UA74815C2 - Substituted 8-arylquinoline inhibitors of phosphodiesterase -4, a pharmaceutical composition based thereon (variants) - Google Patents

Abstract

Novel substituted 8-arylquinolines represented by Formula (I), of a pharmaceutically acceptable salt thereof, wherein S1, S2 and S3 are independently H, -OH; halogen, -C1-C6alkyI, -NO2, -CN, or ûC1-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-C6alkenyI, -C1-C6alkoxy, aryl-, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C1-C6alkylainino, -(C1-C6alkyl)(C1-C6alkyl)amino, -C1-C6,alkyl(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-C6alkyl) 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, -Ñ(O)(heterocyclîC3-Ñ6alkyl), -C(O)-O-(C0-C6alkyl), -C(O)-aryloxy, -C1-C6alkoxy, -(C0-C6alkyloxy, (C0-C6alkyl)(C0-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -ñoñlîÑ3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or ûSOn-(C1-C6alkyl); A is CH, C-ester, or C-R4; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C1-C6alkyl, heterocycloalkyl, -C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C1-C6alkyl)-SOn(C1-C6alkyI), -C(O)N(Co-C6aIkyl)(Co-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-(àrol), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6,alkyl, -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, -cycloÑ3-Ñ6alkol, 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 R; and R3 are both an aryl or heteroaryl, then R; 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

Description of the invention

The present invention relates to compounds that are substituted 8-arylquinolines. In particular, this invention 2 relates to substituted 8-arylquinolines, which are phosphodiesterase-4 inhibitors, where the aryl group in the 8-position contains a substituted alkenyl group as a substituent.

Hormones are compounds that affect cellular activity in different ways. In many ways, hormones act as messengers of specific trigger responses and cell activity. However, many of the effects caused by hormones are not the result of the exclusive action of the hormone alone. Instead, the hormone first binds to the receptor, thus triggering the release of a secondary compound that then acts on cellular activity. In this scheme, the hormone is known as the primary messenger, while the secondary compound is called the secondary messenger. Cyclic adenosine monophosphate (adenosine 3", 5'-cyclic monophosphate, "CAMF" or "cyclic

AMP") is known as a second messenger of hormones, including epinephrine, glucagon, calcitonin, corticotropin, lipotropin, luteinizing hormone, nor-epinephrine, parathyroid hormone, thyroid-stimulating hormone, and 12 vasopressin. Thus, cAMP mediates cellular responses to hormone action. Cyclic AMP also mediates cellular responses to the action of various neurotransmitters.

Phosphodiesterases ("PDEs") refer to a family of enzymes that metabolize 3'', 5'-cyclic nucleotides to 5'i--chucleoside monophosphates, thus limiting the activity of the second messenger cAMP. A particular phosphodiesterase, phosphodiesterase-4 (PDE4'') is also known as "PDE-IM"U), which is a high-affinity, cCAMP-specific IM-type PDE, is of interest as a possible target for the development of new anti-asthmatic and anti-inflammatory compounds. It is known that PDEYA4 exists at least in the form of four isoenzymes, each of which is encoded by a separate gene. Each of the four known PDE4 gene products likely plays different roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, in particular specific isoforms of PDEAY that cause harmful reactions, can successfully affect the symptoms of allergy and inflammation. It would be desirable to develop new compounds and compositions that would inhibit the activity of PDE4. Go)

The main point when using PDE4 inhibitors is their side effect in the form of vomiting, which was observed in some candidate compounds, as described by S. Vygpotsi ei ai!., ("Vygposh"), App. Ker. Ip. Med. Spet., 33: 91- 109 (1998). V. Nidnez ei ai, Vg. 9. Riagtasoi, 118: 1183-1191 (1996); M. 9. Reitu ei ai., Seyi Viospet.

Viorpuz,, 29:113-132 (1998); 5. V. Spgiviepzep ei ai., 9). Honey. Speth., 41:821-835 (1998); and Vygposhi describe a wide variety of serious adverse side effects associated with some compounds. As described by M. 0. "-

Noiziau ei ai., Adu. Ip Riagtasoi, 44:225-342 (1998) and 0. ripa ei ai., Adu. Yip Ripagtasoi, 44:33-89 (1998), there is tremendous interest in the search for therapeutic PDE4 inhibitors. co

International patent publication MMO9422852 describes quinolines as PDE4 inhibitors. "AND

A. N. SookK, ei aiYi.,, 9. Spet. boss, 413-417 (1943) described gamma-pyridylquinolines. Other quinoline compounds 32 are described by Kei Mapare et al, 9U. Ogd. Spet., 58 (24):6692-6700 (1993); Keii Mapare ei ai., 9U. At. Set. -

Boss, 115(12):5324-5325 (1993); and Kei Mapabe ei ai., U. At. Spent Zos, 114(17): 6940-6941 (1992).

Compounds that include ring systems have been described by various researchers as effective for various therapeutic and practical uses. For example, in the international patent publication Mo. U/O « 98/25883 described ketobenzamides as calpain inhibitors, in the European patent publication Mo. ER 811610 Her in With US patents Mo. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidines that block sodium channels, with US Pat. 5736297 describes a ring system used as a photosensitive composition. з» У патентах США 5491147, 5608070, 5622977, 5739144, 5776958, 5780477, 5786354, 5798373, 5849770, 5859034, 5866593, 5891896 і в міжнародній патентній публікації М/УО 95/35283 описані інгібітори ФДЕАЯ4, які є трьома-заміщеними арил або heteroarylphenyl derivatives. In US patent Mo. 5580888 describes PDEYA4 inhibitors, 49 of which are styryl derivatives. In US patent Mo. 5550137 describes PDEYA4 inhibitors, which are phenylaminocarbonyl derivatives. and In US Pat. Mo. 5340827 describes PDEYA4 inhibitors, which are phenylcarboxamide compounds. In US patent Mo. "" 5780478 describes inhibitors of PDEA4, which are tetra-substituted phenyl derivatives. Substituted oxime derivatives used as PDE4 inhibitors are described in the international patent publication UUHO 96/00215. In US patent Mo. bo 5633257 describes PDEA inhibitors, which are cyclo(alkyl and alkenyl)phenylalkenyl(aryl and heteroaryl) compounds. -k 70 However, there remains a need for new compounds and compositions that therapeutically inhibit PDE4 with minimal side effects. sl The present invention relates to new substituted 8-arylquinolines, which are PDEYA4 inhibitors, where the aryl group in the 8-position contains a substituted alkenyl group as a substituent. The present invention also relates to a pharmaceutical composition that includes an effective amount of a new substituted 8-arylquinoline and a pharmaceutically acceptable carrier. This invention, in addition, relates to a method of treatment in mammals, for example, asthma, chronic

HF) bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related conditions such as laminitis and colic in horses), septic shock, ulcer colitis, Crohn's disease, reperfusion injuries of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atonic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive disease in animals, diabetes insipidus, allergic rhinitis , allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, graft rejection and "graft versus host" reactions, hypersecretion of gastric juice, sepsis or septic shock caused by bacterial, fungal and viral infection, with inflammation and cytokine-related chronic tissue degeneration,

osteoarthritis, cancer, cachexia, muscle weakness, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with an inflammatory component, Parkinson's disease,

Alzheimer's, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancer invasion

Into normal tissues by introducing an effective amount of a new substituted 8-arylquinoline or a precursor compound that forms the new substituted 8-arylquinoline.

Figure 1 shows a diagram of the chemical image of the general structure of the compounds according to the present invention.

Figure 2 shows a graph of the value relative to "Tpeb" for X-ray powder diffraction of polymorph form A of benzenesulfonic acid salt 70. 8-P-methyl-1-(methylsulfonyl)ethyl|/-8-I3-KE)-2-|Z- methyl-1,2,4-oxadiazol-5-yl)|-2-(4-(methylsulfonyl)phenyl|ethenyl|phenylquinoline.

Figure 3 shows a graph of the value relative to "Tpeb" for X-ray powder diffraction of the polymorph form in the salt of benzenesulfonic acid 6-P1-methyl-1-(methylsulfonyl)ethyl-8-I3-KE)-2-(3-methyl-1, 2,4-oxadiazol-5-yl|-2-(4-(methylsulfonyl)phenyl|ethene 75 yl|phenylquinoline.

Figure 4 shows a comparison of X-ray powder diffraction of polymorph form A (lower line) and form B (upper line) of the salt of benzenesulfonic acid 6-P1-methyl-1-(methylsulfonyl)ethyl-8-I3-KE)-2-( 3-methyl-1,2,4-oxadiazol-5-yl|-2-(4-(methylsulfonyl)phenyl|ethene yl|phenylquinoline.

Figure 5 shows a graph of the differential characteristic peaks of X-ray powder diffraction of the polymorph form in the salt of benzenesulfonic acid 6-P1-methyl-1-(methylsulfonyl)ethyl-8-I3-KE)-2-(3-methyl-1,2, 4-oxadiazol-5-yl|-2-(4-(methylsulfonyl)phenyl|ethene yl|phenylquinoline.

Figure b shows a graph of the differential characteristic peaks of X-ray powder diffraction of the polymorph form in the salt of benzenesulfonic acid 6-P1-methyl-1-(methylsulfonyl)ethyl-8-I3-KE)-2-(3-methyl-1,2 ,4-oxadiazol-5-yl|-2-(4-(methylsulfonyl)phenyl|ethene and) yl|phenylquinoline.

The compound according to this invention is represented by formula (1):

And h-

Y. anna pini pyt i

ZY A Za so

Shi p « i - ay geo I « d Av Z i Z . ;" On -I k I 0) or its pharmaceutically acceptable salt, where so 51, 5" and 33 independently represent H, -OH, halogen, -C 4-Svalkyl, -MO", -SM or -C--Svalkoxy, where alkyl and -l 20 alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently halogen or

ON; Cl Ku represents H, OH, halogen, carbonyl or -C/-Salkyl, -dicycloC3-Salkyl, -Co-Salkyl, -Ci-Salkyloxy, aryl, heteroaryl, -CM, -heterocycloC3-Salkyl, -amino, -C4 -Salkylamino, -(C4i-Salkyl) (C--Salkyl) amino, -C1-Salkyl (oxy) -Si-Salkyl, -C(O)MH(aryl), -C(O)MH (heteroaryl), - 50,MH (aryl), -500MH (hetersoaryl), -ZOMN(C1-Salkyl), -FSHKSOM(Co-Salkyl) (Co-Salkyl), -MH-5O,-(C4-Salkyl), -504-( C1.Swallyl), o -«-Ci-Swallyl)-O-C(CM)-dialkylamino or the group -(C1-Swallyl)-50,-(C1-Swallyl), where any of the groups is optionally substituted 1-5 substitutes; where each substituent is independently a halogen, -OH, -CM, -C 4-Salkyl, -dicycloC3-Salkyl, -C(O) (heterocycloC3-Salkyl), -C(0)-O-(Co-Salkyl) . or -50,-(S.4-Svalkil);

A is CH, C-complex ether or C-K,;

ER" and Kz independently represent aryl, heteroaryl, H, halogen, -CM, -C 4-Salkyl, heterocyclo-C3 alkyl, -C.-Salkyloxy, carbonyl, carbamoyl, -C(O)OH, -(C4-Salkyl ) -50,-(C1-Svalkyl), -C(O)M(Co-SvalkyluuCo-Svalkyl) or -C41-Svalkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, -MO 5, -C(O)OH, carbonyl, -CM, -C4-Salkyl, -8Op-(C1-Salkyl), -5O-(aryl), aryl oxy, - heteroaryl oxy, Si-Svaloxy, M-oxide,

-F(0)-heterocycloC3-Salkyl, -MH-cycloC3-Salkyl, amino, -OH or -(Co-Salkyl) (Co-Salkyl) amino group, substituent group -C(0)-M(Co-Salkyl) ( Co-Svalkil), where each substituent is independently optionally substituted -OH,

C-Cyloxy, -C--Cylyl, -cycloC3-Cylyl, aryloxy, -C(O)OH, -C(O0)O(C1-Cylyl), halogen, -MO», -Sm, -50,-( C4-Svalkyl) or -(0)-M(Co-Svalkyl) (Co-Svalkyl); one of K» and Kz must be aryl or heteroaryl, optionally substituted; when K" and Kz are both aryl or heteroaryl, then K" and Kz may optionally be linked by a thio, oxy, or (Ci-C;alkyl) bridge to form a fused three-ring system;

Ku represents aryl, -C 1-Svalkyl, heteroaryl, -CM, carbonyl, carbamoyl, -(C4-Svalkyl) -50,-(C.-Svalkyl), 70. or -C.-Svalkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent is independently a carbonyl, -CM, halogen, -С(ОХС o-Svalkyl), -Х0)О(Со -Salkyl), -C4-Salkyl, -50,-(C14-Salkyl), -OH, C-Salkyloxy or -(Co-Salkyl) (Co-Salkyl)amino group; n is independently equal to 0, 1 or 2; and

E" or Kz can be optionally attached to K. with the formation of a ring.

