BG65403B1 - Substituted 8-arylquinolines as phosphodiesterase-4 inhibitors - Google Patents

Abstract

Novel substituted 8-arylquinolines represented by formula

Description

Field of application

The present invention relates to compounds which are substituted 8-arylquinolines. In particular, this invention relates to substituted 8-arylquinolines, which are inhibitors of phosphodiesterase-4, in which the aryl group at the 8-position contains a substituted alkenyl group as a substituent.

BACKGROUND OF THE INVENTION

Hormones are compounds that affect cell activity differently. In many ways, hormones act as informants to switch specific cellular responses and activities. However, many hormone-produced effects are not caused solely by the hormone effect. Instead, the hormone first binds to a receptor, thus switching the release of a second compound that continues to act on cellular activity. In this process, the hormone is known as the first informant, while the second compound is called the second informant. Cyclic adenosine monophosphate (adenosine 3 ', 5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as the second hormone informant including epinephrine, glucagon, calcitonin, corticotrophin, lipotropyrin, lutein, lutein, lutein, -stimulating hormone and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to a variety of neurotransmitters.

Phosphodiesterases (PDEs) are a family of enzymes that metabolize 3 ', 5' cyclic nucleotides into 5 'nucleoside monophosphates, thereby terminating cAMP activity as a second informant. A specific phosphodiesterase, phosphodiesterase-4 ("PDE4", also known as "PDE-IV"), which is cAMP specific, high affinity type IV PDE, has aroused interest as a potential target for the development of novel, anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at least four isoenzymes, each of which is encoded by a separate gene. Each of the four known PDE4 gene products is thought to play distinct roles in allergic and / or inflammatory responses. Thus, inhibition of PDE4, especially specific PDE4 isoforms that produce deleterious responses, is thought to have beneficial effects on allergic and inflammatory symptoms. It is desirable to create new compounds and compositions that inhibit PDE4 activity.

A major problem with the use of PDE4 inhibitors is the side effect of vomiting, which has been observed for several compounds as described in C. Bumouf et al., (“Bumouf”), Ann. Rep. In Med. Chem., 33: 91-109 (1998).

B.Hughes etal., No. J. Pharmacol., 118: 1183-1191 (1996): M .J. Perry et al., Cell Biochem. Biophys., 29: 113-132 (1998); S. B. Christensenetal., J. Med. Chem., 41: 821-835 (1998); and Bumouf describe the wide variation in severity of undesirable side effects shown 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 on therapeutic PDE4 inhibitors.

WO 1994/022852 describes quinolines as PDE4 inhibitors.

A. M. Cook, et al., J. Chem. Soc., 413-417 (1943) describes gamma-pyridyl-quinolines. 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 ring systems have been described by various researchers as being effective for a variety of therapies and applications. For example, WO 1998/025883 describes ketobenzamides as calpain inhibitors, publication EP 811610 and US 5 679 712, US 5 693 672 and US 5 747 541 describe substituted benzoylguanidines as sodium channel blockers, US 5 736 297 describes ring systems useful as photosensitive composition.

US 5 491 147, US 5 608 070, US 5 622 977, US 5 739 144, US 5 776 958, US 5 780 477, US 5 786 354, US 5 798 373, US 5 849 770, US 5 859 034. US 5 866 593, US 5 891 896 and

65403 Bl

WO 1995/035283 describes PDE4 inhibitors that are trisubstituted aryl or heteroaryl phenyl derivatives. US 5 580 888 describes PDE4 inhibitors that are sterile derivatives. US 5 550 137 describes PDE4 inhibitors which are phenylaminocarbonyl derivatives. US 5 340 827 describes PDE4 inhibitors, which are phenylcarboxamide compounds. US 5 780 478 describes PDE4 inhibitors, which are four substituted phenyl derivatives. Publication WO 1996/000215 describes substituted oxime derivatives useful as PDE4 inhibitors. US 5 633 257 describes PDE4 inhibitors that are cyclo (alkyl and alkenyl) phenyl-alkenyl (aryl and heteroaryl) compounds.

However, new compounds and compositions are needed that therapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted 8-arylquinolines, which are PDE4 inhibitors, in which the aryl group at the 8-position is substituted by a substituted alkenyl group. This invention also relates to a pharmaceutical composition that comprises an effective amount of the new substituted 8-arylquinoline and a pharmaceutically acceptable carrier. This invention further relates to a method of treating mammals, for example asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxin-related bacterial, such as bacterial toxicity laminitis and elastic abdominal pain in horses), septic shock, nonspecific ulcerative colitis, Crohn's disease, reperfusion injury to the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulus nephritis, allergic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive pulmonary disease in animals, non-diabetes mellitus, allergic rhinitis, allergen conjunctivitis, proletherosclerosis, pro-inflammatory disease cough, rheumatoid arthritis, ankylosing spondylitis, reject transplant and disease implant against the recipient, over-secretion of gastric acid, bacterial, fungal or viral-induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle atrophy, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with inflammatory components, parasite disease, parasite disease spinal cord, head injury, multiple sclerosis, tumor growth and cancer invasion in normal tissues by administering an effective amount of the new substituted 8-arylquinoline or a precursor compound that forms in vivo new i substituted 8-arylquinoline.

Explanation of the annexed figures

Figure 1 is a diagram of angular momentum pulses for X-ray powder diffraction of polymorph Form A of the benzenesulfonate acid salt 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.

Figure 2 is a diagram of angular momentum pulses for X-ray powder diffraction of polymorph Form B of the benzenesulfonate acid salt 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.

Figure 3 is a comparison of X-ray powder diffractions of polymorph Form A (lower curve) and Form B (upper curve) of the benzenesulfonate acid salt 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.

Figure 4 is a diagram of the difference peaks of X-ray powder diffraction of polymorph Form A of the benzenesulfonate acid salt 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.

Figure 5 is a diagram of the X-ray powder diffraction peaks of benzene sulfonic acid polymorph B

65403 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8 [3 - [(E) -2- [3-methyl-1,2,4-oxadiazol-5-yl] -2 salt - [4 (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline.

DETAILED DESCRIPTION OF THE INVENTION A compound of the invention represented by Formula (I)

or a pharmaceutically acceptable salt thereof, in which:

S _p S ₂ and S ₃ are independently H;

R _| is a -C, -C ₆ alkyl group optionally substituted by -CN or -SO _n - (C 1 -C ₆ alkyl);

AESN;

R 1 and R ₃ are independently an aryl group, heteroaryl group, H, halogen, -CN, -C ₍ -C ₆ alkyl group, -heterocycloC ₃ -C ₆ alkyl, -C 1 -C 6 alkoxy group, carbonyl group, carbamoyl group, - A C (O) OH, - (C ₁ -C _{6 an} C ₁ -N ₆ -C ₁ -C ₆ C ₆ alkyl) group, -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) group, or -C 4 an alkylacylamino group wherein each of the groups is optionally substituted with 1 to 5 substituents, each substituent being independently halogen, -NO ₂ , -C (O) OH, -CN, N-oxide, -OH, or aryl, heteroaryl , carbonyl, -C 1 -C 8 alkyl, -SO (C 1 -C 6 -C 8 alkyl), -SO _n - (apwi), aryloxy, -heteroaryloxy, -C 1 -C 8 alkoxy, -C (O) -heterocycloC ₃ -C ₆ alkyl, -IN cycle loC ₃ -C ₆ alkyl, amino, - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is independently optionally substituted by -OH, -C 1 -C 8 alkoxy, -N, -C 8 alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - (C ₁ -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) , (C ₁ -C ₆ alkyl);

one of R 1 and R ₃ must be aryl optionally substituted and the other must be heteroaryl optionally substituted;

η is independently 0, 1 or 2.

In one embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

S _p S ₂ and S ₃ are each H;

R 1 is a -C 1 -C 8 alkyl group optionally substituted by -CN or -C _{8 n} - (C 1 -C ₆ alkyl);

AESN;

R 1 and R ₃ are independently an aryl group or a heteroaryl group, each optionally substituted with 1 to 5 substituents, wherein each substituent is independently halogen, aryl, heteroaryl, -NO ₂ , -C (O) OH, carbonyl, - CN, -C 1 -C 8 alkyl, -SO _n - (C ₁ -C 8 alkyl), -SO _n - (apwi), aryloxy, -heteroaryloxy, -C, -C ₆ alkoxy, Oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NHcycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, or -C (O) -N (C ₀ - C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is independently optionally substituted by -OH, -C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl. aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen. -NO ₂ , -CN, -SO _n (C 1 -C 6 alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

one of R ₂ and R ₃ must be aryl optionally substituted and the other must be heteroaryl optionally substituted;

η is independently 0, 1 or 2.

As used herein, "alkyl" as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, alkenyl, alkynyl, and the like, means a linear or branched carbon chain or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, N- and t-butyl, pentyl, hexyl substituted with 1-5 substituents; wherein each substituent is independently halogen or OH;

R 1 is H, OH, halogen, carbonyl or -C, -C ₆ alkyl, -cyclo-C 1 -C ₆ alkyl, -C-C ₁ alkenyl, -C 1 -C alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ - C ₆ alkyl, -amino, -C 1 -C 8 alkylamino, - (C 1 -C ₆ alkylXC 1 -C 8 alkyl) amino, -C 1 -C 8 alkyl (oxy) C 1 -C 8 alkyl, -C (O) IN (aryl) , -C (O) NH (xeTepoaryl), -SO _n NH (apnn), -SO _n NH (xeTepoapHn), -SO _n NH (C ₁ -C ₆ aniaui), - C (O) N (C ₀ - C ₆ anKHnXC ₀ -Cg alkyl), -NH-SO _n - (C _t -Cg alkyl), -SO _n - (C ₎ -C ₆

65403 C 1-6 alkyl), - (C 1 -C ₆ alkyl) -O-C (C ₁ -C ₆ ) dialkylamino, or - (C ₁ -C ₆ alkyl) -C _{10 n-} (C ₁ -C ₆ alkyl) group, where each group is optionally substituted with

1-5 substituent; wherein each substituent is independently halogen, -OH, -CN, -Ο, -Ο ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) - O- (C ₀ -C ₆ alkyl), -C (O) -aryloxy, -C ₁ -C ₆ alkoxy, - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, cycloalkyloxy, acyl, acyloxy, -tsikloS ₃ -C ₆ alkyl, heterotsikloS ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or SOg-CC ^ Cg alkyl);

A is CH;

R ₂ and R _{3 are} independently aryl, heteroaryl, H, halogen, -CN, -C 1 -C ₆ alkyl, heterocycloC _3-6 alkyl, -C 1 -C ₆ alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -C ₆ alkyl) -8O _n - (C ₁ -C ₆ alkyl), -C (O) 1 N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C 1 -C ₆ alkylacylamino group , wherein each of the groups is optionally substituted with 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -Ο, -C 8 alkyl, -SO _n - (C _| -C ₆ alkyl), -8O _n - (aryl), aryloxy, -heteroaryloxy, C, -C ₆ alkoxy, bloksid, -C (0) -heterotsikloS ₃ -C ₆ alkyl, - NHcycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) am inno, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -Ο, -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -8O _n - (C 1 -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

one of R ₂ and R ₃ must be aryl or heteroaryl optionally substituted;

when R ₂ and R ₃ are both an aryl or heteroaryl, then R ₂ and R ₃ may be optionally connected by a thio, oxy or (C _t -C alkyl) bridge to form a fused three ring system; and η is independently 0, 1 or 2.

In one embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

S, S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO ₂ , -CN or -Ο, -C 8 alkoxy, where the alkyl and alkoxy groups are optionally substituted by 1 -5 substituent; wherein each substituent is independently halogen or OH;

R 1 is -C 1 -C ₆ alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C 6 alkyl), - ( C ₁ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino;

AESN;

R 1 and R _{3 are} independently aryl, heteroaryl, H, halogen, -CN, -Ο, -C 8 alkyl, heterocycloC _3-6 alkyl, -C-C 8 alkoxy, carbonyl, carbamoyl, -C (O) OH, - (Ο , -Ο ₆ alkyl) -8O _n - _{(C] -C6} alkyl), -C (O) N ( C fl -C ₆ alkyl) (C ₀ -C ₆ alkyl), or -C ^ Cgankilatsilamino group, wherein each of the groups is optionally substituted with 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C, -C ₆ alkyl, -SOg -C 1 -C 6 alkyl), -8 O _n - (aryl), -O-aryl, -O-heteroaryl, C ₁ -C ₆ alkoxy, N-oxide, -C (O) heterocyclo ₃ -C ₆ alkyl, -ΝΗ -ηηκλοΟ ₃ -Ο ₆ alkyl, amino, -OH, or - (C _o -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (o) -N (C _A C ₁ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, Ο, -Ο ₆ alkoxy, C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl , aryloxy, -C (O) OH, -O (O) O (O, N-alkyl), halogen, -NO ₂ , -CN, -SO _n (Ο, -Cg alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

one of R ₂ and R ₃ must be aryl or heteroaryl optionally substituted;

when R ₂ and R ₃ are both aryl or heteroaryl, then R ₂ and R ₃ may be optionally linked by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused three-ring system;

η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

S,, S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO ₂ , -CN or -Ο, -Ο ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted with 1-5 substituents; wherein each substituent is independently halogen or OH;

R, is -tsikloS ₃ -C ₆ alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN,

65403 Bl

-C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, - cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C ₆ alkyl);

AESN;

R 1 and R _{3 are} independently aryl, heteroaryl, H, halogen, -CN, -C 1 -C ₆ alkyl, heterocycloC _3-6 alkyl, -C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -C ₆ alkyl) -8O _n - (C 1 -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C _t -C ₆ an alkylacylamino group wherein each of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C, -C ₆ alkyl, -SO _n - (C 1 -C ₆ alkyl), -8 O _n - (aryl), -O-aryl, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) heterocycloC ₃ -C ₆ alkyl, -N ₁ -cycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, where each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n (C, - C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

one of R ₂ and R ₃ must be aryl or heteroaryl optionally substituted;

when R ₂ and R ₃ are both aryl or heteroaryl, then R ₂ and R ₃ may be optionally linked by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused three-ring system; and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

S ₁ , S ₂ and S ₃ are independently H, -OH, halogen, -C 1 -C ₆ alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted by 1 -5 substituent; wherein each substituent is independently halogen or OH;

R 1 is -C 1 -C ₆ alkenyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C ₆ alkyl);

AESN;

R 1 and R _{3 are} independently aryl, heteroaryl, H, halogen, -CN, -C 1 -C ₆ alkyl, heterocycloC _3-6 alkyl, -C 1 -C ₆ alkoxy, carbonyl, carbamoyl, -C (O) OH, - ( A C 1 -C ₆ alkylN-SO _n - (C 1 -C ₆ alkyl), -C (O) H (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C 1 -C ₆ alkylacylamino group wherein each of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C 1 -C ₆ alkyl , -SO _n - (C 1 -C ₆ alkyl), -SO _n (aryl), -O-aryl, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocycloC ₃ - C ₆ alkyl, -NHcycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₁ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, - C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - (C 1 -C ₆ alkyl) or -C (O) -N (C C ₁ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

one of R ₂ and R ₃ must be aryl or heteroaryl optionally substituted;

when R 1 and R ₃ are both aryl or heteroaryl, then R 1 and R ₃ may be optionally linked by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused triple ring system;

η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (1) or a pharmaceutically acceptable salt thereof, wherein S ₁ , S ₂ and S ₃ are independently H, OH, halogen, -C 1 -C ₆ alkyl, -NO ₂ , -CN or -C, C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted with 1-5 substituents; wherein each substituent is independently halogen or OH;

R 1 is heteroaryl optionally substituted with 1 -5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C ₆ alkyl);

AESN;

R 1 and R _{3 are} independently aryl, heteroaryl, H, halogen, -CN, -C 1 -C ₆ alkyl, heterocycloC _{3 6}

65403 B1 alkyl, -C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -C ₆ alkyl) -8O _n - (C ₍ -C ₆ alkyl), -C (O) N A (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C 1 -C ₆ alkylacylamino group, wherein each group is optionally substituted with 1-5 substituents, each substituent independently being aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C, -C ₆ alkyl, -SO _n - (C ₁ -C ₆ alkyl), -8O _n - (aryl), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, Oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NHcycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) ( A C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group wherein each substituent is the group is optionally substituted by -OH, C ₁ -C ₆ alkoxy, C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C, - C ₆ alkyl), halogen, -NO ₂ , -CN, -SO 4 -C 1-6 alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

one of R 1 and R ₃ must be aryl or heteroaryl optionally substituted;

when R 1 and R ₃ are both aryl or heteroaryl, then R 1 and R ₃ may be optionally linked by a thio, oxy or (C ₃ -C ₄ alkyl) bridge to form a fused three-ring system;

η is independently 0, 1 or 2.

In yet another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein;

S 1, S ₂ and S ₃ are independently H, -OH, halogen. -C-C alkyl, -NO ₂ , -CN, or -C-C alkoxy, these alkyl and alkoxy groups being optionally substituted with 1 -5 substituents; wherein each substituent is independently halogen or OH;

R 1 is -amino, -C 1 -C ₆ alkylamino, or - (C 1 -C ₆ alkyl) (C 1 -C ₆ alkyl) amino group, where each group is optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, tsikloS ₃ -C ₆ alkyl, heterotsikloS ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO _n - (C _| C alkyl);

AESN;

R 1 and R _{3 are} independently aryl, heteroaryl, H, halogen, -CN, -C 1 -C ₆ alkyl, heterocycloC _3-6 alkyl, -C 1 -C ₆ alkoxy, carbonyl, carbamoyl, C (O) OH, - ( C _| -C ₆ alkyl) -8O _n - (C, -C ₆ alkyl),

-C (O) H (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C 1-6 alkylacylamino group, where each group is optionally substituted with 1-5 substituents, wherein each substituent is independently aryl , heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C 1 -C ₆ alkyl, -SO _n - (C ₁ -C ₆ alkyl), -8O _n - (aryl), - O-aryl, -O-heteroaryl, C 1-6 alkoxy, N-oxide, -C (O) heterocycloC ₃ -C ₆ alkyl, -NH-hkhoC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ - C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, --C ^ CC ^ C ^ alkilHS] - alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C _t -C ₆ alkoxy, - _{C] -C6} alkyl, -tsikloS ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C ( ) O _{(C] -C6} alkyl), halogen, -NO _2, -CN, -SO _n - (C ₁ -C ₆ alkyl), or -C (O) -N (C ₀ -C ₆ alkyl) (C ₍ C ₁ -C ₆ alkyl);

one of R 1 and R ₃ must be aryl or heteroaryl optionally substituted;

when R ₂ and R ₃ are both an aryl or heteroaryl group, then Rj and R ₃ may be optionally connected by a thio, oxy or (C _t -C ₄ alkyl) bridge to form a fused three ring system;

η is independently 0, 1 or 2.

