SK8972002A3 - Substituted 8-arylquinoline phosphodiesterase-4 inhibitors - Google Patents

Abstract

Novel substituted 8-arylquinolines represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein S1, S2 and S3 are independently H, -OH; halogen, -C1-C6alkyl, -NO2, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; R1 is a H, OH, halogen, carbonyl, or -C1-C6alkyl, -cycloC3-C6alkyl, -C1-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C1-C6alkylamino, -(C1-C6alkyl)(C1-C6alkyl)amino, -C1-C6alkyl(oxy)C1-C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNH(C1-C6alkyl), -C(O)N(C0-C6alkyl) (C0-C6alkyl), -NH-SOn-(C1-C6alkyl), -SOn-(C1-C6alkyl), -(C1-C6alkyl)-O-C(CN)-dialkylamino, or -(C1-C6alkyl)-SOn-(C1-C6alkal) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C1-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(C0-C6alkyl), -C(O)-aryloxy, -C1-C6alkoxy, -(C0-C6alkyl)(C0-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl); A is CH, C-ester, or C-R4; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C1-C6alkyl, heterocycloC3-6alkyl, -C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -C1-C6alkyl)-SOn-(C1-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), or -C1-C6alkylacylamino group, wherein any of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(C0-C6alkyl)(C0-C6alkyl)amino, -C(O)-N(C0-C6alkyl)(C0-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -NO2, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(C0-C6alkyl)(C0-C6alkyl); one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused three ring system; are PDE4 inhibitors.

Description

-1 Substituted 8-arylquinoline compounds, pharmaceutical composition containing them, precursor compound and use thereof

Technical field

The present invention is directed to compounds which are substituted 8-arylquinolines. In particular, the invention relates to substituted 8-arylquinolines which are inhibitors of phosphodiesterase-4, wherein said aryl group at the 8-position contains a substituted substituted alkenyl group.

BACKGROUND OF THE INVENTION

Hormones are compounds that affect cell activity in various ways. In many respects, hormones act as mediators to trigger specific cellular responses and activities. However, many of the effects caused by hormones are not caused solely by the hormone. The hormone first binds to the receptor, triggering the release of a second compound that affects cell activity. In this scenario, the hormone is the first mediator, while the second compound is referred to as the second mediator. For hormones, including epinephrine, glucagon, calcitonin, corticotropin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroidstimulating hormone, and vasopressin, the cyclic adenosine monophosphate (adenosine 3 ', 5'-cyclic, 5'-phosphate, 5'-cyclophosphate). Thus, cyclic AMP mediates a cellular response to the hormone. Cyclic AMP mediates cellular responses to various neurotransmitters.

Phosphodiesterases (in another PDE) are a group of enzymes that metabolize 3 ', 5' cyclic nucleotides to 5 'nucleoside phosphates, ending cAMP's second mediator activity. A particular phosphodiesterase, phosphodiesterase-4 (also known as PDE-IV in another PDE4), which with high cAMP specific affinity is PDE type IV, has attracted attention as a potential target in the development of novel anti-asthma and anti-inflammatory compounds. PDE4 is known to exist in at least four isoenzymes, each encoded by a different gene. It is believed that each of the four PDE4 gene products has allergic and / or allergic reactions

-2flammatory responses different role. Thus, it is believed that inhibition of PDE4, particularly PDE4 isoforms that produce noxious responses, can have a beneficial effect on allergy and inflammatory symptoms. There is therefore a need for novel compounds and pharmaceutical compositions that suppress PDE4 activity.

The use of PDE4 inhibitors is associated with the greatest concern due to vomiting as a side effect, which is also observed with several candidate compounds, as described by C. Burnouf et al., Ann. Rep. in Med. Chem. 33, 91-109 (1998). B. Hughes et al., Br. J. Pharmacol. 118, 1183-1191 (1996); M. J. Perry et al. Cell Biochem. Biophys. 29: 113-132 (1998); S. B. Christensen et al., J. Med. Chem. 41, 821-835 (1998); and Burnouf disclose a large variability in the severity of adverse side effects caused by various compounds. As reported in: M. D. Houslay et al., Adv. in Pharmacol. 44, pp. 225-34 (1998) and D. Špina et al., 44, 33-89 (1998), are of great interest in therapeutic PDE4 inhibitors and have devoted considerable research efforts.

International patent application WO9422852 discloses quinolines as PDE4 inhibitors.

A. H. Cook et al., J. Chem. Soc., 413-417 (1943) disclose gamma-pyridylquinolines. 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 with ring systems have been described by various investigators as active ingredients for various therapies and uses. For example, International Patent Application WO98 / 25883 discloses ketobenzamides as calpain inhibitors. European patent application EP 811610 and US patents 5,679,712, 5,693,672 and 5,747,541 disclose substituted benzoylguanidine sodium channel blockers, US 5,736,297 discloses ring systems useful as photosensitive agents.

US Patents 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896 and International Patent Application WO 95/35283 discloses PDE4 inhibitors which are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Patent 5,580,888 discloses PDE4 inhibitors which are styryl derivatives. U.S. Patent

-35 550 137 discloses PDE4 inhibitors which are phenylaminocarbonyl derivatives. U.S. Patent 5,340,827 discloses phenylcarboxamide compounds as PDE4 inhibitors. U.S. Patent 5,780,478 discloses tetrasubstituted phenyl derivatives as PDE4 inhibitors. International patent application WO96 / 00215 discloses substituted oxime derivatives useful as PDE4 inhibitors. U.S. Patent 5,633,257 discloses cyclo (alkyl and alkenyl) phenyl-alkenyl (aryl and heteroaryl) compounds as PDE4 inhibitors.

Despite this, there remains a need for novel compounds and pharmaceutical compositions that would therapeutically suppress PDE4 while having minimal side effects.

SUMMARY OF THE INVENTION

The invention is directed to novel substituted 8-arylquinolines, which are PDE4 inhibitors, wherein said aryl group is substituted at the 8-position with a substituted alkenyl group. The invention further relates to a pharmaceutical composition comprising an effective amount of a novel substituted 8-arylquinoline and a pharmaceutically acceptable carrier. The invention further relates to a method of treating, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and equine colic) ), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury to the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, allergic syndrome, respiratory distress syndrome, respiratory distress syndrome, respiratory distress syndrome, rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, host transplant rejection and al. or graft, excessive gastric acid secretion, bacterial, fungal or virus-induced sepsis or septic shock, inflammation or cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle exhaustion, depression, memory impairment, mono

-4-polar depression, acute and chronic neurodegenerative disorders with inflammatory elements, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancer invasion of normal tissue in mammals; said method of treatment comprising administering an effective amount of a new substituted 8-arylquinoline or a precursor compound thereof from which the new substituted 8-arylquinoline is formed in vivo.

The present invention provides substituted 8-arylquinoline compounds of formula I

WITH

(D or pharmaceutically acceptable salts thereof, wherein

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO ₂ , -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each the substituent independently of one another is halogen or -OH;

R ¹ is H, -OH, halogen, carbonyl or -C 1 -C 6 alkyl, -cycloC ₃ -C 6 alkyl, -C ₂ -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 alkylC 1 -C ₆ alkyl) amino, -C 1 -C ₆ alkyloxy, -C 1 -C 6 alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), -SO _n NH (aryl), - 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 _r -C ₆ alkyl), -SO _n - _{(CR 6} alkyl), - _{(CR 6} alkyl) OC (CN) dialkylamino, or - _(Ci-6 alkyl) -SO n (CrC6alkyl); wherein any group is optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 alkyl) (C ₀ -C ₆ alkyl) amino, cycloalkyloxy, acyl, acyloxy , -cycloC ₃ -C ₆

-5alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO _n (C -C _alkyl);

A is CH, C-ester or CR ⁴ ;

R ² and R ³ independently of one another are aryl, heteroaryl, H, halogen, -CN, -C ₁ -C ₆ alkyl, -heterocycloC 3 -C 6 alkyl, -C 1 -C 6 alkoxy, carbonyl, carbamoyl, -C (O) OH, - ( _Ci-6 alkyl) -SO _n - _(C-C6 alkyl), -C (0) N (C ₀ -C ₆ alkyl) _(Co-C6 alkyl) or a group -CrCealkylacylamino, wherein any of the groups is be optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -heteroaryloxy, -C 1 -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), each substituent group independently of each other being optionally substituted by -OH, C _r C6 alkoxy, -C ₆ alkyl, _-cycloC3-C6 alkyl, aryloxy, -C (O) OH, -C (O) O _(Ci-C6 alkyl), halogen, -NO ₂ , -CN, -SO _n - (C 1 -C ₆ alkyl) or o -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 optionally be joined by a thio, oxy or (C ₁ -C ₄ alkyl) bridge to form a fused three-ring system;

R ⁴ is aryl, -C 1 -C ₆ alkyl, heteroaryl, -CN, carbonyl, carbamoyl, - (C 1 -C ₆ alkyl) SO _n - (C 1 -C ₆ alkyl), -C (O) N (Co- (C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C 1 -C 6 alkylacylamino, wherein any of said groups is optionally substituted with 1 to 5 substituents, each substituent independently of each other being a carbonyl, -CN, halogen, -C (O) (C _{0) C6} alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), C _r C ₆ alkyl, -SO _n - _(C-C6 alkyl), -OH, or -C Cealkoxy a - (C 0 -C 6 alkyl) (C 0 -C 6 alkyl) amino group;

n is independently 0, 1 or 2; and

R ² and R ³ may optionally be linked to R ⁴ to form a ring.

In one aspect, a compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C ₁ -C ₆ alkyl, -NO ₂ , -CN or -C ₁ -C ₆ alkoxy, wherein said alkyl or alkoxy groups are optionally

-6-substituted with 1 to 5 substituents, each substituent independently of each other being halogen or -OH;

R ¹ is H, -OH, halogen, carbonyl or -C 1 -C 6 alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -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 6 alkyl (oxy) C 1 -C ₆ alkyl, -C (O) NH (aryl), -C ( O) NH (heteroaryl), -SO _n NH (aryl), -SO _n NH (heteroaryl), -SO _n NH (C 1 -C ₆ alkyl), -C (O) N (C ₀ -C 6 alkyl) (Co- 6 alkyl), -NH-SO _n - _(C-C6 alkyl), -SO _n - _(C-C6 alkyl), - _(Ci-C6 alkyl) OC (CN) dialkylamino or - (CrC6alkyl) -SO _n - (C 1 -C 6 alkyl) wherein any of said groups is optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 alkyl) ) _(Co-C6 alkyl) amino, cycloalkyloxy, acyl, acyloxy, _-cycloC3-C6 alkyl, heterocykloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO _n - (-C ₆ alkyl);

A is CH;

R ² and R ³ each independently of the other is an aryl, heteroaryl, H, halogen, -CN, -CrCealkyl, -heterocycloC3-C6alkyl, -C _r 6 alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C C ₆ alkyl) -SO _n - (C 1 -C 6 alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), or -C 1 -C ₆ alkylacylamino, wherein any of said groups may be optionally substituted 1-5 substituents, each substituent independently of each other being 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), -aryloxy, -heteroaryloxy, -C ₁ -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), each substituent group independently of each other being optionally substituted with -OH, -C _1-6 alkyl. 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 or heteroaryl, optionally substituted;

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

-7n is independently 0,1 or 2; and

In one embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein

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

R ¹ is -C ₁ -C ₆ alkyl, optionally substituted with 1 to 5 substituents, each substituent independently of another 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 0 -C 6 alkyl) (C 0 -C 6 alkyl) amino;

A is CH;

R ² and R ³ independently of each other are aryl, heteroaryl, H, halogen, -CN, -C 1 -C 6 alkyl, -heterocycloC ₃ -C 6 alkyl, -C 1 -C 6 alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -) -C 6 alkyl) -SO 2 - (C 1 -C 6 alkyl), -C (O) N (C 0 -C 6 alkyl) (C ₀ -C ₆ alkyl), or -C 1 -C ₆ alkylacylamino, wherein any of said groups may be optionally substituted with 1 to 5 substituents, each substituent independently of each other is 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, -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), wherein each substituent group is, independently of the others, 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, -SOn-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 aryl or heteroaryl, then R ² and R ³ may optionally be joined by a thio, oxy or (C 1 -C 4 alkyl) bridge to form a fused three-ring system;

n is independently 0, 1 or 2.

In another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein

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

R ¹ is -cycloC 3 -C 6 alkyl, optionally substituted with 1 to 5 substituents, each substituent independently of another 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 and R ³ each independently of one another are aryl, heteroaryl, H, halogen, -CN, -C 1 -C 6 alkyl, -heterocycloC 3 -C 6 alkyl, -C 1 -C 6 alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -C ₆ alkyl) -SOn- (C 1 -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), or -C 1 -C 6 alkylacylamino, wherein any of said groups may be optionally substituted 1 to 5 substituents, each substituent independently of each other being 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, -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), wherein each substituent group is independently 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 (Co) C6alkyl) (Co-C6 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 optionally be joined by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused three-ring system; and n is independently 0, 1 or 2.

In yet another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:

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

. I

R is -C 2 -C 6 alkenyl, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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) ₆ alkyl);

A is CH;

R ² and R ³ each independently of one another are aryl, heteroaryl, H, halogen, -CN, -C 1 -C 6 alkyl, -heterocycloC ₃ -C ₆ alkyl, -C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -C ₆ alkyl) -SO _n - (C 1 -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), or -C 1 -C 6 alkylacylamino, wherein any of said groups may be optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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, -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), each the substituent group is independently of the others 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 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 optionally be joined by a thio, oxy or (C 1 -C 4 alkyl) bridge to form a fused three-ring system; and n is independently 0,1 or 2.

In another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C ₆ alkyl, -NO 2, -CN or -C ₁ -C ₆ alkoxy, wherein said alkyl or alkoxy groups are optionally

-Substituted with 1 to 5 substituents, each substituent independently of one another being halogen or -OH;

R ¹ is heteroaryl, optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 -SOn- ( C _r C ₆ alkyl);

A is CH;

R ² and R ³ each independently of one another are aryl, heteroaryl, H, halogen, -CN, -C 1 -C 6 alkyl, -heterocycloC ₃ -C 6 alkyl, -C 1 -C 6 alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C 1 -C 6 alkyl) -SO _n - (C 1 -C 6 alkyl), -C (O) N (C 0 -C 6 alkyl) (C 0 -C 6 alkyl), or -C 1 -C ₆ alkylacylamino, wherein any of said groups may be optionally substituted with 1 to 6 5 substituents, each substituent independently of the others being 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), -aryloxy, -O-heteroaryl, -C 1 -C 6 alkoxy, N-oxide, -C (O) -heterocykloC ₃ -C 6 alkyl, -NH-cycloC ₃ -C ₆ alkyl, amino, -OH or (Co. -C 6 alkyl) (C 0 -C 6 alkyl) amino, -C (O) -N (C 0 -C 6 alkyl) (C 0 -C 6 alkyl), wherein each substituent group is independently substituted with -OH, -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkoxy, 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 1-6) -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ a (C ₁ -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 optionally be joined by a thio, oxy or (C 1 -C 4 alkyl) bridge to form a fused three-ring system; and n is independently 0, 1 or 2.

In yet another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO ₂ , -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each substituent independently of each other another is halogen or -OH;

- 11 R ¹ is ^an amino group, -C ₆ alkylamino, or C - (CrCealkylXCrCealkylJamino, wherein any of the groups is optionally substituted with 1 to 5 substituents, wherein each substituent is independently a halogen, -OH, -CN, -C ( O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (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 and R ³ each independently of one another are aryl, heteroaryl, H, halogen, -CN, -C 1 -C 6 alkyl, -heterocycloC ₃ -C ₆ alkyl, -C 1 -C ₆ alkoxy, carbonyl, carbamoyl, -C ( O) OH, - (C 1 -C ₆ alkyl) -SO _n - (C 1 -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), or -C ₁ -C ₆ alkylacylamino, wherein any of said groups may be optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -O-heteroaryl, -C 1 -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), each the substituent group independently of each other is 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 ) (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 or heteroaryl, optionally substituted;

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

In another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein

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

-12R ¹ is -C 1 -C ₆ alkyl, -cyclo (C ₃ -C 6) alkyl, -C ₂ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C 6) 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 -C 6 alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl) ), -SO _n NH (aryl), -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-SOn-ÍCrCealkyl), -SO _n - _(C-C6 alkyl), carbamoyl, - _{(CR 6} alkyl) OC (CN) dialkylamino, or - _(Ci-6 alkyl) -SO _n - ( (C 1 -C 6 alkyl) wherein any group is optionally substituted with 1 to 5 substituents, each substituent independently of one another being halogen, -OH, -CN, alkoxy, 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 an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of one another being aryl, heteroaryl, halogen, -NO ₂ , -C (O) OH, carbonyl, -CN, -C 1 -C 6 alkyl, -SO 2 _n - (C 1 -C 6 alkyl), -SO _n - (aryl), -aryloxy, -heteroaryl, -C? -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), wherein any of said groups may be 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-C6 alkyl), or -C (0) n (-C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ³ is a heteroaryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -O-heteroaryl, -C 1 -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), any of said groups independently others may be optionally substituted with -OH, -C 1 -C 6 alkoxy, -C 1 -C 6 alkyl, -cycloC ₃ -C 6 alkyl, -aryloxy, -C (O) O, -C (OOC 1 C 6 -C 6 alkyl), halogen, -NO ₂ , -CN, -SO _n - _(Ci-C6 alkyl), or -C (0) N _(Co-C6 alkyl) _(Co-C6 alkyl);

n is independently 0, 1 or 2.