In the first aspect, the compound according to the present invention is represented by the formula (I) or its pharmaceutically acceptable salt, where 51, З» and З3z independently represent H. C.i-Svalkoxy, where the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent independently represents halogen or

ON;

Ku is H, OH, halogen, carbonyl or -C/-Salkyl, -dicycloC3-Salkyl, -Co-Salkyl, -Ci-Salkyloxy, aryl, heteroaryl, -CM,- heterocycloC3-Salkyl, -amino, -C4- Swallylamino, -(C4-Swallyl) (C--Swallyl) amino, -C1-Swallyl (oxy) S.i-Swallyl, -C(O)MH(aryl), -C(O)MH(heteroaryl), -504MH (aryl), -ZO,MH (hetersoaryl), -300MH (C.-Svalkyl), -C(O)H(Co-Svalkyl). (Co-Svalkyl),, -MH-ZO,-(C4-Svalkyl), -50,-(C4-Svalkyl), -"C4-Svalkyl) -0-FK(SM) -dialkylamino or group -(C4- Svalkil) -504-(С--Svalkil), where any of the groups is optionally substituted with 1-5 substituents; where each substituent independently represents a halogen, -OH, -CM, -C 1-Salkyl, -dicycloC3-Salkyl, -F(O) (heterocycloC3-Salkyl), -C(O0)-0-(Co-Salkyl), - C(O)-aryloxy, -C4-Salkyloxy, -(Co-Salkyl)//uCo-Salkyl) i) amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50-(C1-Svalkil);

A is CH; "ER" and Kz independently represent aryl, heteroaryl, H, halogen, -CM, -C 4-Salkyl, heterocyclo-C3 alkyl, -C1-Salkyloxy, carbonyl, carbamoyl, -C(O)OH, -(C4- Svalkyl) -50-(C4-Svalkyl), -CO)M(Co-SvalkyluCo-Svalkyl) -- or the group -C4-Svalkylacylamino, where any of the groups is optionally substituted with 1-5 substituents, where each substituent is independently represents aryl, heteroaryl, halogen, -MO 5, -С(О0О)OH, carbonyl, -СМ, -С.-Salkyl, -30-(С4-Salkyl), -5О-(aryl), -aryloxy, heteroaryloxy , C.-Svalkoxy, M-oxide, " -F(0)-heterocycloC3-Svalkyl, -MH-cycloC3-Svalkyl, amino, -OH or the group -(Co-Svalkyl)uCo-Svalkyl) amino, y- -E (9)-M (Co-SwalkylCo-Swalkyl), where each substituent is independently optionally substituted by -OH, C 1-Swalkoxy, -C1-Swalkyl, -cycloC3-Swalkyl, -aryloxy, -C(O)OH, - C(0)0(C1-Svalkyl), halogen, -MO", -OM, -504-(C1.Svalkyl) or -(0)-M(Co-SvalkyluU/Co-Svalkyl); one of K» and Kz must be aryl or heteroaryl, optionally substituted; "when K" and Kz are both aryl or heteroaryl, then K" and Kz can optionally be linked to c by means of a thio, oxy, or (C1-C6 alkyl) bridge to form a fused three-ring systems; and n is independently equal to 0, 1 or 2. and? In the first embodiment of this aspect, the compound of the present invention is represented by the formula (I) or a pharmaceutically acceptable salt thereof, where 51, 20, and 33 independently represent H.-OH, halogen, -C 4-Svalkyl, -MO", -CM or - S.-Svalkoxy, where the alkyl and -I alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent independently represents halogen or

ON; pi Ku represents -C 1-Svalkyl, optionally substituted with 1-5 substituents; where each substitute is independent

Go! represents halogen, -OH, -CM, -C(O) (heterocyclosC 3z-Salkyl), -C(0)-0-(Co-Salkyl), -C(0)-O-aryl, alkoxy, 5rCycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, -carbamoyl or -50-(C4-Salkyl), -""Co-SalkylCo-Salkyl) amino; c A represents CH;

EC" and Kz independently represent aryl, heteroaryl, H, halogen, -CM, -C --Salkyl, heterocycloC" with alkyl, -C.-Salkyloxy, carbonyl, carbamoyl, -C(O)OH, -(Si- Svalkyl)-5O-(C4-Svalkyl), -C(O)M(Co-SvalkyluuCo-Svalkyl) or -C.-Svalkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, -MO 5, -С(О0О)OH, carbonyl, -СМ, -С.-Svalkyl,

F) -8O04-(C1-Svalkyl), -"ZOd-(aryl), -O-aryl, -O-heteroaryl, C-Svaloxy, M-oxide, -C(O)-heterocycloC3-Svalkyl, ka -MH -cycloC 3-Salkyl, amino, -OH or -(Co-Salkyl)/("Co-Salkyl) amino, -C(0)-MSH(Co-Salkyl/Co-Salkyl), where each substituent is independently optional substituted -OH, C -Svaloxy, -C4-Svalky, -dicloC3-Svalky, because aryloxy, -C(O)OH, -C(0)O(S1-Svalky), halogen, -MO», -SM, - 5304-(C4-Svalkyl) or -C(0)-M (Co-Svalkyl) (Co-Svalkyl); one of K» and Kz must be aryl or heteroaryl, optionally substituted; when K" and Kz are both aryl or heteroaryl, then K" and Kz may optionally be linked by a thio, oxy, or (Ci-C;alkyl) bridge to form a fused three-ring system; 65 n is independently equal to 0, 1 or 2.

In another embodiment of this aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein 51, 20, and 3 independently represent H, -OH, halogen, -C4-Salkyl, -MO", -CM or -C .-Svalkoxy, where the indicated alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent is independently Halogen or OH;

Ku represents -cycloC3-Svalkyl, optionally substituted with 1-5 substituents; where each substituent is independently halogen, -OH, -CM, -C(O) (heterocycloC 3-Salkyl), -C(0)-O-(Co-Salkyl), -C(0)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50-(C1-Salkyl); 70 A is CH;

K» and Kz independently represent oaryl, heteroaryl group, H, halogen, -CM, -C 4-Svalkyl, heterocycloSusvalkyl, -Si-Svalkoxy, carbonyl, carbamoyl, -C(О0О)OH, -(С.--Svalkyl) -50,-(C1-Salkyl), -F«om(Co-SalkyluCo-Salkyl) or -C4-Salkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent is independently an aryl, heteroaryl, halogen, -MO 5», -ССО)OH, carbonyl, 75. EM, -C1-Salkyl, -5О4-(C4-Salkyl), -5Op-(aryl), -O-aryl, -O-heteroaryl , C.i-Swalkoxy, M-oxide, -C(O) -heterocycloC3-Swalkyl, -MH-cycloC3-Swalkyl, amino, -OH or -(Co-Swalkyl) (Co-Swalkyl) amino group, -0)- Z(Co-Salkyl/uCo-Salkyl), where each substituent is independently optionally substituted with -OH, C/-Salkyloxy, -C1-Salkyl, -cycloC3-Salkyl, aryloxy, -C(O)OH, -C(0 )O(C.i-Svalkyl), halogen, -MO", -SM, -504-(C4-Svalkyl) or -C(0)-M(Co-Svalkyl) (Co-Svalkyl); one of K» and Kz must be aryl or heteroaryl, optionally substituted; when K" and Kz are both aryl or heteroaryl, then K" and Kz may optionally be linked by means of a thio, oxy or (C.i-C;alkyl) bridge to form a fused three-ring system; and n is independently 0, 1, or 2.

In the next embodiment of this aspect, the compound of the present invention is represented by the formula (I) or a pharmaceutically acceptable salt thereof, where 51, Zo, and 3 independently represent H, -OH, halogen, -C4-alkyl, -MO", -CM or - C.-Svalkoxy, where specified (8) alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

Ku represents -C 5-Svalkenyl, optionally substituted with 1-5 substituents; where each substituent independently represents halogen, -OH, -CM, -C(O) (heterocyclosC-Salkyl), -C(O)-O-(Co-Salkyl), -C(O)-O-aryl .

EK" and Kz independently represent aryl, heteroaryl, H, halogen, -CM, -C-Salkyl, heterocycloC" with alkyl, -C-Salkyl, carbonyl, carbamoyl, -C(O)OH, -(C4-Salkyl) -50,-(C1-Svalkyl), -C(O)M(Co-SvalkyluuCo-Svalkyl) " or -C.-Svalkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent is - independently represents oaryl, heteroaryl, halogen, -MO 5, -С(О0О)OH, carbonyl, -СМ, С.-Salkyl, -30,-(С41-Св)alkyl, -5О,-(aryl), -O-aryl, -O-heteroaryl, C--Salkyloxy, -oxide, -C(O)-heterocycloC3-Salkyl, -MH-cyclosC 3-Salkyl, amino, -OH or the group -"Co-Salkyl) (Co -Svalkyl) amino, -C(O)-M (Co-Svalkyl) (Co-Svalkyl), where each substituent is independently optionally substituted (-OH, Co 4-Svalkoxy, -Si-Svalkyl, "7" ChiCcloSz- Svalkyl, aryloxy, -C(O)OH, -K(O0)O(S.-Svalkyl), halogen, -MO", -"CM, -504-(C4-Svalkyl) or -5(0) With c -M (Co-Salkyl)uCo-Salkyl); one of K" and Kz must be aryl or heteroaryl, optionally substituted; ;" when K" and Kz are both aryl or heteroaryl, then K" and Kz may optionally be linked via a thio, oxy, or (C4-Slaylalkyl) bridge to form a fused three-ring system; n is independently 0, 1 or 2. -I In another embodiment of this aspect, the compound of the present invention is represented by formula (1) or a pharmaceutically acceptable salt thereof, where pi 51, Zo, and 3 independently represent H, -OH, halogen, -C4-Salkyl, - MO", -SM or -S.-Svalkoksi, where indicated