In one embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

S 1, S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO 1, -CN or -C ₁ -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted by 1-5 substituent; wherein each substituent is independently halogen or OH;

R _t is -C 1-6 alkyl, -cycloC ₃ -C ₆ alkyl, -C _t -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ -C ₆ alkyl, - amino, C, -C ₆ alkylamino, - (C _t -C ₆ alkilHS, - alkyl) amino, C, -C ₆ alkyl (oxy) C _{(-C 6} alkyl, -C (O) NH- ( aryl), -C (O) IN (heteroaryl), -SO _n NH (apwi), -SO _n NH (heteroaryl), -SO _n NH (C 1 -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C _{6 alkyl), -NH-SO n - (} C | -C ₆ alkyl), -8O _n - _{(C] -C6} alkyl), -carbamoyl, - (C A -C ₆ alkyl) -O-C (C ₁ -C ₆ ) dialkylamino or - (C ₁ -C ₆ alkyl) -C _{10 n} (C 1 -C ₆ alkyl) group, where each group is optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, OH, -CN, alkoxy, cycloa alkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _n - (C 1 -C ₆ alkyl);

65403 Bl

A is CH;

R ₂ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C ₍ -C ₆ alkyl, - SO ^ C, alkyl), -8 O _n - (aryl), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NH- uhioioC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ - A C ₆ alkyl) substituent group, wherein each substituent group is independently optionally substituted by -OH, C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n (C 1 -C ₆ alkyl) or -C (O) -N (C C ₁ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R 1 is heteroaryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C 1 -C ₆ alkyl, - (C 1 -C 6 alkyl), -SO _n - (apnn), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NH- uhioioC ₃ -C ₆ alkyl, amino, -OH or (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH , -C (O) O (C] _-C6 alkyl), halogen, -NO _{2, -CN, -SO n - (C} | -C ₆ alkyl), or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ - C ₆ alkyl); and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

S], S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted with 1-5 substituents; wherein each substituent is independently halogen or OH;

R 1 is halogen, carbonyl, -C ₍ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C 1 -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ - C ₆ alkyl, amino, -C 1 -C ₆ alkylamino, - (C 1 -C ₆ alkylHC, alkyl) amino, -C 1 -C ₆ alkyl (oxy) C 1 -C ₆ alkyl, -C (O) IN - (aryl), -C (O) NH (heteroaryl), -SO _n NH (apnn), -8O _n 1CH (heteroaryl), -SO _n NH (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -NHSO _n - (C 1 -C ₆ alkyl), -SO _n - (C 1 -C ₆ alkyl), -carbamoyl, - (C] -C ₆ alkyl) -O-C (CH) dialkylaminoyl

- (C 1 -C ₆ alkyl) -8O _n - (C ₁ -C ₆ alkyl) group, where each group is optionally substituted with 15 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocyclo-C ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C ( O) -Oaryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _n - (C 1 -C ₆ alkyl);

AESN;

R ₂ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C ₁ -C ₆ alkyl, - SO _n (C 1 -C ₆ alkyl), -8 O _n - (aryl), -aryloxy, -Oheteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) heterocycle C ₃ -C ₆ alkyl, - No. 1-cycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) ( A C ₁ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C] -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - (C ₁ -C ₆ alkyl) or -C (O) -N ( C ₀ -C ₆ alkyl) (C ₁ -C ₆ alkyl);

R ₃ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C 1 -C ₆ alkyl, - SO _n (C ₍ -C ₆ alkyl), -8O _n - (aryl), -aryloxy, -Oheteroaryl, C _t -C ₆ alkoxy, N-oxide, -C (O) heterocycloC ₃ -C ₆ alkyl, -NH -CycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O ) OH, -C (O) O (C] -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - (C ₁ -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₁ -C ₆ alkyl); and η is independently 0, 1 or 2.

In yet another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

S 1, S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted with 1-5 substituents; wherein each substituent is independently halogen or OH;

65403 Bl

R 1 is halogen, carbonyl, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₁ -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ - C ₆ alkyl, -amino, -C ₁ -C ₆ alkylamino, - (C ₁ -C ₆ alkyl) (C 1 -C ₆ alkyl) amino, -C 1 -C 4 alkyl (oxy) C 1 -C ₆ alkyl , -C (O) IN- (aryl), -C (O) b1H (heteroaryl), -BSICNaryl), -SO _n NH (xeTepoapHn), -SO _n NH (C ₁ -C ₆ alkyl), -C ( O) N (C ₀ -C ₆ alkyl) (C ₀ -C _{6 alkyl), -NH-SO n - (} C ₁ -C _{6 alkyl), -SO n - (C |} -C ₆ alkyl) -carbamoyl , - (C 1 -C ₆ alkyl) -O-C (C 1 H) dialkylamino or - (C 1 -C ₆ alkyl) -8O _n - (C 1 -C ₆ alkyl) group, where each group is optionally substituted by 1-5 substituent; wherein each substituent is independently halogen, -OH, -CN, -C (OXheterocyclo-C ₃ -C ₆ alkyl), -O (O) -O- (O, alkyl), -C (O) -O-aryl , alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C ₁ -C ₆ alkyl);

AESN;

Rj is a carbonyl, optionally substituted by 1 substituent which substituent is aryl, heteroaryl, -C (O) OH, carbonyl, -C, alkyl, -O-aryl, -Oheteroaril, -O- (C _{| -C6} alkyl ), -heterocycloC ₃ -C ₆ alkyl, -NH-cycloC ₃ -C ₆ alkyl, amino, -OH or (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino substituent group, where each substituent group is optionally substituted with -OH, -O (O, -O ₆ alkyl), -O, -O ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -O (aryl), -C (O) OH, -O (O) O (O, -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n (C 1 -C ₆ alkyl), -cycloC ₃ -C ₆ alkyl, or -C (O) N (C) C ₁ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ₃ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C 1 -C ₆ alkyl, - SO (C 1 -C ₆ alkyl), -BODaryl), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocyclo C ₃ -C ₆ alkyl, -NH-hkhoC ₃ - C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) a substituent group wherein each substituent group is optionally substituted by -OH, C 1 -C 5. alkoxy, -C-C 1-6 alkyl, -cycloC _3- C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN , -SO _n (C 1 -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl); and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

Sp S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted by 1 -5 the substitute; wherein each substituent is independently halogen or OH;

R 1 is halogen, carbonyl, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C 1 -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ -C ₆ alkyl, -amino, -C 1 -C ₆ alkylamino, - (C 1 -C ₆ alkylHC] -C ₆ alkyl) amino, -C 1-6 alkyl / oxyC 1 -C ₆ alkyl, -C (O) NH- (apHn ), -C (O) NH (xeTepoapHn), -SO _n NH (apnn), -SO _n NH (xerepoapnn), -SO _n NH (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -NH 8 O _n - (C 1 -C ₆ alkyl), -SO _n - (C ₁ -C ₆ alkyl), -carbamoyl, - (C 1 -C ₆₎ alkyl) -O-C (SI) dialkylamino, or - (C, -C ₆ alkyl) -8O _n - (C! _-C6 alkyl) group, wherein each group is optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (OXheterocyclo-C ₃ -C ₆ alkyl), -C (O) -O- (C ₁ -C ₆ alkyl), -C (O) - O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _n - (C 1 -C ₆ alkyl);

AESN;

R 1 is carbamoyl optionally substituted with 1 2 substituents, wherein each substituent is independently carbonyl, -CN, -C 1 -C ₆ alkyl, -SO _n - (C ₁ -C ₆ alkyl), -O-aryl, -O -heteroaryl, -C (O) -heterocycloC ₃ -C ₆ alkyl, -1CH-cycloC ₃ -C ₆ alkyl, amino, -OH or -C _| -C ₆ alkyl (amino) substituent group, wherein each substituent group is optionally substituted by -OH, -O (C ₁ -C ₆ alkyl), -O (aryl), -COOH, -COO (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ₃ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, alkyl, -SO 4 C, alkyl) , -8O _n - (aryl), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocyclo C ₃ -C ₆ alkyl, -IN-cycloC ₃ -C ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group , wherein each substituent group is optionally substituted by -OH, C 1 -C alkoxy, -C-C, alkyl, '16' 16 '-cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, - C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n 10

65 403 Bl (C, -C ₆ alkyl), or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl); and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

S 1, S ₂ and S ₃ are independently H, -OH, halogen, -C 1-4 alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted by 1- 5 substituents; wherein each substituent is independently halogen or OH;

R] is a halogen, carbonyl, -C _t -C ₆ alkyl, -tsikloS ₃ -C ₆ alkyl, C ^^ alkenyl, C] _-C6 alkoxy, aryl, heteroaryl, -CN, -heterotsikloS ₃ -C ₆ alkyl, -amino, -C 1 -C ₆ alkylamino, - (C 1 -C ₆ alkyl) (C ₁ -C ₆ alkyl) amino, -C _| -C ₆ alkyl (oxy) C _| C ₆ alkyl, -C (O) IN (aryl), -C (O) HH (heteroaryl), -SO _n NH (apnn), -SO _n NH (xeTepoapmi), -SO _n NH (C 1 -C ₆ alkyl) ), -C (O) N ( C ₀ -C ₆ alkyl) (C ₀ -C _{6 alkyl), -NHSO n - (C,} -C _{6 alkyl), -SO n - (C |} -C ₆ alkyl) , -carbamoyl, - (C ₁ -C ₆ alkyl) -O-C (CH) -dialkylamino or (C 1 -C ₆ alkyl) -8O _n - (C ₁ -C ₆ alkyl) group, where each of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO (C ₁ -C ₆ alkyl);

AESN;

R ₂ and R ₃ are each independently aryl optionally substituted, bonded together by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused triple ring system; and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (1) or a pharmaceutically acceptable salt thereof, wherein:

S 1, S ₂ and S ₃ are independently H, -OH, halogen, -C-C, alkyl, -NO, -CN, or -C, -C alkoxy;

R 1 is halogen, carbonyl, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C 1 -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ alkyl, -amino, -C 1 -C ₆ alkylamino, - (C 1 -C ₆ alkyl) (C 1 -C ₆ alkyl) amino, -C 1 -C ₆ alkyl (oxy) -C 1-6 alkyl, -C ( O) NH (apnn), -C (O) NH (xeTepoapwi), -SO _n NH (aryl), -SO _n NH (xeTepoapwi), -δΟ ^ ΝΗ ^ - ^ al kil) .- C (O) ^ C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -C _{8 n} - (C 1 -C ₆ alkyl), -SO _n - (C ₁ -C ₆ alkyl), -carbamoyl, - (C] - A C ₆ alkyl) -O-C (C 1 -C ₆ alkylamino or - (C ₁ -C ₆ alkyl) -8O _n - (C ₁ -C ₆ alkyl) group, where each group is optionally substituted with 1 -5 substituents wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycle ° C ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -tsikloS ₃ -C ₆ alkyl , heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C ₆ alkyl);

AESN;

R ₂ is - (C 1 -C ₆ alkyl) -8O _n - (C 1 -C ₆ alkyl) optionally substituted with 1 -5 substituents, wherein each substituent is independently halogen, -NO ₂ , -COOH, carbonyl, -CN, -C ₁ -C ₆ alkyl, -SO _n - (C ₁ -C ₆ alkyl), -O-aryl, -O-heteroaryl, -C (O) -heterocycloC ₃ -C ₆ alkyl, N-H- a cycloC ₃ -C ₆ alkyl, amino, -OH or -C 1 -C ₆ alkyl (amino) substituent group, where each substituent group is optionally substituted by -OH, -O (C 1 -C ₆ alkyl), -O (aryl), -COOH, -COO (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) ;

R ₃ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C ₁ -C ₆ alkyl, - SO _n (C 1 -C ₆ alkyl), -8O _n - (aryl), -aryloxy, -Oheteroaryl, C 1 -C], alkoxy, N-oxide, -C (O) heterocycloC ₃ -C ₆ alkyl, -IN -cycloC-C. alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituted a group wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C ( O) (C _{| -C6} alkyl), halogen, -NO _2, -CN, -SO _n - (C ₁ -C ₆ alkyl), or -C (O) -N (C ₀ -C ₆ alkyl) ( C ₁ -C ₆ alkyl); and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

S _p S ₂ and S ₃ are independently H, -OH, halogen, -C 1 -C ₆ alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted by 1-5 substituent; wherein each substituent is independently halogen or OH;

65403 Bl

R1 is halogen, carbonyl, -C1-6alkyl, -cycloC-Q alkyl, -C-C. alkenyl, -C-C, alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ -C ₆ alkyl, -amino, -C 1 -C ₆ alkylamino, - (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) amino, -C, -C ₆ alkylSoxy) -N 1-4 alkyl, -C (O) 1CH (aryl), -C (O) MH (heteroaryl), -SO _n NH (apiui), -SO _n NH ( xeTepoapnn), -SO _n NH (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -NHSO _n - (C ₁ -C ₆ alkyl) ), -SO _n - (C ₁ -C ₆ alkyl), -carbamoyl, - (C ₁ -C ₆ alkyl) -O-C (CM) -dialkylamino, or - (C ₁ -C ₆ alkyl) an alkyl) group wherein each group is optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C ₆ alkyl);

A is CH;

R ₂ is -C (O) N- (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) optionally substituted with 1 -5 substituents, wherein each substituent is independently halogen, -NO ₂ , -COOH, carbonyl, -CN, -C 1 -C ₆ alkyl, -SO _n (C ₁ -C ₆ alkyl), aryloxy, -heteroaryloxy, -C (O> heterocycloC ₃ -C ₆ alkyl, -H-cycloC ₃ -C ₆ an alkyl, amino, -OH or -C 1 -C ₆ alkyl (amino) substituent group, wherein each substituent group is optionally substituted by -OH, -O (C 1 -C ₆ alkyl), -O (aryl), -COOH , -COO (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ₃ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, alkyl, -SO _n - (C ₁ -C ₆ alkyl), -80 _n - (aryl), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -H-cycloC ₃ -C ₆ alkyl, amino, -OH or (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - (C ₁ -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alc l) (C ₀ -C ₆ alkyl); and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

S, S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₆ alkyl, -NO ₂ , -CN or -C 1 -C ₆ alkoxy, these alkyl and alkoxy groups being optionally substituted with 1-5 substituents; wherein each substituent is independently halogen or OH;

R 1 is halogen, carbonyl, -C ₁ -C 8 alkyl, -cycloC ₃ -C ₆ alkyl, -C 1 -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocycloC ₃ -C ₆ alkyl, amino, -Cj-C ₆ alkylamino, - (C] _-C6 alkilHS ₁ -C ₆ alkyl) amino, -C] -C _b alkyl (oxy) C ₁ -C ₆ alkyl, -C (O ) IN (aryl), -C (O) NH (heteroaryl), SO _n NH (apHn), -SO _n NH (xeTepoapnn), -SO _n NH (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -NH8O _n - (C, -C ₆ alkyl), -SO _n - (C ₁ -C ₆ alkyl) -carbamoyl, - (C _t -C ₆ alkyl) -O-C (CH) -dialkylamino or - (C ₁ -C ₆ alkyl) -8O _n - (C ₁ -C ₆ alkyl) group, where each group is optionally substituted by 1-5 the substitute; wherein each substituent is independently halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C ₁ -C ₆ alkyl);

A is CH;

R ₂ is e-CN;

R ₃ is aryl optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C ₁ -C ₆ alkyl, - SO _n - (C ₁ -C ₆ alkyl), -BO _n - (aryl), -aryloxy, -O-heteroaryl, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -H-cycloC ₃ -C ₆ alkyl, amino, -OH or (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C _t -C ₆ alkoxy, C] _-C6 alkyl, -tsikloS ₃ -C ₆ alkyl, aryloxy, - C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - (C ₁ -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ a alkyl) (C ₁ -C ₆ alkyl); and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

S 1, S ₂ and S ₃ are independently H, -OH, halogen, -C, -C ₁ alkyl, -NO, -CN, or -C-C 5 alkoxy, these alkyl and alkoxy groups being optionally substituted with 1-5 substituents; whereby everyone for

65403 B1 displacement is independently halogen or OH;

R 1 is -C 1 -C ₆ alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O - (C ₀ -C ₆ alkyl), -C (O) -aryloxy, -C 1 -C ₆ alkoxy, - (C ₀ -C ₆ allyl C ₁ -C ₆ alkyl) amino, cycloalkyloxy, acyl, acyloxy, - cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C 1 -C ₆ alkyl);

AESN,

R ₂ and R _{3 are} each independently aryl or heteroaryl, each optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN , -C, -C ₆ alkyl, -SO _n - (C _| -C ₆ alkyl), -8O _n - (aryl), aryloxy, -heteroaryloxy, C, -C ₆ alkoxy, N-oxide, -C (0 ) -heterocycloC ₃ -C ₆ alkyl, -NH-cycloC-C alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C _O- C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C, -C, alkoxy, -C-C. alkyl, -cyclo, -C, alkyl, aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -BODS, -alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ₂ and R ₃ may be optionally bonded via a thio, oxy or (C ₁ -C ₄ alkyl) bridge to form a fused three-ring system; and η is independently 0, 1 or 2.

In another embodiment of this aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

S, S ₂ and S ₃ are each H;

R ₁ is -C ₁ -C ₆ alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C, -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) - O- (C ₀ -C ₆ alkyl), -C (O) -aryloxy, -O, -O ₆ alkoxy, - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SO _n - (C ₁ -C ₆ alkyl);

AESN,

R ₂ and R _{3 are} each independently aryl or heteroaryl, each optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN , alkyl, -SO _n - (C ₁ -C ₆ alkyl), -8O _n - (aryl), aryloxy, -heteroaryloxy, C 1 -C ₆ alkoxy, N-oxide, -C (O) -heterocycloC ₃ C ₆ alkyl, -ΝΗ-πηκηο0 ₃ -0 ₆ alkyl, amino, -OH or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ C ₆ alkyl) (C ₀ -C ₆ alkyl) substituent group, wherein each substituent group is optionally substituted by -OH, C 1 -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C, -C ₆ alkyl), ALOGIA, -NO _2, -CN, -SO ^ C, - ^ alkyl), or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ₂ and R ₃ may be optionally bonded via a thio, oxy or (C ₃ -C ₄ alkyl) bridge to form a fused three-ring system; and η is independently 0, 1 or 2.

As used herein, "alkyl", as well as other groups having the prefix "alk" such as alkoxy, alkanoyl, alkenyl, alkynyl and the like, means a carbon chain which may be linear or branched, or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and t-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and the like include carbon chains containing at least one unsaturated C-C bond.

The term "cycloalkyl" means non-heteroatom-containing carbocycles and includes mono-, bi- and tricyclic saturated carbocycles as well as fused ring systems. Such fused ring systems may include one ring that is partially or completely unsaturated, such as a benzene ring, to form fused ring systems such as benzocondensed carbocycles. Cycloalkyl includes such fused ring systems such as spiro-fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl,

1,2,3,4-tetrahydronaphthalene 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 carbocycles as well as benzo-fused cycloalkenes. Examples of cycloalkenyls include cyclohexenyl, indenyl and the like.

The term "cycloalkyloxy" unless

65403 B1 is specifically expressed to include a cycloalkyl group bonded to the oxygen binding atom.

The term "alkoxy", unless specifically stated otherwise, includes an alkyl group attached to the oxygen bond atom.

The term "aryl", unless specifically stated otherwise, includes multiple ring systems as well as single ring systems such as phenyl or naphthyl.

The term "aryloxy", unless specifically stated otherwise, includes multiple ring systems as well as single ring systems, such as phenyl or naphthyl, bonded through the oxygen bond atom to the binding site.

The term "C ₁ -C ₆ alkyl" includes alkyl containing 6, 5, 4, 3, 2, 1 or no carbon atoms. Carbon-free alkyl is a substituent hydrogen atom or a direct bond, depending on whether the alkyl is a terminal 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 combinations of such atoms. Hetero atoms replace ring carbon atoms. For example, a heterocycloC ₅ alkyl is a five membered ring containing from 5 to no carbon atom.

Examples of heteroaryl include, for example, pyridine, pyrrolidone, and pyrrolidone. oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

The term "heteroaryloxy", unless specifically stated otherwise, describes a heteroaryl group bonded through an oxygen bonding atom to the binding site.

Examples of heteroaryl ^ ^) alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oksazoliletil, isoxazolylmethyl, thiazolylmethyl, tiazoliletil, imidazolylmethyl, imino dazoliletil, benzimidazolilmetil, oxadiazolylmethyl, oxadiazolylethyl, tiadiazolilmetil, tiadiazoliletil, triazolylmethyl, triazoliletil, tetrazolylmethyl , tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterotsikloS _{3 7} alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

Examples of aryl _(C16) alkyl include, for example, phenyl (C _{| -C6)} alkyl and naphthyl (C _{| 6)} alkyl.