In yet another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO ₂ , -CN or

-C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally

13-substituted with 1 to 5 substituents, each substituent independently of one another being halogen or -OH;

R ¹ is halogen, carbonyl, -C 1 -C 6 alkyl, -cyclo (C ₃ -C 6) alkyl, -C ₂ -C ₆ alkenyl, -C 1 -C 6 alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C 6) 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 -C ₆ alkyl, -C (O) NH (aryl), -C (O) NH ( heteroaryl), -SO _n NH (aryl), -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 - (CrCealkyl), -SO _n - (CrC6alkyl), carbamoyl, - (CrC6alkyl) -OC (CN) dialkylamino, or - (Ci-6 alkyl) -SO _n - (C-C6 alkyl), wherein any is optionally substituted with 1 to 5 substituents, each substituent independently of the other being halogen, -OH, -CN, -C (O) -heterocycloC ₃ -C 6 alkyl, -C (O) -O- (C 0 -C 6 alkyl), -C (O) -O-aryl, alkoxy, cycloalkoxy, acyl, acyloxy, -cycloC ₃ -C 6 alkyl, heterocycloC ₃ -C 6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SOn-C 1 -C 6 alkyl);

A is CH;

R ² is an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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), -aryloxy, -O-heteroaryl, -C 1 -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), any of which may be 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);

R ³ is an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -O-heteroaryl, -C ₁ -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), wherein any of said groups independently of each other may be optionally substituted with -OH, -CrC ₆ alkoxy, -CrCealkyl, cyclo-C _{3 -C 6} alkyl, -aryloxy, -C (O) OH, -C (O) O (CrCealkyl), halogen, -N0 _2, -CN, -SO _n - ( C ₁ -C ₆ alkyl) or -C (O) -N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl); and n is independently 0, 1 or 2.

In yet another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO 2, -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each substituent relative to each other independently of one another is halogen or -OH;

R ¹ is halogen, carbonyl, -C 1 -C 6 alkyl, -cyclo (C 3 -C ₆ ) alkyl, -C 2 -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C 3 -C ₆ ) 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 -C ₆ alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), -SO _n NH (aryl), -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 1 -C ₆ alkyl), -SO _n - (C 1 -C ₆ alkyl), carbamoyl, - (C 1 -C ₆ alkyl) -OC (CN) -dialkylamino or - (C 1 -C ₆ alkyl) C 6 alkyl) -SO _n - (C 1 -C 6 alkyl) wherein any group is optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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 a carbonyl group, optionally substituted with 1 substituent, wherein the substituent is aryl, heteroaryl, -C (O) OH, carbonyl, -C 1 -C 6 alkyl, -O-aryl, -O-heteroaryl, -O- (C 1 -C 6 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, any of which may be optionally substituted with -OH, -O ( C 1 -C ₆ alkyl), -C 1 -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -O (aryl), -C (O) OH, -C (O) O (C 1 -C ₆ alkyl), halogen , -NO ₂ , -CN, -SO _n - (C ₁ -C ₆ alkyl), -cycloC ₃ -C ₆ alkyl or -C (O) -N (C 0 -C ₆ alkyl) (C ₀ -C ₆ alkyl);

R ³ is an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), aryloxy, -O-heteroaryl,

-C 1 -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), wherein any of said substituent groups independently of the others may be optionally substituted with -OH, -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy .

-15-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 _(Co-C6 alkyl) _(Co-C6 alkyl); and n is independently 0,1 or 2.

In yet another embodiment, the compound of the invention is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:

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

R ¹ is halogen, carbonyl, -C 1 -C ₆ alkyl, -cyclo (C ₃ -C ₆ ) alkyl, -C ₂ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C ₆ ) ) 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 -C 6 alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), - SO _n NH (aryl), -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 ₁ -C ₆ alkyl), -SOn- (C ₁ -C ₆ alkyl), carbamoyl, - (C 1 -C 6 alkyl) -OC (CN) -dialkylamino or - (C ₁ -C ₆ alkyl) -SOn- (C ₁ -C ₆ alkyl), wherein any of of said groups is optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 a carbamoyl group, optionally substituted with 1 to 2 substituents, wherein the substituent independently of one another is 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, -NH-cycloC ₃ -C ₆ alkyl, amino, -OH or -C 1 -C 6 alkyl (amino), any of which may be optionally substituted with -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 an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -O-heteroaryl,

-C 1 -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), wherein any of the 16 substituent groups independently of each other may be 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); and n is independently 0, 1 or 2.

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

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

R ¹ is halogen, carbonyl, -C 1 -C 6 alkyl, -cyclo (C ₃ -C 6) alkyl, -C ₂ -C 6 alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C 6) 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 -C 6 alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), -SO _n NH (aryl), - 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 ₁ -C ₆ alkyl), -SO _n - (C 1 -C 6 alkyl), carbamoyl, - (C 1 -C 6 alkyl) -OC (CN) -dialkylamino or - (C 1 -C 6 alkyl) -SO 2 - (C 1 -C ₆ alkyl), wherein any group is optionally substituted with 1 to 5 substituents, each the substituent is independently of another 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 and R ³ each independently of the other is an aryl group, optionally substituted, linked to each other by a thio, oxy or (C 1 -C ⁴ alkyl) bridge to form a fused three-ring system; and n is independently 0,1 or 2.

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

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO ₂ -CN or

-CrCôalkoxy;

R ¹ is halogen, carbonyl, -C 1 -C ₆ alkyl, -cyclo (C ₃ -C ₆ ) alkyl, -C ₂ -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C ₆ ) 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 -C ₆ alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), -SO _n NH (aryl), -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 1 -C 6 alkyl), -SOn- (C 1 -C ₆ alkyl), carbamoyl, - (C ₁ -C ₆ alkyl) -OC (CN) -dialkylamino or - (C 1 -C 6 alkyl) -SO _n - (C 1 -C ₆ alkyl) wherein any group is optionally substituted with 1 to 5 substituents, each substituent independently of the other being halogen, -OH, -CN, -C (O) (heterocycloC _3- C6 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 -SOn- (C ₁ -C ₆ alkyl);

A is CH;

R ² is - (C 1 -C 6 alkyl) -SO _n - (C 1 -C 6 alkyl), optionally substituted with 1 to 5 substituents, independently of the other substituents being halogen, -NO ₂ , -COOH, carbonyl, -CN, -Ci -C ₆ alkyl, -SO _n - (C 1 -C ₆ alkyl), -O-aryl, -O-heteroaryl, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NH-cycloC ₃ -C ₆ alkyl, amino, -OH, or -C 1 -C ₆ alkyl (amino), each substituent group independently of each other being optionally substituted with -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 an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -Oheteroaryl, -C 1 -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) _(Co-C6 alkyl) amino, -C (0) N (-C ₆ alkyl) _(Co-C6 alkyl), wherein any of said substituent groups independently of each other may be 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 1-6) 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 n is independently 0, 1 or 2.

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

-18S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO 2, -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each substituent independently of one another is halogen or -OH;

R ¹ is halogen, carbonyl, -C 1 -C 6 alkyl, -cyclo (C 3 -C 6) alkyl, -C ₂ -C 6 alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C ₆ ) 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 -C 6 alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), -SO _n NH (aryl), -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 1 -C ₆ alkyl), -SO _n - (C 1 -C ₆ alkyl), carbamoyl, - (C 1 -C ₆ alkyl) -OC (CN) -dialkylamino or - (C 1 -C ₆ alkyl) -SO _n - ( (C 1 -C 6 alkyl) wherein any group is optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 to 5 substituents, wherein independently of the other substituent is 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, -NH-cycloC ₃ -C 6 alkyl, amino, -OH, or -CrC ₆ alkyl (amino), wherein each substituent group is, independently of the others, optionally substituted with -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 to 5 substituents, each R is independently a aryl, heteroaryl, halo, _-NO2, -C (O) OH, carbonyl, -CN, -C _{r 6} alkyl, - SO _n - (C 1 -C ₆ alkyl), -SO _n - (aryl), -aryloxy, -O-heteroaryl, -C ₁ -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), wherein any of of said substituent groups independently of the others may be 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); and

-19n is independently 0,1 or 2.

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

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO 2, -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each the substituent independently of one another is halogen or -OH;

R ¹ is halogen, carbonyl, -C 1 -C ₆ alkyl, -cyclo (C ₃ -C ₆ ) alkyl, -C 2 -C ₆ alkenyl, -C 1 -C ₆ alkoxy, aryl, heteroaryl, -CN, -heterocyclo (C ₃ -C 6) 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 -C 6 alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), - SO _n NH (aryl), -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 ₁ -C ₆ alkyl), -SO 1 - (C ₁ -C ₆ alkyl), carbamoyl, - (C 1 -C ₆ alkyl) -O-C (CN) -dialkylamino or - (C 1 -C 6 alkyl) -SO _n - (C 1 -C 6 alkyl) wherein any group is optionally substituted with 1 to 5 substituents, each substituent independently of the others being halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C 6 alkyl), -C (O) -O- (Co- (Alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, -heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -SOn-C ₁ -C ₆ alkyl);

A is CH;

R ² is -CN;

about

R is an aryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), -aryloxy, -O-heteroaryl, -C 1 -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), wherein any of said substituent groups independently of the other can be 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 ₆ alkyl), or -C (O) N _{(Co-C6alkyl) (Co-C6} alkyl); and n is independently 0, 1 or 2.

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

S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO 2, -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each substituent independently of each other another is halogen or -OH;

R ¹ is -C ¹ -C 6 alkyl, optionally substituted with 1 to 5 substituents, each substituent independently of another 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 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);

A is CH;

R ² and R ³ each independently of one another is an aryl or heteroaryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), aryloxy, -C ₁ -C ₆ alkoxy, Noxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NH cyclo-C _{3 -C 6} alkyl, amino, -OH or (C ₀ -C ₆ alkyl) - _(Co-C6 alkyl) amino, -C (0) N (-C ₆ alkyl) (Co-C6 alkyl) wherein any of said substituent groups independently of the others may be 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, _-NO2, -CN, -SO _n - (-C ₆ alkyl), or -C (O) N _(Co-C6 alkyl) _(Co-C6 alkyl);

R ² and R ³ may optionally be linked by a thio, oxy or (C 1 -C ⁴ alkyl) bridge to form a fused tripartite system; and n is independently 0,1 or 2.

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

S ¹ , S ² and S ³ are H;

R ¹ is -C 1 -C 6 alkyl, optionally substituted with 1 to 5 substituents, each substituent independently of another halogen, -OH, -CN, -C 1 -C 6 alkyl, -cyclo-21-

C 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, 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 and R ³ each independently of one another is an aryl or heteroaryl group, optionally substituted with 1 to 5 substituents, each substituent independently of the other being 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), aryloxy, -C 1 -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), wherein any of said substituent groups independently of the other can be optionally substituted with -OH, -C 1 -C 6 alkoxy, -C 1 -C 6 alkyl, -cycloC 5 -C 6 alkyl, -aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -NO ₂ , -CN, -SO _n - _(C-C6 alkyl), or -C (O) n (C ₀ -C 6 alkyl) (C ₀ -C ₆ alkyl);

R ² and R ³ may optionally be linked by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused tripartite system; and n is independently 0,1 or 2.

As used herein, the term alkyl as well as other terms prefixed with alk such as alkoxy, alkanoyl, alkenyl, alkynyl and the like are used to denote carbon chains, wherein the chains may be unbranched or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl. heptyl and the like. Alkenyl, alkiriyl and other similar terms include carbon chains containing at least one unsaturated carbon-carbon bond.

The term cycloalkyl means a non-heteroatom-containing carbon ring, including mono-, bi- and tricyclic saturated carbon rings, as well as fused ring systems. The fused ring systems may include a single ring which is partially or fully unsaturated, for example a benzene ring, to form fused ring systems, for example benzocondensed carbocycles. The term cycloalkyl includes said fused ring systems, for example, spiro fused ring systems. Examples of cycloalkyls include cyclopropyl,

-22cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like. Similarly, cycloalkenyl means non-heteroatom-containing carbocycles containing at least one non-aromatic carbon-carbon double bond, including mono-, bi- and tricyclic partially saturated carbocycles, as well as benzo-fused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl and the like.

Unless otherwise indicated, the term cycloalkyloxy means a cycloalkyl group attached to a linking oxygen atom.

Unless otherwise indicated, the term alkyloxy means an alkyl group attached to a linking oxygen atom.

Unless otherwise indicated, the term aryl includes multi-ring systems as well as single-ring systems such as, for example, phenyl or naphthyl.

Unless otherwise indicated, the term aryloxy encompasses multi-ring systems as well as single-ring systems such as phenyl or naphthyl linked via an oxygen linking atom to a binding site.

The term C 0 -C 6 alkyl includes alkyl groups having 6, 5, 4, 3, 2 or 1 carbon atoms or not containing a carbon atom. Alkyl without a carbon atom is a substituting hydrogen atom or a direct bond - depending on whether the alkyl is a terminal moiety or a bridging moiety.

Unless otherwise indicated, the term hetero includes one or more oxygen, sulfur or nitrogen atoms. For example, heterocycloalkyl and heteroaryl include ring systems containing one or more O, S or N atoms in the ring, including a combination of said atoms. Said heteroatoms replace the ring-bound carbon atoms. For example, heterocycloC 5 alkyl is a five membered ring containing from 5 to 0 carbon atoms.

Examples of heteroaryl groups include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, thiazolyl, imidazolyl, thiazolyl, , thiadiazolyl, triazolyl, tetrazolyl.

Unless otherwise indicated, the term heteroaryloxy means a heteroaryl group bonded via a linking oxygen atom to a binding site.

Examples of heteroaryl (C 1 -C 6) alkyl groups include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethylthiazole, oxidazolylethyl, benzimidazolylmethyl, benzimidazolylmethyl, benzimidazolylmethyl, , tetrazolyl methyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC 3 -C 7 alkyl groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one and thiomorpholinyl groups.

Examples of aryl (C _-C 6) alkyl groups include groups such as phenyl (C -C) alkyl and naphthyl (C, ₆₎ alkyl.

Examples of heterocycloC 3 -C 6 alkylcarbonyl (C 1 -C 6) alkyl groups include, for example, azetidinylcarbonyl (C 1 -C 6) alkyl, pyrrolidinylcarbonyl (C 1 -C 6) alkyl, piperidinylcarbonyl (C 1 -C ₆ ) alkyl, piperazinylcarbonyl (C 1 -C ₆ ) alkyl, morpholinylcarbonyl ( C 1 -C 6 alkyl and thiomorpholinylcarbonyl (C 1 -C 6) alkyl.

Unless otherwise indicated, the term amine includes primary, secondary and tertiary amines.

Unless otherwise stated, the term carbamoyl is used to include -NHC (O) _O-R -C ₄ alkyl and -OC (O) _NHC-C4 alkyl.

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

The term optionally substituted is used to include both substituted and unsubstituted groups. For example, an optionally substituted aryl may be a pentafluorophenyl group or a phenyl ring. Further, said substitution may be on any of the groups. For example, substituted aryl (C 1 -C ₆ ) alkyl includes substitution in the aryl group as well as substitution in the alkyl group.

The disclosed compounds contain one or more double bonds, which may result in cis / trans isomers as well as other conformational isomers. The invention includes all possible isomers as well as mixtures of isomers.

The described compounds may contain one or more asymmetric centers and may therefore exist as diastereomers and optical isomers. The invention encompasses all possible diastereomers as well as racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts of said forms of the compounds. The above formula I is shown without certain stereochemistry at certain positions. The invention includes all stereoisomers of formula I and their pharmaceutically acceptable salts. The invention further includes mixtures of stereoisomers as well as isolated individual stereoisomers. In the preparation of said compounds or in racemization or epimerization processes using known methods, products may be formed during the synthesis, which may be mixtures of stereoisomers.

The term pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the invention is acidic, its corresponding salt can conveniently be prepared from a pharmaceutically acceptable base, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper and copper, ferric, ferrous, lithium, magnesium, manganese, and manganese, potassium, sodium, zinc, and the like. Very preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring or synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed including ion exchange resins include, for example, arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminomethanol, ethanolamine, ethylenediamine, N-. ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tetrromamine, tripropylamine.

When the compound of the invention is basic, its corresponding salt can conveniently be prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Suitable acids include, for example, an acid

-25acetic, benzenesulfonic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, apple, hydroxyphenylacetic, methanesulfonic, pantomic, mica, nitric, nitric, nitric, toluenesulfonic. Benzenesulfonic, citric, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids are particularly preferred.

The pharmaceutical compositions of the present invention contain as active ingredients the compounds represented by Formula I (or pharmaceutically acceptable salts thereof), further comprising a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or excipients. Other therapeutic ingredients include, for example, a) leukotriene receptor antagonists; b) leukotriene biosynthesis inhibitors; c) corticosteroids; d) H1 receptor antagonists; e) beta 2 adrenoceptor agonists; f) COX-2 selective inhibitors; g) statins; h) non-steroidal anti-inflammatory drugs (NSAIDs); and i) M2 / M3 antagonists.

Said pharmaceutical compositions include compositions for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular and intravenous administration), although the most suitable route will in any case depend on the individual host and the nature and severity of the condition for which the active agent is administered. Said pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy.

For topical use, creams, ointments, jellies, solutions or suspensions containing a compound of formula I may be used. For the purposes of this invention, mouthwashes and gargles are also included in topical administration.

