1H1), 7.31 1H), 7.08 (d, IHM, 6.6 (bs, 111), 6.7 (bs, 11-1), 2.93 3H), 1.87 6H) 100 SU BSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLE 24 (E)-N-(tert-butyl)-3- 1-cyano- 1-methylethyl)-8-quinolinyl]phenyl 1-2-14- (methyisulfonyl)phenyl]-2-propenanhide N OH 3
'T'CH
3
CH
3
H
3 C N Example 24 was prepared by following the procedure described for Examples 14 and 15 but substituting. the aryl bromide AB4 for ABS and the bromoquinoline Q5 for Q3 as the starting materials., NMvR 'H (500M1{z, Acetone-d, 6 a 8.89 (dd, 1H1), 8.43 (dd, 1H1), 8.08 IN), 7.92 211), 7.79 1M1, 7.58 (in, SN), 7.45 IM), 7.29 IN1), 7.04 (d, 1N), 6.4 (bs, 111), 2.93 3N), 1.87 6M1, 1.36 911).
MS (M 553.
101 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLE (E)-3-[3-(6-isopropy-8-quinolinyl)phenyl-2-[4-(methysufoflyl)phenyII-2-propeloic acid
OCH
3 Example 25 was prepared by following the procedure described for Examples 14 and 15 but substituting thc aryl bromide ABi for AB5, and 8-bromoquinoline (described in International Patent Publication W09422852) for Q3, as the starting materials.
NTMR 'H (500lIhz, Acetone-4) a 8.69 (dd, 1H), 8.26 (dd, 1H), 7.85 1H), 7.83 2Hf), 7.68 1M1', 7.51 2H), 7.49 (in, 2H), 7.36 (dd, 1H), 7.31 (t, 1I), 7.20 1H), 7.13 1H), 3.1 (in, 11K), 2.93 3M, 1.36 6H).
MS (M 472.
102 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 EXAMPLE 26 6-isopropyl-8-(3-{ (B)-2-(3-methyl-1I,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyllethenyl I}phenyl)quinoline
CH
3 ~N CHS
N
H
3 CS
CH
3 Example 26 was prepared by following the procedure described for Examples 14 and 15 using the aryl bromide AB5, and substituting 5-isopropyl-8bromoquinoline (described in International Patent Publication W09422852) for Q3 as the starting materials.
NMIR 1H (500MIHz, Acetone-d 6 a 8.80 (dd, 111), 8.29 (dd, 1H), 8.12 1H), 8.03 2H), 7.76 111), 7.73 (in, 31-1), 7.59 7.53 1H), 7.47 (q, 1H), 7.36 1H1), 7.22 1H), 3.1 (in, 111), 2.93 311), 2.33 311) 1.36 61-1).
MS 510.
103 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLE 27 1-methyl-i -(methylsulfonyl)ethyl]-8-quinolinylI lphenyl)-2-[4- (methylsulfonyl)phenyl]-1 -(1-pyrrolidinyl)-2-propen-1 -one
H
3 C OH 3 N
H
0
H
3 C-S
Z,
Example 27 was prepared by the following procedure.
Step 1: 6-[1-methyl-1-(methylsulfonyl)ethyll-8quinolinyl Iphenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid A mixture of 6-I -methyl-1-(methylsutfonyl)ethyll-8quinolinyl Ibenzaldehyde from step 4 of Example 18 (2.33g, 6.6Ommol), 4- (methylsulfonyl)phenyl acetic acid (1.7 1 g, 7.98mmol) and piperidine (0.2Oxn, 1 .98mmnoI) in lOmL of toluene was refluxed for 2 days. The mixture was cooled to diluted with CH 2
CI
2 subjected to flash chromatography (CH 2
CI
2 /EtOAc/AcOH, 50/50/1) and finally stirred with (Et 2
O/CH
2 Cl 2 and isolated to give 6-[lmethyl-i -(methylsulfonyl)ethyl]-8-quinolinyIl }phenyl)-2-[4-(methylsulfonyl)phenyl]- 2-propenoic acid (single isomer) as a white solid.
NMR 1H (400M4Hz, Acetone-d 6 a 8.89 (dd, 1IM, 8.39 (dd, 111), 8.07 111), 8.03 211), 7.94 IM1, 7.86 111), 7.71-7.68 (in, 3H1) 7.62-7.60 (in, 211), 7.55 (dd, 1IM, 7.45 111) 7.34 IM1, 7.18 1H1), 4.67 3.04 3H1), 2.86 3H) 1.88 (s,3H).
MS (M +1)576.
-104- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 Step 2: (E)-3-(3-1{6-[1-methyl- 1-(methylsulfonyl)ethyll-8quinolinyl }phenyl)-2-[4-(methylsulfonyl)phenyl]- 1 -(1-pyrrolidinyl)-2-propen- 1-one A zj i _'iJ k-t U 7Letll y--U~eIyisu~fI.jt.y~j-8quinolinyl }phenyl)-2-[14-(methylsulfonyl)phenyl] -2-propenoic acid (104mng, .9mmol) from the present step 1 above, pyrrolidine (24pL, O.29mmol), EDCI Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (55mg, 0.29mmol) and HOBt (I1-Hydroxybenzotxiazole hydrate) (34mg, O.25mmol) in Im]- of DMF was stirred at r.t. for 12h. The mixture was diluted with EtOAc, washed with N1H 4 CI (sat),
H
2 0 brine, dried over Na 2
SO
4 filtered and concentrated. Stirring in EtOAc/Hex yielded Example 27 as a white solid.
NiIMR H(400Mz, Acetone-ti 6 a 8.88 (dd, 1H), 8.40 (dd, 1H), 8.22 lH), 8.98 1H), 7.88 211), 7.67 211), 7.60 111) 7.55-7.52 (in, 2H) 7.34 111'), 7.18 (di, 111), 7.03 (bs, NH) 3.58 (bs, 2HM, 3.44 (bs, 2H), 3.02 311, 2.69 (s, 3H1) 1.95 611), 1.88 (bs, 411).
MS (M +1)603.