Examples of heterocycloC _3-7 alkylcarbonyl (C ₁₆ ) alkyl include, for example, azetidinyl carbonyl (C ₁₆ ) alkyl, pyrrolidinyl carbonyl (C _1-6 ) alkyl, piperidinyl carbonyl (C _1-6 ) alkyl, piperazinyl carbonyl (C] ₆ ) alkyl. morpholinyl carbonyl (C ₁₆₎ alkyl, and thiomorpholinyl carbonyl (C, ₆₎ alkyl.

The term "amine", unless specifically stated otherwise, includes primary, secondary and tertiary amines.

Unless otherwise indicated, the term " carbamoyl " is used to include -NHCCO2OC1-C, alkyl, and -OC (O) NCH, -C, alkyl.

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

The term "optionally (optionally) substituted" is intended to include both substituted and unsubstituted. For example, an optionally (optionally) substituted aryl could be a pentafluorophenyl or phenyl ring. Additionally, substitutions can be made in each of the groups. For example, substituted aryl (C ₁₆ ) alkyl includes substitution of the aryl group as well as substitution of the alkyl group.

Compounds described herein contain one or more double bonds and thus may 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 may contain one or more asymmetry centers and may give rise to diastereomers and optical isomers. The present invention includes all

65403 Blank such possible diastereomers as well as their racemic mixtures, their substantially pure separated enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above formula I is shown without definitive stereochemistry in some positions. The present invention includes all stereoisomers of formula I and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the development of the synthesis procedures used to prepare such compounds or the use of racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be a mixture of stereoisomers.

The term "pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt may conveniently be prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cup and cupro), ferrous, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. 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 may be formed include ion exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2 dimethylaminoethanol, ethanolamine, N-ethylenediamine ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrobramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tripropylamine, tripropylamine

When the compound of the present invention is basic, its corresponding salt can conveniently be 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, almond, methanesulfonic, phytoate, phytoate, phytoate, phytoate, phytoate , sulfuric, tartaric, p-toluenesulfonic acid and the like. Benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids are particularly preferred.

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 additives. Such additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, H) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoreceptor agonists, vi) COX-2, vixi, viii) non-steroidal anti-inflammatory drugs (“NSAIDs”), and (ix) M2 / M3 antagonists. The formulations include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most appropriate route will in each case depend on the individual recipient, the nature and severity of the conditions to which he or she was administered the active ingredient. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the field of pharmacy.

For topical application, creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I may be used. For the purposes of this invention, mouthwash and gargle are included.

Dose levels from about 0.001 to about 140 mg / kg body weight per day are useful in the treatment of conditions such as asthma, chrono

65403 Bl atrial bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and benign or malignant proliferative skin diseases, endotoxin bacterial-toxic shock (and related conditions such as laminitis, spastic, and spastic) non-specific ulcerative colitis; Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, allergic dermatitis, hives, respiratory distress syndrome, respiratory distress syndrome conjunctivitis, spring catarrh of the eye, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and disease imp. antithesis to the recipient, over-secretion of gastric acid, bacterial, fungal or viral-induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscular atrophy, depression, depression neurodegenerative diseases with inflammatory components, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancer invasion in normal hearing tissues PDE4 inhibitory or alternatively about 0.05 mg to about 7 g per patient per day. For example, inflammation can be effectively treated by administering from about 0.01 mg to 50 mg of the compound per kilogram body weight per day or alternatively about 0.5 mg to about 2.5 g per patient per day. Additionally, it is understood that the PDE4 inhibitory compounds of this invention can be administered at prophylactically effective dose levels to prevent the conditions cited above.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the recipient being treated and the particular route of administration. For example, a formulation intended for oral administration to humans may suitably contain from about 0.5 mg to about 5 g of active agent mixed with a suitable and convenient amount of carrier, which may vary from about 5 to about 95% of the total composition. Typically, unit dosage forms will contain between about 0.01 and about 1000 mg of the active ingredient, typically 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

However, it is understandable that the specific dose level for each patient will depend on a variety of factors, including age, body weight, general health, gender, diet, timing of administration, route of administration, excretion rate, drug combination and severity of the specific disease to be treated.

In practice, the compounds represented by Formula I or their pharmaceutically acceptable salts of this invention may be combined as active substance in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. The carrier may take various forms depending on the form of preparation desired for administration, e.g., orally or parenterally (including intravenously). Thus, the pharmaceutical compositions of the present invention may be presented as separate units suitable for oral administration, such as capsules, capsules or tablets, each containing a predetermined amount of the active ingredient. Additionally, the compositions may be presented as a powder, granules, solution, suspension in aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. In addition to the usual dosage forms set forth above, the compound represented by formula I or its pharmaceutically acceptable salts may also be administered by controlled release agents and / or delivery devices. The formulations may be prepared by any of the methods of pharmacy. Generally, such methods include the step of bringing the active ingredient into association with a carrier that represents one or more of the necessary ingredients. Generally, compositions are prepared

65403 Bl by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both. The product may then be suitably shaped to the desired presentation.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of formula I. The compounds of formula 1 or their pharmaceutically acceptable salts may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds .

The pharmaceutical carrier used may for example be a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sugar, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are sugar syrup, peanut butter, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In the preparation of the compositions for oral dosage form, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used to form solid preparations such as powders, capsules and tablets. Due to their ease of administration, tablets and capsules are the preferred oral unit doses through which solid pharmaceutical carriers are used. The tablets may optionally be coated by standard aqueous or non-aqueous techniques.

A tablet containing the composition of this invention can be obtained by compression or molding, optionally with one or more auxiliary ingredients or additives. Compressed tablets can be obtained 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, surfactant or dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 to about 500 mg of the active ingredient and each capsule or capsule preferably contains from about 0.1 to about 500 mg 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 such as hydroxypropylcellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Additionally, a preservative may be included to prevent the harmful development of microorganisms.

Pharmaceutical compositions of the present invention suitable for use as injections include sterile aqueous solutions or dispersions. Moreover, the compositions may 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 efficiently fluid for easy injection. Pharmaceutical formulations must be stable under conditions of production and storage; thus, they should preferably be protected against the contaminating effect of such microorganisms as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosol, cream, ointment, lotion, powder, or the like. Additionally, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared using

65403 B1 is a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, by conventional treatment methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water together with about 5 wt. % to about 10 wt. % of the compound, to obtain a cream or ointment having the desired consistency.

The pharmaceutical compositions of this invention may be in a form suitable for rectal administration in which the carrier is a solid. Preferably, the mixture forms single dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be suitably formed first by mixing the composition with a softening or melting carrier (s), followed by freezing and molding.

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, surfactants, thickeners, lubricants, preservatives ( including antioxidants) and the like. Moreover, other adjuvants may be included to make the formulation isotonic with the blood of the recipient in question. Compositions containing a compound described by formula I or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrated 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, for example, of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis, and benign or malignant proliferative skin diseases, endotoxin-related bacterial-bacterial and elastic abdominal pain in horses), septic shock, nonspecific ulcerative colitis, Crohn's disease, reperfusion myocardial and brain damage, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, allergies en dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in babies, chronic obstructive pulmonary disease in animals, non-diabetes mellitus, allergic rhinitis, allergic conjunctivitis, spring catarrh, inflammatory catarrh, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and implant implant disease, gastric acid secretion, bacterial, fungal or viral-induced sepsis or septicemia k, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle atrophy, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with inflammatory components, Parkinson's disease, Parkinson's disease, , head injury, multiple sclerosis, tumor growth and cancer invasion in normal tissues - diseases that are susceptible to improvement by inhibiting the PDE4 isoenzyme and resulting increased cAMP levels - by applying an effect an amount of the compounds of this invention. The term "mammals" includes humans as well as other animals such as dogs, cats, horses, pigs and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinically relevant diseases of the abovementioned examples, which are human diseases.

Additionally, as described above, the compound of this invention can be used in combination with other therapeutic compounds. In particular, combinations of the PDE4 inhibitory compound of this invention can be suitably used in combination with i) leukotriene receptor antagonists, n) 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 adrenoreceptor agonist.

In another aspect, it has been found that the compound of this invention may be an ore

65403 Formulated as metabolite in mammalian system. For example, Example 19: (5 - {(E) -2- (3-} 6- [1-methyl-1- (methylsulfonyl) -ethyl] -8-quinolinyl {phenyl) -1 [4- (methylsulfonyl) phenyl] ethenyl } -1,2,4-oxa-

diazol-3-yl) methanol; H ₃ C. 0 3s - ^CH 3 1 o CH ₃ IL N 3. J a hours HE

which is a PDE4 inhibitor, is formed in vivo as a metabolite when Example 14 is administered:

Accordingly, the present invention includes prodrugs that form PDE4 inhibitors in vivo as metabolites after administration of such mammalian prodrugs. Additionally, this invention includes a method of treating a step of administering a prodrug to the formation in vivo of an effective amount of a PDE4 inhibitor described in Formula I.

The abbreviations used here have the following meanings given in the table. Abbreviations not given in the table below have their meanings as they are usually used, unless otherwise stated.

65403 Bl

Ac = acetyl Bn benzyl CAMP cyclic adenosine-3 ', 5'-monophosphate DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DIBAL = diisobutylaluminum hydride DMAP ₌ 4- (dimethylamino) pyridine DMF N, N-dimethylformamide Et ₃ N triethylamine GST glutathione transferase HMDS hexamethyldisilazide LDA ₌ lithium diisopropylamide m-CPBA = metachloroperbenzoic acid MMPP = monoperoxyphthalic acid MPPM = monoperoxyphthalic acid, magnesium salt 6H ₂ O Ms = methanesulfonyl = mesyl = SO ₂ Me MsO = methanesulfonate = mesylate NSAID = non-steroidal anti-inflammatory drug remedy O-Tol = ortho-tolyl OXONE® = 2KHSO ₅ .KHSO ₄ »K ₂ SO4 PCC = pyridinium chlorochromate PDC = pyridinium dichromate PDE = phosphodiesterase Ph = phenyl Phe = benzenediyl PMB = para-methoxybenzyl Pye = pyridinediyl r.t. = room temperature Rac. racemic SAM = aminosulfonyl or sulfonamide or SO ₂ NH ₂ SEM = 2- (trimethylsilyl) ethoxymethoxy SPA = scintillation approximate analysis TBAF = tetra-n-butylammonium fluoride

65403 Bl

Th 2- or 3-thienyl TFA = trifluoroacetic acid TFAA = trifluoroacetic acid anhydride THP tetrahydrofuran Thi thiofendil TLC = thin layer chromatography TMS-CN = trimethylsilyl cyanide TMSI trimethylsilyl iodide Tz = 1H (or 2H) -tetrazol-5-yl CAN cerium ammonium nitrate C3H5 = allyl

Acronyms of alkyl groups

Me = methyl Et = ethyl l-PR normal prop i-Pi = isopropyl n-Bu - normal butyl / -I will = isobutyl s-Bu = secondary butyl f-Bu tertiary butyl C-PR = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl

Studies demonstrating 4Q biological activity

LPS and FMLP-induced TNF-alpha and LTB4 studies in human undiluted blood Undiluted blood provides protein and cell-enriched media suitable for the study of the biochemical efficacy of anti-inflammatory compounds such as PDE4-selective inhibitors. Normal unstimulated human blood does not contain detectable levels of TNF-alpha and LTB ₄ . When stimulated with LPS, activated monocytes express and secrete

TNF-alpha up to 8 h and plasma levels remain stable for 24 h. Published studies have shown that inhibition of TNF-alpha by intracellular cAMP by PDE4 inhibition and / or increased adenylyl cyclase activity occurs at the transcriptional level. LTB ₄ synthesis is also sensitive to intracellular cAMP levels and can be completely inhibited by POE4-selective inhibitors. Because there is little LTB ₄ produced during 24-hour LPS stimulation of undiluted blood, additional

65403 Bln LPS stimulation followed by fMLP administration of human undiluted blood for LTB ₄ synthesis by activated neutrophils. Thus, using the same blood sample, it is possible to evaluate the efficacy of a compound of two PDE4 activity markers in undiluted blood by the following procedure.

Fresh blood was collected in heparinized tubes by venipuncture from healthy human volunteers (men and women). These subjects did not have any visible inflammatory conditions and did not take any NSAIDs for at least 4 days prior to blood collection. Aliquots of 500 µl of blood were pre-incubated with either 2 µl of vehicle (DMSO) or 2 µl of test compound at various concentrations for 15 min at 37 ° C. This was followed by the addition of either 10 µl of filler (PBS) as a blank or 10 µL of LPS (1 µg / 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 h incubation at 37 ° C, another 10 µl PBS (blank) or 10 µL LPS (1 µg / ml final concentration) were added to the blood and incubated for 30 min at 37 ° C. Then, either 10 µL PBS (blank) or 10 µL fMLP (1 µM final concentration, # F-3506 (Sigma); diluted in 1% w / v BSA (in PBS)) were introduced into the blood for 15 min at 37 ° C. Blood samples were centrifuged at 1500 x g for 10 min at 4 ° C to obtain plasma. An aliquot of 50 µl of plasma was mixed with 200 µl of methanol to precipitate the protein and centrifuged as above. The supernatant was analyzed for LTB ₄ using an enzyme immunoassay kit (# 520111 from Cayman Chemical Co., Ann Arbor, Ml) according to the manufacturer's procedure. TNF-alpha was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NJ) according to the manufacturer's procedure. The 1C ₅₀ values of Examples 1-42 generally ranged from 0.04 to 8.71 microM.

Anti-allergic activity in vivo

Compounds of the invention have been investigated for the effects of IgE-mediated allergic pulmonary inflammation induced by inhalation of guinea pig sensitized antigen. Guinea pigs were initially sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression by intraperitoneal injection of antigen in combination with aluminum hydroxide and pertussis vaccine. Additional doses of antigen were given two and four weeks later. At week six, ovalbumin was administered to the animals in the form of an aerosol while under the protection of an intraperitoneally administered antihistamine agent (mepiramine). After an additional 48 h, bronchial alveolar washes (BAL) were performed and the amount of eosinophils and other leukocytes in BAL fluids was counted. The lungs were also removed for histological examination for inflammatory damage. Administration of the compounds of the Examples (0.001 - 10 mg / kg i.p. or p.o.) up to three times during the 48 hours following antigen administration resulted in a significant decrease in eosinophilia and accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with the compounds of the Examples.

Protocol for a SPA-based PDE activity study

Compounds that inhibit the hydrolysis of cAMP to AMP by cAMP-specific type IV phosphodiesterases were screened in 96-well plate format as follows:

In a 96-well plate at 30 ° C was added the test compound (dissolved in 2 microl DMSO), 188 ml of substrate buffer containing [2,8- ³ H] adenosine 3 ', 5'-cyclic phosphate (cAMP, 100 nM to 50 microM), 10 mM MgCl ₂ , 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 ml of human recombinant PDE4 (the amount was controlled to form -10% product for 10 min). The reaction was stopped after 10 min by the addition of 1 mg PDE-SPA granules (Amersham Pharmacia Biotech, Inc., Piscataway, NJ). The AMP product generated was quantified on a Wallac Microbeta® 96-well counter (EG&G Wallac Co., Gaithersburg, MD). The signal in the absence of an enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with background subtraction. Accordingly, pro22 was calculated

65403 Bl cent inhibition. The IC ₅₀ value was approximated by nonlinear regression smoothing using the standard 4-parameter equation / multiple ten-point titration couplings.

The IC ₅₀ values of Examples 1-42 were determined with 100 nM cAMP using the purified GST fusion protein of human recombinant phosphodiesterase IVa (met-248) produced by the bacillovirus / 81-9 expression system. The IC ₅₀ values of Examples 1-42 in most cases ranged from 0.14 to 10.24 nM, although one example had a 1C _X) value of 109 nM.

The examples that follow are intended to illustrate some preferred embodiments of the invention and do not contain limitations of the invention.

Unless otherwise stated, the experimental procedures were performed under the following conditions. All operations were performed at room or ambient temperature - that is, at a temperature in the range of 1825 ° C. Evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600 - 4000 Pa: 4.5 - 30 mm Hg) with a bath temperature of up to 60 ° C. The course of the reactions was monitored by thin layer chromatography (TLC) and the reaction times are given for illustration only. The melting points are not adjusted and 'd' means decomposition. The melting points given are those obtained for the substances prepared as described. In some embodiments, there may be polymorphism in isolating substances with different melting points. The structure and purity of all end products was provided by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry, or microanalysis data. The yields are for illustrative purposes only. When given, NMR data are in the form of delta values for major diagnostic protons, given in parts per million (ppm) versus tetramethylsilane (TMS) used as an internal standard, determined at 300 MHz, 400 MHz, or 500 MHz using the notation solvent. Common abbreviations used for signal format are: s, singlet; d, doublet; t, triplet; t, multiplet; br, broad; etc. In addition, "Ag" shows an aromatic signal. Chemical symbols have their usual meanings; The following abbreviations were also used: o (volume), t (weight), because (boiling point), m.p. (melting point), 1 (liter (s)), ml (milliliters), g (gram (s)), mg (milligram (s)), mol (mole), mmol (millimole), eq (equivalent (and )).

Methods for synthesis

Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in formula I, unless otherwise defined.

65403 Bl

Scheme 1

Ketone synthesis

XAr ¹ Y.

V

Ah—

E - Ar ¹ ·

AGX IV

SOpMe

SOgMQ

Base or organolithium .Basic or organolithium

2. E or A

3. Base or organolithium

4. A or E

VIII where X = halogen, H

Y = halogen, H

A = 4- (methylthio) benzaldehyde

E = electrophile

Ar = aryl or heteroaryl

Referring to Scheme 1 above and the Table to Scheme 1 below, alcoholic intermediate II can be prepared by reaction of aryl or heteroaryl metal species III, such as organomagnesium halide with 4- (methylthio) benzaldehyde (A) in an organic solvent such as THE Alcohol Intermediate II may also be prepared by treating aryl or heteroaryl hydride or bromide IV with a base or organometallic compound such as n-butyllithium in an organic solvent such as THF, followed by

4- (methylthio) benzaldehyde. Alternatively, alcohol intermediate II may also be prepared by the following chemical transformations: 1) treating aryl or heteroaryl dihydride, halide hydride or dihalide V with a base or organometallic compound such as n-butyllithium in an organic solvent such as THF followed by electrophilic or electrophilic 4 (methylthio) benzaldehyde; 2) post-treatment with a base or organometallic compound such as n-butyllithium in an organic solvent such as THF, followed by electrophile such as acetone or

4- (methylthio) benzaldehyde, wherein the first or second conversion should use 4- (methylthio) benzaldehyde as an electrophile. Sulfonic alcohol VI can be obtained by oxidizing

65403 Blending of sulphide alcohol II with an oxidizing agent such as oxone in a solvent as a mixture of THF / MeOH / H ₂ O. Ketones VII and VIII can be obtained by oxidizing alcohols II and VI respectively with an oxidizing agent such as MnO ₂ in 5 solvent such as CH ₂ Cl ₂ . The sulfonic ketone VIII can also be prepared by oxidizing the sulfide ketone VII with an oxidizing agent such as oxone, in a solvent such as a mixture of THF / MeOH / H ₂ O.

Table to Scheme 1 Ketones

Oh

VII (n = 0)

VIII (n = 2)

SO _n Me

Ah n ketones DG ' 2 K1 H ₃ Cj , N_CH ₂ \\ '' 0 K2 Og ° ^H! 2 K3 cr 0 2 K4 K5 hoJ s / ^H2 2 K6

Ar n ketones nlHg K7 Ι == ν ^0Η! 2 κ, <Α ^Ν K8 / CO MeO ₂ S ^^ K9 CO ² K10 ^h 'sXn ° ^H8 2 ^η ° Ϊη, K11

Ketone K1

KetoneK1 (4-fluorophenyl) [4- (methylsulfonyl)] phenyl ketone

The ketone K1 was prepared by the following procedure.