Go! alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents a 5p hapogen or OH; - Ki is a heteroaryl, optionally substituted with 1-5 substituents; where each substituent independently represents a halogen, -OH, -CM, -C(O) (heterocyclosC 3z-Salkyl), -C(0)-O-(Co-Salkyl), -C(0)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50-(C1-Salkyl); 5B A is CH;

EK" and Kz independently represent aryl, heteroaryl, H, halogen, -CM, -C --Calkyl, heterocycloC"C alkyl,

Ф) -C1-Svaloxy, carbonyl, carbamoyl, -C(O)OH, -(C4-Svalkyl)-50-(C4-Svalkyl), -C(O)M(Co-SvalkyluuSo-Svalkyl) ka or group - C4-Svalkylacylamino, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, -MO 5», -C(O)OH, carbonyl, -CM, -C. -Svalky, in 7ZOp(Si-Svalky), -5O,-(aryl), -aryloxy, -O-heteroaryl, Si-Svaloxy, M-oxide, -F(0)- heterocycloC3-Svalky, -MH-cycloS3- Svalky, amino, -OH or group -(Co-Svalkyl)/Co-Svalkyl) amino, -E(9)-M (Co-SvalkyluCo-Svalkyl), where each substituent is independently optionally substituted -OH, C 1- Svaloxy, -С1-Svalkyl, -cycloC3-Svalkyl, -aryloxy, -С(О0)OH, -С(0)0(С.-Svalkyl) halogen, -MO», -СМ, -504-(С4-Svalkyl) ) or -C(0)-M(Co-Svalkyl)HuSo-Svalkyl); 65 one of K» and Kz must be aryl or heteroaryl, optionally substituted; when K" and Kz are both aryl or heteroaryl, then K" and Kz may optionally be linked by a thio, oxy, or (Ci-C;alkyl) bridge to form a fused three-ring system; n independently represents 0, 1 or 2.

In yet another embodiment of this aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein 51, 20, and 3 are independently H, -OH, halogen, -C4-alkyl, -MO", -CM or -S.-Svalkoxy, where the indicated alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

Ki represents -amino, -C 1-Svalkylamino or -(Ci-SvalkyluC 1-Svalkyl) amino group, where any of the groups 70 is optionally substituted with 1-5 substituents; where each substituent independently represents halogen, -OH, -CM, -C(O) (heterocycloC3-Salkyl), -C(0) -O-(Co-Salkyl), -C(0)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50,-(C1-Salkyl);

A is CH;

EC" and Kz independently represent aryl, heteroaryl, H, halogen, -CM, -C 4-Salkyl, heterocycloC3 alkyl, 75. 7C1-Salkyloxy, carbonyl, carbamoyl, -C(O)OH, -(C-Salkyl )-5O-(C4-Swalkyl), -C(O)M(Co-SwalkyluuCo-Swalkyl) or -C.-Swalkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently is oaryl, heteroaryl, halogen, -MO 5, -C (O)OH, carbonyl, -CM, -C.-Salkyl, -30-(C41-Salkyl), -5O.4-(aryl), -aryloxy . -C(0)-M(Co-SvalkyluUSo-Svalkyl), where

Each substituent is independently optionally substituted by -OH, C 1-Svalkoxy, -C1-Svalkyl, -dicloC3-Svalkyl, -aryloxy, -"FON, -SHCO)O(S. Svalkyl), halogen, -MO", -SM , -5O-(C4-Svalkyl) or -O)-MSH(Co-SvalkylCo-Svalkyl); one of K» and Kz must be aryl or heteroaryl, optionally substituted; when K" and Kz are both aryl or heteroaryl, then K" and Kz can be optionally connected by means of a Tthio, oxy or (Si-Su; alkyl) bridge to form a condensed three-ring system; n is independently equal to 0, 1 or 2. (8)

In an embodiment of this aspect, the compound of this invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, where 51, Zo, and Za independently represent H, -OH, halogen, -C 1-Salkyl, -MO", -SM or C. - Svalkoks, where the alkyl and alkoxy groups specified above are optionally substituted with 1-5 substituents; where each substituent is independently halogen or OH; -

Ki represents -C 1-Salkyl, -cycloC3-Salkyl, -Co-Salkyl, -Ci--Salkyloxy, aryl, heteroaryl, -CM, oz -heterocycloC3-Salkyl, -amino, -Ci-Salkylamino, -(C- -Svalkyl) (C--Svalkyl) amino, -C4-Svalkyl (oxy)-Si-Svalkyl, -C(O)MH (aryl), -C(O)MH (heteroaryl), -500,MH-(aryl ), -500МН (heteroaryl), -500,МН « (C4-Svalkyl), -CHO)M(Co-SvalkyluuCo-Svalkyl), -MH-5O-(C-Svalkyl), -504-(C--Svalkyl ), carbamoyl, -(C-Salkyl) y- -0-FK(SM)-dialkylamino or the group -(C4-Salkyl) -504-(C--Salkyl), where any of the groups is optionally substituted 1 - 5 substitutes; where each substituent is independently halogen, -OH, -CM, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -30-(C4-Salkyl); "

A is CH; in c EK" represents aryl, optionally substituted with 1-5 substituents, where each substituent independently represents . aryl, heteroaryl, halogen, -MO», -C(O)OH, carbonyl, -CM, -C4-Salkyl, -50,-(Ci-Salkyl), -50.-(aryl), and? -aryloxy, -O-heteroaryl, C-Salkyloxy, M-oxide, -C(0)-heterocycloC3-Salkyl, -MH-cycloC3-Salkyl, amino, -OH or -(Co-SalkyluCo-Salkyl) amino, group - C(0)-M (Co-SalkyluCo-Salkyl), where each substituent is independently optionally substituted by -OH, C 4-Salkyloxy, -C4i-Salkyl, -cycloC3-Salkyl, -aryloxy, -C(O)OH, -I -SCHO)O(C 1-Svalkyl), halogen, -MO», -SM, -504-(C1-Svalkyl) or -C(0)-M-(Co-Svalkyl) (Co-Svalkyl);

Kz is heteroaryl, optionally substituted with 1-5 substituents, where each substituent is independently aryl, heteroaryl, halogen, -MO», -CO)OH, carbonyl, -CM, -C4-Salkyl, -50,- (C4-Svalkyl), -50,-(aryl),

Go! -aryloxy, -O-heteroaryl, C-Salkyloxy, M-oxide, -C(0)-heterocycloC3-Salkyl, -MH-cycloC3-Salkyl, amino, 5o СОН or the group -"Co-SalkyluCo-Salkyl) amino, - C(0)-M(Co-SalkylCo-Salkyl), where each substituent is independently - optionally substituted by -OH, C 4-Salkyloxy, -C4i-Salkyl, -cycloC3-Salkyl, -aryloxy, -C(O)OH , sp -SCHO)O(C 1-Svalkyl), halogen, -MO», -SM, -504-(C4-Svalkyl) or -C(0)-M-(Co-Svalkyl) (Co-Svalkyl); and n is independently 0, 1, or 2.

In yet another embodiment of this aspect, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein 51, 30, and 3 are independently H, -OH, halogen, -C4-alkyl, -MO", -CM or -S.-Svalkoksi, where indicated

F) alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents a halogen or OH;

Ki is halogen, carbonyl, -C 4-Salkyl, -dicycloC3-Salkyl, -Co-Salkyl, -C.-Salkyloxy, aryl, bo Heteroaryl, -CM, -heterocycloC3S-Salkyl, amino, -C.4-Salkylamino , -(C4i-Salkyl) (C--Salkyl) amino, -C1-Salkyl (oxy) C.i-Salkyl, -C(O)MH(aryl), -C(O)MH(heteroaryl), - 504MH(aryl), -ZO,MH (hetersoaryl), -50AMH-(C4-Svalkyl), -C(O)M(Co-Svalkyl). (Co-Swallyl),, -MH-5O-(C4-Swallyl), -50,-(C-Swallyl), -carbamoyl, -«-C-Swallyl)-O-C(CM)-dialkylamino or the group - (C1-Svalkil)-50,-(C1-Svalkil), where any of the groups is optionally substituted with 1-5 substituents; where each substituent independently represents a halogen, -OH, -CM, -C(0) 65 (heterocycloC3-Salkyl), -C(0)-O-(Co-Salkyl), -C(0)-O-aryl, alkoxy , cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50,-(C1-Salkyl);

A is CH;

EK" represents aryl, optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, -MO", -C(O)OH, carbonyl, -CM, -C4-Salkyl, -504- (C4-Swalkyl), -50-(aryl), aryloxy, -O-heteroaryl, C--Swalkoxy, M-oxide, -C(O)-heterocycloC3-Swalkyl, -MH-cycloC3-Swalkyl, amino, -OH or the group -(Co-Svalkyl) (Co-Svalkyl) amino, -C(0)-M(Co-Svalkyl) (Co-Svalkyl), where each substituent is independently optionally substituted -OH, C 4-Svalkoxy, - C4i-Salkyl, -cycloC3-Salkyl, -aryloxy, -C(O)OH, -SHCO)O(C 4-Salkyl), halogen, -MO", -CM, -50,-(C1-Salkyl) or - C(0)-(Co-SvalkyluuCo-Svalkyl);

Kz is aryl, optionally substituted with 1-5 substituents, where each substituent independently is /o aryl, heteroaryl, halogen, -MO», -C(O)OH, carbonyl, -CM, -C.4-Svalkyl . -Salkyl, amino, -OH or the group -""Co-Salkyl)uCo-Salkyl) amino, -C(0)-M (Co-Salkyl/Co-Salkyl), where each substituent is independently optionally substituted -OH, C 4-Svaloxy, -C4i-Svalky, -cycloC3-Svalky, -aryloxy, -С(О)OH, -СЩ(О)Ц(С 1-Svalky), halogen, -MO», -СМ, -504- (C4-Svalkyl) or -(0)-M(Co-SvalkylCo-Svalkyl); and n is independently equal to 0, 1 or 2.