Dose levels from about 0.0001 mg.kg ^-1 to about 140 mg.kg ^-1 body weight per day are useful in the treatment of conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and equine colic), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonopritis urticaria,

-26 adult respiratory distress syndrome, child respiratory distress syndrome, chronic obstructive pulmonary animal disease, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, anasthritis, sphincter, anesthesia, cough or graft, overexpression of gastric acid, bacterial, fungal or virus-induced sepsis or septic shock, inflammation or cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle exhaustion, depression, memory impairment, neuropathic depressions, neuropathic depressions, monopolar degeneration inflammatory elements, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth, and normal tissue cancer invasion, which respond to PDE4 inhibition; or alternatively about 0.05 mg to about 7 g per patient per day. For example, an inflammatory disease can be effectively treated by administering from about 0.01 mg to 50 mg of said active compound per kilogram of body weight per day or alternatively by administering about 0.5 mg to about 2.5 g per patient per day. It will further be appreciated that PDE4 inhibiting compounds of the invention may be administered at prophylactically effective doses to prevent the above conditions.

The amount of active ingredient that may be combined with the carrier material per dosage form will vary depending upon the subject being treated and the route of administration. For example, a formulation intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active ingredient mixed with a suitable conventional amount of carrier material, the content of which may vary from about 5 to about 95 percent of the total weight of the pharmaceutical composition. Unit dosage forms will generally contain between about 0.01 mg and about 1000 mg of 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 of the active ingredient.

However, it will be appreciated that a particular dosage level for a particular patient will depend on a number of factors including the age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, elimination rate, drug combination and the severity of the particular disease being treated.

In practice, the compounds of formula (I) or pharmaceutically acceptable salts thereof of this invention can be combined, as an active ingredient, in a homogeneous mixture with a pharmaceutically acceptable carrier using conventional pharmaceutical methods for preparing mixtures. The carrier may take various forms depending on the desired form of preparation for administration, for example, for oral or parenteral (including intravenous) administration. Thus, the pharmaceutical compositions of the invention may be presented as discrete single doses suitable for oral administration, for example, as capsules, powders or tablets, containing a predetermined amount of the active ingredient. The following pharmaceutical compositions may be presented as powders, granules, solutions, suspensions in aqueous media or non-aqueous liquid media, oil-in-water emulsions or water-in-oil emulsions. In addition to the aforementioned conventional dosage forms, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, can also be administered as a controlled release agent and / or a controlled delivery device. Said pharmaceutical compositions may be prepared by any of the pharmaceutical methods. Said methods generally comprise the step of associating the active ingredient with a carrier; the carrier comprises one or more excipients. Said pharmaceutical compositions are generally prepared by uniformly and intimately admixing the active ingredient with liquid carriers or very fine solid carriers, or a combination of carriers may be used. The resulting mixture is formulated in the conventional manner.

The pharmaceutical compositions of the invention may comprise a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof. The compounds of formula I or pharmaceutically acceptable salts thereof may also be included in the pharmaceutical compositions in combination with one or more other therapeutically active compounds.

For example, a solid, liquid or gas may be used as a pharmaceutical carrier. Examples of solid carriers include lactose, white clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

Any conventional pharmaceutical media may be used to prepare the compositions for oral administration. For example, water, glycols, oils, alcohols, fragrances and flavors, preservatives, colorants and the like can be used for liquid formulations such as suspensions, elixirs and solutions. For example, binders, disintegrants and the like can be used to prepare oral solid compositions such as powders, capsules and tablets. Because tablets and capsules are easy to administer, they are preferred oral dosage forms using solid pharmaceutical carriers. The tablets may optionally be coated by conventional aqueous or non-aqueous excipient techniques.

A tablet containing the composition of the invention may be prepared by compression or molding, optionally with one or more accessory or ingredients. Compressed tablets may be prepared by compressing (in a suitable machine) the active ingredient in the form of a free-flowing powder or granulate, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets may be prepared by molding (in a suitable machine) a mixture of the powdered compounds moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient, and each powder or capsule preferably contains from about 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active ingredient in water. A suitable surfactant such as hydroxypropylcellulose may be included in the pharmaceutical composition. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oil. Preservatives may also be included in the compositions as a prevention of harmful growth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. These compositions may further be prepared in the form of sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In any case, the final injectable form must be sterile and must be fluid to the extent that easy syringability exists. Said pharmaceutical preparations must always be in production and storage conditions; should be protected from contamination by micro - organisms such as

-29 bacteria or fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the invention may be prepared in a form suitable for topical use, for example, as an aerosol, cream, ointment, lotion, light powder and the like. The compositions may further be in a form suitable for use in transdermal devices. These formulations may be prepared using a compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof by conventional processing methods. For example, a cream or ointment may be prepared by mixing the hydrophilic material and water together with about 5% to about 10% by weight of the active compound; this produces a cream or ointment with the desired consistency.

The pharmaceutical compositions of this invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably, the mixture forms a unit dose in a suppository. Suitable carriers include cocoa butter and materials commonly used in the art for this purpose. Suppositories may be prepared by first mixing the active ingredient with the softened or melted carrier (s) followed by shaping by molding and cooling.

Said pharmaceutical compositions may, in addition to the aforementioned carrier components, include, if desired, one or more carrier components such as diluents, buffering agents, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. Additional ingredients may be included in the composition to ensure isotonicity of the composition with the blood of the recipient. Said compositions comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or liquid concentrate.

The compounds and pharmaceutical compositions of this invention have been found to be biologically active as PDE4 inhibitors. Accordingly, in another aspect, the invention relates to the treatment of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic) ), septic shock, ulcerative colitis, Crohn's disease, reperfusion myocardial and brain damage,

-30 Inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, child respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic congestive disease, allergic congestive disease, pain, cough, rheumatoid arthritis, ankylosing spondylitis, host transplant or graft rejection, gastric acid overexpression, bacterial, fungal or viral-induced sepsis or septic shock, inflammation or cytokine-mediated chronic tissue cancer, depression, osteoarthritis, , deterioration of memory, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory elements, Parkinson's disease, Alzheimer's disease, ie, head injury, multiple sclerosis, tumor growth and cancer invasion of normal tissue - diseases susceptible to amelioration by inhibition of PDE4 isoenzyme and resulting increase in cAMP levels - in mammals, by administering an effective amount of the compounds of the invention. The term mammals as used herein includes humans as well as animals such as dogs, cats, horses, pigs and cattle. Accordingly, treatment of non-human mammals is a treatment of clinically comparable difficulties in other mammals to those in the human examples.

It has already been stated that the compounds of the invention can be further combined with other therapeutically active compounds. Combinations of PDE4-inhibiting compounds of the invention can be advantageously used in particular in combination! with a) leukotriene receptor antagonists; b) leukotriene biosynthesis inhibitors; c) COX-2 selective inhibitors; d) statins; e) NSAID; f) M2 / M3 antagonists; g) corticosteroids; h) H1 (histamine) receptor antagonists; i) beta 2 adrenoceptor agonists.

In another aspect, it has been found that a compound of the invention may be formed as a metabolite in a mammalian system. For example, the compound of Example 19, (5 - {(E) -2- [3- {6 [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl] phenyl) -1- [4- (methylsulfonyl) phenyl] ethenyl} -1,2,4-oxadiazol-3-yl) -methanol:

is an inhibitor of PDE4 and is produced in vivo as a metabolite by administration of the compound of the invention

Example 14:

Accordingly, the invention encompasses prodrugs that in vivo produce PDE4 inhibitors as metabolites upon administration of said prodrugs to a mammal. The invention further encompasses a method of treatment which is the step of administering a prodrug to produce in vivo an effective amount of a PDE4 inhibitor expressed by Formula I.

Abbreviations have the meaning given in the following table. Abbreviations not listed in the table have their usual meanings unless indicated otherwise.

Ac acetyl Bn benzyl CAMP cyclic adenosine-3'5'-monophosphate DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DIBAL diisobutyl aluminum hydride DMAP 4- (dimethylamino) pyridine DMF N, N-dimethylformamide Et ₃ N triethylamine GST glutathione transferase HMDS hexamethyldisilazide LDA Lithium diisopropylamide mCPBA Metachloroperbenzoic acid MMPP monoperoxyphthalic acid MPPM magnesium monoperoxyphthalic acid hexahydrate ms methanesulfonyl = mesyl = SO ₂ Me MsO methanesulfonate = mesilate NSAIDs a non-steroidal anti-inflammatory drug o-Tol ortho-tolyl OXONE 2KHSO ₅ .KHSO ₄ .K ₂ SO ₄ PCC pyridinium chlorochromate PDC pyridinium dichromate PDE phosphodiesterase ph phenyl Phe benzenediyl PMB p-methoxybenzyl Pye pyridinediyl Rac. racemic ON MY OWN aminosulfonyl or solfonamide or SO ₂ NH ₂ PULL 2- (trimethylsilyl) ethoxymethoxy SPA scintillation proximity analysis

TBAF tetra-n-butyl ammonium fluoride Th 2- or 3-thienyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran Thi thiophenediyl TLC thin layer chromatography TMS-CN trimethylsilyl cyanide TMSI trimethylsilyl tz 1H (or 2H) -tetrazol-5-yl CAN ammonium nitrate C3H5 allyl

Abbreviations of alkyl groups:

Me methyl et ethyl n-Pr normal (unbranched) propyl / Pr isopropyl n-Bu unbranched butyl / Bu isobutyl s-Bu secondary butyl t-butyl tertiary butyl c-Pr cyclopropyl c-Bu cyclobutyl c-Pen cyclopentyl c-Hex cyclohexyl

-34 Assays demonstrating the biological activity of said compounds

Analysis of human whole blood for LPS and FMLP-induced TNF-α and LTB4

Whole blood provides a protein and cell-rich environment suitable for studying the biochemical activity of anti-inflammatory compounds such as selective PDE4 inhibitors. Normal, unstimulated human blood does not contain detectable levels of TNF-α and LTB ₄ . Upon stimulation with LPS, activated monocytes express and secrete TNF-α within 8 hours and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of TNF-α by increasing intracellular cAMP through inhibition of PDE4 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 PDE4-selective inhibitors. Whereas in a 24 hour LPS stimulation of whole blood is produced is little LTB _4, for the synthesis of LTB4 by activated neutrophils are essential additional LPS stimulation of whole blood, followed by fMLP challenge. Using the same blood sample, it is thus possible to evaluate the potency of the compound on two representatives of PDE4 activity markers throughout whole blood as follows.

Fresh blood was collected by venipuncture from healthy human volunteers (men and women) into heparinized tubes. These subjects had no apparent inflammatory condition and did not use any NSAIDs for at least 4 days prior to blood collection. 500 μΙ blood aliquots were pre-incubated with 2 μΙ vehicle (DMSO) or 2 μΙ test compound at various concentrations; the preincubation lasted 15 minutes and was performed at 37 ° C. This was followed by the addition or 10 μΙ of the vehicle (PBS) as a blank or 10 μΙ LPS (g g / ml final concentration, L-2630 (Sigma Chemicals Co., St. Louis, MO) from E. coli, serotype 0111: B4; diluted in 0.1% w / v BSA (in PBS)). After 24 hours incubation at 37 ° C, an additional 10 μΙ of PBS (blank) or 10 μΙ of LPS (final concentration of Ag / ml) was added to the blood and incubated for 30 minutes at 37 ° C. Blood was then tested with 10 μΙ PBS (blank) or 10 μΙ fMLP (1μΜ final concentration, F-3506 (Sigma); diluted in 1% w / v BSA (in PBS)) for 15 minutes at 37 ° C. The blood samples were then centrifuged at 1500 x g at 4 ° C for 10 minutes to obtain plasma. Aliquot of plasma

-35 (50 μΙ) was mixed with 200 μΙ of methanol to precipitate the protein and the sample was centrifuged as above. The supernatant was analyzed for LTB ₄ using the enzyme immunoassay kit (No. 520111 from Cayman Chemical Co., Ann Arbor, MI, USA) according to the manufacturer's recommended method. TNF-α was determined in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NJ, USA) according to the manufacturer's recommended method. The IC ₅₀ values found in Examples 1 to 42 were generally in the range of 0.04 μ 8 to 8.7 μΜ.

Anti-allergic activity in vivo

The compounds of the invention were tested for their effect on IgE-mediated allergic pulmonary inflammation induced by antigen inhalation in sensitized guinea pigs. Guinea pigs were first sensitized to ovalbumin under mild cyclophosphamide induced immunosuppression, intraperitoneal injection of antigen in combination with aluminum hydroxide and pertussis vaccine. Booster doses of antigen were given two and four weeks later. At six weeks, the animals were administered aerosolized ovalbumin under the cover of an intraperitoneally administered anti-histamine agent (mepyramine). After an additional 48 hours, bronchial alveolar lavage (BAL) was performed and the number of eosinophils and other leukocytes was determined in the BAL fluid. Lungs were also collected for histological examination for inflammatory damage. Administration of the compounds of the Examples (0.001 to 10 mg / kg i.p. or p.o.) up to three times over 48 hours after antigen administration resulted in a significant reduction in eosinophils and accumulation of other inflammatory leukocytes. Minor inflammatory lesions of the lungs of animals treated with the compounds of the Examples were also found.

Protocol for SPA-based PDE activity determination

Compounds which inhibit the hydrolysis of cAMP to AMP type IV by cAMP specific phosphodiesterases were sorted on 96 well plate format as follows:

test compound (dissolved in 2 μΙ DMSO), 188 μΙ substrate buffer containing [2,8- ³ H] adenosine-3 ', 5'-cyclic phosphate (cAMP, 100 nM) was added to 96-well plates at 30 ° C up to 50 μΜ), 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

-36 (the amount was controlled to produce approximately 10% of the product in 10 minutes). The reaction was stopped after 10 minutes by the addition of 1 mg PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, NJ, USA). The resulting AMP product was quantified on a Wallac Microbeta® plate reader (EG & G Wallac Co., Gaithersburg, MD, USA). The signal in the absence of enzyme was determined as background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO after background subtraction. The inhibition was expressed as a percentage. IC 50 values were approximated by non-linear regression using standard 4-parameter / fold binding site equations from 10-point titration.

The IC 50 values of Examples 1-42 were determined with 100 nM cAMP using purified GST human recombinant phosphodiesterase IVa (met-248) fusion protein produced from baculovirus / Sf-9 expression system. The IC 50 values of Examples 1 to 42 are generally in the range of 0.14 nM to 10.24 nM, but one Example had an IC 50,019 nM value.

The examples below serve to illustrate some preferred embodiments of the invention in more detail and are not to be construed as limiting the invention in any way.

Unless otherwise indicated, the experimental procedures were performed under the following conditions. All operations were performed at room or ambient temperature, that is, at temperatures in the range of 18-25 ° C. Evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pa (4.5-30 mm Hg) at a bath temperature of up to 60 ° C. The reactions were monitored by thin layer chromatography (TLC) and reaction times are given only on The melting points are uncorrected and given at the melting point means the decomposition of the compound The melting points given refer to the materials prepared as described herein The polymorphism of the compounds may result in the isolation of materials with different melting points in some preparations. end-products have been guaranteed by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalysis Product yields are given for illustration only, where NMR data are given, presented as delta (δ) values of the principal diagnostic protons and are given in lots of parts per million (ppm) in proportion to tetramethylsilane (TMS) as an internal standard, determined at 300

-37ΜΗζ, 400 MHz or 500 MHz when used in the text of the solvents listed. Common abbreviations were used to indicate the shape of the signal: s-singlet, d-doublet, t-triplet, m-multiplet, b or br-wide, and the like. Ar means an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations were used: v for volume, w for weight, I for liter or liters, ml for milliliter or milliliters, g for gram or grams, mg for milligram or milligrams, moles or moles, mmol for millimoles or millimoles, eq for equivalent or equivalents.

Synthesis methods

The compounds of this invention can be prepared by the following methods. Said substituents are the same as in Formula I except where otherwise specified.

Scheme 1

Synthesis of ketone

ar-

ArX (IV

XAr Y.

(V) organol

2. A

1st base α1

OH

1. base or organolithium

E or A

3. base or organolithium

4 · A or E

ArM (III)

Ar '

SMe

(VIII)

-38kde

X = halogen, H; Y = halogen, H; A = 4- (methylthio) benzaldehyde; E = electrophile; Ar = aryl or heteroaryl.

Referring to Scheme 1 above, and to the table below for Scheme 1, the alcohol intermediate II may be prepared by reacting an arylmetallic or heteroarylmetallic compound III, for example an organomagnesium halide with 4- (methylthio) benzaldehyde (A) in an organic solvent environment such as THF. The alcohol intermediate II can also be prepared by treating the aryl or heteroaryl hydride or bromide IV with a base or an organometallic, e.g. n-butyllithium, in an organic solvent, e.g. THF, and reacting with 4- (methylthio) benzaldehyde. The alcohol intermediate II may also be prepared by the following chemical transformations 1) by treating an aryl or heteroaryl dihydride, halide hydride or dihalide V with a base or an organometallic compound such as n-butyllithium in an organic solvent environment such as THF and an electrophile such as acetone or 4- (methylthio) benzaldehyde; 2) sequential treatment with a base or an organometallic such as n-butyllithium in an organic solvent medium such as THF and with an electrophile such as acetone or 4 (methylthio) benzaldehyde, using 4 (methylthio) benzaldehyde as the electrophile in the first or second conversion. Said sulfone alcohol VI may be prepared by oxidizing the sulfide alcohol II with an oxidizing agent such as oxone in a solvent environment, for example a THF / MeOH / H 2 O mixture. Said ketones VII and VIII can be prepared by oxidizing alcohols II or VI with an oxidizing agent such as MnO ₂ in a solvent environment such as CH ₂ Cl ₂ . Said sulfone-ketone VIII may also be prepared by oxidation of sulfide-ketone VII with an oxidizing agent, for example oxone in a solvent medium such as THF / MeOH / H ₂ O.