Step 1: (4-Fluorophenyl) [4-methylthio) phenyl] ketone

To -78 ° C a solution of 4- (methylthio) benzaldehyde (2.5 g, 16.4 mmol) in THF (100 ml) was added dropwise 4-fluorophenylmagnesium bromide (1.0 M bTHF, 19.7 ml, 19.7 mmol). The resulting solution was stirred for 3 h at -78 ° C and the reaction was quenched with saturated aqueous NH ₄ Cl. The mixture was then diluted with EtOAc and 10% HCl, extracted and washed (NaHCO ₃ (saturated), brine). The organic phase was dried over MgSO ₄ and concentrated. The residue was then treated with MnO ₂ (28.6 g, 330 mmol) in CH ₂ Cl ₂ (150 ml) and the reaction mixture was stirred at rt overnight. The mixture was filtered through a pad of silica (EtOAc) to give 2.6 g of (4-fluorophenyl) [4-methylthio) phenyl] ketone compound.

Step 2: (4-Fluorophenyl) [4- (methylsulfonyl) phenyl] ketone

To a solution of sulfide - in other words, (4-fluorophenyl) [4-methylthio) phenyl] ketone - from

65403 B1 present step 1 (2.0 g, 8.1 mmol) in THF / MeOH / H ₂ O (80/40/40 ml) was added oxone (7.5 g, 12.2 mmol). The mixture was stirred for 4 h at rt, quenched with NaHCO ₃ (saturated), and diluted with EtOAc. The organic phase was washed with NaHCO ₃ (saturated), brine, dried over Na ₂ SO ₄ , filtered and concentrated. Crystallization (CH ₂ Cl ₂ / hexanes) gave (4-fluorophenyl) [4 (methylsulfonyl) phenyl] ketone, the K1 ketone compound, as a white solid.

Ketone K2 (1-Methyl-1H-imidazol-2-yl) [4-methylthio) phenyl] ketone

Ketone K2 was prepared by the following procedure.

Step 1: (1-methyl-1H-imidazol-2-yl) [4 (methylthio) phenyl] methanol

To a solution of N-methylimidazole (10.0 g, 122 mmol) in 500 ml THF at -78 ° C was added n-butyllithium (2.5 M in hexanes, 48.7 ml, 118 mmol) dropwise and the resulting solution was stirred for 30 min at - 78 ° C. Then 4 (methylthio) benzaldehyde (14.73 ml, 110 mmol) was added at -78 ° C and the mixture was stirred until TLC was complete and the reaction was quenched with NH ₄ Cl (saturated). The mixture was then diluted with EtOAc, extracted and washed (NaHCO ₃ (saturated), brine). The organic phase was dried over MgSO ₄ , filtered and concentrated. Crystallization (EtOAc / hexanes) gave (1-methyl-1H-imidazol-2-yl) [4- (methylthio) phenyl] methanol.

Step 2: (1-methyl-1H-imidazol-2-yl) [4 (methylthio) phenyl] ketone

To a solution of the alcohol of the present step 1 (25.7 g, 111 mmol) in EtOAc (250 ml) and CH ₂ Cl ₂ (250 ml) was added MnO ₂ (140 g, 1.66 mol) and the reaction mixture was stirred overnight at rt overnight. . The mixture was filtered through a pad of silica (EtOAc) to give ketone K2.

Ketone K3 (4-methylsulfonyl) (phenyl) ketone

Ketone K3 was prepared by the following procedure.

Step 1: (4-methylthio) (phenyl) methanol

To a solution of 4- (methylthio) benzapdehyde (1.0 g, 6.5 mmol) in THF (20 ml) at 0 ° C was added phenylmagnesium chloride (2 M, THF, 3.5 ml, 7.0 mmol). After 0.5 h at rt, the mixture was neutralized with saturated NH ₄ C1 solution, diluted with water and extracted with Et ₂ O. The organic extracts were washed (H ₂ O), (brine), dried (MgSO ₄ ), filtered and concentrated. . Purification by vigorous stirring in hexane / Et, O and filtration gave (4-methylthio) (phenyl) methanol as a white solid.

Step 2: (4-methylthio) (phenyl) ketone (4-methylthio) (phenyl) ketone was obtained by treating (4-methylthio) (phenyl) methanol of the present step 1 with MnO ₂ as in step 2 of the procedure for K4 below.

Step 3: (4-Methylsulfonyl) (phenyl) ketone

To a solution of (4-methylthio) (phenyl) ketone of the present step 2 (0.98 g, 4.3 mmol) in CHCl ₃ (10 ml) at 0 ° C was added mCBA (chloroperbenzoic acid) (1.7 g, 10 mmol). After 0.5 h at rt, Ca (OH) ₂ (1.7 g, 23 mmol) was added to the mixture, which was stirred for 1 h. Filtration through Celite (R) and concentration gave the ketone K3 as a white solid.

Ketone K4 (1,3-thiazol-2-yl) [4- (methylthio) phenyl] ketone

Ketone K4 was prepared by the following procedure.

Step 1: (1,3-Thiazol-2-yl) [4- (methylthio) phenyl] methanol

To -78 ° C, a solution of thiazole (5.0 g, 58.7 mmol) in THF (250 ml) was added dropwise n-butyllithium (2.5 M in hexanes, 23.5 ml, 58.7 mmol) and the resulting solution was stirred for 10 min at -78 ° C. . Then 4 (methylthio) benzaldehyde (7.1 ml, 53.4 mmol) was added at -78 ° C. The resulting mixture was stirred until complete and the reaction was quenched with saturated aqueous NH ₄ Cl. The mixture was then diluted with EtOAc and 10% HCl, extracted and washed (NaHCO ₃ (saturated), brine). The organic phase was dried over MgSO ₄ and concentrated. The residue was then purified by flash chromatography (80% CH ₂ Cl ₂ /20% EtOAc) to give (1,3-thiazol-2-yl) [4 (methylthio) phenyl] methanol.

Step 2: (1,3-Thiazol-2-yl) [4- (methylthio) phenyl] ketone

To a solution of (1,3-thiazol-2-yl) [4 (methylthio) phenyl] methanol of the present step 1 (10.0 g, 42.1 mmol) in EtOAc (250 ml) was added MnO ₂ (70 g, 843 mmol). and the reaction mixture was

65403 B1 stirred at 25 ° C overnight. The mixture was filtered through a pad of silica (EtOAc) to give the K4 ketone compound.

Ketone K5 (1,3-thiazol-2-yl) [4- (methylsulfonyl) phenyl] ketone

Ketone K5 was prepared by the following procedure.

To a solution of K4 (1,3-thiazol-2-yl) [4 (methylthio) phenyl] ketone (8.2 g, 34.7 mmol) in THF / MeOH / H ₂ O (350/175/175 ml) was added oxone ( 42.6 g, 69.4 mmol). The reaction mixture was stirred for 3 h at 25 ° C and the reaction was quenched with saturated aqueous HaNaHCO ₃ . The resulting mixture was then diluted with EtOAc, extracted and washed (NaHCO ₃ (saturated), brine). The organic phase was dried over MgSO ₄ and concentrated. The residue was then purified by crystallization (EtOAc / hexanes) to give (1,3-thiazol-2-yl) [4 (methylsulfonyl) phenyl] ketone.

Ketone K6 [5- (1-hydroxy-1-methylethyl) -1,3-thiazole-

2-yl] [4- (methylsulfonyl) phenyl] ketone

Ketone K6 was prepared by the following procedure.

Step 1: [5- (1-Hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4- (methylthio) phenyl] ketone

To -78 ° C a solution of thiazole (1.0 g, 12.0 mmol) in THF (100 ml) was added dropwise lithium lithium (2.3M in hexanes, 5.3 ml, 12.3 mmol) and the resulting solution was stirred for 10 min at -78 ° C. . Then 4- (methylthio) benzaldehyde (7.1 ml, 53.4 mmol) at -78 ° C was added. The resulting mixture was stirred at rt for 10 min and cooled to -78 ° C. Then n-butyllithium (2.3 M in hexanes, 5.3 ml, 12.3 mmol) was added dropwise, the resulting solution was stirred for 10 min at 25 ° C and the reaction was quenched with acetone (3.0 ml). The mixture was then diluted with EtOAc and 10% HCl, extracted and washed (NaHCO ₃ (saturated), brine). The organic phase was dried over MgSO ₄ and concentrated. The residue was then treated with MnO ₂ (20.4 g, 235 mmol) in CH ₂ Cl ₂ (250 ml) and the reaction mixture was stirred at rt overnight. The resulting mixture was then filtered through a pad of silica (EtOAc). Flash chromatography (90% CH ₂ Cl ₂ /10% EtOAc) gave [5- (1 hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4 (methylthio) phenyl] ketone.

Step 2: [5- (1-Hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4- (methylsulfonyl) phenyl] ketone

To a solution of the sulfide - i.e., [5- (1hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4 (methylthio) phenyl] ketone - of the present step 1 (1.7 g, 5.8 mmol ) in THF / MeOH / H ₂ O (100/50/50 ml), oxone (7.1 g, 11.5 mmol) was added. The reaction mixture was stirred for 3 h at 25 ° C and the reaction was quenched with saturated aqueous NaHCO ₃ . The mixture was then diluted with EtOAc, extracted and washed (NaHCO ₃ (saturated), brine). The organic phase was dried over MgSO ₄ and concentrated. The residue was then purified by crystallization (EtOAc / hexanes) to give ketone K6.

Ketone K7 (6-methyl-3-pyridinyl) [4- (methylsulfonyl) phenyl] ketone

Ketone K7 was prepared by the following procedure.

Step 1: (6-methyl-3-pyridinyl) [4 (methylthio) phenyl] methanol

To a solution of 3-bromo-6-methylpyridine (760 mg, 1 eq) in THF (20 ml) at -78 ° C, n-butyllithium in hexane (1.1 eq) was added slowly. The solution was then stirred for 30 min. Then 4- (thiomethyl) benzaldehyde (738 mg, 1.1 eq) was slowly added. The solution was warmed to rt NH ₄ Cl (saturated) was then added, followed by water and EtOAc. The organic phase was separated, dried over MgSO ₄ and concentrated. (6-methyl-3-pyridinyl) [4- (methylthio) phenyl] methanol was obtained by precipitation with ether / hexane and used without further purification for the next step.

Step 2: (6-methyl-3-pyridinyl) [4 (methylsulfonyl) phenyl] -methanol

Following the procedure in step 2 for ketone K1 above, but by substituting (4-fluorophenyl) [4- (methylthio) phenyl] ketone with (6methyl-3-pyridinyl) [4- (methylthio) phenyl] methanol sulfide from the present step 1, starting material was (6-methyl-3-pyridinyl) [4- (methylsulfonyl) -phenyl] -methanol.

Step 3: (6-methyl-3-pyridinyl) [4- (methylsulfonyl) phenyl] ketone

Following the step 2 procedure for

65403 B1 ketone K2 above but by substituting (1-methyl-1H-imidazol-2-yl) [4- (methylthio) phenyl] methanol with (6-methyl-3-pyridinyl) [4- (methylsulfonyl) phenyl] methanol from the present step 2 as starting material, ketone K7 was obtained.

Ketone K8 (5-methyl-2-pyridinyl) [4- (methylsulfonyl) phenyl] ketone

Ketone K8 was prepared by following the procedure described for ketone K7 but by replacing 3-bromo-6-methylpyridine with 2-bromo-5methylpyridine.

Ketone K9

Bis - [(4-methylsulfonyl) phenyl] ketone

Ketone K9 was prepared by following the procedure described for ketone K7 but by replacing 3-bromo-6-methylpyridine with 4bromothioanisole and using twice the amount of oxone in the sulfoxidation step.

KetoneK10 (2-pyridinyl) [4- (methylsulfonyl) phenyl] ketone

Ketone K10 was prepared following the procedure described for ketone K7, but by replacing 3-bromo-6-methylpyridine with 2bromopyridine.

Ketone N11 [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) -phenyl] ketone

Ketone K11 was prepared by the following procedure.

Step 1: [5- (1-Hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylthio) -phenyl] methanol

To a suspension of 2,5-dibromopyridine (5.12 g, 1 eq) in ether at -78 ° C, n-butyllithium in hexane (1.05 eq) was slowly added. The resulting yellow-orange precipitate was stirred 30 mm.

Acetone (1.54 ml, 1.05 eq) was then added. The solution was kept at -78 ° C for another 30 min. N-butyllithium in hexane (1.1 eq) was slowly injected into the resulting orange suspension. The suspension was then stirred for 1 h at 78 ° C. Then 4- (methylthio) benzaldehyde (2.85 ml, 1.1 eq) was added. The resulting suspension was warmed to -35 ° C and quenched with NH ₄ Cl (saturated) solution. Water and EtOAc were added and the organic layer was dried over MgSO ₄ , evaporated and purified by flash chromatography (EtOAc) to give [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylthio) -phenyl] methanol.

Step 2: [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] methanol

Following the procedure described above for step 2 for ketone K1 but replacing the sulfide - i.e., (4-fluorophenyl) [4- (methylthio) phenyl] ketone with [5- (1-hydroxy-1 - Methyl ethyl) -2-pyridinyl] [4- (methylthio) -phenyl] methanol from the present step 1 as starting material, [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] -methanol was obtained .

Step 3: [5- (1-Hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] ketone

Following the procedure described above for step 2 for ketone K2 but replacing (1-methyl-1H-imidazol-2-yl) [4- (methylthio) phenyl] -methanol with [5- (1-hydroxy) -1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) -phenyl] methanol from the present step 2 as the starting material, ketone K11 was obtained.

The boronate compounds used to prepare the compounds of this invention can be prepared according to Scheme 2 shown below:

65403 Bl

Scheme 2

Boronate synthesis

IX (n = 0)

Ketone (VII or VIII) Ar η Boronate (XII)

K2 On Hat / · '! / 0H ₃ 0 B1 K4 Λ 0 B2 K8 LH ^CH3 h ₂ c <N 2 OT K11 h ₂ c ^ n 2 Q4

The aryl bromides IX and X can be obtained by treating benzylphosphonium bromide XI with a base such as f-BuOK or LiHMDS in an organic solvent such as THF, followed by the addition of ketone VII or VIII to the reaction mixture. Sulfide IX can be converted to sulfone X by treatment with oxone, in a solvent as a mixture of THF (MeOH).

65403 Bl

H ₂ O. The boronate ester XII can be obtained by heating the aryl bromide X with pinacol diboran in the presence of a base such as KOAc and a catalyst such as PdCl ₂ (dppf) in a solvent such as DMF.

Boronate B1

Pinacol 3 - {(E) -2- (1-methyl-1H-imidazol2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate

Boronate B1 was prepared by the following procedure.

Step 1: (E / d) -2- (3-bromophenyl) -1- (1methyl-1H-imidazol-2-yl) -1- [4- (methylthio) phenyl] ethene

To a solution of (3-bromobenzyl) (triphenyl) phosphonium bromide (10.2 g, 19.9 mmol) in THF (200 ml) and CH ₃ CN (50 ml) at 25 ° C was added t-BuOK (1.0 M in THF) dropwise. , 19.9 ml, 19.9 mmol) and the resulting red solution was stirred at rt for 20 min. To this resultant illide was then added at 25 ° C ketone K2 (4.4 g, 18.9 mmol). The resulting mixture was stirred for 2 days at 60 ° C and the reaction was quenched with NH ₄ Cl (saturated). The mixture was then diluted with EtOAc. The organic phase was washed with NaHCO ₃ (saturated), brine, dried over MgSO ₄ , filtered and concentrated, and used directly in the next step 2.

Step 2: (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene

To a solution of crude sulfide - i.e., (E / 7) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2yl) -1- [4- (methylthio) phenyl] ethene - Oxon (23.2 g, 37.8 mmol) was added from the present step 1 (18.9 mmol) in THF / MeOH / H ₂ O (200/100/100 ml). The mixture was stirred for 4 h at rt, quenched with NaHCO ₃ (saturated) and diluted with EtOAc. The organic phase was washed with NaHCO ₃ (saturated), brine, dried over Na ₂ SO ₄ , filtered and concentrated. Flash chromatography (95% EtOAc / 5% Et ₃ N) gave (E) -2- (3bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1 [4- (methylsulfonyl) -phenyl ] -ethene (single isomer) as foam.

Step 3: Pinacol 3 - {(E) -2- (1-methyl-1Himidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate

Bromide suspension - i.e., (E) -2- (3bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1 [4- (methylsulfonyl) phenyl] ethene - of the present step 2 (2.0 g; 4.8 mmol), pinacol diborane (1.5 g; 5.8 mmol), KOAc (1.65 g; 16.8 mmol) and PdCl ₂ (dppf) (0.2 g; 0.24 mmol) in 50 ml of DMF were stirred for 4 h at 90 ° C. The resulting mixture was cooled to rt, diluted with EtOAc, washed with H ₂ O (3x), brine, dried over Na ₂ SO ₄ , filtered and concentrated. Flash chromatography (95% EtOAc / 5% Et ₃ N) gave boronate B1 as foam.

Boronate B2

Pinacol 3 - {(E / g) -2- (1,3-thiazol-2-yl) -2 [4- (methylsulfonyl) -phenyl] ethenyl {phenylboronate

Boronate B2 was prepared by the following procedure.

Step 1: (E) - 2- (3-bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylthio) -phenyl] ethene

LiHMDS (1.0Mv THF, 86.9 ml, 86.9) was added dropwise to a solution of (3-bromobenzyl) (triphenyl) phosphonium bromide (44.5 g, 86.9 mmol) in THF (500 ml) and DMF (200 ml). mmol) and the resulting red solution was stirred for 20 min at rt To the resulting illide was then added at 0 ° C ketone K4 (18.6 g, 79.0 mmol). The mixture was stirred until complete by TLC and the reaction was quenched with NH ₄ Cl (saturated). The mixture was then diluted with EtOAc. The organic phase was washed with NaHCO ₃ (saturated), brine, dried over MgSO ₄ , filtered and concentrated. Flash chromatography (CH ₂ Cl ₂ ) gave (E / Z) -2- (3bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4 (methylthio) phenyl] ethene (1.5 to 1 mixture of isomers).

Step 2: (E / g) -2- (3-bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene

To a solution of the sulfide - i.e., (E / Z) -2- (3bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4 (methylthio) phenyl] ethene - of the present step 1 (24.8 g, 63.9 mmol) in THF / MeOH / H ₂ O (600/300/300 ml) was added oxone (78.5 g, 128 mmol). The resulting reaction mixture was stirred at rt overnight. The reaction was quenched with NaHCO ₃ (saturated) and diluted with EtOAc. The organic phase was washed with NaHCO ₃ (saturated), brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (E / Z) -2- (3bromophenyl) -1- (1,3-thiazole-2- yl) -1- [4 (methylsulfonyl) phenyl] ethene (3 to 2 mixture of isomers).

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Step 3: Pinacol 3 - {(E / g) -2- (1,3-thiazol-2yl) -2- [4- (methylsulfonyl) -phenyl] ethenyl} phenylboronate

Suspension of (E / Z) -2- (3bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene bromide of the present step 2 (15.0 g, 35.7 mmol ), pinacol diborane (10.9 g, 42.8 mmol), KOAc (12.3 g, 125 mmol) and PdCl ₂ (dppf) (1.46 g, 1.78 mmol) in 350 ml of DMF were stirred for 4 h at 90 ° C. The resulting mixture was cooled to rt, diluted with EtOAc, washed with H ₂ O (3x), brine, dried over Na ₂ SO ₄ , filtered and concentrated. Flash chromatography (To1 / acetone, 9/1) gave boronate B2 (3 to 1 mixture of isomers) as foam.