EXAMPLE 28 (E)-N-cyclopropyl-3-(3- 1-methyl-I -(methylsulfonyl)ethyl]-8-quinolinylI phenyl)- 2-[4-(methylsulfonyl)phenyl]-2-propenamide
H
3 C CH 3
I---M
N00
H
0
N
H
3 C S~.
-105 SUBSTI TUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 Example 28 was prepared by following the procedure for step 2 of Example 27 but substituting cyclopropyl amine for pyrrolidine, thus yielding a white soiid.
NMR 1 H (400 MlHz, acetone-d, 6 a 8.8 9 (dci, 1I1), 8.41 (dci, 11H), 8.23 (di, 1H), 7.98 1H), 7.87 214), 7.68 11-1), 7.59-7.53 (in, 4H1), 7.43 111), 7.29 1Ff), 7.04 111), 6.94 (bs, 111), 2.89 311), 2.84-2.80 (in, 111), 2.69 311), 1.96 611), 0.67-0.63 (in, 2117), 0.49-0.45 (in, 21-1).
MS (M +1)589.
EXAMPLE 29 (E)-N-(tert-butyl)-3-(3-{ 6-[1-methyl-1 -(methylsulfonyl)ethyl]-8-quinolinyl Iphenyl)- 2-[4-(inethylsulfonyl)phenyl]-2-propenamidde
H
3 C CH 3 N 00 N
H
H
3 0 0 CH 3 a Example 29 was prepared as a white solid by following the procedure for step 2 of Example 27 but substituting t-butyl amine amine for pyrrolidine.
NMIR HI- (400MIHz, acetone-d 6 a 8.89 (dci, 111), 8.41 (dci, 8.23 111), 7.98 (ci, 11H), 7.90 (di, 2H), 7.59-7.53 (in, 514), 7.43 1H), 7.30 1H), 7.05 11-1), 6.43 (bs, 11H), 2.94 311), 2.69 311), 1.96 611), 1.36 911? 106 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 MS 606.
EXAMPLE 3-[2,2-bis(4-chlorophenyl)vinyllphenyl)}-6-i sopropyiquinoline
OH
3 "N N CH 3
N
Example 30 was prepared by the following procedure. To a mixture of the benzylphosphonate P2 (100mg, 0.25rnmol), 4,4'-dichlorobenzophenone (63mg, 0.25mmol),) in THF (2mL) at r.t. was added potassium t-butoxide (IM, T.HF, 0.35mL, 0.35mmol). After lh at the mixture was diluted with waterfNlb1Cl and extracted with EtOAc. The organic extracts were washed (14 2 (brine), dried (MgSOA) filtered and concentrated. Purification by flash chromatography (IHex:EtOAc, 8:2) yielded Example 30 as a white foam.
NMR 'H (300MG-Iz, acetone-cl 6 a 8.79 (dd, 1I1E), 8.28 (dci, 1I1), 7.74 111), 7.60 (di, Iii), 7.48-7.25 (in, 12H), 7.20-7.16 (mn, 211) 3.13 (hept, 1H), 1.36 6H).
107 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLES 31 AND 32 6-isopropyl-8-(3-{ (E/Z)-2-(6-methyl-3-pyridinyl)-2-[4- Example 31
CH
3 Example 32 108 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 Examples 31 and 32 were prepared by following the procedure described for Example 30 but substituting the ketone K7 for 4,4'dichiorobenzophenone and using the benzyiphosphonate P2 as the starting materials.
NIM 1H (300MHz, Acetone-d 6 isomer (Example 31): a 8.79 (dci, lIH), 8.43 1H), 8.27 (dci, 1H1), 7.95 211), 7.73 1H1), 7.57-7.43 (in, 711), 7.32-7.19 (in, 31H), 7.10 (ci, 111), 3.15 (hept, 111), 2.98 311), 1.34 611).
isomer (Example 32): a 8.79 (dci, 111), 8.35 111), 8.28 (dd, 111), 7.92 7.74 111), 7.61-7.30 (in, 10H1), 7.19 111), 3.13 3M1, 3.11 (hept, 111), 1.35 (di, 6H1).
EXAMPLES 33 AND 34 6-isopropyl-8-(3- {(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl }phcnyl)quinoline Example 33 109 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 Example 34 Examples 33 and 34 were prepared by following the procedure described for Example 30 but substituting the ketone K8 for 4,4'dichlorobenzophenone and using the benzylphosphonate P2 as the starting materials.
NMR 'H (300MIHz, Acetone-d 6 isomer (Example 33): a 8.80 (dd, 111), 8.48 11-1), 8.28 (dd, 11-1), 7.99-7.96 (in, 3H4), 7.97 (in, 111), 7.74 111), 7.6 1- 7.44 (mn, 6M1', 7.27 11-1), 7.07 111), 6.97 111), 3.15 (hept, 111), 2.96 311), 1.36 611.
NMR 'H (300MIHz, Acetone-do5) isomer (Example 34): a 8.79 (dd, 111), 8.52 114), 8.29 (dd, 111), 7.89 2H1), 7.75 111), 7.65-7.54 (in, 411), 7.47 (dd, 111), 7.42-7.23, (in, 5H), 7.11 111), 3.12 311), 3.12 (hept, 111), 1.36 61-1).
110 SUBSTI TUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLE 8-(3-f 2,2-bis [4-(methylsulfonyl)phenyl] vinyl phenyl)-6-isopropylquiinoline
CH
3
H
CH
3 Example 35 was prepared by following the procedure described for Example 30 but substituting the ketone K(9 for 4,4'-dichlorobenzophenone and using the benzylphosphonatc P2 as the starting materials.
NMR 1 H (500Mhz, Acetone-d 6 a 8.80 (dd, 1H), 8.29 (dd, 1H1), 7.98 2H1), 7.93 2M), 7.75 1IM, 7.61 2H1), 7.59-7.56 (in, 3H), 7.50 1IH), 7.48-7.44 (in, 3H1) 7.30 1H), 7.12 111), 3.14 (hept, 111), 3.13 3H), 2.97(s, 3H1), 1.35 6H1).
SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 EXAMPLES 36 AND 37 2-methyl-2-[8-(3-{ (EIZ)-2-(5-methyl-2-pyridinyl)-2-[4- Example 36 Example 37 -112- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 Examples 36 and 37 were prepared by following the procedure described for Example 30 but substituting the ketone K8 for 4,4'starting materials.