Table for Scheme 1

ketones

ABOUT

(Vll> = 0) (Vll1Xn = 2)

SO _n Me

Ar n ketone Ar n ketone _F Cr ^0Hi 2 K1 x x x CH ₃ h ₃ cAt 2 K7 h ₃ c _ζ Ν_.ΟΗ ₂ 0 K2 In ^{CH 2} 2 K8 Or ° ^Hi 2 K3 nn ₂ MeO ₂ S 2 2 K9 0 2 K4 K5 ^CH 2 ^CH 2 2 K10 h ₃ c ^Η0 Ογ ° ^Ηζ 2 K6 CH2V ^CH2 ΗΟΪη ₃ 2 K11

Ketone Κ1 (4-Fluorophenyl) [4- (methylsulfonyl) phenyl] ketone

Ketone K1 was prepared as follows.

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

To a solution of 4- (methylthio) benzaldehyde (2.5 g, 16.4 mmol) in THF (100 mL) cooled to -78 ° C was added dropwise 4-fluorophenylmagnesium bromide (1.0 M in THF, 19, 7 mL, 19.7 mmol). The resulting solution was stirred at -78 ° C for 3 hours and quenched with saturated aqueous ammonium chloride solution. The mixture was then diluted with EtOAc and 10% HCl, extracted and washed (saturated NaHCO ₃ solution followed by brine). The organic layer was dried over anhydrous magnesium sulfate 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 room temperature overnight. The mixture was then filtered through a pad of silica (EtOAc) to give 2.6 g of (4-fluorophenyl) [4- (methylthio) phenyl] ketone.

-40Step 2: (4-Fluorophenyl) [4- (methylsulfonyl) phenyl] ketone

To a solution of the sulfide, (4-fluorophenyl) [4- (methylthio) phenyl] ketone, from previous reaction step 1 (2.0 g, 8.1 mmol) in THF / MeOH / H ₂ O (80/40/40 mL) Oxone (7.5 g, 12.2 mmol) was added. The mixture was stirred at room temperature for 4 hours, quenched with saturated sodium bicarbonate, and diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated. Crystallization (from CH ₂ Cl ₂ / hexane) gave (4-fluorophenyl) [4- (methylsulfonyl) phenyl] ketone, compound ketone 1, as a white solid.

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

Ketone 2 was prepared as follows.

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 of THF at -78 ° C was added dropwise n-butyllithium (2.5 M solution in hexane, 48.7 mL, 118 mmol) and the resulting the solution was stirred at -78 ° C for 30 minutes. Then 4- (methylthio) benzaldehyde (14.73 mL, 110 mmol) was added at -78 ° C and the mixture was stirred until completion of the reaction (TLC) and mixed with saturated ammonium chloride solution. The mixture was then diluted with EtOAc, extracted and washed (saturated NaHCO ₃ solution, then brine). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. Crystallization from EtOAC / hexane gave (1-methyl-1 H -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 from previous 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 mmol) and the reaction mixture was stirred overnight stirring. The mixture was then filtered through a pad of silica (EtOAc) to give the ketone K2.

-41 Ketone K3 (4-Methylsulfonyl) (phenyl) ketone

Ketone K3 was prepared as follows.

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

To a solution of 4- (methylthio) benzaldehyde (1.0 g, 6.5 mmol) in THF (20 mL) at 0 ° C was added phenylmagnesium chloride (2 M solution in THF, 3.5 mL, 7.0 mmol). After 1/2 hour at room temperature, the mixture was neutralized with saturated NH 4 Cl solution, diluted with water and extracted with Et ₂ O. The organic extracts were washed with water, brine, dried over MgSO ₄ , filtered and concentrated. Purification by vigorous stirring in hexane / Et ₂ O and filtration afforded (4-methylthio) (phenyl) methanol as a white solid.

Step 2: (4-Methylthio) (phenyl) ketone (4-Methylsulfonyl) (phenyl) ketone was obtained by treating (4-methylthio) (phenyl) methanol from the previous step 1 with MnO2, similar to step 2 of ketone K4 ( further).

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

To a solution of (4-methylthio) (phenyl) ketone from previous reaction step 2 (0.98 g, 4.3 mmol) in CHCl ₃ (10 mL) at 0 ° C was added mCPBA (m-chloroperbenzoic acid) (1, 7 g, 10 mmol). After 1/2 hour at room temperature, calcium hydroxide (1.7 g, 23 mmol) was added to the reaction mixture and then stirred for 1 hour. Filtration with Celite® and concentration afforded ketone K3 as a white solid.

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

Ketone K4 was prepared as follows.

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

To a solution of thiazole (5.0 g, 58.7 mmol) in THF (250 mL at -78 ° C was added dropwise butyllithium (2.5 M solution in hexane, 23.5 mL, 58.7 mmol) and the resulting solution was stirred at -78 [deg.] C. for 10 minutes, then 4- (methylthio) benzaldehyde (7.1 mL, 53.4 mmol) was added at -78 [deg.] C. The resulting mixture was stirred until the reaction was complete, then mixed. The mixture was then diluted with EtOAc and 10% HCl, extracted and washed (saturated NaHCO ₃ solution, then brine), and the organic phase was dried over MgSO ₄ and concentrated, and the residue was 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 from previous step 1 (10.0 g, 42.1 mmol) in EtOAc (250 mL) was added MnO ₂ (70 g). , 843 mmol); the reaction mixture was then stirred at 25 ° C overnight. Then the mixture was filtered through a pad of silica (EtOAc) to give the ketone K4.

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

Ketone K5 was prepared as follows. To a solution of ketone 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) Oxone (42.6 g, 69.4 mmol) was added. The reaction mixture was stirred at 25 ° C for 3 hours, then treated with saturated aqueous sodium bicarbonate. The mixture was then diluted with EtOAc, extracted and washed (saturated NaHCO 3 solution, then brine). The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was then purified by crystallization from EtAOc / hexane to give (1,3-thiazol-2-yl) [4- (methylsulfonyl) phenyl] ketone.

Ketone K6 [5- (1-Hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4- (methylsulfonyl) phenyl] ketone

-43Ketone K6 was prepared as follows.

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

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

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

To the sulfide solution - that is, [5- (1-hydroxy-1-methyl-ethyl) -1,3-thiazol-2-yl] [4 (methylthio) phenyl] ketone - from reaction step 1 (1.7 g, 5, 8 mmol) in THF / MeOH / H 2 O (100/50/50) was added oxone (7.1 g, 11.5 mmol). The reaction mixture was stirred at 25 ° C for 3 hours and then treated with saturated aqueous sodium bicarbonate. The mixture was then diluted with EtOAc, extracted and washed (saturated NaHCO ₃ , then brine). The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by crystallization from EtOAc / hexane to afford the ketone K6.

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

Ketone K7 was prepared as follows.

-44Step 1: (6-Methyl-3-pyridinyl) [4- (methylthio) phenyl] methanol

To a solution of 3-bromo-6-methylpyridine (760 mg, 1 equivalent) in THF (20 mL) at -78 ° C was slowly added n-butyllithium in hexane (1.1 equivalents). The solution was then stirred for 30 minutes. 4- (Thiomethyl) benzaldehyde (738 mg, 1.1 equivalents) was then added slowly. The solution was warmed to room temperature, saturated ammonium chloride solution was added, followed by water and EtOAc. The organic phase was separated, dried over anhydrous magnesium sulfate and concentrated. Precipitation with ether / hexane gave (6-methyl-3-pyridinyl) [4- (methylthio) phenyl] methanol, which was used in the next reaction step without further purification.

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

In the same manner as in step 2 for the preparation of ketone K1, except for substituting (4-fluorophenyl) [4- (methylthio) phenyl] ketone with (6-methyl-3-pyridinyl) - [4- (methylthio) phenyl] ketone sulfide from the previous one. of step 1 as starting material gave (6-methyl-3-pyridinyl) [4- (methylsulfonyl) phenyl] methanol.

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

In the same manner as in step 2 for the preparation of ketone K2, except for substituting (1-methyl-1 H -imidazol-2-yl) [4- (methylthio) phenyl] methanol (6-methyl-3-pyridinyl) [4- (methylsulfonyl) phenyl] methanol from the previous step 2 prepared as the starting material ketone K7.

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

Ketone K8 was prepared as described for the preparation of ketone K7 with the exception of 3-bromo-6-methylpyridine replacement with 2-bromo-5-methylpyridine.

Ketone K9

Bis - [(4-methylsulfonyl) phenyl] ketone

-45Ketone K9 was prepared as described for the preparation of ketone K7, with the exception of the replacement of 3-bromo-6-methylpyridine with 4-bromothioanisole and the use of twice the amount of oxone in the sulfide oxidation reaction step.

Ketone K10 (2-Pyridinyl) [4- (methylsulfonyl) phenyl] ketone

Ketone K10 was prepared as described for the preparation of ketone K7 except for the replacement of 3-bromo-6-methylpyridine with 2-bromopyridine.

Ketone K11 [5- (1-Hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] ketone

Ketone K11 was prepared as follows.

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

To a suspension of 2,5-dibromopyridine (5.12 g, 1 equivalent) in ether at -78 ° C was slowly added n-butyllithium in hexane (1.05 equivalents). The resulting yellow-orange precipitate was stirred for 30 minutes, then acetone (1.54 mL, 1.05 equivalents) was added. The solution was kept at -78 ° C for an additional 30 minutes, then n-butyllithium in hexane (1.1 equivalents) was slowly pipetted into the orange suspension. The suspension was stirred at -78 ° C for 1 h. 4- (Methylthio) benzaldehyde (2.85 mL, 1.1 equivalents) was then added. The resulting suspension was warmed to -35 ° C and quenched with saturated aqueous ammonium chloride solution. Water and EtOAc were added, the organic layer was separated, dried over MgSO ₄ 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

The method described for step 2 of the preparation of ketone K1 with the exception of (4-fluorophenyl) [4- (methylthio) phenyl] methanol [5- (1-hydroxy-1-methylethyl) 2-pyridinyl] [4- (methylthio) sulfide ) phenyl] methanol from the previous step 1 as starting material gave [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] methanol.

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

As described for step 2 of the preparation of ketone K2 with the exception of (1-methyl-1 H -imidazol-2-yl) [4- (methylthio) phenyl] methanol [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] methanol from the previous step 2 as starting material gave ketone K11.

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

Scheme 2

Synthesis of boronates

Ketone (VII or VIII) Ar n Boronate (XII) K2 Y h ₂ cn ch ₃ 0 B1 K4 h ₂ c ^a s ^? 0 B2 K8 jfr ^{CH 3} h ₂ c ^ n 2 B3 K11 h ₂ cyn 2 B4

Arylbromides IX and X can be prepared by treating a benzylphosphonium bromide XI with a base such as t -BuOK or LiHMDS in an organic solvent, such as THF, then adding the ketone VII or VIII to the reaction mixture. The sulfide in IX can be converted to sulfone X by treatment with oxone in a solvent such as THF / MeOH / H ₂ O. The boronate ester X 11a can be prepared by heating the aryl bromide X with pinacoldiborane 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-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate

Boronate B1 was prepared as follows.

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

To a solution of (3-bromobenzyl) (triphenyl) phosphonium bromide (10.2 g, 19.9 mmol,

19.9 ml) and CH ₃ CN (50 ml) were added dropwise at 25 ° C with t-BuOK (1.0 M solution in

THF, 19.9 mL, 19.9 mmol); the resulting red solution was stirred at room temperature for 20 minutes

-48miestnosti. To this ylide was then added the ketone K2 (4.4 g, 18.9 mmol) at 25 ° C. The mixture was stirred at 60 ° C for 2 days and quenched with saturated ammonium chloride solution. The mixture was then diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated; was used directly in the next reaction step 2.

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

To a solution of the crude sulfide, i.e. to a solution of (E / Z) -2- (3-bromophenyl) -1 (1-methyl-1H-imidazol-2-yl) -1- [4- (methylthio) phenyl] ethene from previous step 1 (18.9 mmol) in THF / MeOH / H 2 O (200/100/100 mL) was added oxone (23.2 g, 37.8 mmol). The mixture was stirred at room temperature for 4 hours, treated with saturated NaHCO 3 solution and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography of the residue (95% EtOAc / 5% Et 3 N) gave (E) -2- (3-bromophenyl) -1- (1-methyl-1 H -imidazol-2-yl) -1- [4 (methylsulfonyl) ) phenyljetene as a foam.

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

Bromide suspension, i.e. (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene, from the previous 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 (0.2 g, 0.24 mmol) ) in 50 ml of DMF was stirred at 90 ° C for 4 hours. The mixture was then cooled to room temperature, diluted with EtOAc, washed with water (3x), then brine, and dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography of the residue (95% EtOAc / 5% Et 3 N) gave the boronate B1 as a foam.

Boronate B2

Pinacol 3 - {(EHR) -2- (1,3-thiazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate

-49 Boronate B2 was prepared as follows.

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

To a solution of (3-bromobenzyl) (triphenyl) phosphonium bromide (44.5 g, 86.9 mmol) in THF (500 mL) at 0 ° C was added dropwise LiHMDS (1.0 M in THF, 86.9 mL, 86.9 mmol) and the resulting red solution was stirred at room temperature for 20 minutes. The ketone K4 (1836 g, 79.0 mmol) was then added to the prepared ylide at 0 ° C. The mixture was then stirred until completion of the reaction (TLC), mixed with saturated aqueous ammonium chloride solution. The mixture was then diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO 3, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ΟΗ ₂ ΟΙ ₂ ) to give (EZZ) -2- (3-bromophenyl) -1- (1,3-thiazol-2-yl) -1 [4- (methylthio) phenyl] ethene (1.5: 1 isomer mixture).

Step 2: (EZZ) -2- (3-Bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene

To the sulfide solution, i.e. to (EZZ) -2- (3-bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylthio) phenyl] ethene solution from previous 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 room temperature overnight. It was then diluted with saturated sodium bicarbonate solution and EtOAc. The organic phase was washed with saturated NaHCO 3 solution, then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (EZZ) -2- (3-bromophenyl) -1 (1,3-thiazol-2-yl) - 1- [4- (methylsulfonyl) phenyl] ethene (3: 2 mixture of isomers).

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

(E / Z) -2- (3-Bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene bromide suppression from previous reaction 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 (1.46 g, 1.78 mol) in 350 mL DMF was stirred at 90 ° C for 4 hours. The mixture was then cooled to room temperature, diluted with EtOAc, washed with water (3x), then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The rest

Purification by flash chromatography (Tol / acetone, 9/1) afforded the boronate B2 (3: 1 mixture of isomers) as a foam.

Boronate B3

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

Boronate B3 was prepared as follows.

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

The title boronate was prepared as described in Step 1 for the preparation of the boronate B1, except for the replacement of ketone K2 with ketone K8 as the starting material. After separation of the isomers by flash chromatography, (E) -2- (3-bromophenyl) -1- (5-methyl-2-pyridinyl) -1- [4- (methylsulfonyl) phenyl] ethylene was obtained.

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

The title boronate B3 was prepared as described in step 3 for the preparation of boronate B1 except for substituting (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [ 4- (methylsulfonyl) phenyl] ethylene (E) -2- (3-bromophenyl) -1- (5-methyl-2-pyridinyl) -1- [4- (methylsulfonyl) phenyl] ethylene from the previous step 1 as starting material.

Boronate B4 Pinacol-3 - {(E) -2- (5- (1-hydroxy-1-methylethyl) -2-pyridinyl) -2- [4- (methylsulfonyl) phenyljetenyl} phenylboronate

Boronate B4 was prepared as follows.

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

The title boronate was prepared as described in step 1 for the preparation of boronate B1, except for the replacement of ketone K2 with ketone K11 as the starting material. After separation of the isomers by flash chromatography, (E) -2- (3-bromophenyl) -1- [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] -1- [4- (methylsulfonyl) phenyl] ethene was obtained .

Step 2: Pinacol-3 - ((E) -2- (5- (1-hydroxy-1-methylethyl) -2-pyridinyl) -2- [4- (methylsulfonyl) phenyljetenyl] phenylboronate

The title boronate B4 was prepared as described in step 3 for the preparation of boronate B1, except for the substitution of (E) -2- (3-bromophenyl) 1- (1-methyl-7 H -imidazol-2-yl) bromide ) -1- [4- (methylsulfonyl) phenyl] ethene (E) -2- (3-bromophenyl) -1- [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] -1- [4- ( methylsulfonyl) phenyl] ethene from the previous step 1 as a starting material.

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

Scheme 3

Synthesis of oxadiazole p-MsOPhOH + Cl 2 CN - p-MeOPhO 2 CN Otília)

RCN

(XVI) (XIII)

R Oxadiazole (XVI) Me 0X1 p-MeOPhOCH ₂ 0x2

According to Scheme 3 above, the nitrile intermediate XIIa can be prepared by alkylating 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

Treating the 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 activation of arylacetic acid XV with carbonyldiimidazole in a solvent medium such as DMF followed by addition of amide oxime XIV and heating of the reaction mixture.

Scheme 4

Synthesis of aryl bromide

(XVIIIc) (AB5)

R R ² Arylbromide (XVIIIb) H / Pr AB2 H H AB3 H t-Bu AB4

In Scheme 4 above, condensation of aldehyde XVII by heating with arylacetic acid XV in the presence of a base such as piperidine in a solvent such as toluene produces an unsaturated acid XVIIIa. After 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, the amine is added to the reaction mixture to form the amide XVIIIb. Said oxadiazole-ethene XVIIIc may be formed by heating

-530X1 with XVII in the presence of a base such as piperidine in a solvent such as toluene.