OT boronate

Pinacol 3 - {(E) -2- (5-methyl-2-pyridinyl) 2- [4- (methylsulfonyl) -phenyl] ethenyl} phenylboronate

Boronate B3 was obtained by the following procedure.

Step 1: (E) -2- (3-bromophenyl) -1- (5-methyl2-pyridinyl) -1- [4- (methylsulfonyl) phenyl] ethylene

Using the procedure described for step 1 for boronate B1 but substituting ketone K2 with ketone K8 as the starting material, (E) -2- (3-bromophenyl) -1- (5-methyl-2-pyridinyl) was obtained ) 1- [4- (methylsulfonyl) -phenyl] ethylene, after separation of the isomers by flash chromatography.

Step 2: Pinacol 3 - {(E) -2- (5-methyl-2pyridinyl) -2- [4- (methylsulfonyl) -phenyl] ethenyl} phenylboronate

Using the procedure described for step 3 for boronate B1 but replacing bromide (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [4- ( methylsulfonyl) phenyl] ethene with (E) -2- (3-bromophenyl) -1- (5-methyl2-pyridinyl) -1- [4- (methylsulfonyl) phenyl] ethylene of the present step 1 as a starting material, boronate was obtained OT.

Boronate B4

Pinacol 3 - {(E) -2- (5- (1-hydroxy-1methylethyl) -2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate

Boronate B4 was obtained by the following procedure.

Step 1: (E) -2- (3-bromophenyl) -1- [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] -1- [4 (methylsulfonyl) phenyl] ethene

Using the procedure described for step 1 for boronate B1 but replacing ketone K2 with ketone K11 as the starting material, (E) -2- (3-bromophenyl) -1- [5- (1hydroxy-1-) was obtained methyl ethyl) -2-pyridinyl] -1- [4 (methylsulfonyl) phenyl] ethene, after separation of the isomers by flash chromatography.

Step 2: Pinacol 3 - {(E) -2- (5- (1-hydroxy-methylethyl) -2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate

Using the procedure described for step 3 for boronate B1 but replacing bromide (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [4- ( methylsulfonyl) phenyl] ethene with (E) -2- (3-bromophenyl) -1- [5 (1-hydroxy-1-methyl-ethyl) -2-pyridinyl] -1- [4 (methylsulfonyl) phenyl] ethene from present step 1 as starting material, boronate B4 was obtained.

The aryl bromide compounds used to prepare the compounds of this invention can be prepared according to Schemes 3 and 4, shown below:

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Scheme 3

Oxadiazole Synthesis of p-MeOPhOH + CI- ^ CN p-MaOPhCk ^ CN

Xllla

R Oxadiazole (XVI)

Me 0X1 p-MeOPhOCH ₂ 0X2

Referring to Scheme 3 above, the nitrile intermediate XIIIa can be prepared by alkylation of 4-methoxyphenol with chloroacetonitrile in the presence of a base such as potassium carbonate in a solvent such as acetone. The amide oxime XIV can be prepared by treating nitrile XIII with hydroxylamine in a solvent such as methanol in the presence of a base such as sodium acetate. The formation of oxadiazole XVI can be achieved by activating the aryloacetic acid XV with carbonyldiimidazole in a solvent such as DMF followed by the addition of amide oxime XIV and subsequent heating of the reaction mixture.

Scheme 4 Aryl bromide synthesis

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Referring to Scheme 4 above, the condensation of aldehyde XVII by heating with aryloacetic acid XV in the presence of a base such as piperidine in a solvent such as toluene results in unsaturated 5 acid XVIIIa. The formation of the acid chloride XVIIIa in situ by treatment with thionyl chloride and a base such as triethylamine in a solvent such as toluene is followed by the addition of an amine to the reaction mixture to give the amide XHPB6. Oxadiazole-ethene XVIIIc can be formed by heating OX 1 with XVII in the presence of a base such as piperidine in a solvent such as toluene.

Scheme 4 annex

Aryl bromide synthesis

Referring to Scheme 4 of Annex, above, treatment of acid XVIIIa with diazomethane in a solvent such as THF results in the methyl ester XVIIId. Reduction of ester XVIIId using DIB AL-H in a solvent such as THP gives allyl alcohol XVIIIe. Conversion of the alcohol group in XVIIIe to a leaving group such as mesylate using reagents such as methanesulfonyl chloride and triethylamine in a solvent such as THF, followed by replacement with a nucleophile such as dimethylamine, in a solvent such as DMF, yields compound XVIIIf.

Aryl bromide AB1 (E) -3- (3-bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid

The aryl bromide AB1 was prepared by the following procedure. To a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in toluene (100 ml) was added 4- (methylsulfonyl) phenylacetic acid (15 g, 70 mmol) and piperidine (2 ml).

XVIIIf (AB6)

After refluxing overnight, the mixture was cooled to r.t. Toluene (10 ml) was added to the suspension thus obtained. 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- [4 (methylsulfonyl) phenyl] -2-propenamide

The aryl bromide AB2 was prepared by the following procedure. To a solution of AB 1 (24.9 g, 65 mmol) in toluene (250 ml) was added thionyl chloride (14.3 ml, 196 mmol) and triethylamine (34 ml, 245 mmol). After stirring at rt for 0.5 h, isopropylamine (28 ml, 327 mmol) was added. After an additional 2 h at rt, the mixture was cooled to 0 ° C and neutralized with saturated NH ₄ Cl solution, then extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Flash purification

65403 B1 chromatography (Hex: EtOAc, 1: 1 to pure EtOAc) gave (E) -N-isopropyl-3- (3-bromophenyl) -2- [4 (methylsulfonyl) phenyl] -2-propenamide.

Aryl bromide AB3 (E) -3- (3-bromophenyl) -2- [4- (methylsulfon-5-yl) phenyl] -2-propenamide

The aryl bromide AB3 was prepared by following the procedure described for aryl bromide AB2, but by replacing isopropylamine with ammonium hydroxide as the starting material. 10 Aryl bromide AB4 (E) -N- (t-butyl) -3- (3-bromophenyl) -2- [4 (methylsulfonyl) phenyl] -2-propenamide Aryl bromide AB4 was prepared following the procedure described for Aryl bromide AB2 but 15 by replacing isopropylamine with tbutylamine as starting material.

Aryl bromide AB5 (E) -1- (3-bromophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] - 20 ethene

Aryl bromide AB5 was prepared by the following procedure.

Step 1 (Scheme 3, Oxadiazole 0X1): (3methyl-1,2,4-oxadiazol-5-yl) [4- (methylsulfonyl) phenyl] methane

To a solution of 4- (methylsulfonyl) phenylacetic acid (15 g, 70 mmol) in DMF (300 ml) at rt was added carbonyldiimidazole (12.5 g, 30 mmol). After 0.5 h at rt, acetamide oxime (5.7 g, 77 mmol) was added. After stirring the resulting mixture overnight at rt, the mixture was heated to 120 ° C for 6 h. After cooling to rt, the mixture was sharply cooled with H ₂ O and extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 1: 1) gave (3-methyl-1,2,4-oxadiazol-5-yl) [4 (methylsulfonyl) phenyl] methane.

Step 2 (Scheme 4): (E) -1- (3-bromophenyl) 2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4 (methylsulfonyl) phenyl] ethene

To a solution of 3-bromobenzaldehyde (2.2 g,

11.9 mmol) in toluene (30 ml) was added the product of step 1 (0X1) (3.0 g, 11.9 mmol) and piperidine (0.4 ml). After refluxing overnight, the mixture was cooled to r.t. MeOH (30 ml) was added to the resulting suspension. After additional reflux and then cooled to 0 ° C, filtration gave (E) -1- (3-bromophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethene as a white solid.

The bromoquinolines used to prepare the compounds of this invention can be prepared according to Scheme 5, shown below.

Figure 5

Preparation of bromoquinolines

Br

XIX

Br

XXs

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Referring to Scheme 5 above and the Table to Scheme 5 below, treatment of 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 prepare the compounds Xha. Compound XXb can be obtained by treating XXa with a base such as potassium t-butoxide (1.1 eq) in a solvent such as THF, followed by the addition of the resulting mixture to a solution of methyl iodide in a solvent such as THF. Compound XXc can be obtained by treating XXb with a base such as potassium butoxide (1.1 eq) in a solvent such as THF, followed by the addition of the resulting mixture to a solution of methyl iodide in a solvent such as THF. The compound XXc (where R ¹ = CN) can also be obtained by treating XXa with a base such as potassium m-butoxide (2.2 eq) and methyl iodide in a solvent such as THF.

The compound XXc (where R ¹ = SO ₂ Me) can also be obtained by treating 10 of XXa with a base such as potassium t-butoxide (1.3 eq) and methyl iodide (1.6 eq) in a solvent such as THF, followed by additional methyl iodide (1.6 eq) and an additional quantity of the same base (1.0 eq).

Table to Scheme 5 Bromoquinolines

XX

R ¹ R ² R ³ Bromoquinoline (XX)

SO ₂ Me H H Q1 SO ₂ Me Me H Q2 SO ₂ Me Me Me Q3 CN H H Q4 CN Me Me Q5

Bromoquinoline Q1

6- (methylsulfonyl) methyl-8-bromoquinoline

Bromoquinoline Q1 was prepared by 40 following procedure. DMF (500 ml) was added to 6-bromomethyl-8-bromoquinoline (60 g, 200 mmol) (described in WO 1994/022852) and sodium methanesulfinate (27.6 g, 270 mmol). After stirring overnight at rt, the mixture was poured 45 with H ₂ O (2000 ml), stirred for one hour, isolated by filtration and washed with Et ₂ O to give 6- (methylsulfonyl) methyl-8bromoquinoline.

Bromoquinoline Q2 50

6- [1- (methylsulfonyl) ethyl] -8-bromoquinoline

Bromoquinoline Q2 was prepared by the following procedure. To a solution of bromoquinoline QI (16.1 g, 54 mmol) in THF (500 ml) at -78 ° C was added potassium m-butoxide (59 ml, 1 N in THP). After 0.5 h at -78 ° C, the resulting mixture was stirred for 45 min at 0 ° C and then cannulated dropwise into a solution of Mel (16.7 ml,

268.3 mmol) in THF (160 ml).

After stirring overnight at rt, the mixture was neutralized with saturated NH ₄ Cl solution and extracted with EtOAc. Organic

65 403 Bl extracts were washed (H ₂ O), (brine), dried (MgSO _4), filtered and concentrated. Stirring in ether followed by isolation by filtration gave 6- [1- (methylsulfonyl) ethyl] -8 bromoquinoline. 5

Bromoquinoline Q3

6- [1-methyl-1- (methylsulfonyl) ethyl] -8bromoquinoline

Bromoquinoline Q3 was prepared by the following procedure. To a solution of bromoquino-10 lin Q2 (15.7 g, 50 mmol) in THP (500 ml) at -78 ° C was added potassium m-butoxide (55 mL, 1 N in THF). After stirring 0.5 n at -78 ° C, the resulting mixture was stirred at 0 ° C for 45 min and then transferred dropwise to a solution of Mel 15 (15.6 ml, 250 mmol) in THF (40 ml) at 0 ° C. After stirring overnight at rt, the mixture was neutralized with saturated NH ₄ Cl solution and extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried 20 (MgSO _4), filtered and concentrated. Stirring in ether followed by isolation by filtration gave 6- [1-methyl-1- (methylsulfonyl) ethyl] -8-bromoquinoline.

Bromoquinoline Q4 25

6-cyanomethyl-8-bromoquinoline Bromoquinoline Q4 was prepared by the following procedure. To 6-bromomethyl-8 bromoquinoline (3 g, 10 mmol) (described in WO

1994/022852) and potassium cyanide (1.6 g, 25 mmol) were added DMF (10 ml) and H ₂ O (5 ml). After heating at 100 ° C for 1 h, the resulting mixture was quenched by pouring with H ₂ O (100 ml) and extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 3: 1) gave 6-cyanomethyl-8-bromoquinoline.

Bromoquinoline Q5

6- [1-Methyl-1-cyanoethyl] -8-bromoquinoline Bromoquinoline Q5 was prepared by the following procedure. To a solution of bromoquinoline Q4 (3 g, 12.1 mmol) in THF (100 ml) at -78 ° C, Mel (1.7 ml, 27 mmol) was added followed by potassium m-butoxide (27 ml, 27 mmol). After 2 h at -78 ° C, the mixture was warmed to 0 ° C and neutralized with saturated NH ₄ Cl solution, then extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 3: 1) gave 6- [1methyl-1-cyanoethyl] -8-bromoquinoline.

The benzylphosphorus reagents used to prepare the compounds of this invention can be prepared according to Scheme 6 shown below:

Figure 6

Preparation of benzylphosphorus reagents

^{XX |} XXII / XXIII (X = Br)

XXV

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R ¹ R ² Benz. phos. reagent (XXV) N. CH ₂ P (Ph) ₃ + Br ' P1 N. CH ₂ P (O) (OEt) ₂ P2 CN CH ₂ P (O) (OEt) ₂ RE

The arylquinolines of formula XXII can be prepared by coupling bromoquinoline XX with boric 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 DME. Alcohol XXII can be converted to bromide XXIII by treatment with HBr (aqueous) in a solvent such as acetic acid. The alcohol XXII can be converted to the methyl sulfonate ester XXIV with methanesulfonyl chloride in the presence of a base such as triethylamine, in a solvent such as di-20 chloromethane. Benzylphosphorus reagents XXV can be obtained either by heating the

XXIII in the presence of PPh ₃ , in a solvent such as acetonitrile, or by treatment with XXIII or

XXIV with diethylphosphite and a base such as potassium t-25 butoxide, in a solvent such as THE

Benzylphosphonium bromide P1 [3- (6-isopropyl-8-quinolinyl) benzyl] (triphenyl) phosphonium bromide

Benzylphosphonium bromide P1 was obtained by the following procedure.

Step 1: 6-Isopropyl-8- [3- (hydroxymethyl) phenyl] quinoline

Mixture of 6-isopropyl-8-bromoquinoline (11.1 g, 44.4 mmol) (described in WO 1994/022852), 35 3- (hydroxymethyl) phenylboronic acid (8.70 g,

57.2 mmol), Na ₂ CO ₃ (2 Μ, 71 ml, 142 mmol) and Pd (PPh ₃ ) ₄ (2.51 mg, 2.17 mmol) in 280 ml DME were stirred for 5 h at 80 ° C. The resulting mixture was cooled to rt, diluted with EtOAc, washed 40 with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Flash chromatography (Hex / EtOAc, 1/1) and stirring in CH ₂ Cl ₂ / hexane (1/9) gave 6-isopropyl-8- [3- (hydroxymethyl) phenyl] quinoline as a white solid. 45

Step 2: 6-Isopropyl-8- [3- (bromomethyl) phenyl] quinoline

A suspension of the hydroxymethyl product of the present step 1 (7.40 g, 26.7 mmol) in AcOH (50 ml) and HBr (50 ml, 48% aqueous) was stirred h at 100 ° C. The mixture was cooled to rt, 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 give 6-isopropyl-8- [3- (bromomethyl) phenyl] quinoline as a yellow solid.

Step 3: [3- (6-Isopropyl-8-quinolinyl) benzyl] (triphenyl) phosphonium bromide

To a solution of the bromomethyl product of the present step 2 (3.807 g, 11.1 mmol) in 40 ml of CH ₃ CN was added triphenylphosphine (3.22 g, 12.3 mmol). The mixture was stirred for 12 h at 60 ° C, cooled to rt, diluted with ether, filtered and washed with ether to give [3- (6isopropyl-8-quinolinyl) benzyl] (triphenyl) phosphonium bromide.

Benzylphosphonate P2

Diethyl 3- (6-isopropyl-8-quinolinyl) benzylphosphonate

Benzylphosphonate P2 was obtained by the following procedure. The bromomethyl compound of step 2 above from the synthesis of Pl (11.34 g, 1 eq) was dissolved in THF (170 ml). Diethylphosphite (3.87 ml, 1.05 eq) was added and the solution was cooled to 0 ° C. Then t-BuOK was slowly added. (3.87 ml, 1N in THF). The reaction mixture was stirred for 2 h and the reaction was quenched by the addition of MH 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.

Benzyl phosphonate RE

Diethyl 3- [6- (1-cyano-1-methylethyl) -8quinolinyl] benzylphosphonate

Benzylphosphonate P3 was prepared by the following procedure.

Step 1: 6- (1-cyano-1-methylethyl) -8- [3 (hydroxymethyl) phenyl] quinoline

65403 Bl

Following step 1, described above, of the benzylphosphonium bromide P1 procedure, but by substituting 6-isopropyl-8-bromoquinoline with bromoquinoline Q5 as the starting material, 6- (1-cyano-1-methylethyl) was obtained - 8- [3- 5 (hydroxymethyl) phenyl] quinoline.

Step 2: 3- [6- (1-Cyano-1-methylethyl) -8quinolinyl] benzyl methanesulfonate

To a solution of the alcohol 6- (1-cyano-1-methylethyl) -8- [3- (hydroxymethyl) phenyl] quinoline 10 of the present step 1 (5.15 g, 17 mmol) in CH ₂ Cl ₂ (150 ml) at -78 ° C was added Et ₃ N (3.6 ml, 26 mmol) and methanesulfonyl chloride ("MsCl") (1.6 ml, 21 mmol). After 0.5 h at -78 ° C, the mixture was neutralized with saturated NH ₄ Cl solution, 15 diluted with water and extracted with ether. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated to give 3- [6- (1-cyano)

-methylethyl) -8-quinolinyl] benzyl methanesulfonate as a white foam.

Step 3: Diethyl 3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] benzyl phosphonate

To a solution of diethylphosphite (2.5 ml, 18 mmol) in THF (100 ml) at -78 ° C was added potassium m-butoxide (IM, THF, 16 ml, 16 mmol) and the mesylate compound 3- [6- (1 - cyano-1 methylethyl) -8-quinolinyl] benzyl methanesulfonate of the present step 2 (5.1 g, 13.5 mmol). After 0.5 h at -78 ° C and 12 h at rt, the resulting mixture was neutralized with saturated NH ₄ Cl solution, diluted with water and extracted with ether. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 1: 4 to 1:10) gave diethyl 3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] benzyl phosphonate as an oil.

Scheme 7

Benzylphosphorus reagent - ketone coupling

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Compounds of formula I can be prepared using the reaction pathways outlined in Scheme 7 above. Compound XXVI can be prepared by adding a solution of ketone VII in a solvent such as THF, to a mixture of benzylphosphorus reagent XXV and a base such as potassium m-butoxide, in a solvent such as THF. The compounds of formula I can then be prepared by treating XXVI with oxone in a solvent mixture such as THF / MeOH / water. Alternatively, the compounds of formula I can be prepared by reacting ketone VIII with 5 XXV in the presence of a base such as potassium shbutoxide in a solvent such as THE Referring to Scheme 7 above and

Table 1 below, the coupling of the ketones with the benzyl phosphorus reagents resulted in the 10 examples given in the table.

Table 1 Benz. phos. pear. Ketone Example P2 CZ 1 P2 CZ 2 P1 K5 3 P1 K2 4 P2 K1 5 P2 K1 6 P2 K6 7 RE K6 8 RE K2 9 P2 Commercial 30 P2 K7 31 P2 K7 32 P2 K8 33 P2 K8 34 P2 K9 35 RE K8 36 RE K8 37

Table 1 Benz. phos. pear. Ketone Example RE K9 38 RE K10 39

SCHEME 8

Aryl bromide - bromoquinoline binding

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Aryl bromide

Boronate

Example (I) (XVIII) (used in situ)

Referring to Scheme 8, compounds of formula I can be prepared by in situ conversion of aryl bromide XVIII to the corresponding boronate ester by heating with a diboric pinacol ester, a catalyst such as [1,1 '-bis (diphenylphosphino) -ferocene] dichloropalladium ( N) and a base such as potassium acetate in a solvent such as DMF, followed by the addition of bromoquinoline XX, an additional amount of the same catalyst, an additional amount of a base such as sodium carbonate (aqueous) and an additional heating period.