INMR 'H (500M~h, Acetone-dr 6 isomer (Example 36): a 8.90 (dd, 1H), 8.47 8.43 (dd, 1H), 8.08 (di, IM1, 8.00 1H1), 7.97 211), 7.83 (d, 1H1) 7.57-7.53 (in, 5H)J, 7.50 1H), 7.28 111), 7.06 I1H), 6.96 (di, 1H1), 2.96 (s, 31H). 2.33 311), 1.88 611).
NMR 'H (300Mfh, Acetone-4) isomer (Example 37): a 8.89 (dcl, 1H1), 8.51 1H1), 8.45 (dci, 111), 8.09 (di, 1H1), 7.89 2H1), 7.72 (di, 1H1), 7.62- 7.56 (in, 5H), 7.43-7.42 (in, 2H1) 7.30 LH), 7.25 (ci, 111), 7.10 (ci, 111), 3.11 (s, 31H), 2.34 311), 1.87 611).
EXAMPLE 38 2-[8-(3-1{2,2-bis [4-(methylsulfonyl)phenyll vinyl phenyl)-6-quinolinyll-2methyipropanenitrile
H
3 C CH 3
NN
CH
3 0 113 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 Example 38 was prepared by following the procedure described for Example 30 but substituting the ketone K9 for 4,4'-dichlorobenzophenone and 2 IF- JU L as E OLO..L 1,Lcu;l 1Unateicadk.
NMIR 'H (500MIHz, Acetone-16): Z9 8.90 (dd, 1H1), 8.44 (dd, 8.09 111), 7.97 211), 7.92 211), 7.81 1H1), 7.61 211) 7.58-7.55 (in, 311), 3 1 7.44 I 7.32 111), 7.13 11H), 6.96 11H), 3.13 311), 2.97 3H), 1.86 6H).
EXAMPLE 39 2-methyl-2-(8-143-[(E)-2-[4-(mnethylsulfonyl)phenyl]-2-(2-pyridinyl)ethenyl]pheny
I-
6-quinolinyl)propanenitile
H
3 C
CH
3 N
N
N
s=o
//I
OCH
3 Example 39 was prepared by following the procedure described for Example 30 but substituting the ketone K1O for 4,4'-dichlorobenzophenone and substituting the benzylphosphonate P3 for P2 as the starting materials.
NUR 1H (300M4Hz, Acetone-d,4): a 8.90 (dd, 1H), 8.45 (dd, 111), 8.11-8.09 (in, 211), 7.84-7.80 (mn, 3H4), 7.72-7.69 (mn, 111), 7.63-7.52 (in, 511), 7.43- 7.38 (in, 211), 7.33 111) 7.28 1H), 7.14 1H), 2.97 311), 1.86 611) 114 SUBSTITUTE SHEET (RULE 26) WO OV46151 WO 0146151PCT/CAOO/01559 EXAMPLES 40 AND 41 6-[i -inihyi- i -(rnlediyisuifonyi)ethyi j-8-tj- j (ni4Z-2-(5-methyi-2-pyridiny)-2-[4- (methylsulfonyl)phenyllethenyl I phenyl)quinoline
H
3 C
OH
3 N. CH3
N
H
3 C S, H 3 Example
H
3 C
CH
3 N- CH 3
N
H3C sCH 115 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 Example 41 Examples 41 and 42 were prepared by following the procedure described in Example 10 but substituting bromoquinoline Q3 for Q2 and substituting boron ate B3 for boronate B2.
NMR 'H (400MIHz, Acetone-d6) isomer (Example 40): a) 8.91 (dd, 8.45 1H), 8.41 (dd, 1H1), 8.23 1H), 8.01-8.00 (in, 2H), 7.95 (d, 2H), 7.57-7.54 (in, 4H), 7.51 1H) 7.49 111), 7.28 1H), 7.07 1Hi), 6.96 11-1), 2.94 311, 2.69 311), 2.33 311), 1.97 6M1.
NMR 'H (400M~H, Acetone-do5) isomer (Example 41): a 8.88 (dd, 111), 8.49 111), 8.42 (dd, 11H), 8.24 (dd, I1H), 7.94 1I-H), 7.8 8 2H), 7.61 7.55 (in, 514), 7.47 1H), 7.40 1H1), 7.29 1H1), 7.24 111), 7.06 1H1), 3.12 311, 2.68 311, 2.33 311), 1.96 611).
EXAMPLE 42 {6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl Iphenyl)- 1- [4-(methylsulfonyl)phenyl]ethenyl }-3-pyridinyl)-2-pTopanoI
H
3 C CH 3 N- 00
N
-116- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 Example 42 was prepared by following the procedure described in Example 10 but substituting bromoquinoline Q3 for Q2 and substituting boronate B4 for boronate i2.
NMR tH (500 MHz, Acetone-d6): a 8.91 (dd, 1H), 8.80 1H), 8.42 (dd, 1H), 8.23 1H), 8.03-8.01 2H), 7.96 1H), 7.82 (dd, 1H), 7.58-7.54 (m, 4H), 7.51 1H), 7.29 1H), 7.08 1H), 7.01 1H), 4.31 1H), 2.96 3H), 2.70 3H), 1.96 6H), 1.56 6H).
EXAMPLE 43
.N\
0 0 0 Example 43 was prepared following the procedure described previously for Examples 14 and 15 but substituting the aryl bromide AB6 for and the bromoquinoline Q5 for Q3 as the starting materials.
Additional Examples are the following: -117- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559
S
0 0 0 0/1 0 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/O 1559 119 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCTCAOO/01559
S
0 0 120 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 0
N>
SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CA00101559 0 0 122 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 123 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PTCO/15 PCT/CAOO/01559 .s.