Scheme 4 - Supplement

Synthesis of aryl bromide

in

(XVIIlf) (AB6)

In Scheme 4, supra, acid XVIIIa is treated with a diazomethane in a solvent such as THF to give the methyl ester XVIIId. Reduction of ester XVIIId using DIBAL-H in a solvent such as THF affords allyl alcohol XVIIIe. Conversion of an alcohol group in XVIIIe to a displaceable group such as mesilate using reagents such as methanesulfonyl chloride and triethylamine in a solvent such as THF followed by nucleophile replacement such as dimethylamine in a solvent environment such as DMF affords compound XVIIIf.

Arylbromid AB1

(E) -3- (3-Bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid

Aryl bromide AB1 was prepared as follows. 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). The reaction mixture was heated to reflux overnight, then cooled to room temperature

-54miestnosti. Toluene (10 mL) was added to the suspension. Filtration gave (E) -3- (3-bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid as a white solid.

Aryl bromide B2 (E) - N -isopropyl-3- (3-bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenamide

Aryl bromide B2 was prepared as follows. To a solution of aryl bromide AB1 (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 room temperature for half an hour, isopropylamine (28 mL, 327 mmol) was added. The mixture was stirred for another two hours at room temperature, then cooled to 0 ° C and neutralized with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic extracts were washed (water and then brine), dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography (hexane / EtOAc 1: 1 to neat EtOAc) gave (E) - N -isopropyl-3- (3-bromophenyl) -2- [4 (methylsulfonyl) phenyl] -2-propenamide.

Aryl bromide AB3 (E) -3- (3-Bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenamide

The arylbromide AB3 was prepared as described for the preparation of AB2, except for the replacement of isopropylamine with ammonium hydroxide as the starting material.

Arylbromide AB4 (E) -N- (tert-Butyl) -3- (3-bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenamide

Arylbromide AB4 was prepared as described for the preparation of AB2, except for the replacement of isopropylamine with tert-butylamine as the starting material.

-55Arylbromide AB5 (E) -1- (3-Bromophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethene

Arylbromide AB5 was prepared as follows.

Step 1 (Scheme 3, Oxadiazole OX1): (3-Methyl-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) was added carbonyldiimidazole (12.5 g, 77 mmol). After half an hour at room temperature, acetamidoxime (5.7 g, 77 mmol) was added. The reaction mixture was stirred overnight at room temperature, then heated at 120 ° C for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic extracts were washed (water and then brine), dried (MgSO ₄ ), filtered and concentrated. Purification of the residue by flash chromatography (hexane / EtOAc 1: 1) afforded (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 from previous step 1 (OX1) (3.0 g, 11.9 mmol) and piperidine (0.4 mL). ). The reaction mixture was heated to reflux overnight and then cooled to room temperature. MeOH (30 mL) was added to the resulting suspension. After further refluxing, the reaction mixture was cooled to 0 ° C and filtered to give (E) -1- (3-bromophenyl) -2- (3-methyl-1,2,4-oxadiazole-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 below.

Scheme 5

Preparation of bromoquinolines

(XXc)

According to Scheme 5 above and the Scheme 5 table 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 compound XXa. Compound XXb can be prepared by treating XXa with a base such as potassium tert -butoxide (1.1 equivalents) in a solvent such as THF and then adding this mixture to a solution of methyl iodide in a solvent such as THF. Compound XXc can be prepared by treating XXb with a base such as potassium tert -butoxide (1.1 equivalents) in a solvent such as THF and then adding this mixture to a solution of methyl iodide in a solvent such as THF. Said compound XXc (where R ¹ = CN) can also be prepared by treating compound XXa with a base such as potassium tert-butoxide (2.2 equivalents) in a solvent such as THF and methyl iodide in a solvent such as THF. Said compound XXc (where R ¹ = SO ₂ Me) can also be prepared by treating XXa with a base such as potassium tert -butoxide (1.3 equivalents) and methyl iodide (1.6 equivalents) in a solvent such as THF and then adding an additional amount methyl iodide (1.6 equivalents) and another amount of the same base (1.0 equivalents).

Figure 5 - Table

bromoquinoline

R ¹ 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 as follows. To a mixture of 6-bromomethyl-8-bromoquinoline (60 g, 200 mmol) (described in WO 94/22852) and sodium methanesulfinate (27.6 g, 270 mmol) was added DMF (500 mL). The reaction mixture was stirred at room temperature overnight, then diluted with water (2000 mL), stirred for an hour and filtered and washed with Et ₂ O to give 6- (methylsulfonyl) methyl-8-bromoquinoline.

Bromoquinoline Q2

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

Bromoquinoline Q2 was prepared as follows. To a solution of bromoquinoline Q1 (16.1 g, 54 mmol) in THF (500 mL) at -78 ° C was added potassium tert-butoxide (59 mL, 1 M solution in THF). After half an hour at -78 ° C, the reaction mixture was stirred at 0 ° C for 45 minutes and then transferred dropwise to a solution of methyl iodide (16.7 mL, 268.3 mmol) in THF (160 mL). The mixture was stirred overnight at room temperature, then neutralized with saturated ammonium chloride solution and extracted with EtOAc. The organic extracts were washed (water and then brine),

-58sušili _(MgSO4), filtered and concentrated. Stirring in ether followed by isolation by filtration gave 6- [1- (methylsulfonyl) ethyl] -8-bromoquinoline.

Bromoquinoline Q3

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

The bromoquinoline Q3 was prepared as follows. To a solution of bromoquinoline Q2 (15.7 g, 50 mmol) in THF (500 mL) at -78 ° C was added potassium tert-butoxide (55 mL, 1 M solution in THF). After stirring at -78 ° C for half an hour, the mixture was stirred at 0 ° C for 45 minutes and then added dropwise to a solution of methyl iodide (15.6 mL, 250 mmol) in THF (40 mL). The reaction mixture was stirred overnight at room temperature, then neutralized with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic extracts were washed (water and then brine), dried (MgSO ₄ ), filtered and concentrated. Stirring the residue in ether followed by isolation by filtration gave 6- [1-methyl-1- (methylsulfonyl) ethyl] -8-bromoquinoline.

Bromoquinoline Q4

6-cyanomethyl-8-bromoquinoline

The bromoquinoline Q4 was prepared as follows. To a mixture of 6-bromomethyl-8-bromoquinoline (3 g, 10 mmol) (described in WO 94/22852) and potassium cyanide (1.6 g, 25 mmol) was added DMF (10 mL) and H ₂ O (5 mL). ). After heating at 100 ° C for 1 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc. The organic extracts were washed (water and then brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (hexane: EtOAc 3: 1) gave 6-cyanomethyl-8-bromoquinoline.

Bromoquinoline Q5

6- [1-Methyl-1-cyanomethyl] -8-bromoquinoline

-59Bromoquinoline Q5 was prepared as follows. To a solution of bromoquinoline Q4 (3 g, 12.1 mmol) in THF (100 mL) at -78 ° C was added methyl iodide (1.7 mL, 27 mmol) followed by potassium tert-butoxide (27 mL, 1 M solution, 27 mmol). After 2 hours at -78 ° C, the mixture was warmed to 0 ° C and neutralized with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic extracts were washed (water and then brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (hexane: EtOAc 3: 1) afforded 6- [1-methyl-1-cyanomethyl] -8-bromoquinoline.

The benzylphosphorous reagents used to prepare the compounds of this invention can be prepared according to Scheme 6 below.

Scheme 6

Preparation of benzylphosphorus reagents

(XXII) λλλιιι ^ α = βγ | / (ΧΧίνχχ = OSO ₂ Me)

(XXV)

R R Benzylphosphite reagent (XXV H CH ₂ P (Ph) ₃ ⁺ Br · P1 H CH ₂ P (O) 2 (OEt) ₂ P2 CN CH ₂ P (O) 2 (OEt) ₂ P3

The aryl quinolines of formula XXII can be prepared by reacting bromoquinoline XX with boronic acid XXI by heating in the presence of a catalyst such as Pd (PPh ₃ ) ₄ and a base such as sodium carbonate (aqueous solution) in a solvent such as DME. The alcohol XXII can be converted to bromide XXIII by treatment with HBr (aq) in a solvent such as acetic acid. The alcohol XXII can be converted to the methylsulfonate ester XXIV by methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane. Benzyl phosphorous reagents XXV can be prepared or by heating XXIII in the presence of PPh ₃ in a solvent such as acetonitrile or by reaction between XXIII or XXIV with diethyl phosphite and a base such as potassium tert-butoxide in a solvent such as THF.

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

Benzylphosphonium bromide P1 was prepared as follows.

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

A mixture of 6-isopropyl-8-bromoquinoline (11.1 g, 44.4 mmol) (described in WO 94/22852), 3- (hydroxymethyl) phenylboronic acid (8.70 g, 57.2 mmol), Na ₂ CO ₃ (2 M solution, 71 mL, 142 mmol) and Pd (PPh ₃ ) ₄ (2.51 mg, 2.17 mmol) in 280 mL DME were stirred at 80 ° C for 5 h. The mixture was then cooled to room temperature, diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography (hexane: 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.

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

A suspension of the hydroxymethyl product of the compound from the previous reaction step 1 (7.40 g, 26.7 mmol) in AcOH (50 mL) and HBr (50 mL, 48% aqueous solution) was stirred at 100 ° C for 12 h. The mixture was then cooled to room temperature, poured into a solution of NaOH (2 M solution) with ice, the pH was adjusted to 8 and the mixture was diluted with ether. The organic phase was washed with brine,

-61 dried over anhydrous magnesium sulfate, 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 from previous reaction 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 at 60 ° C for 12 hours, then cooled to room temperature, diluted with ether, filtered and washed with ether to give [3- (6-isopropyl-8-quinolinyl) benzyl] (triphenyl) phosphonium bromide.

Benzylphosphonate P2

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

The benzylphosphonate P2 was prepared as follows. The bromomethyl compound from Step 2 of the synthesis of the above P1 (11.34 g, 1 equivalent) was dissolved in THF (170 mL). Diethyl phosphite (3.87 mL, 1.05 equivalent) was added and the solution was cooled to 0 ° C. Potassium tert-butoxide (3.87 mL, 1 M solution in THF) was then added slowly. The reaction mixture was stirred for 2 hours and then diluted with saturated aqueous ammonium chloride solution, water, and EtOAc. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by flash chromatography on silica gel (hexane: EtOAc, 1/9) gave diethyl 3- (6-isopropyl-8-quinolinyl) benzylphosphonate as a light oily substance.

Benzylphosphonate P3 Diethyl 3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] benzylphosphonate

Benzylphosphonate P3 was prepared as follows.

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

Step 1 of the preparation of the benzylphosphonium bromide compound P1 was followed as described above, with the exception of the replacement of 6-isopropyl-8-bromoquinoline with bromo-62quinoline Q5 as the starting material; 6- (1-cyano-1-methylethyl) -8 [3- (hydroxymethyl) phenyl] quinoline was obtained.

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

To a solution of 6- (1-cyano-1-methylethyl) -8- [3- (hydroxymethyl) phenyl] quinoline alcohol from previous reaction 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 half an hour at -78 ° C, the mixture was neutralized with saturated ammonium chloride solution, diluted with water and extracted with ether. The organic extracts were washed (water and then brine), dried (MgSO 4), filtered and concentrated to give 3- (6- (1-cyano-1-methylethyl) -8-quinolinyl] benzyl methanesulfonate as a white foam.

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

To a solution of diethyl phosphite (2.5 mL, 18 mmol) in THF (100 mL) at -78 ° C was added potassium tert-butoxide (1 M solution, 16 mL, 16 mmol) and the mesylate compound 3- (6- (1)). (cyano-1-methylethyl) -8-quinolinyl] benzyl methanesulfonate from previous reaction step 1 (5.1 g, 13.5 mmol) After half an hour at -78 ° C and 12 hours at room temperature, the resulting mixture was neutralized with a chloride solution The organic extracts were washed (water and then brine), dried (MgSO4), filtered and concentrated to purify the residue by flash chromatography (hexane: EtOAc 1: 4 to 1:10) to give diethyl-3. - [6- (1-Cyano-1-methylethyl) -8-quinolinyl] benzylphosphonate as an oil.

Scheme 7

Binding of benzylphosphorous reagent and ketone

benzylphosphorous reagent (XXV)

Example (I)

Compounds of formula I can be prepared by the reaction route shown in Scheme 7. Compound XXVI can be obtained by adding a solution of ketone VII in a solvent such as THF to a mixture of benzylphosphorous reagent XXV and a base such as potassium tert-butoxide in a solvent such as THF. The compounds of formula I can then be prepared by treating compound XXVI with oxone in a solvent mixture such as THF / MeOH / water. Alternatively, compounds of Formula I may be prepared by reacting ketone VIII with XXV in the presence of a base such as potassium tert-butoxide in a solvent environment such as THF.

For each Example, the following Table 1 shows the reactions of different ketones with various benzylphosphorous reagents according to Scheme 7 above.

Table 1

Benzylphosphite reagent ketone Example P2 K3 1 P2 K3 2 P1 K5 3 P1 K2 4 P2 K1 5 P2 K1 6

P2 K6 7 P3 K6 8 P3 K2 9 P2 commercial 30 P2 K7 31 P2 K7 32 P2 K8 33 P2 K8 34 P2 K9 35 P3 K8 36 P3 K8 37 P3 K9 38 P3 K10 39

Scheme 8

Binding of aryl bromide and bromoquinoline

H ₃ C ch ₃ AA br ° 'B' ° ^ ιΊ (11L Cj R ¹ jfj R ¹ MeO ₂ S ^ ^OT ^ MeO ₂ S ^^ aryl bromide boronate (XVIII) (used in situ)

Compounds corresponding to Formula I can be prepared according to Scheme 8 by converting in situ aryl bromide XVIII to the corresponding boronate ester by heating the diboronepinacol ester with a catalyst such as [1,1'-bis (diphenyl-65phosphino) ferrocene] dichloropalladium and a base such as potassium acetate in a solvent such as DMF followed by addition of bromoquinoline XX, an additional amount of the same catalyst, an additional amount of a base such as sodium carbonate (aqueous solution) and further heating.

According to Scheme 8 above, the following Table 2 and the Appendix to Table 2 refer to the individual Examples of the binding of aryl bromide to bromoquinoline.

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 AB3 Q5 23 AB4 Q5 24 AB1 WO94 / 22852 25 AB5 WO94 / 22852 26

Appendix to Table 2

aryl bromide bromoquinoline  Example AB6 Q5 43

Compounds of the invention can be prepared by the procedure of Scheme 9 below.

-66Scheme 9

(XXXVil) (Example 19)

Example (I)

OR ² R ² = p-MeOPh (Example 18)

NR * R ³ C Example 27 NH <] Example 28 CH ₃ ^ΝΗ γΌΗ ₃ ch ₃ Example 29

Scheme 9 illustrates a process for preparing compounds of Formula I, wherein said aldehyde XXVII can be prepared by heating bromoquinoline XX, 3formylbenzeneboronic acid, a catalyst such as Pd (PPh ₃ ) ₄ and a base such as sodium carbonate (aqueous solution) in a solvent such as DME. Said aldehyde XXVII can be converted to the compound of Example 18 by heating with XVI in the presence of a base such as piperidine in a solvent such as toluene. The product of Example 19 can be obtained by treating the product of Example 18 with ammonium nitrate (CAN) in a mixture

-67 solvents such as acetonitrile / water. Alternatively, the aldehyde XXVII can be converted to the unsaturated acid XXVIII by heating with XV and a base such as piperidine in a solvent such as toluene. XXVIII can then be converted to amide I (Examples 27, 28 and 29) by treatment with a coupling system such as ERDCI, HOBt, and an amine in a solvent environment such as DMF.

The compounds of this invention can be prepared by coupling the bromoquinoline to the boronate compound of Scheme 10 below.

Scheme 10

Binding of bromoquinoline with boronate

Bromoquinoline (XX)

(XII)

Scheme 10 illustrates 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 , PPh _3, and a base such as sodium carbonate (aqueous solution) in a solvent such as n-propanol. Table 3 shows Examples of Binding of Bromoquinoline with Boronate.

Table 3

bromoquinoline boronate Example Q2 B2 10 Q3 B2 11

Q2 B1 12 Q3 B1 13 Q3 B3 40 Q3 B3 41 Q3 B4 42

Overview of the figures in the drawing

Fig. 1 is a chemical schematic representation of the general structure of the compounds of this invention.

Fig. 2 depicts the intensities (in pulses) as a function of the aunt angle (in degrees) in diffraction by X-ray diffraction pattern of the benzenesulfonic acid salt polymorph A and 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.

Fig. 3 shows the intensities (in pulses) as a function of the aunt angle (in degrees) in diffraction by X-ray diffraction pattern of the polymorph B of the benzenesulfonic acid salt and 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.

Fig. 4 shows a comparison of X-ray diffraction patterns of polymorph A (lower curve) and polymorph B (upper curve) of benzenesulfonic acid salts with 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.

Fig. 5 shows different peaks in the X-ray diffraction pattern of polymorph A from polymorph B of the benzenesulfonic 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] fenyljchinolínom.

Fig. 6 shows different peaks in the X-ray diffraction pattern of polymorph B from polymorph A of the benzenesulfonic 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] fenyljchinolínom.

Examples of Embodiments of the Invention

Examples 1 and 2

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

Examples 1 and 2 were carried out as follows XXXXX. To a mixture of benzyl phosphonate P2 (330 mg, 0.83 mmol) and ketone K3 (200 mg, 0.77 mmol) in THF (6 mL) was added potassium tert-butoxide (1 M solution, THF, 0.83) at room temperature. ml, 0.83 mmol). After an hour at room temperature, the mixture was diluted with water and extracted with diethyl ether. The organic extracts were washed (water, then brine), dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification

Flash chromatography (hexane: EtOAc 7/3) gave the products of Examples 1 and 2 as a white foam, one product being less polar than the other. In Example 1 the less polar Z-isomer and in Example 2 the product obtained were the more polar E-isomer.