In yet another embodiment of this aspect, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein 51, Zo, and 3 independently represent H, -OH, halogen, -C4-alkyl, -MO", -CM or - Co-Svaloxy, where the specified alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

Ki represents halogen, carbonyl, -C 1-Salkyl, - cycloC3-Salkyl, -C--Salkyl, -C-Salkyloxy, aryl, heteroaryl, -CM, -heterocycloC3-Salkyl, -amino, -C4-Salkylamino, - (C4-Salkyl) (C--Salkyl) amino, -C1-Salkyl (oxy) C-Salkyl, -C(O)MH-(aryl), -C(O)MH(heteroaryl), -504MH(aryl ), -ZO,MH (hetersoaryl), -BO4MH (C3-Svalkyl), -C(O)M(Co-Svalkyl). (Co-Salkyl),, -"MH-5O-(C4-Salkyl), -50,-(C1-Salkyl), -carbamoyl, ch two 7(C1-Salkyl)-O-C(CM)-dialkylamino or group -(C4-Svalkyl) -50,-(C4-Svalkyl), where any of the groups is optionally substituted with 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -C(0) (8) (heterocycloC3z-Salkyl), -C(0)-0-(Co-Salkyl), -C(0)-O- aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50,-(C1-Salkyl);

A is CH; is carbonyl, optionally substituted with 1 substituent, where the substituent is aryl, heteroaryl, -C(O)OH, carbonyl, -C4i-Salkyl, -O-aryl, -O-heteroaryl, -O- (Ci-Salkyl), -heterocycloC3-Salkyl, E" -MH-cycloC 3-Salkyl, amino, -OH or -(Co-Salkyl) (Co-Salkyl)uamino group, where each substituent independently is optionally substituted with -OH . -MO», -CM, -5O-(C4--Salkyl) -cycloC3-Salkyl or -F5(0) -M " zv "Co-SalkylCo-Salkyl);

Kz is aryl, optionally substituted with 1-5 substituents, where each substituent is independently aryl, heteroaryl, halogen, -MO", -С(О)OH, carbonyl, -СМ, -С4 Svalkyl, -504-( C1-Swalkyl), -50,-(aryl), -aryloxy, -O-heteroaryl, C-Swalkoxy, M-oxide, -C(0)-heterocycloC3-Swalkyl, -MH-cycloC3-Swalkyl, amino, -OH or the group -"Co-SvalkyluuSo-Svalkyl) amino, -C(O) -M(Co-Svalkyl) (Co-Svalkyl), where each substituent is independently "optionally substituted -OH, C 4-Svalkoxy, -Si- Svalky, -cycloC3-Svalky, -aryloxy, -C(O)OH, c) with -S0)O(C1-Svalky), halogen, -MO", -CM, -504-(C4-Svalky) or -C (0)-M (Co-SvalkyluCo-Svalkyl); and n is independently equal to 0, 1 or 2. and? In the next embodiment of this aspect, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, where 51, Zo, and 3 are independently H, -OH, halogen, -C4-Salkyl, -MO", -CM or - Co-Svalkoxy, where the specified -I alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent is independently halogen or OH; o Ki represents halogen, carbonyl, -C 4-Salkyl, - cycloC3-Salkyl, -Co-Salkyl, -C--Salkyl, aryl,

Go! heteroaryl, -CM, -heterocycloC3-Salkyl, -amino, -C--Salkylamino, -(C4i-Salkyl) (C--Salkyl) amino, in 7b1-Salkyl (oxy) C.i-Salkyl, -C(O )MH(aryl), -C(O)MH(heteroaryl), -ZO0MH(aryl), -ZOMHN (heteroaryl), - -VOAMN (S.i-Svalkyl), -CSO)M(Co-SvalkyluCo-Svalkyl ), -MH-5O-(C1-Salkyl), -50,4-(C4-Salkyl), -carbamoyl, sp -«-Si-Salkyl)-O-C(CM)-dialkylamino or the group -(C1- Svalkil)-50,-(С1-Svalkil), where any of the groups is optionally substituted with 1-5 substituents; where each substituent is independently halogen, -OH, -CM, -C(0) (heterocycloC3-Salkyl), -C(0)-O-(Co-Salkyl), -C(0)-O-aryl, alkoxy , cycloalkyloxy, acyl, acyloxy, - cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50,-(C--Salkyl);

A is CH; (F) K" represents carbamoyl, optionally substituted with 1-2 substituents, where each substituent independently represents carbonyl, -CM, -Ci-Salkyl, -50,-(C1-Cv-alkyl), -O- aryl, -O-heteroaryl, -C(O)-heterocycloC3-Salkyl, -MH-cycloC3-Salkyl, amino, -OH or a -C4-Salkyl (amino) group, where each substituent is independently optionally substituted -OH . );

Kz is aryl, optionally substituted with 1-5 substituents, where each substituent is independently aryl, heteroaryl, halogen, -MO», -C(O)OH, carbonyl, -CM, -C4-Salkyl, -50, -(Ci-Swalkyl), -50.-(aryl), -aryloxy, -O-heteroaryl, C-Swalkoxy, M-oxide, -C(0)-heterocycloC3-Swalkyl, -MH-cycloC3-Swalkyl, amino, 65 -OH or the group -""Co-Svalkyl)uCo-Svalkyl) amino, -С(0)-M (Co-Svalkyl/Co-Svalkyl), where each substituent is independently optionally substituted -OH, С 4-Svalkoxy , -C4i-Swalkyl, -cycloC3-Swalkyl, -aryloxy, -C(O)OH,

-ХЧО0)О(С -Svalkyl), halogen, -MO», -СМ, -504-(С4-Svalkyl) or -С(0)-М (Со-Svalkyl) (Со-Svalkyl); and n independently represents 0, 1, or 2.

In another embodiment of this aspect, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, where 51, Zo, and 3 independently represent H, -OH, halogen, -C4-Salkyl, -MO", -CM or - S.-Svalkoxy, where the indicated alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent is independently halogen or OH;

Ki is halogen, carbonyl, -C 4-Salkyl, -dicycloC3-Salkyl, -Co-Salkyl, -Co-Salkyloxy, aryl, /o Heteroaryl, -CM, -heterocycloC3-Salkyl, -amino, -Ci-Salkylamino, -(C.i-Salkyl) (C--Salkyl) amino, -C1-Salkyl (oxy) C-Salkyl, -C(O)MH-(aryl), -C(O)MH(heteroaryl), - 504MH(aryl), -ZO,MH (hetersoaryl), -50OAMH (C1-Swallyl), -C(0) M (Co-Swallyl) (Co-Swallyl), -"MH-50,-(C1-Swallyl) . - which of the groups is optionally replaced by 1-5 substitutes; where each substituent independently represents a halogen, -OH, -CM, -C(O) 7/5 (heterocycloCu-Salkyl), -C(O)-O-(Co-Salkyl), -C(O)-O-aryl , alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50,-(C1-Salkyl);

A is CH;

E" and Kz each independently represent an optionally substituted aryl, connected to each other by a thio, oxy or (C4-C.alkyl) bridge to form a condensed three-ring system; and n is independently 0, 1, or 2.

In yet another embodiment of this aspect, the compound of the present invention is represented by the formula (I) or a pharmaceutically acceptable salt thereof, where 51, 5", and 33 independently represent H, -OH, halogen, -C4-alkyl, -MO", -CM or -C4-Svalcoxy;

Ki is a halogen, carbonyl, -C 4-Salkyl, -dicloC3-Salkyl, -Co-Salkyl, -C.-Salkyloxy, aryl, sc sov Heteroaryl, -CM, -heterocycloC3-Salkyl, amino, -C.4- Swallylamino, -(C--Swallyl)u (C.--Swallyl) amino, -C1-Swallyl (oxy) S.i-Swallyl, -C(O)MH(aryl), -C(O)MH( heteroaryl), -504MH(aryl), -ZO,MH (hetersoaryl), and) -5B0IMH (S.i-Svalkyl), -C(0) M (Co-Svalkyl) (Co-Svalkyl),, -MH- 5O-(C1-Salkyl), -504-(C1-Salkyl), -carbamoyl, -(Si-Salkyl) -0O-C(CM) -dialkylamino or the group -(C4i-Salkyl)-ZO,-(Si- Svalkil) where any of the groups is optionally replaced by 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -C(O) or zo (heterocycloCu-Salkyl), -C(O)-O-(Co-Salkyl), -C(O)-O-aryl . --

A is CH; co

Co represents -(C 4-Svalkyl)u -50,-(C4-Svalkyl), optionally substituted with 1-5 substituents, where each substituent is independently a halogen, -MO 5", -СООН, carbonyl, -СМ . - -S.-Svalkyl (amino), where each substituent is independently optionally substituted by -OH, -O (C 4-Svalkyl), -O(aryl), -СОоОН, -СОО (S.-Svalkyl), halogen, -MO», -SM or C(O)-M(Co-SvalkyluUSo-Svalkyl);

Kz is aryl, optionally substituted with 1-5 substituents, where each substituent is independently aryl, heteroaryl, halogen, -MO», -C(O)OH, carbonyl, -CM, -C4-Salkyl, -50, -(Ci-Salkyl), -50.-(aryl), « aryloxy, -O-heteroaryl, Si-Salkyloxy, M-oxide, -C(O)-heterocycloC3z-Salkyl, -MH-cycloC3-Salkyl, amino, st») with -OH or the group (Co-Svalkyl/Co-Svalkyl)amino, -C(0)-M(Co-SvalkylSo-Svalkyl), where each substituent independently. optionally substituted by -OH, C 4-Salkyloxy, -Ci-Salkyl, cycloC3-Salkyl, -aryloxy, -C(O)OH, and? -CH0)O(C 1-Svalkyl), halogen, -MO», -SM, -504-(C1-Svalkyl) or -C(O)-M(Co-Svalkyl) (Co-Svalkyl); and n is independently 0, 1, or 2.

In another embodiment of this aspect, the compound of the present invention is represented by the formula (I) or its -I pharmaceutically acceptable salt, where 51, Zo, and 33 independently represent H, -OH, halogen, C 4-Svalkyl, -MO", - SM or C.-Svalkoxy, where the indicated alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

Ki is halogen, carbonyl, -C 4-Salkyl, -dicycloC3-Salkyl, -Co-Salkyl, -C-Salkyloxy, aryl, - heteroaryl, -CM, -heterocycloC3-Salkyl, -amino, -C--Salkylamino . 504MH(aryl), -50,MH(heteroaryl), -VOAMN (S.i-Svalkyl),, -ССО)M(Co-SvalkyluCo-Svalkyl), -MH-5O-(C1-Svalkyl), -50, 4-(C4-Salkyl), -carbamoyl, -«-Ci-Salkyl)-O-C(CM)-dialkylamino or -(C1-Salkyl)-50,-(C1-Salkyl), where any of groups optionally replaced by 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -C(0) (heterocycloC3-Salkyl), -C(0)-0O-(Co-Salkyl), -C (0)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -

F) cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or 50,-(C1-Salkyl); ka A is CH;

Co is -C(0)M-(C o-Svalkyl/uCo-Svalkyl), optionally substituted with 1-5 substituents, where each substituent is independently a halogen, -MO 5", -СООН, carbonyl, - CM, -C4-Salkyl, -50-(C4-Salkyl), aryloxy, -heteroaryloxy, -C(O)-heterocycloC3-Salkyl, -MH-cycloC3-Salkyl, amino, -OH or -C.-Salkyl ( amino), where each substituent is independently optionally substituted by -OH, -FO(C 4-Svalkyl), -O (aryl), -СООН, -СОО (С.-Svalkyl), halogen, -MO", -OM or C(O0)-(Co-Svalkyl) (Co-Svalkyl);

Kz is aryl, optionally substituted with 1-5 substituents, where each substituent is independently 65 aryl, heteroaryl, halogen, -MO", -C(O)OH, carbonyl, -CM, -C.4-Salkyl, -50,-(C--Calkyl), -5O,-(aryl), -aryloxy, -O-heteroaryl, C--Calkoxy, M-oxide, -C(O)-heterocycloC3-Cv-alkyl, -MH -cycloC3-Svalkyl, amino,

-OH or group (Co-Salkyl) (Co-Salkyl) amino, -C(0)-M(Co-SalkylCo-Salkyl), where each substituent is independently optionally substituted -OH, C 4-Salkyloxy, -C4i- Swalkyl, -cycloC3-Swalkyl, -aryloxy, -C(O)OH, -SHCO)O(C 1-Swalkyl), halogen, -MO", -CM, -504-(C4-Swalkyl) or -C(O ) -M (So-Svalkil) (So-Svalkil); and n is independently 0, 1, or 2.