Referring to Scheme 8 above, Table 2 and Table 2 annex below, the binding of aryl bromide to bromoquinoline resulted in the examples given in the tables.

Table 2 Aryl bromide Bromoquinoline Example AB5 Q3 14 AB5 Q3 15 AB2 Q5 16 AB2 Q5 17 AB2 Q3 20 AB1 Q5 21 AB5 Q5 22 ATS Q5 23 AB4 Q5 24 AB1 WO 94/22852 25 AB5 WO 94/22852 26

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Table 2 Annex

Aryl bromide Bromoquinoline Example AB6 Q5 43

Compounds of this invention can be prepared by the following Scheme 9, shown below.

SCHEME 9

NR ² R ³

(Example 18) \

r ² = h (Example 19) nr ² r ³ hQ Example 27

NH- <} Example 28 £ n ₃ ^NH ~ pCH ₃ Example 29

CH ₃

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Scheme 9 outlines the preparation of compounds of formula I wherein the aldehyde XXVII can be obtained by heating bromoquinoline XX, 3-formylbenzenic acid, a catalyst such as Pd (PPh ₃ ) ₄ and a base such as sodium 5 carbonate (aqueous), in a solvent such as DME . The aldehyde XXVII can be converted to Example 18 by heating with XVI in the presence of a base such as piperidine, in a solvent such as toluene. Example 19 can be obtained by treating Example 18 with cerium ammonium nitrate ("CAN") in a solvent mixture such as acetonitrile / water. Alternatively, the aldehyde XXVII may be converted to unsaturated acid XXVIII by heating with XV and a base such as piperidine in a solvent such as toluene. The acid XXVIII can then be converted to the amide I (Examples 27, 28 and 29) by treatment with a binding system such as EDC1, HOBt and an amine in a solvent such as DMF.

Compounds of this invention can be prepared by coupling bromoquinoline compounds with boronate compounds according to Scheme 10 below.

Figure 10

Bromoquinoline - boronate binding

Bromoquinoline (XX) Boronate (XII)

Example (I)

Scheme 10 describes how compounds of formula I can be prepared by coupling bromoquinoline XX with boronate ester XII in the presence of a catalyst such as Pd (OAc) ₂ , 35

PPh ₃ , and a base such as sodium carbonate (aqueous), in a solvent such as n-propanol. Referring to Table 3, the binding of bromoquinoline to boronate resulted in the examples given in the table.

Table 3 Bromoquinoline Boronate Example Q2 B2 10 Q3 B2 11 Q2 B1 12 Q3 B1 13 Q3 OT 40 Q3 OT 41 Q3 Q4 42

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Examples 1 and 2

6-isopropyl-8- (3 - {(r / E) -2- [4- (methylsulfonyl) phenyl] -2-phenylethenyl} phenyl) quinoline

Examples 1 and 2 were obtained by the following procedure. Potassium m-butoxide (1 M, THF, 0.83 mmol) was added to a mixture of benzyl phosphonate P2 (330 mg, 0.83 mmol) and ketone K3 (200 mg, 0.77 mmol) in THF (6 ml). After 1 h at rt, the mixture was diluted with water and extracted with Et ₂ O, the Organic extracts were washed (H ₂ O), (brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 7: 3) gave Examples 1 and 2 as white foam, and one product was 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 Ή (400 MHz, Acetone-bb) δ 8.79 (q, 1H), 8.28 (q, 1H), 7.94 (d, 2H),

7.73 (d, 1H), 7.6-1.1 (m, 14H), 3.14 (t, 1H),

2.97 (s, 3H), 1.34 (d, 6H).

Example 2: NMR Ή (400 MHz, Acetone-bb) δ 8.78 (q, 1H), 8.25 (q, 1H), 7.89 (d, 2H),

7.71 (d, 1H), 7.6 (t, 3H), 7.45 (t, 3H), 7.39 - 7.2 (t, 8H), 3.11 (t, 4H), 1.34 (d, 6H).

Example 3

6-isopropyl-8- {3 - [(E / g) -2- [4- (methylsulfonyl) phenyl] -2- (1,3-thiazol-2-yl) ethenyl] phenyl} quinoline

Example 3 was obtained by the following procedure. To a suspension of benzylphosphonium bromide P1 (320 mg, 0.531 mmol) in

2.5 ml of THF at -78 ° C was added dropwise fBuOK (1.0 M in THF, 0.55 ml, 0.55 mmol) and the resulting red solution was stirred for 30 min at 0 ° C. Ketone K5 (122 mg, 0.455 mmol) in 2 ml of THF was then added dropwise to this illide at -78 ° C. The mixture was warmed to rt, then stirred for 1 h, quenched with 1 H 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, Hex / EtOAc 10 to 100% for 20 min) gave Example 3 (1.5 to 1 mixture of isomers).

NMR Ή (500 MHz, acetone-bb) δ 8.79

- 8.78 (m, 1H), 8.26 - 8.23 (m, 1H), 8.01 - 7.92 (m, 3H), 7.84 (d, 0.4H, minor), 7.78 (d,

65403 Bl

0.6H, major), 7.73 - 7.47 (m, 10H), 7.43 (dd, 1H),

7.34 (t, 0.6H, major), 7.27 (t, 0.4H, minor), 7.18 (d, 0.6H, major), 7.09 (d, 0.4H, minor), 3.12 (m, 1H), 3.11 (s , 1.8H, major), 2.99 (s, 1.2H, minor), 1.36 -1.33 (m, 6H).

MS (M + 1) 511.

Example 4

6-isopropyl-8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Example 4 was obtained by the following procedure.

Step 1: 6-Isopropyl-8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylthio) phenyl] ethenyl} phenyl) quinoline

Following the procedure of Example 3, but by replacing the ketone K5 with K2 as the starting material, 6-isopropyl-8- (3 - {(E) -2 (1-methyl-1H-imidazol-2-yl) was obtained ) -2- [4- (methylthio) phenyl] ethenyl} phenyl) quinoline.

Step 2: 6-Isopropyl-8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Following the procedure used to prepare borate B1 (step 2 of Scheme 2) but replacing (E / d) -2- (3-bromophenyl) -1 (1-methyl-1H-imidazol-2- yl) -1- [4- (methylthio) phenyl] ethenasate sulfide, obtained in this step 1 as starting material, was obtained Example 4.

NMR Ή (500 MHz in acetone-bb) δ 8.77 (dd, 1H), 8.24 (dd, 1H), 7.88 (d, 2H), 7.71 (d, 1H),

7.59 (d, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.41 (dd, 1H), 7.28 (t, 1H), 7.23 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 3.51 (s, 3H), 3.10 (m, 1H),

2.99 (s, 3H), 1.32 (d, 6H).

MS: (m + 2): 509.4

Examples 5 and 6

6-isopropyl-8- (3 - {(2 / E) -2- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Example 6

Examples 5 and 6 were obtained by the following procedure. Following the procedure for Example 1 but replacing the ketone K3 with K1 as the starting material and purification by flash chromatography (50% EtOAc / 50%

65403 Bl hexanes) gave Examples 5 and 6.

NMR 1 H (500 MHz in acetone-bb) Example 5: Principal (Z) isomer: delta 8.78 (dd, 1H), 8.25 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.55 7.40 (w, 6H), 7.35 (m, 2H), 7.25 (t, 1H), 7.23 (s, 1H), 7.11 (t, 2H), 7.05 (d, 1H), 3.12 (t, 1H). 2.96 (s, 3H),

1.34 (d, 6H).

NMR Ή (500 MHz in aiIETOH-d6) Example 6: Secondary (E) isomer: delta 8.78 (dd, 1H)

8.35 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.65 7.55 (w, 3H), 7.45 (dd, 1H), 7.35-7.15 (t, 9H).

3.12 (m, 4H), 1.34 (d, 6H).

Example 7

2- (2 - {(E / g) -2- [3- (6-isopropyl-8-quinolinyl) phenyl] -1- [4- (methylsulfonyl) phenyl] ethenyl} -1,3-thiazole-5- yl) -2-propanol

Example 7 was prepared by following the procedure for Example 1 but replacing the ketone K3 with K6 as the starting material. Purification by flash chromatography (100% EtOAc) gave Example 7 as a mixture of isomers.

NMR Ή (400 MHz in acetone-bb) δ 8.80 (m, 1H), 8.30 (m, 1H), 8.05 (b (major), 1.44H),

7.93 (b (minor), 0.55H), 7.85 (major), 0.72H), 7.77 (s, (secondary), 0.28H), 7.75 -

7.45 (m, 7H) 7.35 O (secondary), 0.28H), 7.28 C (major), 0.72H), 7.21 (b (secondary), 0.28H), 7.10 (d (major), 0.72H), 4.7 ( m, 1H), 3.15 (m, 1H), 3.15 (c (minor), 0.84), 2.99 (c (major), 2.16H), 1.60 (m, 6H), 1.35 (m, 6H).

MS (m + 1): 569.6

Example 8

2- (8- (3 - {(E / Z) -2- [5- (1-hydroxy-1-methylethyl) -1,3-thiazol-2-yl] -2- [4- (methylsulfonyl) phenyl ] ethenyl} phenyl) -6-quinolinyl] -2methylpropanenitrile

Example 8 was prepared by following the procedure for Example 1, but by replacing the ketone K3 with K6 and the benzyl phosphonate P2 with P3 as starting materials. Purification by flash chromatography (20% CH ₂ Cl ₂ /80% EtOAc) gave Example 8 as a mixture of isomers.

NMR Ή (400 MHz in acetone-bb) δ 8.92 (m, 1H), 8.45 (m, 1H), 8.10 (m, 1H), 8.05 (m, 1H), 7.93 (m, 1H), 7.85 (m, 2H), 7.77-7.55 (m, XH), 7.40 (^ secondary), 0.43H), 7.28 C (major), 0.57H), 7.21 (b (secondary), 0.43H), 7.10 (b (major), 0.57H), 4.67 (s, (major), 0.57H), 4.63 (h (minor), 0.43H), 3.15 (h (secondary), 1H, 3H), 2.99 (h (major), 1.7H).

1.90 (rn, 6H), 1.65 (s, (major), 3.4H), 1.45 (h (minor), 2.6H).

MS (m + 1): 594.6

Example 9

2-methyl-2- [8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6-quinolinyl] propanenitrile

65403 Bl

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 following the procedure for Example 1, but by replacing the ketone K3 with K2 and the benzylphosphonate P2 with P3 as starting materials.

Step 2: 2-methyl-2- [8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6 -quinolinyl] propanenitrile, Example 9, was. obtained by following the procedure used to prepare the B1 harrow (step 2 of Scheme 2), but by substituting (E / 7) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazole- 2yl) -1- [4- (methylthio) phenyl] ethene with the sulfide obtained in the present step 1 as starting material. Example 9 was obtained after purification by flash chromatography (97% EtOAc / 3% Et ₃ N).

NMR Ή (400 MHz in acetone-06) δ 8.92 (dd, 1H), 8.45 (dd, 1H), 8.10 (d, 1H), 7.93 (d, 2H),

7.76 (d, 1H), 7.60 - 7.50 (m, 5H), 7.38 (t, 1H),

7.35 (s, 1H), 7.19 (m, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 3.55 (s, 3H), 3.00 (s, 3H), 1.85 (s, 6H).

MS (m + 1): 533.3

Example 10

6- [1- (methylsulfonyl) ethyl] -8- {3 - [(E) -2- [4 (methylsulfonyl) phenyl] -2- (1,3-thiazol-2yl) ethenyl] phenyl} quinoline

0.33 mmol), B2 boronate (236 mg, 0.51 mmol), Na ₂ CO ₃ (2M, 0.65 ml, 1.3 mmol), Pd (OAc) ₂ (6.3 mg, 0.028 mmol) and PPh ₃ (28 mg, 0.11 mmol) in 4 ml n-propanol was stirred for 2 h at 90 ° C. The mixture was cooled to rt, diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Flash chromatography (To1 / acetone; 4/1) and stirring in hexane / EtOAc gave Example 10 (single isomer) as a white solid.

NMR Ή (400 MHz, Acetone-bb) δ 8.89 (dd, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71 - 7.68 (t, 3H) 7.62 - 7.60 (t, 2H), 7.55 (dd, 1H), 7.45 (s, 1H) 7.34 (t, 1H), 7.18 (d, 1H), 4.67 (q , 1H), 3.04 (s, 3H), 2.86 (s, 3H), 1.88 (s, 3H).

MS (M + 1) 576.

Example 11

6- [1-methyl-1- (methylsulfonyl) ethyl] -8- {3 [(E) -2- [4- (methylsulfonyl) phenyl] -2- (1,3thiazol-2-yl) ethenyl] phenyl} quinoline OD,

0 N . Ms ₃ | l V Oh

n ₃ sec

Example 11 was prepared by following the procedure described in Example 10 but by replacing bromoquinoline Q2 with Q3 and using boronate B2. Flash chromatography (To1 / Acetone; 9/1) and stirring in EtOAc / Hex gave Example 11 (single isomer) as a white solid.

NMR Ή (400 MHz, Acetone-bb) δ 8.90 (dd, 1H), 8.41 (dd, 1H), 8.23 (s, 1H), 8.02 - 7.99

Example 10 was obtained by the following procedure. A mixture of bromoquinoline Q2 (105 mg,

65403 B1 (d, 3H), 7.95 (s, 1H), 7.86 (d, 1H), 7.70 (d, 2H),

7.60 - 7.54 (m, 4H), 7.32 (t, 1H), 7.13 (d, 1H), 3.00 (s, 3H), 2.69 (s, 3H), 1.96 (s, 6H).

MS (M + 1) 523.

Example 12

8- (3 - {(Z) -2- (1-methyl-1H-imidazol-2-yl) 2- [4- (methylsulfonyl) -phenyl] ethenyl} phenyl) -6 [1- (methylsulfonyl) ethyl ] quinoline

Example 12 was prepared by following the procedure described in Example 10 using bromoquinoline Q2 but replacing harrow B2 with boronate B1. Flash chromatography (95% CH ₂ Cl ₂ /5% EtOH) gave the compound of Example 12.

NMR Ή (400 MHz, in acetone-bb) δ 8.92 (dd, 1H). 8.45 (dd, 1H), 8.10 (s, 1H), 7.93 (d, 2H), 7.76 - 7.65 (w, 4H), 7.59 (dd, 1H), 7.39 (t, 1H), 7.26 (s, 1H) , 7.18 (s, 1H), 7.05 (m, 2H), 4.70 (q, 1H), 3.40 (s, 3H), 3.13 (s, 3H), 2.93 (s, 3H),

1.87 (d, 3H).

MS (m + 1): 572.4

Example 13

8- (3 - {(Z) -2- (1-methyl-1H-imidazol-2-yl) 2- [4- (methylsulfonyl) phenyl] -ethenyl} phenyl) -6 [1-methyl-1 - (methylsulfonyl) ethyl] quinoline

Example 13 was obtained by following the procedure described in Example 10, but by replacing bromoquinoline Q2 with Q3 and harrow B2 with boronate B1. Flash chromatography (95% EtOAc / 5% Et ₃ N) gave Example 13 (single isomer) as foam.

NMR Ή (400 MHz in acetone-bb) δ 8.92 (dd, 1H), 8.45 (dd, 1H), 8.37 (d, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.69 (d, 2H), 7.65 (d, 1H), 7.59 (dd, 1H), 7.38 (t, 1H), 7.31 (s, 1H),

7.18 (s, 1H), 7.05 (m, 2H), 3.40 (s, 3H), 3.13 (s, 3H), 2.70 (s, 3H), 1.95 (s, 6H).

MS (m + 1): 586.2

Examples 14 and 15

6- [1-methyl-1- (methylsulfonyl) ethyl] -8- (3 {(E / g) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4 (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

65403 Bl

Examples 14 and 15 were obtained by the following procedure. A solution of aryl bromide AB5 (249 mg, 0.57 mmol), diboric pinacol ester (167 mg, 0.66 mmol), [1,1'-bis (diphenylphosphino) -ferocene] dichloropalladium (II) (12 mg, 0.015 mmol) and potassium acetate (176 mg, 1.8 mmol) in DMF (N, N-dimethylformamide) (10 ml) was degassed and stirred for 3 h at 80 ° C. Bromoquinoline Q3 (150 mg, 0.46 mmol), [(, Γ bis (diphenylphosphino) -ferocene] dichloropalladium (II) (12 mg, 0.015 mmol) and sodium carbonate (0.6 ml) were then added to this mixture at 25 ° C. , 2 M). After degassing, the mixture was heated at 80 ° C overnight. The mixture was then cooled to rt, quenched with H ₂ O and extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (hexane: EtOAc: Et ₃ N, 22:68:10 then hexane: EtOAc, 3: 1) yielded both isomers (Example 14 and Example 15).

NMR Ή (400 MHz, Acetone-bb) Principal (E) isomer (Example 14): delta 8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 8.00 (d, 2H), 7.70 (t, 3H), 7.64 (s, 1H), 7.55 (dd, 1H), 7.38 (t, 1H), 7.23 (d, 1H), 3.03 ( s, 3H),

2.69 (s, 3H), 2.33 (s, 3H), 1.96 (s, 6H).

MS (M + 1): 588.2

Secondary (7) isomer (Example 15): delta 8.92 (dd, 1H), 8.45 (dd, 1H), 8.29 (d, 1H), 8.07 (d, 1H), 7.99 (d, 2H), 7.88 (s, 1H), 7.75 (w, 3H), 7.62 (s, 1H), 7.58 (q, 1H), 7.48 (t, 1H), 7.24 (d, 1H) 3.16 (s, 3H), 2.70 (s, 3H) , 2.38 (s, 3H), 2.00 (s, 6H).

MS (M + 1): 588.2

Alternatively, Example 14 can be obtained by the following procedure:

65403 Bl

Step 1. Skraup reaction

glycerol

65403 Bl

Methanesulfonic acid (8-10 eq) at 20 ° C was added sodium t-nitrobenzenesulfonate (0.6 - 0.8 eq), followed by ferrous sulfate heptahydrate (0.01 - 0.05 eq). To the resulting mixture was added 2-bromo-4-methylaniline (1 eq). 5

Glycerol (2-3 eq) was added and the resulting solution was heated at 120-140 ° C and allowed to stand 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 tert-butyl ether) was added, the mixture was filtered and the phases were separated (the product was in the MTBE layer).

Step 2. Bromination

The solvent in the MTBE solution of step 1 was replaced by chlorobenzene. After filtration through silica gel and partial concentration, N-bromosuccinimide (NBS, 0.6 - 0.8 eq) and 2,2'-azobisisobutylnitrile (AIBN, 0.01 - 0.1 eq) were added. The degassed mixture was heated at 55-85 ° C.

The resulting mixture was diluted with cyclohexane. Additional NBS (0.3-0.5 eq) and AIBN (0.01-0.05 eq) were added. The degassed mixture was heated at about 55-85 ° C until the reaction was complete. The mixture was cooled to 10-40 ° C, diluted with cyclohexane and allowed to stand. The solid was isolated by filtration.

Step 3. Sulfone formation

To a solution of bromomethyl-bromoquinoline (product of the previous step, 1 eq) in DMF was added powdered sodium methanesulfinate (1.0 - 1.5 eq) at 10-60 ° C. The mixture was heated at about 50-70 ° C for 30 min. It was diluted with water while maintaining the temperature at about 50-70 ° C with vigorous stirring, then cooled to about 10-20 ° C and allowed to stand. The mixture was filtered, the solid washed successively with 1: 4 DMF / water and then water, and dried.