0 0 124 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAGO/01559 ol IN 0 0 0 125 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559
N
0
N
SI0 0 0 0 126 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAGO/01559 127 SUBSTITUTE SHEET (RULE 26) WO 01146151 WO 01/6 151PCT/CAOO/01559 128 SUBSTiTUTE SHEET (RULE 26) WO 01146151 WO 0146151PCT/CAOO/01559 129 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/O 1559 -130- SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 0
S,
131 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 132 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 o0 o0 133 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCTICAOO/01559 134 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/0 1559 135 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 136 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 137 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 0 138 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CA00101559 F yF 0 139 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 140 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 141 SUBSTITUTE SHEET (RULE 26) WO 01/46 151 PCTICAOO/01559 142 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 143 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 144 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 145 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 146 SUBSTITUTE SHEET (RULE 26) WO 01146151 WO 01/615 1PCT/CAOO/01559 147 SUBS TITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 -148- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 149 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/0 1559 150 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 151 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 152 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 153 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 154 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559
S
0 0 -155- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 156 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 157 SUBSTITUTE SHEET (RULE 26) WO 01/46151PT/A PCT/CAGO/01559 158 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 159 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559 160 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559
S
161 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 >0
S
162 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 163 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 164 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559
S
O O 0 0 -165- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 o00 -166- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 0 0
/I
0 -167- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/0I559
SO
o'/I -168- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 169 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAGO/01559 0 0 170 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 -171- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 172 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAOO/01559
F
F
F
173 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PC T/CAOO/0 1559
S
0 0 174 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 175 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559
-S
0 176 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 177 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 -178- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOOI/6151PCT/CAOO/01559 179 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559
\F
F
1
F
180 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 0 0 181 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559
S
0 0
NN
182 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 -183- SUBSTiTUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 184 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 185 SUBSTiTUTE SHEET (RULE 26) WO 01/46 151 PCT/CAOO/01559 0 o0 186 SUBSTITUTE SHEET (RULE 26) WO 0146151PCT/CAOO/01559 WO 01/46151 187 SUBSTITUTE SHEET (RIULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 188 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01559 WOO01/46151 189 SuBSTTUTESHEET (RULE 26)1 WO 01/46151 PCT/CADO/01559 0 -190- SUBSTITUTE SHEET (RULE 26) PCTICAO/0155 9 Wo 01/46 151 191 SUBSTITUTE SHEET (RULE 26) PCTCAO/IO1559 Wo 01/46151 192 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/0155 9 Wo 01/46151 193 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 559 Wo 01/46151 194 SUBSTITUTE SHEET (RULE 26) WO 0146151PCT/CAGO/01 5 9 00 N 9 SUBSTITUTE SHEET (RULE 26) WO 0146151PCT/CAOO/01 59
NN
00
N
196 SUBSTITUTE SHEET (RULE 26)1 PCT/CAOIO155 9 Wo 01/46151 197 SUBSTITUTE SH-EET (RULE 26) PCT/CAOO/01 559 Wo 01/46151 198 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 559 Wo 01/46151 0 0 199 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 559 WO ol/461 5 1
S
0l 0 200 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 55 9 Wo 01/46151 0 0-- -201- SUBSTITUTE SHEET (RULE 26) PCT/CAO/0155 9 Wo 01/46151 202 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 55 9 W0 01/4 6 1 5 1 203 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 55 9 Wo 01/46151 204 SUBSTITUTE SHEET (RULE 26) PCT/CAGO/01 55 9 WO 01/46151 0 N4 -205- SUBSTITUTE SHEET (RULE 26) WO 01/46 151 PCT/CADO/01559
S/I
0 206 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WOO1/6151PCT/CAGO/01559 0 0 207 SUBS TITUTE SHEET (RULE 26) PCT/CAGO/01 5 59 WO 01/461 5 1 Ni 0 -208- SUBSTITUTE SHEET (RULE 26) PCTCAOOIO 1559 Wo 01/46151 209 SUBSTITUTE SHEET (RULE 26) PCT/CAOO/01 559 WO 01/46151 0 0 -210- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 211 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCTCAOOO 1559 212 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 Salts of the Examples As discussed above, pharmaceutically acceptable salts are often desirable. Examples of such salts are described below: General Method for Salt Preparation Salts of the compounds of this invention that are basic may be prepared in several ways: a) The compound is dissolved in acceptable solvent such as ethyl acetate. An acceptable acid such as hydrochloric acid in an acceptable solvent such as 1,4- -213- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 dioxane is then added. The precipitated salt slurry is aged and the salt is then isolated by filtration.
b) The compound and an acceptable acid such as benzenesulfonic acid are dissolved in an acceptable solvent such as isopropyl acetate or in a mixture of solvents such as isopropyl acetate and methanol. The salt may then be isolated by concentration or a solvent switch, leading to precipitation, followed by filtration. The more stable crystal form of the salt may be obtained by equilibration of the precipitated salt slurry by heating and aging prior to filtration. Seed crystals from previous batches may also be added prior to equilibration of the salt slurry, to initiate the process of crystallization and equilibration.
SULFURIC ACID SALT OF THE EXAMPLE 14 COMPOUND The sulfuric acid salt of the example 14 compound was prepared by dissolving the compound (1.00 equiv) in refluxing ethyl acetate. After cooling to room temperature, sulfuric acid (1.04 equiv) was added slowly, while stirring. The resulting suspension was stirred a further 40 minutes and the solid was isolated by filtration and washed with ethyl acetate to give the sulfuric acid salt of the example 14 compound.
1H NMR (500 MHz, acetone-d6): d 9.45 1H), 9.23 1H), 8.65 (d, 1H), 8.25 IH), 8.16 (dd, 1H), 8.10 1H), 7.99 2H), 7.80 2H), 7.60 1H), 7.49 1H), 7.45 1H), 7.30 1H), 3.09 3H), 2.77 3H), 2.33 3H), 2.01 6H).
METHANESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND The methanesulfonic acid salt of the example 14 compound was prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate. After cooling to room temperature, methanesulfonic acid (1.1 equiv) was added slowly, while stirring. The resulting suspension was stirred, allowed to concentrate by evaporation and the solid was isolated by filtration and washed with ether to give the methanesulfonic acid salt of the example 14 compound.
-214- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 1H NMR (500 MHz, acetone-d6): d 9.45 1H), 9.32 1H), 8.70 (s, 1H), 8.27 IH), 8.22 1H), 8.11 1H), 7.99 2H), 7.78 2H), 7.61 1H), 7.49 21). 7.35 1H), 3.09 3H) 2.78 3H), 2.33 31H) 2.01 6H).
p-TOLUENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND The p-toluenesulfonic acid salt of the example 14 compound was prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate. After cooling to room temperature, p-toluenesulfonic acid (1.1 equiv) in ethyl acetate was added slowly. The solution was concentrated and the suspension was aged with stirring and periodic sonication at room temperature for 3 days. The solid was then isolated by filtration and washed with ethyl acetate to give the p-toluenesulfonic acid salt of the example 14 compound).
mp 184-185 "C.