In yet another embodiment of this aspect, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, where 51, Zo, and Za independently represent H, -OH, halogen, -C 1-Svalkyl, -MO», -SM or C.-Svalkoxy, where the indicated alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents /o hapogen or OH;

Ki is halogen, carbonyl, -C 4-Salkyl, -dicycloC3-Salkyl, -Co-Salkyl, -C-Salkyloxy, aryl, heteroaryl, -CM, -heterocycloC3-Salkyl, -amino, -C--Salkylamino, -(C4i-Salkyl) (C--Salkyl) amino, -C1i-Salkyl (oxy) C.i-Salkyl, -C(O)MH(aryl), -C(O)MH(heteroaryl), -500MH ( aryl), -50,MH (heteroaryl), -5B0IMH (S.i-Svalkyl), -C(0) M (Co-Svalkyl) (Co-Svalkyl),, -MH-5O-(C1-Svalkyl), -504-(C1-Svalkyl), -carbamoyl, 75 7ХС1-Svalkyl) -О-С(СМ) -dialkylamino or the group -(С4-Svalkyl)u -50,-(Ci-Svalkyl) where any of the groups optionally substituted with 1-5 substituents; where each substituent is independently halogen, -OH, -CM, -C(O) (heterocycloC3-Salkyl), -C(0)-O-(Co-Salkyl), -C(0)-O-aryl, alkoxy , cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or 5O,-(C--Salkyl);

A is CH;

E" represents -CM;

Kz is aryl, optionally substituted with 1-5 substituents, where each substituent is independently aryl, heteroaryl, halogen, -MO», -C(O)OH, carbonyl, -CM, -S.-Svalkyl, -50 ,-(C4-Swalkyl), -50,-( aryl), -aryloxy, -O-heteroaryl, C-Swalkoxy, M-oxide, -C(0)-heterocycloC3-Swalkyl, -MH-cycloC3-Swalkyl, amino . , -cycloC3-Salkyl, -aryloxy, -C(O)OH, -ЧО0)О(С -Salkyl), halogen, -MO», -СМ, -504-(С4-Salkyl) or -С(0)- M (So-Svalkil) (So-Svalkil); and i) n is independently equal to 0, 1 or 2.

In yet another embodiment of this aspect, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, where zo 51, Zo, and 3 independently represent H, -OH, halogen, -C4-Svalkyl, -MO", -SM or C.i-Svalkoxy, where the indicated alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents -- halogen or OH; co

Ku represents -S.-Svalkil, optionally substituted with 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -C4-Salkyl, -dicycloC3-Salkyl, -C(O) (heterocycloC3-Salkyl), -C(0)-O-(Co-Salkyl), " -SF(O)-aryloxy, -Ci-Salkyloxy, -(Co-Salkyl) (Co-Salkyl) amino, cycloalkyloxy, acyl, acyloxy, y- -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or 5O,-(S.--Svalkil);

A is SN,

Ko" and Kz are each independently aryl or heteroaryl, where each is optionally substituted with 1-5 substituents, where each substituent is independently aryl, heteroaryl, halogen, -MO 5", -C(O)OH, carbonyl, " 400 EM, -C1-Svalkyl, -ZO4-(C4-Svalkyl), -5Op-(aryl), aryloxy, -heteroaryloxy, C.--Svalkyloxy, M-oxide, -C(0) n s -heterocycloC3-Svalkyl , -MH-cycloC3-Salkyl, amino, -OH or the group -(Co-Salkyl/Co-Salkyl) amino, -C(0)-M. (Co-Svalkyl)/Co-Svalkyl), where each substituent is independently optionally substituted -OH, С 4-Svalkoxy, and? -C1-Svalkyl, -cycloC3-Svalkyl, aryloxy, -C(O)OH, -C(0)O(C.i-Svalkyl), halogen, -MO», -CM, -50-(C1-Svalkyl) or -C(0)-M(Co-SvalkylCo-Svalkyl);

Ko" and Kz can optionally be connected by a thio, oxy or (C 4-Slalkyl) bridge with the formation of a -I condensed three-ring system; and n is independently equal to 0, 1 or 2; In yet another embodiment of this aspect, the compound of the present invention is represented by formula (I) or its pharmaceutically acceptable salt, where 51, 5", and C3 each represent H; - Ku represent -C 4-Svalkyl, optionally substituted with 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -C 4-Salkyl, -dicycloC3-Salkyl, -C(O) (heterocycloC3-Salkyl), -C(O) -0- (Co-Salkyl) . or 5О,-(С.--Svalkil); 5БА is CH,

Ko" and Kz each independently represents aryl or heteroaryl, where each is optionally substituted with 1-5 (F) substituents, where each substituent independently represents aryl, heteroaryl, halogen, -MO", -CHO)OYN, ka carbonyl, - CM, -C4-Svalkyl, -50,-(C1-Svalkyl), -5O,-(aryl), aryloxy, -heteroaryloxy, C-Svaloxy, M-oxide, -F(0)-heterocycloC3-Svalkyl, -МН -cycloC3-Salkyl, amino, -OH or the group -(Co-Salkyl) (Co-Salkyl) amino, in 7 E(0)-MS(Co-Salkyl)uCo-Salkyl), where each substituent is independently optionally substituted -OH, C 4-Swalkyl, -C1-Swalkyl, -cycloC3-Swalkyl, aryloxy, -C(O)OH, -C(0)O(S.i-Swalkyl), halogen, -MO», -SM, -504-(C4-Svalkyl) or -C(0)-M(Co-Svalkyl)HuCo-Svalkyl);

Co and Kz may optionally be linked by means of a thio, oxy or (C --C;alkyl) bridge to form a condensed three-ring system; and 65 n is independently equal to 0, 1, or 2.

As used herein, "alkyl" as well as other groups prefixed with "alk" such as, for example, alkoxy,

alkanoyl, alkenyl, alkynyl and the like mean carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other similar terms

Include carbon chains containing at least one unsaturated C-C bond.

The term "cycloalkyl" refers to carbocycles that do not contain heteroatoms and includes mono-, 6- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems may include one ring that is partially or fully unsaturated, such as a benzene ring, to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such 7/0 fused ring systems as spiro fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene, and the like. Similarly, "cycloalkenyl" means carbocycles that do not contain heteroatoms and that contain at least one non-aromatic C-C double bond, and include mono-, 6- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl /5 include cyclohexenyl, indenyl and the like.

The term "cycloalkyloxy", unless otherwise specifically defined, includes a cycloalkyl group attached to the oxy linking atom.

The term "Alkoxy7", unless otherwise specified, includes an alkyl group attached to the oxy linking atom.

The term "aryl", unless otherwise specifically defined, includes polyring systems as well as monoring systems, such as, for example, phenyl or naphthyl.

The term "aryloxy"7, unless specifically defined otherwise, includes polyring systems as well as monoring systems, such as, for example, phenyl or naphthyl, attached through an oxy linking atom to the site of attachment. with

The term "Co-alkyl" includes alkyls containing 6, 5, 4, 3,2, 1 or no carbon atoms.

Alkyl, which does not contain carbon atoms, is a substitute for a hydrogen atom or a direct bond, depending on (8) whether the alkyl is a terminal or bridging group.

The term "hetero", unless otherwise specifically defined, includes one or more O, 5 or M atoms.

For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more 0, 3, or M atoms in the ring, including mixtures of such atoms. Heteroatoms replace the carbon atoms of the ring.

Thus, for example, heterocyclo-Svalkyl is a five-membered ring containing from 5 to 0 carbon atoms. co

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

The term "heteroaryloxy", unless otherwise specifically defined, describes a heteroaryl group attached through an oxy linking atom to the site of attachment.

Examples of heteroaryl(Ci)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, trizolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, with pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, ppyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl. and quinoxalinylmethyl.

Examples of heterocycloSalkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, -I piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-OH, piperidin-2-OH and thiomorpholinyl.

Examples of aryl(C.C)alkyl include, for example, phenyl (C.C)alkyl and naphthyl (C.C)alkyl. Examples of heterocycloC3-7alkylcarbonyl(C1.c)alkyl include, for example,

Go! azetidinylcarbonyl(C 4 c)alkyl, pyrrolidinylcarbonyl(C c)alkyl, piperidinylcarbonyl(C c)alkyl, piperazinylcarbonyl(C 4 d)alkyl, morpholinylcarbonyl(C c)alkyl and thiomorpholinylcarbonyl(C c)alkyl. - The term "amine", unless otherwise specifically defined, includes primary, secondary and tertiary amines. sp Unless otherwise defined, the term "carbamoyl" includes -MHC(O)OC.-Sulfyl and -0OC(0)MHC. - Sualkil.

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

The term "optionally substituted" is intended to mean both substituted and unsubstituted. In these two ways, for example, an optionally substituted aryl can be a pentafluorophenyl or a phenyl ring.

In addition, substitution can be made in any group. For example, substituted aryl(C 4 c)alkyl includes

F) substitution in the aryl group, as well as substitution in the alkyl group. ka The compounds described here contain one or more double bonds and this may be the reason for the existence of cis/gtrans isomers, as well as other conformational isomers. The present invention includes all such possible isomers, as well as mixtures of such isomers.

The compounds described here may contain one or more asymmetric centers and this may be the reason for the existence of diastereomers and optical isomers. The present invention includes all such possible diastereomers, as well as their racemic mixtures, their essentially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts. The aforementioned formula | presented without specifying the stereochemistry of some 65 positions. The present invention includes all stereoisomers of formula I and their pharmaceutically acceptable salts. In addition, both mixtures of stereoisomers and isolated specific stereoisomers are also included. In the process of synthetic methods used to obtain such compounds, or when using processes of racemization or epimerization known to specialists in this area, the products of such processes can be in the form of a mixture of stereoisomers.

The term "pharmaceutically acceptable salts" refers to salts obtained from pharmaceutically acceptable non-toxic bases or acids. When a compound of the present invention is acidic, its corresponding salt may be suitably prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts obtained from such inorganic bases include salts of aluminum, ammonium, calcium, copper (I and 1), iron (I), iron (I), lithium, magnesium, manganese (I and IM), potassium, sodium, zinc and more like that. Particularly preferred are 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 natural and substituted amines, which are synthesized.

Other pharmaceutically acceptable organic non-toxic bases from which the salts may be derived include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, M,M'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, M-ethylmorpholine,

M-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When a compound of the present invention is a base, its corresponding salt may be suitably prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrogen bromide, hydrogen chloride, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, nitric, palmic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrogen chloride, maleic, phosphoric, sulfuric and tartaric acids.

Pharmaceutical compositions according to the present invention include, as an active substance, a compound represented by i) formula I! (or its pharmaceutically acceptable salts), a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, i) leukotriene biosynthesis inhibitors, i) corticosteroids, i) NO receptor antagonists, M) beta 2 adrenoceptor agonists, i) selective COX-2 inhibitors, i) statins , my) nonsteroidal anti-inflammatory drugs (NSAID3) and their) M2/M3 antagonists. The compositions include "XU" compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most appropriate route in any given case will depend on the particular patient and the nature and severity of the condition a disease in which the active substance is administered. Pharmaceutical compositions can be conveniently presented in the form of a standard dosage form and obtained by any method well known in the field of pharmaceuticals.

For local use, creams, ointments, jellies, solutions or suspensions containing compounds of formula I can be used. Mouth and throat rinses are included in the scope of local use according to the present invention.