65403 Bl

Step 4. Methylation

A solution of the sulfone (a product of the previous step, 1 eq) in DMF was cooled to about -10 to 0 ° C. Sodium t-butoxide (~ 1 eq) was added. A solution of methyl iodide / DMF solution (~ 1 eq of Mel) was slowly added while maintaining the temperature at about -10 to 0 ° C.

A second portion of solid sodium m-butoxide (~ 1 eq) was added, followed by methyl iodide / DMF solution (~ 1 eq), maintaining the temperature at -5 to 10 ° C (when the reaction was not complete, additional bases could be added and Mel). The reaction was quenched by the addition of water and the product crystallized, isolated and dried.

Step 5. Suzuki coupling

Pd / C

K ₂ CO3 / DMF

P

To a solution of the sulfone from the previous step (1 eq) was added Pd / C (5 or 10 wt%, 0.005 0.1 eq), potassium carbonate (2-3 eq) and 3-formylphenylboronic acid (1-2 eq). The degassed reaction mixture was heated at 60-120 ° C, 5 D 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

65403 Bl

To the mixture of hydroxybenzotriazole ("HOBt") hydrate (1-1.5 eq), 4-methylsulfonylphenylacetic acid (1 eq) in acetonitrile was added EDC hydrochloride (1 - 1.5 eq). The suspension was allowed to stand at about 20-30 ° C 5 for 30 min.

Other N-OH compounds, such as Nhydroxyphthalimide, 2-hydroxypyridine Oxide, N-hydroxysuccinimide, can also be used to replace HOBt. Another 10 carbodiimides, such as dicyclohexylcarbodiimide and diisopropylcarbodiimide, can be used to replace EDC hydrochloride (ethyl dimethylaminopropylcarbodiimide hydrochloride).

Acetamide oxime (1-1.5 eq) was added to the suspension. The resulting mixture was then refluxed until the reaction was complete. The resulting solution was concentrated and diluted with ethyl acetate. The resulting mixture was washed with aqueous sodium bicarbonate. The solvent from the solution was replaced with 2-propanol and upon cooling crystallized a product which was isolated and dried.

Step 7. Condensation to Form Example 14

To the suspension of the aldehyde from step 5 above (1 eq) in 2-propanol, was added the oxadiazole from step 6 above (1 - 1.5 eq), followed by piperidine (0.2 - 1.5 eq).

Instead of 2-propanol, other solvents such as DMF, acetonitrile, 1-propanol, toluene, esters and other alcohols can be used. Pipiperidine serves as a major initiator. Instead of piperidine, other amine bases, 40 especially secondary amines, may be used.

The resulting mixture was refluxed over molecular sieves until the reaction was complete. After cooling, the product was isolated by filtration and dried.

Examples 16 and 17 (E / Z) -3- {3- [6- (1-cyano-1-methylethyl) -8 quinolinyl] phenyl} -L-isopropyl-2- [4- (methylsulfonyl) phenyl] -2 -propenamide

H ₃ sec / CH ₃ fry A kA and n Y ^N yCH, H ₃ (B ^ ⁰ CH ₃ ³ ο Example 16

65403 Bl

Examples 16 and 17 were prepared following the procedure previously described for Examples 14 and 15, but by replacing the aryl bromide AB5 with AB2 and bromoquinoline Q3 with Q5 as starting materials. Examples 16 and 17 were obtained as a 4: 1 mixture.

NMR Ή (500 MHz, Acetone-bb) Principal (E) isomer (Example 16): delta 8.89 (dd, 1H), 8.43 (dd, 1H), 8.09 (d, 1H), 7.90 (d, 2H), 7.81 (d, 1H),

7.68 (s, 1H), 7.57 (m, 4H), 7.45 (s, 1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.71 (bd, 1H), 4.13 (t, 1H) 2.92 ( s, 3H), 1.87 (s, 6H), 1.12 (d, 6H).

MS (M + 1): 538.3

Secondary (7) isomer (Example 17): delta 8.93 (dd, 1H), 8.48 (dd, 1H), 8.14 (d, 1H),

7.94 (t, 4H), 7.85 (d, 2H), 7.70 (dd, 2H), 7.59 (q, 1H), 7.50 (t, 2H), 7.28 (s, 1H), 4.15 (t, 1H).

3.13 (s, 3H), 1.91 (s, 6H), 1.04 (d, 6H).

MS (M + 1): 538.3

Example 18

8- (3 - {(E) -2- {3 - [(4-methoxyphenoxy) methyl] -1,2,4-oxadiazol-5-yl} -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl ) -6- [1-methyl-1- (methylsulfonyl) ethyl] -quinoline

Example 18 was obtained by the following procedure.

Step 1 (Scheme 3): (4-Methoxyphenoxy) acetonitrile

A mixture of 4-methoxyphenol (10 g, 80 mmol), chloroacetonitrile (7.0 ml, 111 mmol) and K ₂ CO ₃ (26 g, 188 mmol) in acetone (150 ml) was stirred for 18 h at rt. The mixture was filtered, concentrated and purified by flash chromatography (Hex: EtOAc, 4: 1) to give (4-methoxyphenoxy) acetonitrile as a clear oil.

Step 2 (Scheme 3): (4-Methoxyphenoxy) acetamide oxime

A mixture of (4-methoxyphenoxy) acetonitrile product (5.0 g, 31 mmol) from step 1, hydroxylamine hydrochloride (4.3 g, 62 mmol) and sodium acetate (5.1 g, 62 mmol) in MeOH (100 ml) was stirred for 2 h at rt The resulting mixture was filtered on Celite (R), concentrated, stirred for 18 h in CHCl ₃ and filtered. The resulting solution was concentrated to give (4-methoxyphenoxy) acetamide oxime as a resin.

Step 3 (Scheme 3, Oxadiazole OX2): 3 - [(4methoxyphenoxy) methyl] -5- [4- (methylsulfonyl) benzyl] -1,2,4-oxadiazole

3 - [(4-methoxyphenoxy) methyl] -5- [4- (methylsulfonyl) benzyl] -1,2,4-oxadiazole was obtained by following the procedure as described in Scheme 3 for AB5 step 1 (OX 1) , but by replacing the acetamide oxime with the (4-methoxyphenoxy) acetamide oxime of step 2 above and heating the reaction mixture at 90 ° C for 6 h. Purification by flash chromatography (Hex: EtOAc, 3: 2 to 1: 4) gave the desired substance as a pale brown solid.

Step 4: 3- {6- [1-Methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} -benzaldehyde

To bromoquinoline Q3 (10.1 g, 30.9 mmol), 3-formylbenzenic acid (5.8 g, 38.7 mmol), tetrakis (triphenylphosphine) -palladium (0) (2.1 g 1.86 mmol) and sodium carbonate (39 ml, 2M) were added DME (330 ml). After degassing, the mixture was heated at 80 ° C overnight. After cooling to rt, the resulting mixture was sharply cooled by H ₂ O pouring and extracted with EtOAc. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Stirring in ether followed by isolation by filtration gave 3- {6- [1-methyl-1- (methylsulfonyl) -ethyl]

65403 Bl

8-quinolinyl} benzaldehyde.

Step 5: 8- (3 - {(E) -2- {3 - [(4-methoxyphenoxy) methyl] -1,2,4-oxadiazol-5-yl} -2- [4 (methylsulfonyl) phenyl] ethenyl } phenyl) -6- [1methyl-1- (methylsulfonyl) ethyl] quinoline

A mixture of the product of this step 4 (150 mg, 0.42 mmol), the oxadiazole 0X2 of the present step 3 above (175 mg, 0.47 mmol) and piperidine (0.1 ml, 1.0 mmol) in toluene (0.6 ml) was heated 3 h at 120 ° C. The mixture was purified by flash chromatography (Hex: EtOAc, 3: 2 to 1: 4) to give Example 18 as a foam.

NMR Ή (400 MHz, Acetone-bb) δ 8.90 (q, 1H), 8.42 (q, 1H), 8.24 (d, 1H), 8.20 (s, 1H), 8.02 (m, 3H), 7.75 - 7.66 ( m, 4H), 7.55 (q, 1H),

7.39 (t, 1H), 7.25 (d, 1H), 7.00 (d, 2H), 6.87 (d, 2H), 5.17 (s, 2H), 3.73 (s, 3H), 3.03 (s, 3H), 2.80 (s, 3H), 1.96 (s, 6H).

Example 19 (5 - {(E) -2- (3- {6- [1-methyl-Ι-ίΜβτ ^ κ ^ πφοΗΗΠ ^ τΗπΙ-δ-ΧΗΗΟΗΗΗΗπΙφβΗΗΠ ^ Ι-ΙΑ-ίΜβΤΗΠsulfonyl) phenyl] ethenyl} -1, 2,4-Oxadiazol-3-yl) methanol

Example 19 was prepared by the following procedure. To a solution of the compound of Example 18 (250 mg, 0.35 mmol) in acetonitrile: water (4: 1, 8 ml) in two portions was added CAN (330 mg, 0.62 mmol) at rt After 3 h at rt, the mixture was diluted with saturated NaHCO ₃ solution, diluted with water and extracted with EtOAc. The organic extracts were washed (H ₂ O), (brine), dried (MgSO _4), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 3: 7) gave (5 - {(E) -2- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) - 1- [4- (methylsulfonyl) phenyl] -ethenyl} -1,2,4-oxadiazol-3yl) methanol as a pale yellow foam.

NMR Ή (400 MHz, Acetone-bb) δ 8.90 (q, 1H), 8.42 (q, 1H), 8.25 (d, 1H), 8.15 (s, 1H), 8.02 (t, 3H), 7.73 - 7.65 ( t, 4H), 7.55 (q, 1H), 7.38 (t, 1H), 7.23 (d, 1H), 4.67 (t, 3H), 3.04 (s, 3H), 2.82 (s, 3H), 1.96 (s , 6H).

Example 20 (Ε) -Ε-Η3θπροπΗΠ-3- (3- {6- [1-methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2 [4- (methylsulfonyl) phenyl] -2-propenamide

H I _S Fr. V_'S- ^CH 3 Fr. SN ₃ ° N a . ^NsS in ^dream ₃ rv kJ and Fr. NHSG ^

Example 20 was obtained by following the procedure described above for Examples 14 and 15, but by replacing the aryl bromide AB5 with AB2 and using bromoquinoline Q3 as starting materials.

NMR 1 H (300 MHz, Acetone-bb) delta 8.89 (dd, 1H), 8.41 (dd, 1H), 8.22 (d, 1H), 7.99 (d, 1H), 7.88 (d, 2H), 7.67 (s , 1H), 7.53 (m, 4H),

7.43 (s, 1H), 7.28 (t, 1H), 7.05 (d, 1H), 6.71 (bd, 1H), 4.14 (t, 1H) 2.9 (s, 3H), 1.95 (s, 6H), 1.13 ( d, 6H).

MS (M + 1): 591.3

Example 21 (E) -3- {3- [6- (1-cyano-1-methylethyl) -8quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid

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Example 22 was obtained by following the procedure described for Examples 14 and 15 using aryl bromide AB5 and replacing bromoquinoline Q3 with Q5 as starting materials. Δ NMR Ή (500 MHz, Acetone-bb) δ 8.90 (dd, 1H), 8.43 (dd, 1H), 8.1 (d, 2H), 8.01 (d, 2H),

7.83 (d, 1H), 7.71 (t, 3H), 7.66 (s, 1H), 7.56 (q, 1H), 7.55 (dd, 1H), 7.38 (t, 1H), 7.22 (d, 1H), 3.03 (s, 3H), 2.33 (s, 3H), 1.87 (s, 6H)

MS (M + 1): 535.2

Example 23 (E) -3- {3- [6- (1-cyano-1-methylethyl) -8quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenamide

Example 21 was prepared by following the procedure described above for Examples 14 and 15, but by replacing the aryl bromide AB5 with AB 1 and bromoquinoline Q3 with Q5 as starting materials.

NMR Ή (500 MHz, Methanol) δ 8.8 (dd, 1H), 8.38 (dd, 1H), 8.04 (d, 2H), 7.88 (d, 2H),

7.66 (d, 1H), 7.55 (m, 4H), 7.36 (t, 1H), 7.29 (s, 1H), 7.18 (d, 1H), 2.93 (s, 3H), 1.88 (s, 6H).

MS (M - CO ₂ ): 451.4 (negative ion).

Example 22

2-methyl-2- [8- (3 - {(E) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) - 6-quinolinyl] propanenitrile

Example 23 was prepared by following the procedure described above for Examples 14 and 35 15, but by replacing the aryl bromide AB5 with AB3 and bromoquinoline Q3 with Q5 as starting materials, the title compound was obtained.

NMR Ή (500 MHz, Acetone-bb) δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08 (d, 1H), 7.93 (d, ⁴⁰ 2H), 7.8 (d, 2H), 7.6 (m , 4H), 7.48 (s, 1H), 7.31 (t, 1H), 7.08 (d, 1H), 6.6 (bs, 1H), 6.7 (bs, 1H),

2.93 (s, 3H), 1.87 (s, 6H)

Example 24 (E) -B1- (tert-butyl) -3- {3- (6- (1-cyano- ^1-4 $ methylethyl) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl ] -2-propenamide

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Example 24 was obtained by following the procedure described for Examples 14 and 15, but by replacing the aryl bromide AB5 with AB4 and bromoquinoline Q3 with Q5 as starting materials.

NMR Ή (500 MHz, Acetone-bb) δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08 (d, 1H), 7.92 (d, 2H),

7.79 (d, 1H), 7.58 (m, 5H), 7.45 (s, 1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.4 (bs, 1H), 2.93 (s, 3H), 1.87 (s, 6H), 1.36 (s, 9H).

MS (M + 1) 553.

Example 25 (E) -3- [3- (6-Isopropyl-8-quinolinyl) phenyl] -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid

Example 25 was obtained by following the procedure described for Examples 14 and 15, but by replacing the aryl bromide AB5 with AB1, and Q3 with

5-Isopropyl-8-bromoquinoline (described in WO 1994/022852) as starting materials.

NMR 1 H (500 MHz, Acetone-bb) delta 8.69 (dd, 1H), 8.26 (dd, 1H), 7.85 (s, 1H), 7.83 (d, 2H), 7.68 (s, 1H), 7.51 (d , 2H), 7.49 (m, 2H),

7.36 (dd, 1H), 7.31 (t, 1H), 7.20 (s, 1H), 7.13 (d, 1H), 3.1 (m, 1H), 2.93 (s, 3H), 1.36 (d, 6H).

MS (M + 1) 472.

Example 26

6-isopropyl-8- (3 - {(E) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Example 26 was obtained by following the procedure described for Examples 14 and 15 using aryl bromide AB5 and replacing Q3 with 5-isopropyl-8-bromoquinoline (described in WO 1994/022852) as starting materials.

NMR <1> H (500 MHz, Acetone-bb) delta 8.80 (dd, 1H), 8.29 (dd, 1H), 8.12 (s, 1H), 8.03 (d, 2H). 7.76 (s, 1H), 7.73 (w, 3H), 7.59 (s, 1H),

7.53 (d, 1H), 7.47 (q, 1H), 7.36 (t, 1H), 7.22 (d, 1H), 3.1 (m, 1H), 2.93 (s, 3H), 2.33 (s, 3H), 1.36 (d, 6H).

MS (M + 1) 510.

Example 27 (E) -3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4 (methylsulfonyl) phenyl] -1- (1- pyrrolidinyl) -2-propen-1-one

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Example 27 was prepared by the following procedure.

Step 1: (E) -3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} -phenyl) -2- [4 (methylsulfonyl) phenyl] -2-propenoic acid

A mixture of 3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} -benzaldehyde from step 4 of Example 18 (2.33 g, 6.60 mmol), 4- (methylsulfonyl) phenylacetic acid (1.71 g , 7.98 mmol) and piperidine (0.20 ml, 1.98 mmol) in 10 ml of toluene was refluxed for 2 days. The mixture was cooled to rt, diluted with CH ₂ Cl ₂ , subjected to flash chromatography (CH ₂ Cl ₂ / EtOAc / AcOH, 50/50/1) and finally stirred with (Et ₂ O / CH ₂ Cl ₂ ) and isolated to preparation of (E) -3- (3- {6- [1-methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2 [4- (methylsulfonyl) -phenyl] -2-propenoic acid (single isomer) as a white solid.

NMR Ή (400 MHz, Acetone-bb) δ 8.89 (dd, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71 - 7.68 (t, 3H) 7.62 - 7.60 (t, 2H), 7.55 (dd, 1H), 7.45 (s, 1H) 7.34 (t, 1H), 7.18 (d, 1H), 4.67 (q , 1H), 3.04 (s, 3H), 2.86 (s, 3H), 1.88 (s, 3H).

MS (M + 1) 576.

Step 2: (E) -3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} -phenyl) -2- [4 (methylsulfonyl) phenyl] -1- (1 -pyrrolidinyl) -2-propen-1-one

Mixture of (E) -3- (3- {6- [1-methyl 1- (methylsulfonyl) ethyl] -8-quinolinyl} -phenyl) -2- [4- (methyl sulfonyl) phenyl] -2-propenoic acid (104 mg, 0.19 mmol) of the present step 1 above, pyrrolidine (24 microl, 0.29 mmol), EDC1 (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (55 mg, 0.29 mmol) and HOBt (1hydroxybenzotriazole hydrate) (34 mg, 0.25 mmol) in 1 ml DMF, stirred for 12 h at rt. The mixture was diluted with EtOAc, washed with NH ₄ Cl (saturated), H ₂ O (3x), brine, dried over Na ₂ SO ₄ . filtered and concentrated. Stirring in EtOAc / Hex gave Example 27 as a white solid.

NMR Ή (400 MHz, Acetone-bb) δ 8.88 (dd, 1H), 8.40 (dd, 1H), 8.22 (d, 1H), 8.98 (d, 1H), 7.88 (d, 2H), 7.67 (d, 2H), 7.60 (d, 1H) 7.55 - 7.52 (m, 2H) 7.34 (t, 1H), 7.18 (d, 1H), 7.03 (bs, NH), 3.58 (bs, 2H), 3.44 (bs, 2H) ), 3.02 (s, 3H),

2.69 (s, 3H), 1.95 (s, 6H), 1.88 (bs, 4H).

MS (Μ + 1) 603.

Example 28 (E) -H-cyclopropyl-3- (3- {6- [1-methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2 [4- (methylsulfonyl) phenyl] -2-propenamide

Example 28 was obtained by following the procedure for step 2 of Example 27, but by substituting pyrrolidine with cyclopropylamine to give a white solid.

NMR Ή (400 MHz, acetone-bb) δ 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.87 (d, 2H), 7.68 (s, 1H), 7.59 - 7.53 (t, 4H), 7.43 (s, 1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.94 (bs, 1H), 2.89 (s, 3H), 2.84 - 2.80 (m, 1H), 2.69 (s, 3H), 1.96 (s, 6H), 0.67 - 0.63 (m, 2H), 0.49 0.45 (m, 2H).

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MS (M + 1) 589.

Example 29 (E) -1H- (tert-butyl) -3- (3- {6- [1-methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4 (methylsulfonyl) phenyl ] -2-propenamide

H ₃ With CH ₃ (ΎΎ Ο. 1 < _q ^ CH ₃ 0 ° 1 0 ll and CH3 H ₃ c-% About CH ₃

Example 30 was obtained by the following procedure. To a mixture of benzylphosphone P2 (100 mg, 0.25 mmol), 4,4'-dichlorobenzophenone (63 mg, 0.25 mmol) in THF (2 ml) at rt, potassium m-butoxide (1 M, THF, 0.35 ml) was added. 0.35 mmol). After 1 h at rt, the mixture was diluted with water / 1H ₄ Cl and extracted with EtOAc. The organic extracts were washed (H ₂ O), (brine), dried (MgSO _4), filtered and concentrated. Purification by flash chromatography (Hex: EtOAc, 8: 2) gave Example 30 as a white foam.