1H NMR (500 MHz, acetone-d6): d 9.58 1H), 9.22 1H), 8.63 (s, 1H), 8.23 1H), 8.16 1H), 8.03 1H), 7.94 2H), 7.73 2H), 7.55 3H), 7.45 1H), 7.40 1H), 7.27 1H), 7.12 2H), 3.07 3H), 2.75 3H), 2.33 3H), 2.29 3H), 2.01 6H).
2-NAPHTHALENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND The 2-naphthalenesulfonic acid salt of the example 14 compound was prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate. After cooling to room temperature, 2-naphthalenesulfonic acid (1.1 equiv) in ethyl acetate was added slowly, followed by ethanol. Toluene was then added to the solution, followed by concentration. More toluene was then added and the suspension was aged with stirring and periodic sonication at room temperature for 24h. The solid was then isolated by filtration and washed with toluene to give the 2-naphthalenesulfonic acid salt of the example 14 compound.
mp 202-204 "C.
1H NMR (500 MHz, acetone-d6): d 9.64 1H), 9.30 1H), 8.67 (d, 1H), 8.25 1H), 8.23 1H), 8.16 1H), 7.99 1H), 7.91 2H), 7.87 2H), 7.82 1H), 7.72 (dd, 1H), 7.68 2H), 7.54 1H), 7.52 2H), 7.43 (brs, 1H), 7.37 1H), 7.22 1H), 3.03 3H), 2.76 3H), 2.33 3H), 2.02 6H).
-215- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 HYDROCHLORIDE SALT OF THE EXAMPLE 43 COMPOUND The hydrochloride salt of the example 43 compound was prepared by dissolving the compound (1.0 equiv) in ethyl acetate with heating and sonication.
After cooling the solution to room temperature, HC1 in 1,4-dioxane (4M, 1.0 equiv) was added while stirring. The suspension was stirred for a further 5 minutes and the solid was isolated by filtration to give the mono-hydrochloride salt of the example 43 compound.
BENZENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND The benzenesulfonic acid salt of the Example 14 compound is available in two crystalline forms ("Form A" and "Form The forms are produced by the following procedures: Salt Formation
SO
2 Me SO 2 Me N S Ethyl Acetate
HO
3 S 1 S 0-s-0methanol MeO 2 Me0 Form A To a slurry of the Example 14 compound (1 equiv) in ethyl acetate was added benzenesulfonic acid (1-1.2 equiv). Other esters may be used in place of ethyl acetate. Methanol was added and the resulting mixture was heated until the solid dissolved. Other alcohols such as ethanol or propanol may be used in place of the methanol.
216 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 The resulting solution was filtered and concentrated. The product crystallized during concentration. The resulting mixture was diluted with ethyl acetate and aged. The yellow solid was collected by filtration.
HPLC indicated a 1:1 molar ratio of 6-[1-methyl-1- (methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl- ,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl]quinoline and benzenesulfonic acid.
m.p. by DSC: 193 0
C.
The X-ray Powder Diffraction ("XRPD") Spectrogram for the Form A is shown in Fig. 1. The identifying peaks are tabulated below and shown in Fig. 4.
Peaks Identifying Form A Polymorph (°2Theta) 10.0 19.5 21.4 22.4 30.5 Form B To a slurry of the Example 14 compound (1 equiv) in a mixture of isopropyl acetate (i-PrOAc) and methanol was added benzenesulfonic acid (1- 1.2 equiv). Other esters may be used in place of i-PrOAc and other alcohols such as ethanol or propanol may be used in place of methanol. The mixture was aged at 20 °C until the solids dissolved. The resulting solution was filtered and distilled while the volume was maintained by addition of a 9:1 mixture of i- PrOAc/methanol. The product crystallized during the distillation.
The resulting mixture was aged at 20 70 °C for 2-10 h to ensure complete formation of Form B. The resulting off-white solid was isolated by filtration and dried.
-217- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 HPLC indicated a 1:1 molar ratio of 6-[1-methyl-1- (methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl]quinoline and benzenesulfonic acid.
m.p. by DSC: 210°C The XRPD Spectrogram for the Form B is shown in Fig. 2. The identifying peaks are tabulated below and shown in Fig. 5. The spectra are compared in Fig. 3 with the identifying peaks pointed out by arrows.
Peaks Identifying Form B Polymorph 2Theta) 14.4 17.7 20.0 20.2 23.7 28.9 Other variations or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention. This invention is not to be limited except as set forth in the following claims.