Dose levels from about 0.001mg/kg to 14O0mg/mg body weight per day can be used in the treatment of over 70 conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic cs granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related conditions such as laminitis and equine colic), septic shock, ulcerative colitis, Crohn's disease, ;" myocardial and brain damage related to blood supply, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atonic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, graft rejection and graft-versus-host disease, hypersecretion of gastric juice, sepsis or septic shock caused by

Go! bacterial, fungal and viral infection, inflammation and cytokine-related chronic tissue degeneration, 5-year osteoarthritis, cancer, cachexia, muscle weakness, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with an inflammatory component, Parkinson's disease, Alzheimer's disease, spinal cord injury, head trauma, multiple sclerosis, tumor growth, and cancerous invasion of normal tissue that are sensitive to PDE4 inhibition, or alternatively, from about 0.05 mg to about 7 g per patient per day. For example, inflammation can be effectively treated by administering from about 0.01mg to 5Omg of the compound per kilogram of body weight per day or, alternatively, from about 0.5mg to about 2.5g per patient per day. In addition, it is clear that the PDE4-inhibiting compounds of the present invention can be administered to

F) prophylactically effective dose levels for the prevention of the aforementioned conditions. The amount of active substance that can be combined with the carrier substance to form a single dosage form can vary depending on the subject being treated and the specific route of administration. For example, a composition intended for oral administration to a human may conveniently contain from about 0.5 mg to about 5 g of the active ingredient together with a suitable and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. Standard dosage forms will usually contain from about 0.0 mg to about 100 mg of the active substance, usually 0.01 mg, 0.05 mg, 0.25 mg, mg, B5 mg, 25 mg,

Bomg, 10Omg, 200mg, 30Omg, 40Omg, 50Omg, b0Omg, v0Omg or 100Omg. 65 However, it is clear that the specific dose level for an individual patient will depend on a variety of factors, including age, body weight, general condition, sex, diet, time of administration, routes of administration, rate of elimination, combination with another medicinal product, and the severity of a given disease, which undergoing treatment

In practice, the compounds represented by formula I or their pharmaceutically acceptable salts according to the present invention as an active ingredient can be combined into a homogeneous mixture with a pharmaceutical carrier in accordance with conventional pharmaceutical methods of obtaining compositions.

The carrier can be selected from a wide variety of forms, depending on the form of the desired drug for administration, for example, oral or parenteral (including intravenous). Thus, the pharmaceutical compositions according to the present invention can be presented as discrete units suitable for oral administration, such as capsules, porridges or tablets, each containing a predetermined amount /o of the active substance. In addition, the compositions can be presented in the form of powders, in the form of granules, in the form of a solution, in the form of a suspension in an aqueous liquid, in the form of a non-aqueous liquid, in the form of an "oil-in-driver" emulsion or in the form of a "water-in-oil" emulsion. In addition to the usual dosage forms indicated above, the compound represented by the formula !, or its pharmaceutically acceptable salts may also be administered by controlled release and/or delivery methods. The compositions may be prepared by any of the pharmaceutical methods. Such methods usually include an association step an active ingredient and a carrier which consists of one or more of the necessary ingredients. Naturally, the compositions are obtained by homogeneously and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both. The product can then be suitably shaped into the desired form.

Thus, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of formula I. Compounds of the formula | or their pharmaceutically acceptable salts can also be part of pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used can be, for example, a solid, liquid or gas.

Examples of solid carriers include lactose, white clay, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut butter, olive oil, and water.

Examples of gaseous carriers include carbon dioxide and nitrogen.

Any conventional pharmaceutical medium can be used to prepare the compositions for oral dosage form. For example, for oral liquid medicinal preparations such as oral suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavors, preservatives, dyes and the like may be used; whereas for solid oral dosage forms such as powders, capsules and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like may be used . The preferred oral standard dosage forms are tablets and "

Since capsules are easy to administer, solid pharmaceutical carriers are used. Optionally, the tablets may be coated using standard aqueous or non-aqueous methods.

A tablet containing a composition according to the present invention can be obtained by compression or molding, optionally with one or more additional ingredients or adjuvants. Compressed tablets can be obtained by pressing, in a suitable machine, the active substance in a loose form, such as powder or granules, optionally mixed with a binding agent, a lubricant, an inert diluent, a surfactant or a dispersing agent. Molded tablets can be obtained. by forming in a suitable machine a mixture of compound powder moistened with an inert liquid diluent. Each and the tablet preferably contains from about 0.1mg to about 50Omg of the active substance, and each porridge or capsule preferably contains from about 0.1mg to about 50Omg of the active substance.

Pharmaceutical compositions according to the present invention, suitable for parenteral administration, can be obtained in the form of solutions or suspensions of active compounds in water. A suitable surface-active compound such as, for example, hydroxypropyldelulose may be included. Dispersions can also be obtained in glycerol, liquid polyethylene glycols and their mixtures in oils. In addition, a preservative may be included

Go! to prevent the harmful growth of microorganisms.

Pharmaceutical compositions according to the present invention, suitable for use as injections, include sterile - aqueous solutions or dispersions. In addition, the compositions can be in the form of sterile powders for the preparation of sp before the direct use of such sterile solutions and dispersions for injection. In any case, the final form for injection should be sterile and should be liquid enough to be easily injected via syringe. Pharmaceutical compositions must be stable under production and storage conditions; thus, preferably, they should be protected from the harmful effects of microorganisms, such as bacteria and fungus. The carrier can be a solvent or dispersion medium containing, for example, water,

F) ethanol, polyol (for example, glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils and their respective mixtures.

The pharmaceutical compositions according to the present invention can be in a form suitable for local use, such as, for example, an aerosol, cream, ointment, lotion, powder in the form of a powder or the like. Additionally, the compositions may be formulated in a form suitable for use in transdermal delivery devices. These preparations can be prepared using the compound represented by the formula | according to the present invention, or its pharmaceutically acceptable salts, by conventional technological techniques. As an example, a cream or ointment is obtained by mixing a hydrophilic substance and water together with about 5 wt. 906 to about 65 1Omas. 95 compound to obtain a cream or ointment having the desired consistency.

Pharmaceutical compositions according to the present invention can be in a form suitable for rectal administration,

where the carrier is a solid. It is preferable to prepare suppositories in the form of a single dose from the mixture. Suitable carriers include cocoa butter and other substances commonly used in the art. Suppositories can be conveniently manufactured by first mixing the composition with an emollient or Dosed carrier(s) and then cooling and shaping in molds.

In addition to the aforementioned carrier ingredients, the pharmaceutical compositions described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binding agents, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. In addition, other adjuvants may be included to render the 7/0 Composition isotonic with respect to blood and the intended recipient. Compositions containing a compound described by formula I or its pharmaceutically acceptable salts may also be prepared in the form of a powder or a liquid concentrate.

It was found that the compounds and pharmaceutical compositions according to the present invention are biologically active as inhibitors

FDEIA4. Accordingly, another aspect of the invention is the treatment in mammals of, for example, asthma, chronic bronchitis, 7/5 chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related conditions, such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain damage related to the blood supply, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atonic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress 2 about bindrom in infants, chronic obstructive disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and reactions" graft against the host", hypersecretion of gastric so sepsis or septic shock caused by bacterial, fungal and viral infection, inflammation and cytokine-related chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle weakness, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with an inflammatory component, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancerous invasion of normal tissue, diseases that could be alleviated by inhibiting the PDEAA isoenzyme and by reducing the levels of CAMP with the introduction of effective quantities of compounds according to the present invention. The term "mammals" includes humans as well as animals such as, for example, dogs, cats, horses, pigs and cattle. Accordingly, it is clear that the treatment of mammals, excluding humans, is the treatment of diseases clinically correlated with the above examples of human diseases. co

Further, as described above, the compound of the present invention may be used in combination with other therapeutic compounds. In particular, combinations of compounds that inhibit PDE4 according to the present invention can be appropriately used in combination with i) leukotriene receptor antagonists, i) inhibitors of i- leukotriene biosynthesis, i) selective COX-2 inhibitors, i) statins, M) NSAIDs ii mi) antagonists

M2/M3, mi) corticosteroids, mii) NO (histamine) receptor antagonists and their) beta 2 adrenoceptor agonists.

In another aspect, it has been found that a compound of the present invention can be formed as a metabolite in a mammalian system. For example, the compound according to example 19, « 40. 5-SHE)-2-(3-6-11-methyl-1-(methylsulfonyl)ethyl)-8-quinolinylphenyl)-1-I(4-(methyl-sulfonyl) phenyl|vinyl)-1,2,4-0 with cxadiazole-3-yl)umethanol: ;» -I sh" (ee) - 50 sl

F) name) 60 b5 no o re pn 5 SN. with 5 2 СН » M and F 7 o m o. M-- ch 5 o not

With in! which is an inhibitor of PDEIA4, is formed as a secondary metabolite when the compound of example 14 is administered: o

NS o iy i s ts n, 57o « | M: in M.

M СНа "shi s;" -I i so M - Ot -sn ; With s o o ' r: sho

Accordingly, the present invention includes prodrugs that spontaneously form PDE4 inhibitors as a metabolite following administration of such prodrugs to a mammal. In addition, the present invention includes a method of treatment by introducing prodrugs with the formation of an effective amount of the PDE4 inhibitor described by formula I.

Abbreviations used in this description have the following meanings presented in the table.

Abbreviations not shown in the table below have the usual meaning used, unless specifically defined otherwise. b5

Vp - Benzyl yu z yu zh o yu zo - zv m « 2 z s sh ' - m zo z yu s lo yo 60 Studies demonstrating biological activity

Quantitative IR and EMI analysis of R-induced TMP-A and ITV4 in human blood

Whole blood provides a protein and cell-rich environment suitable for studying the biochemical efficacy of anti-inflammatory compounds such as POE4-selective inhibitors. Normal, unstimulated human blood does not contain detectable levels of TME-A and HTV4. Upon stimulation of I P5, activated 65 monocytes are expressed and TME-a is secreted for up to 8 hours, and plasma levels remain stable for 24 hours. In published studies, it has been shown that inhibition of TME-a by increasing intracellular CAMP by inhibiting PDEA and/or enhancing adenyl cyclase activity occurs at the transcriptional level. Synthesis

And T84 is also sensitive to the levels of intracellular CAMP and can be completely inhibited by PVE4-selective inhibitors. Since within 24 hours, ІТ84 slightly stimulates АРЖ in whole blood, for the synthesis of ІТВ4 by activated neutrophils, additional stimulation of І РІ after stimulation of YAMI R of human whole blood is necessary. Thus, using the same blood sample, it is possible to evaluate the effect of the compound on the activity of two PDEA replacement marker genes in whole blood according to the following method.

Fresh blood was collected in heparin-containing tubes by venipuncture of healthy volunteers (men and women). These subjects had no obvious inflammatory conditions and had not taken any NSAIDs (MAU) for at least 70 4 days prior to blood sampling. Blood aliquots of 50 μl were pre-incubated either with 2 μl of the carrier (DMSO) or with 2 μl of the compound under study at different concentrations for 15 minutes at 37 2C. After that, either 1 omcl of vehicle (PB5) was added as a control, or 1 omcl of I P5 (final concentration Tmkg/ml; I! -2630 bidt

Spetis! So., 5. I otsiv, MO) with E. soii, serotype 0111:84; dilution in 0.195 mass/vol. VZA (in RV5)). After 24 hours after incubation at 372, another 1 μl of RVZ (control) or 10 μl of IR (final concentration of μg/ml) was added to the blood and 75 was incubated for 30 minutes at 372C. The blood was then stimulated with either 10 μl RVZ (control) or 100 μl MI R (final concentration tmM; 2E-3506 (Zidta); dilution in 195 wt/vol. VZA (in RV5)) for 15 minutes at 3720. Blood samples were centrifuged at 1500 d for 10 minutes at 42C to obtain plasma. A 5μl aliquot of plasma was mixed with 200μl of methanol for protein precipitation and centrifuged as described above.