NMR Ή (300 MHz, acetone-bb) δ 8.79 (dd, 1H), 8.28 (dd, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.48 - 7.25 (m, 12H), 7.20 - 7.16 (t, 2H)

3.13 (hept., 1H), 1.36 (d, 6H).

Examples 31 and 32

6-isopropyl-8- (3 - {(EH) -2- (6-methyl-3-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Example 29 was obtained as a white solid following the procedure for step 2 of Example 27 but by replacing the pyrrolidine with m-butylamine amine.

NMR Ή (400 MHz, acetone-bb) δ 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H),

7.90 (d, 2H), 7.59 - 7.53 (m, 5H), 7.43 (s, 1H),

7.30 (t, 1H), 7.05 (d. 1H), 6.43 (bs, 1H), 2.94 (s, 3H), 2.69 (s, 3H), 1.96 (s, 6H), 1.36 (s, 9H)

MS (M + 1) 606.

Example 30

8- {3- [2,2-bis (4-chlorophenyl) vinyl] phenyl} -6-isopropylquinoline

Example 32

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Examples 31 and 32 were prepared by following the procedure described for Example 30, but by substituting the 4,4'-dichlorobenzophenone with the ketone K7 and using the benzyl phosphonate P2 as starting materials.

NMR Ή (300 MHz, Acetone-bb) (E) isomer (Example 31); delta 8.79 (dd, 1H), 8.43 (d, 1H),

8.27 (dd, 1H), 7.95 (d, 2H), 7.73 (d, 1H), 7.57 -

7.43 (m, 7H), 7.32 - 7.19 (w, 3H), 7.10 (d, 1H),

3.15 (hept., 1H), 2.98 (s, 3H), 1.34 (d, 6H).

(Z) isomer (Example 32): delta 8.79 (dd, 1H), 8.35 (d, 1H), 8.28 (dd, 1H), 7.92 (d, 2H),

7.74 (d, 1H), 7.61 - 7.30 (m, 10H), 7.19 (d, 1H),

3.13 (s, 3H), 3.11 (hept., 1H), 1.35 (d, 6H).

Examples 33 and 34

6-isopropyl-8- (3 - {(E / g) -2- (5-methyl-2pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Examples 33 and 34 were prepared following the procedure described for Example 30, but by replacing 4,4'-dichlorobenzophenone with ketone K8 and using benzyl phosphonate P2 as starting materials.

NMR Ή (300 MHz, Acetone-bb) (E) isomer (Example 33): delta 8.80 (dd, 1H), 8.48 (s, 1H),

8.28 (dd, 1H), 7.99 - 7.96 (t, 3H), 7.97 (t, 1H),

7.74 (d, 1H), 7.61 - 7.44 (t, 6H), 7.27 (t, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 3.15 (hept., 1H), 2.96 (s, 3H ), 1.36 (d, 6H).

NMR Ή (300 MHz, AneTOH-d6) (Z) isomer (Example 34): delta 8.79 (dd, 1H), 8.52 (s, 1H),

8.29 (dd, 1H), 7.89 (d, 2H), 7.75 (d, 1H), 7.65 -

7.54 (m, 4H), 7.47 (dd, 1H), 7.42 - 7.23. (m, 5H),

7.11 (d, 1H), 3.12 (s, 3H), 3.12 (hept., 1H), 1.36 (d, 6H).

Example 35

8- (3- (2,2-bis [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6-isopropylquinoline

Example 34

Example 35 was prepared by following the procedure described for Example 30, but by substituting the 4,4'-dichlorobenzophenonas ketone K9 and using the benzyl phosphonate P2 as starting materials.

NMR Ή (500 MHz, Acetone-bb): delta 8.80 (dd, 1H), 8.29 (dd, 1H), 7.98 (d, 2H), 7.93 (d, 2H), 7.75 (d, 1H), 7.61 (d , 2H), 7.59 - 7.56 (w, 3H), 7.50 (d, 1H), 7.48 - 7.44 (t, 3H) 7.30 (t, 1H), 7.12 (d, 1H), 3.14 (hept., 1H). 3.13 (s, 3H),

2.97 (s, 3H), 1.35 (d, 6H).

Examples 36 and 37

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2-methyl-2- [8- (3 - {(E / Z) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) -phenyl] ethenyl} phenyl) -6-quinolinyl] propanenitrile

Example 36

Example 37

Examples 36 and 37 were prepared following the procedure described for Example 30, but by substituting the 4,4'-dichlorobenzophenone with the ketone K8 and replacing the benzyl phosphonate P2 with P3 as starting materials.

NMR Ή (500 MHz, Acetone-bb): (E) isomer (Example 36): delta 8.90 (dd, 1H), 8.47 (s, 1H),

8.43 (dd, 1H), 8.08 (d, 1H), 8.00 (s, 1H), 7.97 (d, 2H), 7.83 (d, 1H) 7.57 - 7.53 (m, 5H), 7.50 (s, 1H). 7.28 (t, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 2.96 (s, 3H), 2.33 (s, 3H), 1.88 (s, 6H).

NMR Ή (300 MHz, Acetone-bb): (Z) isomer (Example 37): delta 8.89 (dd, 1H), 8.51 (s, 1H),

8.45 (dd, 1H), 8.09 (d, 1H), 7.89 (d, 2H), 7.72 (d, 1H), 7.62 - 7.56 (m, 5H), 7.43 - 7.42 (t, 2H)

7.30 (t, 1H), 7.25 (d, 1H), 7.10 (d, 1H), 3.11 (s, 3H), 2.34 (s, 3H), 1.87 (s, 6H).

Example 38

2- (8- (3- {2,2-bis [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6-quinolinyl] -2-methylpropanenitrile

Example 38 was prepared by following the procedure described for Example 30, but by replacing 4,4'-dichlorobenzophenone with ketone K9 and replacing the benzyl phosphonate P2 with P3 as starting materials.

NMR (500 MHz, Acetone-bb): delta 8.90 (dd, 1H), 8.44 (dd, 1H), 8.09 (d. 1H), 7.97 (d, 2H), 7.92 (d, 2H), 7.81 (d , 1H), 7.61 (d, 2H) 7.58 - 7.55 (w, 3H), 7.53 (s, 1H), 7.44 (s, 1H), 7.32 (t, 1H), 7.13 (d, 1H), 6.96 (d , 1H), 3.13 (s, 3H), 2.97 (s, 3H), 1.86 (s, 6H).

Example 39

2-methyl-2- (8- {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (2-pyridinyl) ethenyl] phenyl} -6quinolinyl) propanenitrile

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Example 39 was prepared by following the procedure described for Example 30, but by replacing the 4,4'-dichlorobenzophenonas ketone K10 and replacing the benzyl phosphonate P2 with P3 as starting materials.

NMR (300 MHz, Acetone-bb): delta 8.90 (dd, 1H), 8.45 (dd, 1H), 8.11 - 8.09 (m, 2H), 7.84 - 7.80 (m, 3H), 7.72 - 7.69 (m, 1H), 7.63 - 7.52 (t, 5H), 7.43 - 7.38 (t, 2H), 7.33 (t, 1H) 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, 3H), 1.86 ( s, 6H).

Examples 40 and 41

6- [1-methyl-1- (methylsulfonyl) ethyl] -8- (3 {(E / 7) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Examples 41 and 42 were prepared by following the procedure described in Example 10 but by replacing bromoquinoline Q2 with Q3 and replacing harrow B2 with harrow B3.

NMR Ή (400 MHz, Acetone-bb): (E) isomer (Example 40): delta 8.91 (dd, 1H), 8.45 (s, 1H),

8.41 (dd, 1H), 8.23 (d, 1H), 8.01-8.00 (m, 2H),

7.95 (d, 2H), 7.57- 7.54 (m, 4H), 7.51 (d, 1H)

7.49 (s, 1H), 7.28 (t, 1H), 7.07 (d, 1H), 6.96 (d, 1H), 2.94 (s, 3H), 2.69 (s, 3H), 2.33 (s, 3H), 1.97 (s, 6H).

NMR Ή (400 MHz, Acetone-bb) (Z) isomer (Example 41): delta 8.88 (dd, 1H), 8.49 (s, 1H),

8.42 (dd, 1H), 8.24 (dd, 1H), 7.94 (d, 1H), 7.88 (d, 2H), 7.61 - 7.55 (m, 5H), 7.47 (s, 1H), 7.40 (s, 1H) , 7.29 (t, 1H), 7.24 (d, 1H), 7.06 (d, 1H), 3.12 (s, 3H), 2.68 (s, 3H), 2.33 (s, 3H), 1.96 (s, 6H).

Example 42

2- (6- {(E) -2- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -1- [4- (methylsulfonyl) phenyl] ethenyl} -3-pyridinyl) -2-

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Example 42 was prepared by following the procedure described in Example 10 but by replacing bromoquinoline Q2 with Q3 and replacing harrow B2 with boronate B4.

NMR Ή (500 MHz, Acetone-bb): delta 8.91 (dd, 1H), 8.80 (d, 1H), 8.42 (dd, 1H), 8.23 (d, 1H), 8.03 - 8.01 (m, 2H), 7.96 (d, 1H), 7.82 (dd, 1H), 7.58 - 7.54 (m, 4H), 7.51 (s, 1H), 7.29 (t, 1H), 7.08 (d, 1H), 7.01 (d, 1H). 4.31 (s, 1H), 2.96 (s, 3H), 2.70 (s, 3H), 1.96 (s, 6H), 1.56 (s, 6H).

Example 43 was prepared by following the procedure previously described for Examples 14 and 15, but by replacing the aryl bromide AB5 with AB6 and bromoquinoline Q3 with Q5 as starting materials.

Additional examples are the following:

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The salts of the compounds of the examples

As indicated above, pharmaceutically acceptable salts are often desired. Examples of 25 such salts are described below:

General method for the preparation of salt

Salts of the compounds of this invention that are basic can be prepared in several ways: 30

a) The compound is dissolved in a suitable solvent such as ethyl acetate. An acceptable acid such as hydrochloric acid is then added in an acceptable solvent such as 1,4-dioxane. The precipitated suspension of the salt was maintained and then the salt 35 was 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 iso- ⁴ θ propyl acetate and methanol. The salt can then be isolated by concentration or by changing the solvent, leading to a precipitate followed by filtration. The more stable crystalline form of the salt can be obtained by equilibration of the precipitated suspension of the salt by heating and standing before filtration. Crystalline embryos from previous batches may also be added prior to equilibration of the salt suspension, until crystallization and equilibrium are initiated.

The sulfuric acid salt of the compound of Example 14

The sulfuric acid salt of the compound of Example 14 was obtained by dissolving the compound (1.00 eq) in boiling ethyl acetate. After cooling to room temperature, sulfuric acid (1.04 eq) was slowly added with stirring. The resulting suspension was stirred for an additional 40 min and the solid was isolated by filtration and washed with ethyl acetate to give the sulfuric acid salt of the compound of Example 14.

Ή NMR (500 MHz, acetone-bb): d 9.45 (d, ΙΗ), 9.23 (d, 1H), 8.65 (d, 1H), 8.25 (d, 1H), 8.16 (dd, 1H), 8.10 (s , 1H), 7.99 (d, 2H), 7.80 (d, 2H),

7.60 (d, 1H), 7.49 (s, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 3.09 (s, 3H), 2.77 (s, 3H), 2.33 (s, 3H), 2.01 (s, 6H).

The methanesulfonic acid salt of the compound of Example 14

The methanesulfonic acid salt of the compound of Example 14 was obtained by dissolving the compound (1.0 eq) in boiling ethyl acetate. After cooling to room temperature, methanesulfonic acid was slowly added

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65403 Bl (1.1 eq), with stirring. The resulting slurry 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 compound of Example 14.

Ή NMR (500 MHz, acetone-bb): d 9.45 (d, 1H), 9.32 (d, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 8.22 (t, 1H), 8.11 (s , 1H), 7.99 (d, 2H), 7.78 (d, 2H), 7.61 (d, 1H), 7.49 (m, 2H), 7.35 (d, 1H), 3.09 (s, 3H), 2.78 (s. 3H), 2.33 (s, 3H), 2.01 (s, 6H).

The p-toluenesulfonic acid salt of the compound of Example 14 The p-toluenesulfonic acid salt of the compound of Example 14 was obtained by dissolving the compound (1.0 eq) in boiling ethyl acetate. After cooling to room temperature, p-toluenesulfonic acid (1.1 eq) in ethyl acetate was slowly added. The solution was concentrated and the suspension was allowed to stand 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 compound of Example 14.

M.P. Mp 184 - 185 ° C.

Ή NMR (500 MHz, acetone-bb): d 9.58 (d, 1H), 9.22 (d, 1H), 8.63 (s, 1H), 8.23 (d, 1H), 8.16 (m, 1H), 8.03 (s , 1H), 7.94 (d, 2H), 7.73 (d, 2H), 7.55 (m, 3H), 7.45 (s, 1H), 7.40 (t, 1H), 7.27 (d, 30 1H), 7.12 (d , 2H), 3.07 (s, 3H), 2.75 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.01 (s, 6H).

The 2-naphthalenesulfonic acid salt of the compound of Example 14

The 2-naphthalenesulfonic acid salt of 35 the compound of Example 14 was obtained by dissolving the compound (1.0 eq) in boiling ethyl acetate. After cooling to room temperature, 2-naphthalenesulfonic acid (1.1 eq) was slowly added in ethyl acetate followed by ethanol. Toluene was then added to the solution, followed by concentration. More toluene was then added and the suspension was allowed to stir with stirring and periodically treated with sound at room temperature for 24 h. The solid was then isolated by filtration and washed with toluene to give 10 the 2-naphthalenesulfonic acid salt of the compound of Example 14.

M.P. 202-204 ° C.

Ή NMR (500 MHz, acetone-bb): d 9.64 (d,

1H), 9.30 (d, 1H), 8.67 (d, 1H), 8.25 (d, 1H), 8.23 15 (m, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.91 (d. 2H),

7.87 (m, 2H), 7.82 (d, 1H), 7.72 (dd, 1H), 7.68 (d, 2H), 7.54 (d, 1H), 7.52 (m, 2H), 7.43 (br s, 1H).

7.37 (t, 1H), 7.22 (d, 1H), 3.03 (s, 3H), 2.76 (s, 3H), 2.33 (s, 3H), 2.02 (s, 6H).

The hydrochloride salt of the compound of Example 43

The hydrochloride salt of the compound of Example 43 was obtained by dissolving the compound (1.0 eq) in ethyl acetate with heating and 25 sonic treatments. After cooling the solution to room temperature, HCl in 1.4 dioxane (4 M, 1.0 eq) was added with stirring. The suspension was stirred for an additional 5 min and the solid was isolated by filtration to give the monohydrochloride salt of the compound of Example 43.

The benzenesulfonic acid salt of the compound of Example 14

The benzenesulfonic acid salt of the compound of Example 14 is available in two crystalline forms ("Form A" and "Form B"). Forms are obtained by the following procedures: Salt formation

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65403 Bl

Form A

Benzene sulfonic acid (1 -1.2 eq) was added to a suspension of the compound of Example 14 (1 eq) in ethyl acetate. Other esters may be used instead of ethyl acetate. Methanol was added and the resulting mixture was heated to dissolve the solid. Other alcohols such as ethanol or propanol may be used instead of methanol.

The resulting solution was filtered and concentrated. The product crystallizes during concentration. The resulting mixture was diluted with ethyl acetate and allowed to stand. The yellow solid was collected by filtration.

HPLC showed 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: 193 ° C.

The X-ray powder diffraction spectrogram (“XRPD”) for Form A is shown in Figure 1. The identification peaks are set out in the table below and are shown in Figure 4.

alcohols such as ethanol or propanol. The mixture was allowed to stand at 20-50 ° C until dissolved solids. The resulting solution was filtered and distilled, maintaining the volume by the addition of a 9: 1 (v / v) mixture of i-PrOAc / methanol. The product crystallizes during distillation.

The resulting mixture was allowed to stand at 20-70 ° C for 2-10 hours to complete the formation of Form B. The resulting off-white solid was isolated by filtration and dried.

HPLC showed 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.

T.T. by DSC: 210 ° C

The XRPD spectrogram for Form B is shown in Figure 2. The identification peaks are set out in the table below and are shown in Figure 5. The spectra are compared in Figure 3, with the identification peaks indicated by arrows.

Form B

Benzenesulfonic acid (1-1.2 eq) was added to a suspension of the compound of Example 14 (1 eq) in a mixture of isopropyl acetate (i-PrOAc) and methanol (1: 1). Other esters may be used instead of i-PrOAc and other esters may be used instead of methanol

Other variations or modifications that are apparent to those skilled in the art are within the scope of this invention. This invention should not be limited, except as claimed in the following claims.

Claims (5)

Claims 1. A compound represented by formula I: (I) or a pharmaceutically acceptable salt thereof, in which: S 1, S ₂ and S ₃ are independently H; R 1 is a -C 1 -C ₆ alkyl group optionally substituted by -CN or -SO _n - (C 1 -C ₆ alkyl); AESN; R ₂ and R ₃ are independently an aryl group, heteroaryl group, H, halogen, -CN, -C 1 -C ₆ alkyl group, -heterocycloC ₃ -C ₆ alkyl, -C 1 -C ₆ alkoxy group, carbonyl group, carbamoyl group , -C (O) OH, - (C 1 -C ₆ alkyl) -8O _n - (C 1 -C ₆ alkyl) group, -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ an alkyl) group, or a N- (alkyl) alkylamino group, where each of the groups is optionally substituted with 1 to 5 substituents, each substituent being independently halogen, -NO ₂ , -C (O) OH, -CN, N-oxide , -OH, or aryl, heteroaryl, carbonyl, -C 1 -C ₆ alkyl, -SO _n - (C 1 -C ₆ alkyl), -8O _n - (aryl), aryloxy, -heteroaryloxy, -C 1 -C ₆ alkoxy, -C (O) -heterotsikloS ₃ - ₆ alkyl, -NHtsikloS ₃ -C ₆ alkyl, amino, - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, or -C (O) -X (C ₀ -C ₆ alkyl) (C _{An O-} C ₆ alkyl) substituent group, wherein each substituent group is independently optionally substituted with -OH, -C 1 -C ₆ alkoxy, -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n (C 1 -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl), (C ₀ -C ₆ alkyl); one of R1 and R1 must be aryl optionally substituted and the other must be heteroaryl optionally substituted; η is independently 0, 1 or 2. A compound according to claim 1 comprising 161 65403 Bl 162 65403 Bl 163 65403 Bl 164 65403 Bl Ο 165 65403 Bl 166 65403 Bl 167 65403 Bl 168 65403 Bl 169 65403 Bl 170 65403 Bl 171 65403 B1 or a pharmaceutically acceptable salt thereof. 20 A compound of formula I according to claims 1 and 2, or a pharmaceutically acceptable salt thereof, for use as a phosphodiesterase inhibitor. Use of a compound of formula I 25 according to claims 1 and 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), βθ eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and elastic abdominal pain in horses), septic 35 shock, ulcerative colitis, Crohn's disease, reperfusion myocardial damage brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, allergic dermatitis, urticaria, respiratory distress syndrome in adults, chronically obstructive pulmonary, , atherosclerosis, neurogenic 45 inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and disease implant against recipient, gastric over-secretion acid, bacterial, fungal or viral-induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle atrophy, depression, memory impairment, unipolar depression, acute and chronic diseases, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancer invasion in normal tissues. 5. Pharmaceutical composition - a phosphodiesterase-4 inhibitor comprising an acceptable phosphodiesterase-4 inhibitory amount of a compound of formula I as defined in claims 1 and 2, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.