218 SUBSTITUTE SHEET (RULE 26)

Claims (24)

  1. 01-02-2002 CO~ CA000155s' WHAT IS CLAIMED IS: 1. A copound represented by Formula S, S 2 N S3 I A YR 3 or a pharmaceutically acceptable salt thereof, wherein: S1, S2, and S3 are independently H, -OH, halogen, -Cl-C6alkyl, -N02, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; R 1 is a H, OH, halogen, -C I -C6alkyl group, -cycloC2-C6alkyl group, -C I-C6alkenyl group, -C I-C6alkoxy group, aryl group, heteroaryl group, -CN, -heterocycloC3-C6alkyl group, -amino group, -Cl-C~alkylamino group, I -C6a~kyl)(C I -C6alkyl)amino group, -C I -C6allcyl(oxy)C 1 -C6 Ialkyl group, -C(O)NH(aryl) group, -C(O)NI{(heteroaryl) group, -SOnNH(aryl) group, -SOnNH(heteroaryl) group, -SOnNH(Cl1-C6allcyl) group, -C(O)N(CO-C6a~kYl)(CO-C6alkyl) group, -NH-SOn-(Cl1-C6alkyl) group, -SOn-(C 1 -C6allcyl) group, -(Ci1 -C6alkyi)-O-C(CN)-dialcylanino group, or l-C6alkyl)-SOn-(Cl-C6alkyl) group, wherein any of the groupis is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C I-C6alcyl, -cycloC3-C6alkyl, -C(O)(hetercyco C6allcyl), -C(O)-O-(CO-C6alkyl), -C(O)-aryloxy, -C I -C6allcoxy, -(CQ-C6a~kYl)(CO-C6allcyl)anlino, cycloalkyloxy, acyl, acyloxy, -cYcloC3- C6alkyl, heterocycloC3 -C6atkyl, aryl, heteroaryl, -NHC(O)OC 1 :4 alkyl, -OC(O)NHCI-C 4 alkyl, or -SOn-(Cl-C6alcyl); A is CH, C-ester, or C-R4; R2 and R3 independently is an aryl group, heteroI (I group, H, halogen, -CN, -C I-C6alkyl group, -heterocycloC3 -C6alkyl, -C I-O6alcoxy group, AMENDED SHEET 0 2 -2 02 O.%O39 \C A 0 0 0 155 Is -NHC(O)0C I-C 4 ailkyl, -OC(O)NHC I-C 4 alkyl, -C(O)OH, -(Ci -C6alkyl)-SOn-(C1-C6alcyl) group, -C(O)N(CO-C6alkyl)i(CO1-C6alcYl) group, or -C I -C~akylacylamino group, wherein any of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently a halogen, -N02, -C(O)OH, -CN, N-oxide, -OH, or an aryl, heteroaryl, -C I -C6alcyl, -SOn-(C I -C6all), -SOn-(aryl), aryloxy, -heteroaryloxy, C I C6alkoxy, -C(O)-heterocycloC3-C6alcyl, -NH-cycloC3-C6alkyl, amino, -(CO-C6allcyl)(CO-C6alkyl)amino, or -C(O)-N(CO-C6allcyl)(CO-C6alcyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C I-C6allcoxy, -C I-C6alkyl, -cycloC3-C6al IkYl, aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1- I 6alkyl), or -C(O)-N(CO-C6alklcy)(CO-C6alkyl), -CH 2 -O-C 6 H 5 -OCH 3 or-()NJ; one of R2 and R3 must be an aryl or heteroaryl, op tionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optionally connected by a thio, oxy, or (Cl-C4alkyl)bridge to frm a fused three ring system; R4 is an aryl group, -C I -C6alkyl group, heteroaryl group, -CN, NHC(O)0C 1 -C 4 ailkyl, -OC(O)NHC 1 -04 ailkyl, -(Ci -C6alkyl)-SOn-(CI1-C6alkyl) group, -C(O)N(CO-C6alky1)(CO-C6alkyl) group, or -C I-C6alkylacylamino group, wherein any of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently a -CN, halogen, -C(O)(CO-C6alkyl -C(O)O(CO-C6alcyl), -Cl -C6alkyl, -SOn-(C 1-C6alkyl)$ -OH, Ci- -Callcoxy, or -(CO-C6alkyl)(CO-C6a~kyl)amino; n is independently 0, 1, or 2; and R2 or R3 may optionally be joined to R4 by a bond to form a ring.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is CH.
  3. 3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R I is a -C I-C6alcyl, optionally substituted with 1-5 substit Ulents; wherein each substituent is independently a halogen, -OH, -ON, -C(O)(heterocYcloC3- AMEN DED SHEET 01-02-2002 COO 3 A 0 0 0 15 5 c- C6alkyl), -C(O)-O-(CO-C6alcyl), -G(O)-O-aryl, alkoxy, cycloall acyloxy, -cYcloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, hetero, MNIC(OU)0C 1 j-C 4 aikyi, -OC(ONI-C 1 -C 4 ailkyl, -(CO-C6alkyl)(CC or -SOn-(G 1 -C6alkyl). yloxy, acyl, -C6allcyl)axnino
  4. 4. The compound according to claim 2, or a Oharmaceutically acceptable salt thereof, wherein RI is a -cyclOC3-C6alkyl, optionally substituted with substituents; wherein each substituent is independently a halIogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(C0-C6alkyl),' -G(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cyclOC3-G6alkyl, heterocYcloC3- C6alkyl, aryl, heteroaryl, -NI{C(O)0CI-G 4 alkyl, -OC(O)NHC 1 -G 4 alkyl, -(CO-C6alkyl)(CO-C6alkyl)amino, or -SOn-(C I -C6alkyl).
  5. 5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, whereinI RI is a -C2-C6alkenyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocYclOC3 -C6allcyl), -C(O)-O-(CO-C6alcyl), -G(O)-O-arl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cyclOC3-C6alkyl, heterocycloC3-C alkl aryl, heteroaryl, -NHC(O)0CI-C 4 alkyl, -OC(O)NHI{C-C 4 ailkyl, -(CO-C6alkyl)(CO-C6alcyl)amino, or -SOn-(C I -C6alkyl).
  6. 6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, whereinI RI is a heteroaryl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -GN, -C(O)(heterocYclOC3-C~alkyl), -C(O)-O-(Cc,-C6alkyl), -C(O)-O-aryl, alkoxy, cycloatkyloxy, acyl, acyloxy, -cYcloC3-C6alcyl, heterocycloC3-C6alkyl, aryl, heteroaryl, -NHC(O)0C 1 -C 4 alkyl, -OC(O)NHC 1 -C 4 alkyl, -(CO-C6allcyl)(CO-C6allcyl)amino, or -SOn-(Cl1-C6allcyl). AMENDED SHEET
  7. 7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is an -amino group, -C 1 -C 6 alkylamino group, or -(Ci-C 6 alkyl)(CI-C 6 alkyl)amino group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC 3 -C 6 alkyl), -C(O)-O-(Co-C 6 alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC 3 -C 6 alkyl, heterocycloC 3 -C6alkyl, aryl, heteroaryl, -NHC(O)OCI-C 4 alkyl, -OC(O)NHCi-C 4 alkyl, -(Co-C 6 alkyl)(Co-C 6 alkyl)amino, or -SOn-(Ci-C6alkyl).
  8. 8. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl, optionally substituted with 1-5 substituents; and R 3 is a heteroaryl, optionally substituted with 1-5 substituents.