The supernatant was analyzed for ITV4 using an immunoassay enzyme kit (2520111 from Southap Spetisai

So., App Agrog, MI) according to the technological method. TME-A was analyzed in diluted plasma (in RV5) using the EGISA kit (Sivigop Vioiespoiodu, Ripe VgooK, M) according to the technological method.

The IS values of examples 1-42 usually ranged from О0.04 mm to 8.71 mm.

Antiallergic activity of ip mimo

The compounds of the invention were tested for their effect on allergic lung inflammation caused by ISE induced by antigen inhalation in sensitized guinea pigs. Guinea pigs were first sensitized to ovalbumin under moderate cyclophosphamine-induced immunosuppression by intraperitoneal injection of the antigen in combination with aluminum oxide and pertussis vaccine. Stimulating doses of antigen were administered after two and four weeks. On the sixth week, animals were stimulated with aerosolized ovalbumin simultaneously with intraperitoneal administration of an antihistamine agent (mepyramine). Another 48 hours later, bronchial alveolar lavage (BAL) was performed and the number of eosinophils and other leukocytes in BAL fluids was counted. "-

Lungs were also removed for histological examination for inflammatory damage. Administration of the compounds of the examples (0.001-10mg/kg i.r. or p.o.) up to three times within 48 hours after antigenic stimulation led to d) a significant decrease in eosinophils and the accumulation of other inflammatory leukocytes. Also, the animals that were injected with the compounds of the examples had less inflammatory damage to the lungs.

Research protocol of 5RA based on the activity of ROE and

Compounds that inhibit the hydrolysis of CAMP to AMP by CAMP-specific phosphodiethylesterase type IM were tested in a 96-well plate as follows:

On a 9b-well plate at 302С, the compound under study was applied (dissolved in 2 μl of DMSO), 188 ml of "substrate buffer containing 12,8-ZNIadenosine 3", 5'-cyclic phosphate (CAMP, from TO0OHM to 5ΩmM), 10 mM

Masi", 1 mM EDTA, 50 mM TCs, pH 7.5. The reaction was initiated by the addition of 100 ml of human recombinant POE4 o, s (the amount was controlled in such a way that 1095 of the product was formed within 10 minutes). The reaction "" was stopped after 10 minutes by adding 1 mg of glass beads (Ategepat Rnagptasia Vioyesi, Ips., Rizsaijau, M).

Umaijas So., Zaipegsrygo, MO). The signal in the presence of the enzyme was determined as background. 100905 activity was determined as the signal detected in the presence of the enzyme and DMSO, subtracting the background. The percentage of inhibition was calculated accordingly. IC values 5) were approximated by non-linear regression using the equation of their standard 4-parameter/multiplet binding site from ten titration points.

The value of ISvo in examples 1-42 was determined with 100NM CMR, using the purified C5T-related protein of human recombinant phosphodiesterase Ma (tei-248), obtained from the express system baculovirus/81-9. --3 20 ICeo values in Examples 1-42 are usually in the range from 0.14nM to 10.24nM, although one example had an ICeo value equal to T09NM. The following examples are provided to illustrate certain preferred embodiments of the invention and are not intended to limit the invention.

Unless otherwise specified, experimental methods were performed under the following conditions. All operations 22 were carried out at room temperature or at ambient temperature, namely: at

GF! temperature that is in the region from 18-25 Sat. Evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (6004000 pascals: 4.5-30 mm Hg) at a bath temperature of 6090 o After the reaction, thin layer chromatography (TLC) was performed, and the reaction time is indicated for illustration only. Melting points are given in intervals and 4" means decomposition. Melting points given are obtained 60 for substances prepared as described. In some preparations, polymorphism can lead to separation of substances with different melting points. The structure and degree of purification of all final products were confirmed, at least , by one of the following methods: TLC, mass spectroscopy, nuclear magnetic resonance (NMR) spectrum, or microanalytical data. The output is for illustrative purposes only. If specified, the data

NMRs are presented as delta (5) values for the main diagnostic protons, given in 62 parts per million (ppm) relative to tetramethylsilane (TM5) as an internal standard, determined at ZOOMHz, 400MHz or

BOOMHz using an indicator solvent. The usual abbreviations are given for the signal peaks: p. singlet; d. doublet; t. triplet; m. multiplet; width, widened; and so on. In addition, "Ag" means an aroma signal. Chemical symbols have their usual meanings; the following abbreviations were also used: vol. (volume), mass (mass), boiling point (boiling point), m.p. (melting point), l (liter(s)), ml (milliliters), g (gram(s)), mg (milligrams), mol (moles), mmol (millimoles), eq. (equivalent(s)).

Methods of synthesis

The compounds of the present invention can be prepared according to the following methods. Substituents are the same as in Formula I unless otherwise specified. 70 Scheme 1

Synthesis of ketones

XAH 1 Age ovo BenAgNYA

AH U

M

I. The base or , | y I. Base or g her sp ich I tem HA organolithium compound 2. Rab A n 3. Base or dim A lithium organocompound cm tni tt pni SHO

Vi A about zZMe

IS)

ON ra o

A «- ov A so 50Me

U i - 0) "about 50.Me " with Mp o s de a x halogen, H ," U halogen, H

A - 4-(methylthio)benzaldehyde

E - electrophile - and Ag - aryl or heteroaryl 1» According to scheme 1 above and the table according to scheme 1 below, the intermediate alcohol compound II can be obtained by the interaction of a metal-derived aryl or heteroaryl PS, such as a halide of an organomagnesium compound, with (ee) 4- (methylthio)benzaldehyde (A) in an organic solvent such as THF. The alcohol intermediate II can also be prepared by treating an aryl or heteroaryl hydride or bromide IM with a base or an organometallic compound such as n-butyllithium in an organic solvent such as THF and then with sl 4-(methylthio)benzaldehyde. Alternatively, intermediate alcohol compound II can also be obtained by the following chemical transformations: 1) treatment of aryl- or heteroaryl dihydrogen, halide or dihalide of compound M with a base or an organometallic compound such as n-butyllithium in an organic solvent such as THF, then with an electrophile, such as acetone or 4-(methylthio)benzaldehyde; 2) By successive treatment with a base or an organometallic compound such as n-butyllithium in an organic solvent such as

THF, then an electrophile such as acetone or 4-(methylthio)benzaldehyde, where in the first or second transformation, 4-(methylthio)benzaldehyde must be used as the electrophile. Sulfone-alcohol MI can be obtained by oxidation of sulfide-alcohol I with an oxidant such as oxone in a solvent such as a mixture of THF/MEON/H»OO. Ketones MI! and MI can be obtained by oxidation of alcohols, II and MI, respectively, with an oxidizing agent such as MpO" in a solvent such as СНоСиИ". Sulfone-ketone MIII can also be prepared by oxidation of sulfide-ketone MIII with an oxidant such as oxone in a solvent such as a mixture of TTF/MEOSN/H2»O.

Scheme table:

Ketones b5 and Khv

ZOOMe t U (p-2)

DE " Ketone Ag by Ketone

Y, pd inn pi pdv pnia pini z zal llllnlannnnitnyayai vdan lllly p llllllli laziness no and papi ish tires in yo 4 n 2 Kk n 2 Kk nos

Mosn A: sne de 2 YO K2 2 Ka

Power Sn, y Y 2 KZ 2 koyuzo mmeO»U U - s p o ka 2 ch mi 2 ko

M 2 KB a -

1

With 5 - in 2 ke vo com a Ky s " M N with I i in.

Ketone KI (4-Fluorophenyl)|(4-(methylsulfonyl)|phenylketone - and Ketone KI was obtained in the following way. 1» Stage 1: (4-Fluorophenyl)|(4-methylthio)phenyl|ketone

To a solution of 4-(methylthio)benzaldehyde (2.5g, 16.4mmol) in THF (100ml) at -78C, 4-fluorophenylmagnesium bromide (ee) (1.0M in THF, 19.7ml, 19.7mmol) was added dropwise. . The resulting solution was stirred at -782C for 3 -1 270 hours and quenched with a saturated aqueous solution of MNASI. Then the mixture was diluted with E(SO4 and 1090HCl), extracted and washed with (MannHsSoO»z (sat.), saturated saline solution). The organic phase was dried over MoS, and the solution was concentrated. Then the precipitate was treated with MpO» (28.6 g, 33 mmol) in СНоС » (15Oml) and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a plug of silica gel (E(OAc) to give 2.6 bg of (4-fluorophenyl)|(4-methylthio)phenyl)|ketone compound. oo Stage 2 : (4-Fluorophenyl)|(4-(methylsulfonyl)phenyl|ketone o To a sulfide solution, specifically (4-fluorophenyl)(4-methylthio)phenyl|iketone, from stage 1 (2.0g, 8.1mmol) in tgF /Meon/NOO (80/40/40ml) was added oxone (7.5g, 12.2mmol). The mixture was stirred at room temperature for 4 hours, quenched with Manceau with (sat.) and diluted with EtOAc. The organic phase was washed with Manceau with ( sat.), saturated saline solution, dried over Ma»5O), filtered and concentrated. Crystallization (CH2SiO/hexane) gave (4-fluorophenyl)(4-(methylsulfonyl)phenyl|ketone, ketone compound KI, in the form of a white solidsubstances

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

Ketone K2 was obtained in the following way. b5 Stage 1: (1-methyl-1H-imidazol-2-yl)I(4-(methylthio)phenyl|-methanol

n-butyllithium (2.5 M in hexane, 48.7 ml, 118 mmol) was added dropwise to a solution of M-methylimidazole (10.0 g, 122 mmol) in 5000 ml of THF at -782С and the resulting solution was stirred at -782С for 30 minutes. Then 4-(methylthio)benzaldehyde (14.7 mL, 110 mmol) was added at -782C, and the mixture was stirred until the reaction was complete according to

TSH and extinguished MNASI (sat.). Then the mixture was diluted with E(Ac, extracted and washed (Manso with (saturated), saturated saline solution). The organic phase was dried over MazO), filtered and concentrated.

Crystallization (EuAc/hexane) gave (1-methyl-1H-imidazol-2-yl)|4-(methylthio)phenyl)methanol.

Stage 2: (1-methyl-1H-imidazol-2-yl)|4-(methylthio)phenyl/|-ketone

To a solution of the alcohol from stage 1 (25.7 g, 111 mmol) in EtOAc (250 mL) and NaCl (250 mL) was added MpO (140 g, 1.6 bmol) and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through 70 plugs of silica gel (E(OAc)) to obtain ketone KO.

Ketone KZ (4-Methylsulfonyl)(phenyl)ketone

Ketone KZ was obtained in the following way.

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

Phenylmagnesium chloride (2M,

TTF, 3.5 ml, 7.Omol). After holding the mixture for 0.5 hours. at room temperature, it was neutralized with a saturated solution of MNACI, diluted with water and extracted with Ebg250. The organic extracts were washed (Nogo), (saturated saline solution), dried (MaZO)), filtered and concentrated. Purification by vigorous stirring in hexane/E2O and filtration afforded (4-methylthio)(phenyl)methanol as a white solid

Step 2: (4-methylthiophenyl)ketone (4-methylthio)Xphenyl)ketone was prepared by treating (4-methylthio)-(phenyl)methanol from step 1 with

Mpo", as described for stage 2 of the method of obtaining Ki below.