Example 1, ¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.79 (q, 1H), 8.28 (q, 1H), 7.94 (d, 2H), 7.73 (d, 1H), 7.6-7.1 (m, 14H), 3.14 (m, 1H), 2.97 (s, 3H), 1.34 (d, 6H).

Example 2, ¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.78 (q, 1H), 8.25 (q, 1H), 7.89 (d, 2H), 7.71 (d, 1H), 7.6 (m, 3H), 7.45 (m, 3H), 7.39-7.2 (m, 8H), 3.11 (m, 4H), 1.34 (d, 6H) ).

Example 3

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

Example 3 was carried out as follows. To a suspension of benzylphosphonium bromide P1 (320 mg, 0.531 mmol) in 2.5 mL THF at -78 ° C was added dropwise potassium tert-butoxide (1 M solution in THF, 0.55 mL, 0.55 mmol) and the resulting red the solution was stirred at 0 ° C for 30 minutes. To this ylide was added dropwise ketone K5 (155 mg, 0.455 mmol) in 2 mL THF at -78 ° C. The mixture was then warmed to room temperature, stirred for one hour, diluted with a saturated aqueous solution of NH ₄ Cl, followed by ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography of the residue (silica, eluting with hexane: EtOAc 10-100% over 20 min) gave the product of Example 3 (1.5: 1 isomer mixture).

-71 ¹ H NMR (500 MHz, in acetone-d ₆ ): 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, 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).

Example 4

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

Example 4 was carried out as follows.

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

The procedure was as described in Example 3 except for the replacement of ketone K5 with ketone K2 as the starting material to give 6-isopropyl-8- (3 - {(E) -2- (1-methyl-1 H -imidazol-2-yl)) 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

Follow the procedure outlined in Step 2 of Scheme 2 to prepare boronate B1 except for substituting (E / Z) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [4- (methylthio) phenyl] ethene sulfide obtained in step 1 of this Example as starting material. The product of Example 4 was obtained.

-72 ¹ H NMR (500 MHz, Acetone-d _6): 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, 1H), 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 - {(Z / E) -2- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Example 6

Examples 5 and 6 were carried out as follows. The procedure was as in Example 1 except for replacing ketone K3 with ketone K1 as the starting material and the products were purified by flash chromatography (50% EtOAc / 50% hexane) to give the title products.

Example 5, major isomer (Z), ¹ H NMR (500 MHz, in acetone-de): δ 8.78 (dd, 1H), 8.25 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.55-7.40 (m, 6H), 7.35 (m, 2H), 7.25 (t, 1H), 7.23 (s, 1H), 7 11 (t, 2H), 7.05 (d, 1H), 3.12 (m, 1H), 2.96 (s, 3H), 1.34 (d, 6H). Example 6, major isomer (E), ¹ H NMR (500 MHz, in acetone-d ₆ ): δ 8.78 (dd, 1H), 8.35 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.65 - 7.55 (m, 3H), 7.45 (dd, 1H), 7.35 - 7.15 (m, 9H), 3.12 ( m, 4H), 1.34 (d, 6H).

Example 7

2- (2 - {(E7Z) -2- [3- (6-isopropyl-8-quinolinyl) phenyl] -1- [4- (methylsulfonyl) phenyl] ethenyl} -1,3-thiazol-5-yl) -2 propanol

In Example 8, the method of Example 1 was used except for the replacement of ketone K3 with ketone K6 as the starting material. Purification of the product by flash chromatography (100% EtOAc) afforded the product of Example 7 as a mixture of isomers.

¹ H NMR (400 MHz, in acetone-d ₆ ): δ 8.80 (m, 1H), 8.30 (m, 1H), 8.05 (d (major), 1.44H), 7, 93 (d (minor), 0.55H), 7.85 (s (major), 0.72), 7.77 (s (minor), 0.28H), 7.75-7.45 (m, 7H) ), 7.35 (t (minor), 0.28H), 7.28 (t (major), 0.72H),

-747.21 (d (minor), 0.28H), 7.10 (d (major), 0.72H), 4.7 (m, 1H), 3.15 (m, 1H),

3.15 (s (minor), 0.54H), 2.99 (s (major), 2.16H), 1.60 (m, 6H), 1.35 (m, 6H). MS (M + 1): 569.6.

Example 8

2- [8- (3 - {(EHR) -2- [5- (1-hydroxy-1-methylethyl) -1,3-thiazin-2-yl] -2- [4- (methylsulfonyl) phenyl] ethenyl } phenyl) -6-quinolinyl] -2-methylpropanenitrile

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

¹ H NMR (400 MHz, in acetone-d ₆ ): 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 (t (minor), 0.43H), 7.28 ( t (major), 0.57H), 7.21 (d (minor), 0.43H), 7.10 (d (major), 0.57H), 4.67 (s (major), 0.57H), 4.63 (s (minor), 0.43H), 3.15 (s (minor), 1.3H), 2.99 (s (major), 1.7H), 1.90 (m, 6H), 1.65 (s (major), 3.4H), 1.45 (s (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] -2-methylpropanenitrile

The following method was used in Example 8.

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

The title compound was prepared as described in Example 1, with the exception of replacing ketone K3 with ketone K2 and benzylphosphonate P2 with benzylphosphonate 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] -2-methylpropanenitrile

The title compound in this Example 9 was prepared by the method used to prepare boronate 1 (step 2 of Scheme 2), except for substituting (E / Z) -2- (3-bromophenyl) -1- (1-methyl-1 H -imidazole). 2-yl) -1- [4- (methylthio) phenyl] ethene sulfide prepared in step 1 of this example as starting material. Purification of the residue by flash chromatography (97% EtOAc / 3% Et ₃ N) gave the title product of Example 9.

¹ H NMR (400 MHz, in acetone-d ₆ ): 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 76

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

H

The following method was used in Example 10. A mixture of bromoquinoline Q (105 mg, 0.33 mmol), boronate B (236 mg, 0.51 mmol), sodium carbonate solution (2 M solution, 0.65 mL, 1.0 mmol), Pd (OAc) ₂ (6 (3 mg, 0.028 mmol) and PPh ₃ (28 mg, 0.11 mmol) in 4 mL of n-propanol were stirred at 90 ° C for two hours. The mixture was then cooled to room temperature, diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Tokacetone 4: 1) and stirring in hexane / EtOAc to give the title product of Example 10 (single isomer) as a white solid.

¹ H NMR (400 MHz, in acetone-d ₆ ): 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 (m, 3H), 7.62-7.60 (m, 2H), 7.55 (dd) 1 H, 7.45 (s, 1 H), 7.34 (t, 1 H), 7.18 (d, 1 H), 4.67, q, 1 H, 3.04 (s, 3 H), 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- (1,3-thiazol-2-yl) ethenyl] phenyl } quinoline

In Example 11, the method described in Example 10 was used except for the replacement of bromoquinoline Q2 with bromoquinoline Q3 and using boronate B2. Flash chromatography (Tokacetone 9/1) and stirring in EtOAc / hexane gave the title product of Example 11 (single isomer) as a white solid.

¹ H NMR (400 MHz, in acetone-d ₆ ): δ 8.90 (dd, 1H), 8.41 (dd, 1H), 8.23 (s, 1H), 8.02

7.99 (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) ) etyljchinolín

In Example 12, the method described in Example 10 was used using bromoquinoline Q2 but excluding the replacement of boronate B2 with boronate B1. Flash chromatography (95% CH ₂ Cl ₂ /5% EtOAc) gave the title compound of Example 12.

¹ H NMR (400 MHz, in acetone-d ₆ ): δ 8.92 (d, 1H), 8.45 (dd, 1H), 8.10 (s, 1H), 7.93 (d, 2H) 7.76-7.65 (m, 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

In Example 13, the method described in Example 10 was used except for the replacement of the bromoquinoline Q2 with the bromoquinoline Q3 and the replacement of the boronate B2 with boronate B1. Flash chromatography (95% EtOAc / 5% Et ₃ N) gave the title compound as a single isomer as a foam.

¹ H NMR (400 MHz, in acetone-d ₆ ): 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 (dd); 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): 596.2.

-79Examples 14 and 15

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

Examples 14 and 15 were carried out as follows. A solution of aryl bromide AB5 (249 mg, 0.57 mmol), diborone pinacol ester (167 mg, 0.66 mmol), [1,1bis (diphenylphosphino) -ferocene] palladium dichloride (12 mg, 0.015 mmol) and potassium acetate (176 mg, 1.8 mmol) in DMF (N, N -dimethylformamide) (10 mL) was degassed and stirred at 80 ° C for 3 h. To this mixture was then added bromoquinoline Q3 (150 mg, 0.46 mmol), [1,1'-bis (diphenylphosphino) -ferocene] palladium dichloride (12 mg, 0.015 mmol) and sodium carbonate (0.6 mL) at 25 ° C. ml, 2 M solution). After degassing, the mixture was overnight

-80 heated to 80 ° C. The mixture was then cooled to room temperature, diluted with water and extracted with EtOAc. The organic extracts were washed (water and then brine), dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography (hexane: EtOAc: Et 3 N 22:68:10 and then hexane: EtOAc 3: 1) gave both isomers (Example 14 and Example 15).

Predominant isomer (E), (Example 14), ¹ H NMR (500 MHz, in acetone-de): δ 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 (m, 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

Minority Isomer (Z), (Example 15), ¹ H NMR (500 MHz, in acetone-d ₆ ): δ 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 (m, 3H), 7.62 (s, 1H), 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.

Example 14 may alternatively be performed as follows:

br

To methanesulfonic acid (8-10 equivalents) was added sodium mnitrobenzenesulfonate (0.6-0.8 equivalents) at 20 ° C, followed by iron sulfate heptahydrate (0.01-0.05 equivalents). 2-Bromo-4-methylaniline (1 equivalent) was then added to the mixture. Glycerol (2-3 equivalents) was then added and the solution heated to 120-140 ° C until completion of the reaction. The mixture was then cooled to 70-90 ° C and diluted with water. The solution was cooled to about 20 ° C, neutralized with aqueous NaOH and sodium bicarbonate. MTBE (methyl tert-butyl ether) was added, the mixture was filtered and the phases were allowed to separate (the product was in the MTBE layer).

br

br

The solvent in the MTBE solution from reaction step 1 was replaced with chlorobenzene. The solution was filtered through a silica gel and partially concentrated; N-bromosuccinimide (NBS, 0.6 to 0.8 equivalents) and 2,2'-azobisisobutylnitrile (AIBN, 0.01 to 0.1 equivalents) were added. The degassed mixture was heated to 55-85 ° C. The resulting mixture was diluted with cyclohexane. Additional NBS (0.3 to 0.5 equivalents) and AIBN (0.01 to 0.05 equivalents) were added. The degassed mixture was again heated to about 55 to 85 ° C until completion of the reaction. The mixture was then cooled to 10-40 ° C, diluted with cyclohexane and a solid precipitated. The solid was collected by filtration.

Step 3: Sulfone formation

To a solution of bromomethyl-bromoquinoline (product from previous step 1) (1 equivalent) in DMF at 10-60 ° C was added triturated sodium methanesulfinate (1.0-

1.5 equivalents). The mixture was heated at 50-70 ° C for 30 minutes. The mixture was then diluted with water while maintaining the temperature between 50 and 70 ° C and stirred vigorously, cooled to about 10 to 20 ° C and aged. It was then filtered and the solid was washed successively with DMF / water (1: 4), then water and dried.

Step 4: Methylation

A solution of the sulfone (product from the previous step) (1 equivalent) in DMF was cooled to about -10 ° C. Sodium tert-butoxide was added. Then slowly added

A solution of methyl iodide in DMF (about 1 equivalent of Mel) and the temperature was maintained between about -10 and 0 ° C. A second portion of solid sodium tert-butoxide was then added, maintaining the temperature between -5 and 10 ° C. (Additional portion of base and Mel can be added if reaction is not complete). The reaction mixture was then diluted with water and crystallized to give the product which was isolated and dried.

Example 5: Suzuki coupling

Pd / C

K ₂ CO ₃ ZDMF

SO C

To the sulfone solution from the previous reaction step (1 equivalent) was added Pd / C (5 or 10 wt%, 0.05 to 0.1 equivalent), potassium carbonate (2-3 equivalents) and 3-formylphenylboronic acid (1-2). eq). The degassed mixture was heated to 60-120 ° C until completion of the reaction. The mixture was then filtered, and the filtrate was diluted with water. The product was crystallized, isolated by filtration and dried.

Step 6: Oxadiazole

To a mixture of hydroxybenzotriazole hydrate (HOBt) (1 to 1.5 equivalents), 4-methylsulfonylphenylacetic acid (1 equivalent) in acetonitrile was added EDC hydrochloride (1 to 1.5 equivalents). The suspension was allowed to react for 30 minutes at 20-30 ° C. Other N-OH compounds can also be used in place of HOBt, for example, N-hydroxyphthalimide, 2-hydroxypyridine N -oxide, N-hydroxysuccinimide. Other carbodiimides, such as dicyclohexylcarbodiimide and diisopropylcarbodiimide, may also be used in place of EDC (ethyl dimethylaminopropylcarbodimide) hydrochloride. Acetamidoxime (1 to 1.5 equivalents) was added to the suspension. The mixture was then heated to reflux until the reaction was complete. The resulting solution was concentrated and diluted with ethyl acetate. The mixture was then washed with an aqueous sodium bicarbonate solution. Then the solvent was exchanged for 2-propanol and the product crystallized upon cooling; isolated and dried.

Step 7: Condensation to give Example 14

To a suspension of the aldehyde from reaction step 5 (1 equivalent) in 2-propanol was added oxadiazole from reaction step 6 (1 to 1.5 equivalents) followed by piperidine (0.2 to 1.5 equivalents). Other solvents such as DMF, acetonitrile, 1-propanol, toluene, esters and other alcohols may also be used in place of 2-propanol. Piperidine serves as a basic initiator. Other amine bases, in particular secondary amines, may be used in place of piperidine. The resulting mixture was heated to reflux with molecular sieve until the reaction was complete. After cooling, the product was isolated by filtration and dried.

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

Examples 16 and 17 were carried out as described in Examples 14 and 15 above, with the exception of substituting aryl bromide AB5 with aryl bromide AB2 and bromoquinoline Q3 for bromoquinoline Q5 as starting materials. The products of Examples 16 and 17 were obtained as a 4: 1 mixture.

Predominant isomer (E), (Example 16), ¹ H NMR (500 MHz, in acetone-d ₆ ): δ 8.89 (dd,

1H), 8.43 (dd, 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 (m, 1H), 2.92 (s, 3H), 1, 87 (s,

6H), 1.12 (d, 6H).

MS (M + 1): 538.3

-86 Minorite Isomer (Z), (Example 17), ¹ H NMR (500 MHz, in acetone-de): δ 8.93 (dd, 1H), 8.48 (dd, 1H), 8.14 (d, 1H), 7.94 (m, 4H), 7.70 (dd, 2H), 7.59 (q, 1H), 7.50 (m, 2H), 7.28 (s, 1H), 4, 15 (m, 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 carried out as follows.

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

A mixture of 4-methoxyphenol (10 g, 80 mmol), chloroacetonitrile (7.0 mL, 111 mmol) and potassium carbonate (26 g, 188 mmol) in acetone (150 mL) was stirred at room temperature for 18 hours. The mixture was then filtered, concentrated and purified by flash chromatography (hexane: EtOAc 4: 1) to give (4-methoxyphenoxy) acetonitrile as a light oil.

Step 2 (Scheme 3): (4-Methoxyphenoxy) acetamidoxime

-87Mixes of (4-methoxyphenoxy) acetonitrile product (5.0 g 31 mmol) from reaction step 1, hydroxylamine hydrochloride (4.3 g, 62 mmol) and sodium acetate (5.1 g, 62 mmol) in MeOH (100 mL) ) was stirred at room temperature for two hours. The resulting mixture was filtered through Celite®, concentrated, stirred in CHCl ₃ for 18 hours, and filtered. The resulting solution was concentrated to give (4-methoxyphenoxy) acetamidoxime as a gum.

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

3 - [(4-Methoxyphenoxy) methyl] -5- [4- (methoxysulfonyl) benzyl] -1,2,4-oxadiazole was prepared as described in Scheme 3 for AB5 Step 1 (0x1) except for acetamidoxime replacement. (4-methoxyferioxy) acetamidoxime from step 2 of this Example and heating the reaction mixture at 90 ° C for 6 hours. Purification by flash chromatography (hexane: EtOAc 3: 2 to 1: 4) gave the title compound as a light brown solid.

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

To a mixture of bromoquinoline Q3 (10.1 g, 30.9 mmol), 3-formylbenzeneboronic acid (5.8 g, 38.7 mmol), tetrakis (triphenylphosphine) palladium (2.1 g, 1.86 mmol) and carbonate Sodium (39 mL, 2 M solution) was added DME (330 mL). After removal of the gases, the mixture was heated at 80 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were combined and washed (water and then brine), dried (MgSO4), filtered and concentrated. The residue was triturated in ether and isolated by filtration to give 3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -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- [1-methyl-1- (methylsulfonyl) etyljchinolín

A mixture of the product of step 4 of this Example (150 mg, 0.42 mmol), oxadiazole OX2 of step 3 of this Example (175 mg, 0.47 mmol) and piperidine (0.1 mL, 1.0 mmol) in toluene (0). (6 mL) was heated at 120 ° C for 1 h. The mixture was then purified rapidly

Flash chromatography (hexane: EtOAc 3: 2 to 1: 4) afforded the title product as a foam.