  9. 9. The compound according to claim 2, or a pharmaceutically acceptable 15 salt thereof, wherein R 2 i an aryl, optionally substituted with 1-5 substituents; and R 3 is an aryl, optionally substituted with 1-5 substituents; and The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein 20 R 2 is -NHC(O)OCI-C 4 alkyl, -OC(O)NHCi-C 4 alkyl, optionally substituted with 1-2 substituents; and R 3 is an aryl, optionally substituted with 1-5 substituents. str 11. The compound according to claim 2, or a pharmaceutically acceptable •salt thereof, wherein 222 [R:\LIBZZ]8041 .doc:JIN R2 ad R3arc achindependently an aryl, optionally substituted, connected to each other by a thio, oxy, or (ClI-C4alcyl) bridge to form a fused three ring system.
  10. 12. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a -(C1-C6alkyl)-SO-(Cl-CacyJ), optionally substituted with 1-5 substituents, wherein each substituent is independently a halogen, -N02, -COOH, -CN, -Cl-C6alkyl, -SOn-(Cl-C6alcyI), -0-aryl, -0-heteroaryl, -G(O)-heterocycloC3-C6dlkyl, -NH-cycloC3-C6acyL, -OH, or -(Co-.C6alkyl)(CO-C6alkyl)ainino substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(ClI-C,6alcyl), -O(aryl), -COOH,. -COO(C I-C6alkyl), halogen, -N02, CN, or 15 -C(O)-N(Co -C6alkYl)(CO-C6alcyl); and R3 is an aryl, optionally substituted with 1-5 substituents. 6% 0
  11. 13. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein **R2 is a -C(O)N-(CO-C6alkyl)(CO-C~alkyl), optionAlly substituted with 1-5 substituents; and R3is anaryl, -optionally substituted with 1-5 substituents.
  12. 14. The compound according to claim 2, or a pharmaceutically ****acceptable satthereof, wherein R3 is an -aryl, optionally substituted with 1-5 ubstituents R2 and R3 each independently is an aryl or heteroaryl, wherein each is optionally substituted with 1-5 substituents; and R2 and R3 may be optionally connected by a thio, oxy, or (Ci- C4alkyl) bridge to form a fused three ring system.
  13. 16. Tihe compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein S1, S2, and S3 are each H; RI is -CGI-C6alkyl, optionally substituted with 1-5 substituents; R2 and R3 each independently is an aryl or heteroaryl, wherein each is optionally substituted with 1-5 substituents; and R2 and R3 may be optionally connected by a thio, oxy, or (Ci- C4alkyl) bridge to form a fused three ring system. 10I17 The compound according to claim 1, comprising CH 3 OH 3 N H3 S C* 11* *0 224 WO 01/46151 PCT/CAOO/01559 OH 3 OH 3 N S,-N ~S-CH3 225 SUBSTITUTE SHEET (RULE 26) WO 01/46151PC/A PCT/CAOO/01559 OH 3 H 3 N- H3C.I 26 SUBTIUT SEET(RLE26 WO 01/46151 WO 01/615 1PCT/CAOO/01559 9H 3 227 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 HH 3 C 228 SUBSTITUTE SHEET (RULE 26) WO 01/4615 1 PTCO/1 PCT/CAOO/01559 ,CH 3 229 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 'CH 3 0 0. CH 3 CH3 CH 3 N N s-CCI 3 230 SUBSTiTUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 CH 3 0 -231- SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 1krH N N rCH 3 s A 0 OH 3 H 3 C* X 0 H 3 C CHH 3 OH 3 0 232 SUBSTITUTE SHEET (RULE 26) C C C C C C C C. C C. C CC C. C C -233- WO 01/46151 WO 0146151PCT/CAOO/01559 H 3 C 0 C H 0 ~JCH 3 I H 3 C H N 0 HAC CH 3 OH 234 SUBSTITUTE SHEET (RULE 26) WO 01/6 151PCT/CAOO/01559 WO 01/46151 NH 2 235 SUBSTITUTE SHEET (RULE 26)1 WO 01/46151 WO 01/6 151PCT/CAOO/0 1559 N OH 3 YCH 3 0 CH 3 CH 3 N C H 3 OH 0 236 SUBSTITU..TE SHEET (RULE 26) WO 01/46151 WO 01/6 151PCT/CAOO/01559 H3C CH 3 H1 3 C CH 3 -l- N'N H C-S, 0 237 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 s CH 3 IS 238 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CA00/01559 -239- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 CH 3 N. CH 3 N N 0::s CH3 CH3 CH 3 CHH3 3"C I~ CH 3 -240- SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 CH 3 CHs 241 SUBSTITUTE SHEET (RULE 26) WO 01/46151 PCT/CAOO/01559 CH 3 242 SUBSTIUTE SHEET (RULE 26) WO 01/46151 WO 01/615 1PCT/CAOO/01559 H 3 N N N s=o //I OCH 3 243 SUBSTITUTE SHEET (RULE 26) WO 01/46151 WO 0146151PCT/CAOO/01559 244 SUBSTITUTE SHEET (RULE 26) V r N\ r r S O(/1 I O or a pharmaceutically acceptable salt thereof. 8. The compound according to claim i, selected from 6-isopropyl-g-(3-~ (2/E)-2-~4-(methylsuIlonyl)phenyl]-2- phenylethen~l) phenyl)quinoline; -245- 6 -isopropyl-8- 3 -[(E/Z)-2-[4-(methylsulfonyl)phnyly2.(1 ,3 -tbiazol-2- Yl)ethenyl]phenyl quinoline; 6 -isopropyl-8-(3- {(E)-2-I-.methyl- IH-imidazol-2-yl)-2-[4. (methylsulfonyl)pieny]etIeny1}phenyl)quinoline; 6 -isopropyl-8-(3- {(ZL)-2-(4-fluorophenyl)2.{4 (methylsulfonyl)phenyl] effenyl}pheny)qunoie; {(E/Z)-2-[3-{6-isopropyl.s.quinoiny)pheny}..l (methylsulfonyl)plienyljethenyl} -l, 3 -thiazol-5-yl).2-propanol; -hydroxy-1-methylethyl)4 ,3-thiazol-2-yl]-2-[4- (mtysloy~hnlehnlpey)--unlnl--ehlrpnntie 1-methyl-i H-imidazol-2-yl)-2-[4. .(methylsu~ony)pheny 1]teytheyl)phenyiiaoiy1propaeatde; l-(methylsulfonyl)effivllg..{ 3 -[(E)-2-[4-(methylsulfonv1'~ohenyl]i24(1, Sthiazol-2-yl)ethenyl]phenyl}qioie 6-Imty--(ehl fny~tyj8{ 3 -[(E)-2-[4-{methylsuifonyl)phenyl]-2- 0. 5(1 3 -thiazol-2-yl)ethenyl]phenyl} qu'- -oline; (methylsufonyl)pheny]ethenyl~pheny)6[ l-(methylsulfonyl)etiyl]quinoine; -Iethyl-IHl{imidazol-2.yl)-2-[4- (methylsulfonyi)phenyl]ethlenyl~phenyl)6[l 1 tyll (methylsulfony)ethylquinoie; 1-methyl--(methylsulfonyl)ethyl.8-(3- {(E/Z)-2-(3-methl 24oaizl5 S. y)- 2 4 -(methylsulfonyl)phenyljethenyl~phenyl)quinoline; SE.: 6-cyano-l-methylethyl)-8-quinolinyjphenyl} -N-isopropyl-2-[4- (methylsulfonyl)phenyl]y2-.propenmide; l-methyl-l-(methylsulfonyl)ethyl-8-quinoinyl~phenylyd (raethylsulfonyl)phenyljethenyl} 2 4 -oxadiazol-3-yl)methanol; (E)-N-isopropy-3-.