¹ H NMR (400 MHz, in acetone-d ₆ ): 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-1- (methylsulfonyl) ethyl] -8-quinolinyl) phenyl) -1- [4- (methylsulfonyl)] phenyl] ethenyl} -1,2,4-oxadiazol-3-yl) -methanol

The compound of Example 19 was prepared as follows. To a solution of the compound of Example 18 (250 mg, 0.35 mmol) in a mixture of acetonitrile and water (4: 1, 8 mL) was added CAN (330 mg, 0.62 mmol) at room temperature in two portions. After three hours at room temperature, the mixture was diluted with saturated aqueous sodium bicarbonate solution, diluted with water and extracted with EtOAc. The combined organic extracts were washed (water and then brine), dried (MgSO ₄ ), filtered and concentrated. Purification of the residue by flash chromatography (hexane: 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-3-yl) methanol as a yellow foam.

¹ H NMR (400 MHz, in acetone-d ₆ ): δ 8.90 (q, 1H), 8.42 (q, 1H), 8.25 (d, 1H), 8.15 (s,

1H), 8.02 (m, 3H), 7.73-7.65 (m, 4H), 7.55 (q, 1H), 7.38 (t, 1H), 7.23 (d, 1H) ), 4.67 (m, 3H), 3.04 (s, 3H), 2.82 (s, 3H), 1.96 (s, 6H).

Example 20 (E) - N -isopropyl-3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methyl-

sulfonyl) phenyl] -2-propenamide h ₃ c 0 \ __ s- * CH3 T 3 o ₃ t) N á . H ₃ ^C y CH ₃ IN U 0 H ₃ cx

In Example 20, the procedure used in Examples 14 and 15 was followed except for the replacement of the aryl bromide AB5 with the aryl bromide AB2 and using the bromoquinoline Q3 as starting materials.

¹ H NMR (300 MHz, in acetone-d ₆ ): δ 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 (m, 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) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid

Example 21 was followed as described in Examples 14 and 15 above, with the exception of substituting aryl bromide AB5 with aryl bromide AB1 and using bromoquinoline Q3 instead of Q5 as starting materials.

¹ H NMR (500 MHz, in acetone-d ₆ ): 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-thiadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl) nitrile } phenyl) -6-quinolinyl] propanoic acid

In Example 22, the procedure used in Examples 14 and 15 was followed using the aryl bromide AB5 and substituting the bromoquinoline Q3 instead of Q5 as the starting material.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 8.9 (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) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenamide

In Example 23, the procedure used in Examples 14 and 15 was followed except for substituting aryl bromide AB5 with aryl bromide AB3 and using bromoquinoline Q5 instead of Q3 as starting materials.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08 (d, 1H), 7.93 (d, 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) -N- (tert-Butyl) -3- {3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenamide

Example 24 was followed as described in Examples 14 and 15 above, with the exception of substituting aryl bromide AB5 with aryl bromide AB4 and using bromoquinoline Q5 instead of Q3 as starting materials.

¹ H NMR (500 MHz, in acetone-d ₆ ): 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

In Example 25, the procedure used in Examples 14 and 15 was followed except for the replacement of aryl bromide AB5 with aryl bromide AB1 and using 5-isopropyl-8-bromoquinoline (described in WO 94/22852) instead of Q3 as starting materials.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 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 (d, 2H); 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

In Example 26, the procedure used in Examples 14 and 15 was followed using the aryl bromide AB5 and with the exception of the bromoquinoline Q3 substitution with 5-isopropyl-8-bromoquinoline (described in WO 94/22852) as starting material.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 8.80 (dd, 1H), 8.29 (dd, 1H), 8.12 (s, 1H), 8.03 (d, 2H) 7.76 (s, 1H); 7.73 (m, 3H); 7.59 (s, 1H); 7.53 (d, 1H); 7.47 (q, 1H); 7.36 (s) 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-β-ropen-1-one

Example 27 was carried out as follows.

Step 1: (R) -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 prepared in Step 4 of Example 18 (2.33 g, 6.60 mmol) of 4- (methylsulfonyl) phenylacetic acid (1.71 g, 7.98 mmol) and piperidine (0.20 mL, 1.98 mmol) in 10 mL toluene were heated at reflux for 2 days. The mixture was then cooled to room temperature, diluted with CH 2 Cl 2 purified by flash chromatography (CH ₂ Cl ₂ / EtOAc / AcOH 50/50/1) and finally stirred in Et ₂ O / CH ₂ Cl ₂ to isolate the title acid. (E) -3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -2-propene as a white solid substances.

¹ H NMR (400 MHz, in acetone-d ₆ ): 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 (m, 3H), 7.62-7.60 (m, 2H), 7.55 (dd) 1 H, 7.45 (s, 1 H), 7.34 (t, 1 H), 7.18 (d, 1 H), 4.67 (q, 1 H), 3.04 (s, 3 H), 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

(E) -3- (3- {6- [1-Methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid (104 mg) , 0.19 mmol) prepared in the previous step 1, pyrrolidine (24 μΙ, 0.29 mmol), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (55 mg, 0.29 mmol) and HOBt (1-hydroxybenzotriazole) (34 mg, 0.25 mmol) in 1 mL DMF was stirred at room temperature for 2 hours. The mixture was then diluted with EtOAc, washed with saturated ammonium chloride solution, water (3x), brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was slurried in EtOAc / hexane to give Example 27. The product was a white solid.

¹ H NMR (400 MHz, in acetone-d ₆ ): δ 8.88 (dd, 1H), 8.40 (dd, 1H), 8.40 (dd, 1H), 8.22 (d, 1H) 7.98 (d, 1H), 7.88 (d, 2H), 7.67 (d, 2H), 7.60 (d, 1H), 7.55-7.52 (m, 2H),

-957.34 (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 (M + 1): 603.

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

In Example 28, the procedure was as described in Step 2 of Example 27, except that the pyrrolidine was replaced with cyclopropylamine; a white solid product was obtained. ¹ H NMR (400 MHz, in acetone-d ₆ ): 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 (m, 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).

MS (M + 1) 589.

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

In Example 29, the procedure used in Step 2 of Example 27 was followed except for the replacement of the pyrrolidine with tert-butylamine; a white solid product was obtained.

¹ H NMR (400 MHz, in acetone-d ₆ ): 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) .0.67-0 63 (m, 2H), 0.49-0.45 (m, 2H).

MS (M + 1): 606;

Example 30

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

In Example 30, the following procedure was followed. To a mixture of benzyl phosphonate P2 (100 mg, 0.25 mmol), 4,4'-dichlorobenzophenone (63 mg, 0.25 mmol) in

THF (2 mL) was added potassium tert-butoxide (1 M solution in THF, 0.35 mL, 0.35 mmol).

After 97 hours at room temperature, the mixture was diluted with aqueous ammonium chloride solution and extracted with EtOAc. The organic extracts were washed (water and then brine), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography (hexane: EtOAc 8: 2) to give the title compound as a white foam.

¹ H NMR (300 MHz, in acetone-d ₆ ): 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 (m, 2H), 3.13 (hept, 1H), 1.36 (d, 6H).

Examples 31 and 32

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

Example 32

Examples 31 and 32 were followed as described in Example 30, except that the 4,4'-dichlorobenzophenone ketone was replaced by K7, starting with P2 benzylphosphonate.

(E) Isomer (Example 31), ¹ H NMR (300 MHz, in acetone-d ₆ ): δ 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 (m, 3H), 7.10 (d) 1H, 3.15 (hept, 1H), 2.98 (s, 3H), 1.34 (d, 6H).

(Z) isomer (Example 32), ¹ H NMR (300 MHz, in acetone-d 5): δ 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 - {(EHR) -2- [5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline

Example 34

Examples 31 and 32 were followed as described in Example 30, except for the replacement of 4,4'-dichlorobenzophenone ketone with K8 and using benzylphosphonate P2 as starting materials.

(E) Isomer (Example 33), ¹ H NMR (300 MHz, in acetone-d ₆ ): δ 8.80 (dd, 1H), 8.48 (s, 1H), 8.28 (dd, 1H) 7.99-7.96 (m, 3H), 7.97 (m, 1H), 7.74 (d, 1H), 7.61-7.44 (m, 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).

(Z) isomer (Example 34), ¹ H NMR (300 MHz, in acetone-d ₆ ): δ 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

In Example 35, the procedure of Example 30 was followed, except for the substitution of 4,4'-dichlorobenzophenone with ketone K9, using benzylphosphonate P2 as the starting material.

¹ H NMR (300 MHz, in acetone-d ₆ ): δ 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 (m, 3H), 7.50 (d, 1H), 7.48-7.44 (m, 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

-1002-methyl-2- [8- (3 - {(E / Z) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6-quinolinyl] propanenitrile

Example 37

In Examples 36 and 37, the procedure used in Example 30 was followed except for substituting the ketone 4,4'-dichlorobenzophenone with the ketone K8 to replace the benzyl phosphonate with benzyl phosphonate P3 as starting materials.

(E) isomer (Example 36), ¹ H NMR (500 MHz, in acetone-d ₆ ): δ 8.90 (dd, 1H), 8.47 (s, 1H), 8.43 (dd, 1) H), 8.08 (d, 1H), 8.00 (s, 1H), 7.97 (d, 2H), 7.83 (d, 1H), 7.57 - 7.53

-101 (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).

(Z) isomer (Example 37), ¹ H NMR (300 MHz, in acetone-d ₆ ): δ 8.89 (dd, 1H), 8.51 (s, 1H), 8.51 (s, 1) H), 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 (m, 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

In Example 38, the procedure used in Example 30 was followed except for the replacement of the ketone 4,4'-dichlorobenzophenone with the ketone K9, and the replacement of the benzylphosphonate P2 with benzylphosphonate P3 as starting materials.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 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 (m, 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), 3.13 (s 3H), 2.97 (s, 3H), 1.86 (d, 6H).

Example 39

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

-102 -

In Example 39, the procedure used in Example 30 was followed except for the replacement of the ketone 4,4'-dichlorobenzophenone with the ketone K10, and the replacement of the benzylphosphonate P2 with benzylphosphonate P3 as starting materials.

¹ H NMR (300 MHz, in acetone-d ₆ ): δ 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 (m, 5H), 7.43-7.38 (m, 2H), 7, 33 (t, 1H), 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, 3H), 1.86 (d, 6H).

Examples 40 and 41 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8- (3 - {(E7Z) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ] ethenyl} phenyl) quinoline

Example 40

103-

In Examples 40 and 41, the procedure used in Example 10 was followed except for the replacement of the bromoquinoline Q2 with the bromoquinoline Q3 and the replacement of the boronate B2 with boronate B3 as starting materials.

(E) Isomer (Example 40), ¹ H NMR (400 MHz, in acetone-d ₆ ): δ 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) 1 H, 7.49 (s, 1 H), 7.28 (t, 1 H), 7.07 (d, 1 H), 6.96 (d, 1 H), 2.94 (s, 3 H), 2 69 (s, 3H), 2.33 (s, 3H), 1.97 (s, 6H).

(Z) isomer (Example 41), ¹ H NMR (400 MHz, in acetone): δ 8.88 (dd, 1H), 8.49 (dd, 1H), 8.42 (dd, 1H), 8.24 (dd, 1 H), 7.94 (d, 1 H), 7.88 (d, 2 H), 7.61-7.55 (m, 5H), 7.47 (s, 1 H), 7 40 (s, 1H); 7.29 (t, 1H); 7.24 (d, 1H); 7.06 (d, 1H); 3.12 (s, 3H); 2.68 (s, 1H); 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-propanol

-104

In Example 42, the procedure used in Example 10 was followed except for the replacement of the bromoquinoline Q2 with the bromoquinoline Q3 and the replacement of the boronate B2 with boronate B4 as starting materials.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 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

Example 43 was followed as described in Examples 14 and 15 above, with the exception of the replacement of aryl bromide AB5 with aryl bromide AB6 and bromoquinoline Q3 with bromoquinoline Q5 as starting materials.

The following are additional examples:

about

-106-

- 107-

ΑΧ

ο.

-108-

XX

-109-

ABOUT

-110-

-111 -

-112-

-113-

-114-

- 115-

γ / γ ⁰

Αχ

- 116-

- 117-

-118-

-119-

-120-

- 121 -

-122-

-123-

- 124-

- 125-

-126-

-127-

-128-

-129-

- 130-

- 131 -

-132-

XX

- 133-

-134-

- 135-

-136-

-137-

- 138-

-139-

-140 -

-141 -

° ° ΑΑ

- 142-

- 143-

-144-

- 145-

\ ΑΖ

-146-

-147-

gy-y y = N

- 148-

-149-

- 150-

-151 -

Αχ ° χχ °

οχ

- 152-

-153-

- 154-

-155-

N-

H \

-156-

- 157-

N

-158-

- 159-

-160-

F

-161 -

Ο

-162 -

Ο

- 163-

- 164-

'/IN

- 165-

\ r7

ο

-166 -

- 167-

-168-

-169-

- 170-

- 171 -

-172-

-173-

- 174-

A

A ^N in ^p

- 175-

-176-

-177-

- 178-

-179-

-180-

-181 -

-182-

/\ IN

-183-

-184-

-185-

-186-

-187-

-188-

-189 -

you

-190-

- 191 -

-192-

-193-

-194-

-195-

7/77

-196-

-197-

- 198-

- 199-

-200-

Salts of the compounds mentioned in the Examples

As mentioned, pharmaceutically acceptable salts of the active compounds are often required. The following are some examples of salts:

General methods for preparing salts

The compounds of this invention are basic in nature and salts can be prepared from them in a number of ways:

a) The compound is dissolved in a suitable solvent, for example ethyl acetate. A suitable acid, for example hydrochloric acid in a suitable solvent, for example 1,4-dioxane, is added. The precipitate suspension is then aged and the desired salt is then isolated by filtration.

b) The compound and a suitable acid such as benzenesulfonic acid are dissolved in a suitable solvent such as isopropyl acetate or in a mixture of solvents such as isopropyl acetate and methanol. The salt can then be isolated by concentration or solvent exchange resulting in salt precipitation and subsequent filtration. A more stable crystal form of the salt can be obtained by precipitation under conditions close to equilibrium, heating and maturing the suspension prior to filtration. Before equilibrating the salt suspension, seed crystals from previous batches may be added to initiate the crystallization and equilibrium process.

-201 -

Sulfuric acid salt of the compound of Example 14

The sulfuric acid salt of the compound of Example 14 was prepared by dissolving the compound (1.00 equivalents) in boiling (reflux) ethyl acetate. After cooling to room temperature, sulfuric acid (1.04 equivalents) was added slowly with stirring. A suspension was formed which was stirred for 40 minutes and the solid collected by filtration and washing with ethyl acetate to give the salt of the compound of Example 14 with sulfuric acid.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 9.45 (d, 1H), 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).

A salt of the compound of Example 14 with methanesulfonic acid

A salt of the compound of Example 14 with methanesulfonic acid was prepared by dissolving the compound (1.0 equivalent) in boiling (reflux) ethyl acetate. After cooling to room temperature, methanesulfonic acid (1.1 equivalents) was added slowly with stirring. The resulting suspension was concentrated by evaporation and the solid collected by filtration and washing with ether to give the salt of the compound of Example 14 with methanesulfonic acid.

¹ H NMR (500 MHz, in acetone-d ₆ ): δ 9.45 (d, 1H), 9.32 (d, 1H), 8.70 (s, 1H), 8.27 (s 1 H, 8.22 (t, 1 H), 8.11 (s, 1 H), 7.99 (d, 2 H), 7.78 (d, 2 H), 7.61 (d, 1 H), 7 49 (m, 2H), 7.35 (d, 1H), 3.09 (s, 3H), 2.78 (s, 3H), 2.33 (s, 3H), 2.01 (s) , 6H).

A salt of the compound of Example 14 with p-toluenesulfonic acid

A salt of the compound of Example 14 with methanesulfonic acid was prepared by dissolving the compound (1.0 equivalent) in boiling (reflux) ethyl acetate. After cooling to room temperature, p-toluenesulfonic acid (1.1 equivalents) was added slowly with stirring. The solution was concentrated and the suspension was aged at room temperature with stirring and occasional Ultrasonic exposure. The solid was isolated by filtration and washing with ethyl acetate to give the salt of the compound of Example 14 with p-toluenesulfonic acid. Mp 184-185 ° C.

-202 ¹ H NMR (500 MHz, in acetone-d ₆ ): δ 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, 1H), 7.12 (d, 2H), 3.07 (s, 3H), 2.75 (s, 3H) 1.33 (s, 3H), 2.29 (s, 3H), 2.01 (s, 6H).

Salt of the compound of Example 14 with 2-naphthalenesulfonic acid

A salt of the compound of Example 14 with methanesulfonic acid was prepared by dissolving the compound (1.0 equivalent) in boiling (reflux) ethyl acetate. After cooling to room temperature, 2-naphthalenesulfonic acid (1.1 equivalents) in ethyl acetate was added slowly, then ethanol was added. Toluene was then added to the solution and the mixture was concentrated. Additional toluene was added and the suspension was aged at room temperature for 24 hours while still stirring and occasionally sonicated. The solid was then collected by filtration and washed with toluene to give the 2-naphthalenesulfonic acid salt of Example 14. The product melted at 202-204 ° C. ¹ H NMR (500 MHz, in acetone-d ₆ ): δ 9.64 (d, 1H), 9.30 (d, 1H), 8.67 (d, 1H), 8.25 (d, 1H) 8.23 (m, 1H); 8.16 (s, 1H); 7.99 (s, 2H); 7.91 (d, 2H); 7.87 (m, 2H); d, 1H), 7.72 (dd, 1H), 7.68 (d, 2H), 7.54 (d, 1H), 7.52 (m, 2H), 7.43 (bs, 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).

Hydrochloric acid salt of the compound of Example 43

A salt of the compound of Example 43 with hydrochloric acid was prepared by dissolving said compound (1.0 equivalent) in ethyl acetate; upon dissolution, the suspension was heated and sonicated. After cooling to room temperature, HCl in 1,4-dioxane (4 M solution, 1.0 equivalent) was added to the solution with stirring. The suspension was stirred for an additional 5 minutes and the solid collected by filtration to give the salt, monohydrochloride of the compound of Example 43.

Benzenesulfonic acid salt of Example 14

The benzenesulfonic acid salt of the compound of Example 14 is available in two crystal forms (Form A and Form B). These forms are formed as follows:

-203Salt formation

Form A

To a suspension of the compound of Example 14 (1 equivalent) in ethyl acetate was added benzenesulfonic acid (1 to 1.2 equivalents). Other esters may be used in place of ethyl acetate. Methanol was added and the resulting mixture was heated until the solid dissolved. Other alcohols, such as ethanol or propanol, may be used in place of methanol. The resulting solution was filtered and concentrated. Upon concentration, the product crystallized. The resulting mixture was diluted with ethyl acetate and aged. The yellow solid product was isolated by filtration. HPLC showed the 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 equal to 1: 1. The melting point by DSC was 193 ° C.

The X-ray powder diffraction pattern (XRPD) of Form A is shown in FIG. 1. The identification peaks are shown in the following table and shown in FIG. 4th

-204Form B

To a suspension of the compound of Example 14 (1 equivalent) in a mixture of isopropyl acetate (i-PrOAc) and methanol (1: 1) was added benzenesulfonic acid (1 to 1.2 equivalents). Other esters may be used instead of i-PrOAc and other alcohols such as ethanol or propanol may be used instead of methanol. The mixture was allowed to stand at 20 to 50 ° C until the solid was dissolved. The prepared solution was filtered and distilled while keeping the volume of the solution the same by adding i-PrOAc / methanol (9: 1, v / v). The product crystallized during distillation. The resulting mixture was aged for 2 to 10 hours at 20 to 70 ° C to ensure complete formation of Form B. The resulting off-white solid product was isolated by filtration and drying.

HPLC showed 6- [1-methyl-1- (methylsulfonyl) ethyl] -8- (3 - {(E) -2 (3-methyl-1,2,4-oxadiazol-5-yl) -2-) molar ratio [4- (methylsulfonyl) phenyl] ethenyl} phenyl] quinoline and benzenesulfonic acid equal to 1: 1. The melting point by DSC was 210 ° C.

The X-ray powder diffraction pattern (XRPD) of Form B is shown in FIG. 2. The identification peaks are shown in the following table and shown in FIG. 5. The diffraction patterns of both forms are compared to each other in FIG. 3, wherein the identification peaks are indicated by arrows

It will be apparent to those skilled in the art that various variations or modifications are possible and are intended to be included within the scope, intent and description of the invention. The invention is not limited to the following claims.

Claims (28)

PATENT CLAIMS Substituted 8-arylquinoline compounds of general formula I or pharmaceutically acceptable salts thereof, wherein S ¹ , S ² and S ³ independently of one another are H, -OH, halogen, -C 1 -C 6 alkyl, -NO ₂ , -CN or -C 1 -C 6 alkoxy, wherein said alkyl or alkoxy groups are optionally substituted with 1 to 5 substituents, each substituent is independently from each other halogen or -OH; R ¹ is H, -OH, halogen, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -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 ₆ alkyl (oxy) C 1 -C ₆ alkyl, -C (O) NH (aryl), -C (O) NH (heteroaryl), -SO _n NH (aryl), -SO _n NH (heteroaryl), -SO _n NH (C _{r C6)} 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 ₁ -C ₆ alkyl), - (C ₁ -C ₆ alkyl) -OC (CN) dialkylamino, or - (C 1 -C 6 alkyl) -SO _n - (C 1 -C 6 alkyl) wherein any of said groups is optionally substituted with 1 to 5 substituents, each substituent independently of the others being 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 alkyl) (C ₀ -C ₆ alkyl) amino, cycloalkyloxy, acyl, acyloxy, -cycloC 3 -C 6 alkyl, heterocycloC ₃ -C 6 alkyl, aryl, heteroaryl, -NHC (O) OC ₁ -C ₄ alkyl, -OC (O) NHC ₁ -C ₄ alkyl, or -SO _n - (C ₁ -C ₆ alkyl); A is CH, C-ester or CR ⁴ ; R ² and R ³ each independently of one another are aryl, heteroaryl, H, halogen, -CN, -C ₁ -C ₆ alkyl, -heterocycloC ₃ -C ₆ alkyl, -C ₁ -C ₆ -alkoxy, -NHC (O) OCi-C ₄ alkyl, -OC (O) NHC 1 -C ₄ alkyl, -C (O) OH, - (C 1 -C ₆ alkyl) -SO _n (C 1 -C 6 alkyl), -C (O) N (C 0 -C 6 alkyl) ( (C 1 -C 6 alkyl) or -C 1 -C 6 alkylacylamino, wherein any of said groups may be optionally substituted with 1 to 5 substituents, each substituent independently of the other being halogen, -NO ₂ , -C (O) OH, -CN, N-oxide , -OH or aryl, heteroaryl, -C 1 -C 6 alkyl, -SO _n - (C 1 -C 6 alkyl), -SO _n - (aryl), -aryloxy, -heteroaryloxy, -C ₁ -C ₆ alkoxy, -C (O) -heterocycloC ₃ -C 6 alkyl , -NH-cycloC 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), each substituent group being independently of the other 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), -CH 2 -O-C 6 H 5 -OCH 3 or - (O) -NH ₄ H ₈ ; 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 optionally be joined by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused three-ring system; R ⁴ is aryl, -CrCealkyl, heteroaryl, -CN, -NHC (O) OCrC ₄ alkyl, -OC (O) _r NH-C ₄ alkyl, - (-C ₆ alkyl) -SO n (-C ₆ alkyl), - C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C ₁ -C ₆ alkylacylamino, wherein any of said groups is optionally substituted with 1 to 5 substituents, each substituent independently of each other is -CN, halogen , -C (O) (C ₀ -C ₆ alkyl), -C (O) -O (C ₀ -C ₆ alkyl), -C ₁ -C ₆ alkyl,, -SO ₂ - (C ₁ -C ₆ alkyl), -OH, -C ₁ -C ₆ alkoxy or - (C 0 -C 6 alkyl) (C 0 -C 6 alkyl) amino; n is independently 0,1 or 2; and R ² and R ³ may optionally be linked to R ⁴ to form a ring. The substituted 8-arylquinoline compounds of claim 1 or pharmaceutically acceptable salts thereof, wherein A is CH. Substituted 8-arylquinoline compounds according to claim 2 or pharmaceutically acceptable salts thereof, wherein R ¹ is -C 1 -C 6 alkyl, optionally substituted with 1 to 5 substituents, each substituent independently of the other being halogen, -OH, -CN, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, -207cycloalkyloxy, acyl, acyloxy, -cycloC ₃ -C 6 alkyl, heterocycloC 3 -C 6 alkyl, aryl, heteroaryl, -NHC (O) OC ₁ -C ₄ alkyl, -OC (O) NHC 1 -C ₄ alkyl, - (Co-C ₆ alkyl) (C _a -C ₆ alkyl) amino, or -SO _n - (C-C6 alkyl). The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -cycloC ₃ -C 6 alkyl, optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 6 alkyl, heterocykloC ₃ -C 6 alkyl, aryl, heteroaryl, -NHC (O) OC ₁ -C ₄ alkyl, -OC (O) NHCrC ₄ alkyl, _(Co-C6 alkyl) (Co-C6 alkyl) amino, or -SO ÍCrCealkyl). The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -C 2 -C ₆ alkenyl, optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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 6 alkyl, heterocykloC ₃ -C ₆ alkyl, aryl, heteroaryl, -NHC (O) OCrC ₄ alkyl, -OC (O) _r NH-C ₄ alkyl, (C ₀ -C ₆ alkyl) _(Co-C6 alkyl) amino or -SO _n - (C 1 -C ₆ alkyl). The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is heteroaryl, optionally substituted with 1 to 5 substituents, each substituent independently of one another being 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, -NHC (O) O _r C ₄ alkyl, -OC (O) _NHC-C4 alkyl, _(C0-C6 alkyl) _(Co-C6 alkyl) amino, or -SO _n - (C 1 -C ₆ alkyl). The substituted 8-arylquinoline compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -amino, -C 1 -C 6 alkylamino or - (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) amino, each of which may be be optionally substituted with 1 to 5 substituents, each substituent -208- independently of one another is 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, cyclo-C _{3 -C 6} alkyl, heterocykloC ₃ -C 6 alkyl, aryl, heteroaryl, -NHC (O) OC _C4 alkyl, -OC (O) NHCrC4alkyl, (Co-C6 alkyl) (C 0 -C 6 alkyl) amino or -SO _n - (C 1 -C 6 alkyl). The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is aryl, optionally substituted with 1 to 5 substituents, and R ³ is heteroaryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is aryl, optionally substituted with 1 to 5 substituents, and R ³ is aryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is carbonyl, optionally substituted with 1 substituent, and R ³ is aryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is -NHC (O) OC 1 -C 4 alkyl, -OC (O) NHC 1 -C 4 alkyl, optionally substituted with 1 to 2 substituents; and R ³ is aryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ each independently of each other is an aryl group, optionally substituted, and are joined together by a thio, oxy or (C 1 -C 4 alkyl) bridge, wherein form a condensed three-ring system. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is - (C 1 -C 6 alkyl) -SO 2 -C 1 -C 6 alkyl, optionally substituted with 1 to 5 substituents, wherein the substituent independently of the others is halogen, -NO 2, -COOH, carbonyl, -CN, -C 1 -C 8 alkyl, -SO _n - (C 1 -C 6 alkyl), -O-aryl, -O-heteroaryl, -C (O) -heterocycloC ₃ -C ₆ alkyl, -NH-cycloC ₃ -C6alkyl, -OH -209- or - (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, wherein each substituent group independently of each other is optionally substituted with -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); and R ³ is aryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is -C (O) N- (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), optionally substituted with 1 to 5 substituents, and R ³ is aryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ² is -CN and R ³ is aryl, optionally substituted with 1 to 5 substituents. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C 1 -C 6 alkyl, optionally substituted with 1 to 5 substituents, R ² and R ³ , each independently of the other being aryl or heteroaryl, each of which may be be optionally substituted with 1 to 5 substituents, and R ² and R ³ may optionally be linked to each other by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused three-ring system. The substituted 8-arylquinoline compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein S ¹ , S ² and S ³ are each H, R ¹ is -C ¹ -C 6 alkyl, optionally substituted with 1 to 5 substituents, R ² and R ³ each. independently of one another may be an aryl or heteroaryl group and R ² and R ³ may optionally be joined together by a thio, oxy or (C 1 -C ₄ alkyl) bridge to form a fused three-ring system. The substituted 8-arylquinoline compound of claim 1, selected from the group consisting of: -210- -211 - -212- -213 -214- 215- -216- -CH ₃ -217- -218- -219- -220- -221 - -222- -223- -224- -225- -226-respectively -227- -228- -229- Or a pharmaceutically acceptable salt thereof. The substituted 8-arylquinoline compound of claim 1 selected from the group consisting of: 6-isopropyl-8- (3 - {(Z / E) -2- [4- (methylsulfonyl) phenyl] -2-phenylethenyl} phenyl) quinoline; 6-isopropyl-8- {3 - [(Z / E) -2- [4- (methylsulfonyl) phenyl] -2- (1,3-thiazol-2-yl) ethenyl] phenyl} quinoline; -231 6-isopropyl-8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline; 6-isopropyl-8- (3 - {(Z / E) -2- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline; 2- (2 - {(EHR) -2- [3- (6-isopropyl-8-quinolinyl) phenyl] -1- [4- (methylsulfonyl) phenyl] ethenyl} -1,3-thiazol-5-yl) -2 propanol; 2- [8- (3 - {(E / Z) -2- [5- (1-Hydroxy-1-methyl-ethyl) -1,3-thiazol-2-yl] -2- [4- (methylsulfonyl) phenyl] ] ethenyl} phenyl) -6-quinolinyl] -2-methylpropanenitrile; 2-methyl-2- [8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6 quinolinyl] propanenitrile; 6- [1- (methylsulfonyl) ethyl] -8- {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (1,3-thiazol-2-yl) etenylJfenyljchinolín; 6- [1-methyl-1- (methylsulfonyl) ethyl] -8- {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (1,3-thiazol-2-yl) ethenyl] phenyl } quinoline; 8- (3 - {(Z) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6- [1 (methylsulfonyl)] ethyl] quinoline; 8- (3 - {(Z) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6- [1-methyl-1- (methylsulfonyl ) ethyl] quinoline; 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8- {3 - [(E / Z) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [ 4 (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline; (EHR) -3- {3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] phenyl} - / V-isopropyl-2- [4- (methylsulfonyl) phenyl] -2-propenamide; 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; (5 - {(E) -2- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl) phenyl) -1- [4- (methylsulfonyl) phenyl] ethenyl} - 1,2,4-oxadiazol-3-yl) methanol; (E) - N -isopropyl-3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -2- propenamide; (E) -3- {3- [6- (1-Cyano-1-methylethyl) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid; 2-methyl-2- [8- (3 - {(E) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl ) -6-quinolinyl] propanenitrile; -232 (E) -3- {3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2-propenamide; (E) - / V- (tert-butyl) -3- {3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] phenyl} -2- [4- (methylsulfonyl) phenyl] -2 propenamide; (E) -3- [3- (6-Isopropyl-8-quinolinyl) phenyl] -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid; 6-isopropyl-8- (3 - {(E) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline; (E) -3- [3- {6- [1-Methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -1- (1-pyrrolidine) Inyl) -2-propen-1-one; (E) - N -cyclopropyl-3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4 (methylsulfonyl) phenyl] -1 - ( 1-pyrrolidinyl) -2-propenamide; (E) -N / - (tert-butyl) -3- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4 (methylsulfonyl) phenyl] -2-propenamide; 8- {3- [2,2-bis (4-chlorophenyl) vinyl] phenyl} -6-isopropylquinoline; 6-isopropyl-8- (3 - {(EHR) -2- (6-methyl-3-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline; 6-isopropyl-8- (3 - {(EHR) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline; 8- (3- {2,2-bis [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6-isopropylquinoline; 2-methyl-2- [8- (3 - {(EHR) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6-quinolinyl] propanenitrile; 2- [8- (3- {2,2-bis [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6-quinolinyl] -2-methylpropanenitrile; 2-methyl-2- (8- {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (2-pyridinyl) ethenyl] phenyl} -6chinolinyl) propanenitrile; 6- [1-methyl-1- (methylsulfonyl) ethyl] -8- (3 - {(E / Z) -2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl } phenyl) quinoline; 2- (6 - {(E) -2- (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -1- [4- (methylsulfonyl) phenyl] ethenyl} 3-pyridinyl) -2-propanol; or a pharmaceutically acceptable salt thereof. -233- A pharmaceutical composition comprising a therapeutically effective amount of a substituted 8-arylquinoline compound of formula I according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 21. The pharmaceutical composition of claim 20 comprising a leukotriene receptor antagonist, a leukotriene biosynthesis inhibitor, an M2 / M3 antagonist, a corticosteroid, an H1 receptor antagonist, or a β-2-adrenoceptor agonist. 22. A pharmaceutical composition according to claim 20 comprising a selective COX-2 inhibitor, a statin or an NSAID. Substituted 8-arylquinoline compounds for use in the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease COPD, eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock and associated conditions such as laminitis and equine colic, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury to the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, allergic respiratory distress syndrome, chronic palsy conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondillitis, host transplant rejection but graft, excessive gastric acid secretion, bacterial, fungal or viral-induced sepsis or septic shock, inflammation or cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle exhaustion, depression, memory impairment, neuropathic depressions, neuropathic depressions, neuropathic depressions, neuropolar degeneration inflammatory elements, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth, and normal tissue cancer invasion; said method comprising A step of administering a therapeutically effective amount or a prophylactically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. A prodrug compound that forms an in vivo substituted 8-arylquinoline compound of formula I according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof. Use of a prodrug compound which generates in vivo a therapeutically effective amount or a prophylactically effective amount of a substituted 8-arylquinoline compound according to claim 1 for use in treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease - COPD, eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock and associated conditions such as laminitis and equine colitis, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, atopic dermatitis respiratory distress syndrome in children, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, host transplant or graft rejection, gastric acid excretion, bacterial, fungal or viral-induced sepsis or septic shock, inflammatory sphdyrosis or septic shock, inflammatory sphdyrosis or septic shock, , cachexia, muscle exhaustion, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory elements, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancer invasion of normal. Substituted 8-arylquinoline compounds of formula I according to any one of claims 1 to 19, or pharmaceutically acceptable salts thereof, for use as a phosphodiesterase inhibitor. -235- Use of substituted 8-arylquinoline compounds of formula I according to any one of claims 1 to 19, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease - COPD, eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock and associated conditions such as laminitis and equine colic, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, atopic dermatitis, atopic dermatitis respiratory distress syndrome in children, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neuro gene inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, host transplant or graft rejection, gastric acid overexpression, bacterial, fungal or viral-induced sepsis or septic shock, inflammation or cytokine-mediated cancer, osteoarthritis-related cancer, fatigue, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory elements, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancer invasion of normal tissue. 28. A phosphodiesterase-4 inhibiting pharmaceutical composition comprising an acceptable phosphodiesterase-4 inhibiting amount of a compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.