(3- 1-methyl-i {methylsulfonyl)ethyl] -8- quinolinyllphenyl).2[4-(methysulfonyl)phenyl] -2-propenamide; -246- -cyano-1-methylethyl)-8-quinolinyl]phenyl} -24[4- (methylsuLfonayl)phenyl]-2-propenoic acid; 2-methyi1-2-[8-(3 -{(E)-2-(3-inethyl- 1,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl] prop anenitrile; {3-[6-(l1-cyano-1-methylethyl)-8-quinolinyllphenyl} (methylsulfonyl)phenyl]-2-propenaniide; (E)-N-(tert-butyl)-3- -cyano-l-methylethyl)-8-quinolinyl]phenyl} (methylsulfonyl)phenyl]-2-propenamide; 3 -[3-(6-isopropyl-8-quinolinyl)plienyl]-2-[4-(methylsulfonyl)phenyl]p2 propenoic acid; 6-isopropyl-8-(3- {(E)-2-(3-methy1- 1,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; (E)-N-cyclopropyl-3-(3- {6-[l1-inethyl-1-(methylsulfonyl)ethyl]-8- quinolinyl}phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide; (E)-N-(tert-butyl)-3 1 -inethyl-1-(methylsulfonyl)ethyl] -8- quinolinyl}phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide; 8- 13 -[2,2-bis(4-chlorophenyl)vinyl]phenyl} -6-isopropylquinoline; 6-isopropyl-8-(3- {(E/Z)-2-(6-methyl-3-pyridinyl)-2-[4- (methyLs-ulfonyl)phenyl] ethenyl}phenyl)quinoline; 6-isopropyl-8-(3- f(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl~phenyl)quinoline; 2 2 -bis [4-(methylsulfonyl)phenyl] vinyl} phenyl)-6-sopropylquinoline; 2-methyl-2-[8-(3- {(FIZ)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyllphenyl)-6-quinolinyl]propanenitrile; 2-[8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl} phenyl)-6-quinolinyl]-2- methyipropanenitrile; 2-methyl-2-(8- {3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(2- pyridinyl)ethenyl]plienyl} -6-quinolinyl)propanenitrile; 1-methyl-l-(methylsulfonyl)ethyl]-8-(3- {(.E/Z)-2-(5-methyl-2-pyrilinyl)-2-[4. (methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; 247 -methyl-1 -(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-1 (methylsulfonyl)phenyl]ethenyl} -3-pyridinyl)-2-propanol; or a pharmaceutically acceptable salt thereof.
  14. 19. A compound represented by Formula substantially as hereinbefore s described with reference to any one of the examples excluding examples 18 and 27. A compound according to claim 1, wherein the compound is H3C 0 O CH3 SCH3 H3C O 0 or a pharmaceutically acceptable salt thereof.
  15. 21. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  16. 22. The pharmaceutical composition according to claim 21, further comprising a Leukotriene receptor antagonist, a Leukotriene biosynthesis inhibitor, an 15 M2/M3 antagonist, a corticosteroid, an HI receptor antagonist or a beta 2 adrenoceptor agonist.
  17. 23. The pharmaceutical composition according to claim 21, further comprising a COX-2 selective inhibitor, a statin, or an NSAID.
  18. 24. A method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory 248 [R:\LIBZZ]8041.doc:JIN distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal chord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. A method of treatment or prevention of asthma, chronic bronchitis, 15 chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, "i osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary S*i disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic 25 shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of forming in vivo a therapeutically effective amount, or a prophylactically effective amount, of the compound according to any one of claims 1 to
  19. 26. A compound of formula according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof for use as phosphodiesterase inhibitors.
  20. 27. Use of a compound of formula according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a 249 [R:\LLBZZ]8041 .doc:JIN medicament for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory I15 components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, :multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.
  21. 28. A phosphodiesterase-4 inhibitor pharmaceutical composition "comprising an acceptable phosphodiesterase-4-inhibiting amount of a compound of formula as defined in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  22. 29. A compound of formula or a pharmaceutically acceptable salt 25 thereof according to any one of claims 1 to 20 when used in the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary diseasc in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, 250 [R:\LIBZZ]8041.doc:JIN fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues. A pharmaceutical composition substantially as hereinbefore described with reference to any one of the examples excluding examples 18 and 27.
  23. 31. A method of treatment or prevention comprising the steps substantially o0 as hereinbefore described with reference to any one of the examples excluding examples 18 and 27.
  24. 32. Use of a compound of formula substantially as hereinbefore described with reference to any one of the examples excluding examples 18 and 27. Dated 19 October 2004 Merck Frosst Canada Co. ~Patent Attorneys for the Applicant/Nominated Person 2 9 SPRUSON FERGUSON 251 [R:\LIBZZ]8041 .doc:JIN
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