Stage 3: (4-methylsulfonyl)(phenyl)ketone Ge

To a solution of (4-methylthio)(phenyl)ketone from stage 2 (0.98g, 4.3mmol) in SNCIZ (1Oml) at 09 was added mhPBK o (m-chloroperbenzoic acid) (1.7g, 1Omol). After holding the mixture for 0.bh. at room temperature, Ca(OH)" (1.7 g, 23 mmol) was added to the mixture and stirred for 1 hour. Filtration through Celite (Seyjef)) and concentration gave the ketone KZ as a white solid.

Ketone KA iv) (1, 3-Thiazol-2-yl)|4-(methylthio)phenyl|ketone -

Ketone K4 was obtained in the following way.

Stage 1: (1,3-thiazol-2-yl)|4-(methylthio)phenyl|methanol (ee)

n-butyllithium (2.5 M in hexane, 23.5 ml, 58.7 mmol) was added dropwise to a solution of thiazole (5.0 g, 58.7 mmol) in THF (250 ml) at -782С, and the resulting solution was stirred at -782С for 10 minutes. Then added

From 4-(methylthio)-benzaldehyde (7.1 mL, 53.4 mmol) at -782C. The resulting mixture was stirred until the reaction was complete and quenched with a saturated aqueous solution of MNACI Then the mixture was diluted with EtOAc and 1095 NOCI, extracted and washed (Manso" (saturated), saturated saline solution). The organic phase was dried over MozO) and concentrated. Then the precipitate was purified by flash chromatography (8095 СНоСиЛ»/20956 EUAs) to obtain « (1,3-thiazol-2-yl)|(4-(methylthio)phenyl|methanol.

Stage 2: (1,3-Thiazol-2-yl)|I4-(methylthio)phenyl|ketone C with the (1,3-thiazol-2-yl)(4-(methylthio)phenyl)|methanol solution from stage 71 (10.0g, 42.1mmol) in EtOAc (250ml) was added MnO (70g, 8433mmol) and the reaction mixture was stirred at 2523 overnight. The mixture was filtered through a plug of silica gel (EtOAc) to give ketone compound Ka.

Ketone K5 - 45 (1,3-thiazol-2-yl)|4-(methylsulfonyl)phenyl|ketone

Ketone K5 was obtained in the following way. To a solution of KA (1,3-thiazol-2-yl)|(4-(methylthio)phenyl|ketone (8.2 g, "" 34.7 mmol) in THF/Meon/nH2oo (350/175/175 ml) was added oxone (42.6 bg, 69.4 mmol). The reaction mixture was stirred at 2523 for 3 hours and quenched with a saturated aqueous solution of Manso 3. The resulting mixture was then diluted with EOAc, extracted and washed (Manso" (sat.), saturated saline). The organic the phase was dried over - 70 Ma5O); and concentrated. Then the precipitate was purified by crystallization (E(OAc/hexane) to obtain (1,3-thiazol-2-yl)(4-(methylsulfonyl)phenylketone). sl Ketone Kb

15-(1-Hydroxy-1-methylethyl)-1,3-thiazol-2-yl||(4--"methylsulfonyl)phenyl|ketone

Ketone Kb was obtained in the following way. 99 Stage 1: I5-(1-Hydroxy-1-methylethyl)-1,3-thiazol-2-yl|(4-(methylthio)phenyl|ketone

n-butyllithium (2.3M in hexane, 75.3ml, 12.3mmol) was added dropwise to a solution of thiazole (1.0g, 12.0mmol) in THF (100ml at -782C) and the resulting solution was stirred at -782C for 10 minutes. Then 4-(methylthio)benzaldehyde (7.1 mL, 53.4 mmol) was added at -782 C. The resulting mixture was stirred at room temperature at 100 °C and cooled at -782 C. Then n-butyllithium (2, 3M in hexane, 5.3 ml, 12.3 mmol), and the resulting solution was stirred at 2523 for 10 min and quenched with acetone (3.0 ml). Then the mixture was diluted with E(Ac and 1095 NOS, extracted and washed (Manso uz (sat. ), saturated saline solution).

The organic phase was dried over Mo950O and concentrated. The precipitate was then treated with MpO (20.4 g, 235 mmol) in SiOCl (250 mL), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then filtered through a plug of silica gel (EUAs). Flash chromatography (9095 CH 2C12/1096 EtOAc) gave

15-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl(4-(methylthio)phenyl)-ketone.

Step 2: 15-(1-Hydroxy-1-methylethyl)-1,3-thiazol-2-yl) (4-(methyl sulfonyl)phenyl)ketone

In a sulfide solution, that is, 1|5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl| |4-(methylthio)phenyl|ketone, from stage 1 (1.7g, 5.8mmol) in THF/Meon/Nhno (100/50/50ml) was added oxone (7.1g, 11.5mmol). The reaction mixture was stirred at 259C for 3 hours and quenched with a saturated aqueous solution of Manso 3. Then the mixture was diluted with E(OAc), extracted and washed with (Manso" (sat.), saturated saline solution). The organic phase was dried over NaOH and concentrated. Then the precipitate purified by crystallization (E(OAc/hexane) to obtain ketone Kb.

Ketone K7 (6-Methyl-3-pyridinyl)(4-(methylsulfonyl)phenyl|ketone 70 Ketone K7 was obtained by the following method.

Stage 1: (6-Methyl-3-pyridinyl)|(4-(methylthio)phenyl|methanol

n-butyllithium in hexane (1.Eq.) was slowly added to a solution of 3-bromo-6-methylpyridine (7 mg, Eq.) in THF (20 ml) at -782C. Then the solution was stirred for 30 minutes. After that, 4-(thiomethyl)benzaldehyde (738 mg, 1.1 eq.) was slowly added. The solution was heated to room temperature, added МН, сИ 75 (sat.), then water and EUAs. The organic phase was separated, dried over Mo5O,; and concentrated. (6-Methyl-3-pyridinyl)(4-(methylthio)phrenyl|methanol was obtained by ether/hexane precipitation and used in the next step without further purification. Step 2: (6-Methyl-3-pyridinyl)(4-(methylsulfonyl) phenyl|-methanol

Following the method described above from stage 2 of obtaining ketone K1, but using as the starting product 2o instead of (4-fluorophenyl)(4-(methylthio)phenyl) ketone sulfide (b-methyl-3-pyridinyl)(4-(methylthio)phenyl) of methanol from stage 1, obtained (b-methyl-3-pyridinyl)(4-(methylsulfonyl)phenyl|methanol.

Stage 3: (6-Methyl-33-pyridinyl)(4-(methylsulfonyl)phenyl|-ketone

Following the method described above from stage 2 of obtaining ketone K2, but using as the starting product instead of /(1-methyl-1H-imidazol-2-yl)|4-(methylthio)phenyl)| of methanol (b-methyl-3-pyridinyl)|4-(methylsulfonyl)su phenyl| methanol from stage 2, ketone K7 was obtained.

Ketone KV o (5-methyl-2-pyridinyl)|(4--"methylsulfonyl)phenyl|ketone

Ketone KV was prepared according to the method described for ketone K7, but replacing 3-bromo-b6-methylpyridine with 2-bromo-5-methylpyridine. i am

Ketone KO

Bis-K4-methylsulfonyl)phenyl|ketone --

Ketone KO was obtained according to the method described for ketone K7, but replacing 3-bromo-b6-methylpyridine with ee 4-bromothioanisole and using a double amount of oxone in the stage of sulfide oxidation.

Ketone K10 Z (2-Pyridinyl)(4-(methylsulfonyl)phenyl|ketone h-

Ketone K10 was prepared according to the method described for ketone K7, but replacing 3-bromo-b-methylpyridine with 2-bromopyridine.

Ketone K11 «

15-(1-Hydroxy-1-methylethyl)-2-pyridinyl|(4-methyl-sulfonyl)phenyl|ketone

Ketone K11 was obtained in the following way. - c Stage 1: I5-(1-Hydroxy-1-methyl ethyl)-2-pyridinyl|(4-(methylthio)phenyl)| methanol c. To a suspension of 2,5-dibromopyridine (5.12 g, Teq.) in ether at -789C, n-butyllithium in hexane (1.05 eq.) was slowly added. The resulting yellow-orange precipitate was stirred for 30 minutes. Then it was added acetone (1.54 mL, 1.05 eq.) The solution was kept at -7892 C for another 30 minutes. n-butyllithium in hexane (1.Eq.) was slowly injected into the resulting orange suspension using a syringe. The suspension was then stirred for 1 hour - and at -782 C. After that, 4-(methylthio)benzaldehyde (2.85 ml, 1.1 equiv.) was added. The resulting suspension was heated to -359 C and quenched with MNACI solution (sat.). Water and EtOAc were added, and the organic layer was dried over M9505, evaporated and purified by flash chromatography (EUAs) to obtain 1(|5-(1-hydroxy-1-methylethyl)-2-pyridinyl)|(4-(methylthio)bophenyl|methanol. -oUu 70 Stage 2: I5- (1-hydroxy-1-methylethyl)-2-pyridinyl) (4-(methylsulfonyl)phenyl|methanol

15-(1-hydroxy-1-methylethyl)-2-pyridinyl). (4--""methyl-sulfonyl)phenyl|methanol was obtained according to the method described above for stage 2 of the preparation of ketone KI, but using as the starting product instead of (4-fluorophenyl)(4-(methylthio)phenyl|-4- fluorophenyl ketone sulfide, ie

I5-(1-Hydroxy-1-methylethyl)-2-pyridinyl|(4-(methylthio)phenyl|methanol, from stage 1. 29 Stage 3: I5-(1-Hydroxy-1-methylethyl)-2-pyridinyl) (4-(methylsulfonyl)phenyl)| ketone

GF! Ketone K1I1 was prepared according to the method described above for stage 2 of the preparation of ketone K2, but using as a starting product instead of (1-methyl-1H-imidazol-2-yl)|(4-(methylthio)phenyl|methanol about I5-( 1-hydroxy-1-methylethyl)-2-pyridinyl((4-(methylsulfonyl)-phenyl)|methanol from step 2.

Boronate compounds, which are used to prepare the compounds of the present invention, can be prepared 60 according to scheme 2 below: b5

SCHEME 2; Synthesis of boronates with He is

P. 7

R"RizVe vOyMe (fi Ag

Hi MI zbo UCI MeOu ' X (n-2) nose-3-. about "to" iv); is "-

And (se)

Sh: from Meb25 y, kh « shi s Keton (MY og MI) De po Boronat (XII) :z" "dir ni ratits prin io r oo DN OO pn To Nord bno Dion iNLnoitsyn

SU 0 0ВИ1

K2 Н M z vn "" Z so u 0 2 schika that Z sl y SN"

KE I. 2 BZ ih M

F. Ne vi ime) o

Ky Ya s 2 va bo ns M

Aryl bromides Х and Х can be obtained by treating benzylphosphonium bromide ХХ with a base such as tert-HGOK or ГИНМО5 in an organic solvent such as THF, with subsequent addition to the reaction mixture of the ketone MI! or

E. The sulfide in YH can be converted to sulfone X by treatment with oxone in a solvent such as a mixture of THF/MeOH/H2O. Boronate ester XII can be prepared by heating aryl bromide X with pinacoldiborane in the presence of a base such as COAc and a catalyst such as Rasi(arry) in a solvent such as DMF.

Boronate B1

Pinacol. 3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl|ethenyl/phenylboranate

Boronate B1 was obtained in the following way.

Stage 1: (E/2)-2-(3-Bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-1-I4-(methylthio)phenyl|ethene

To a solution of (3-bromobenzyltriphenyl)phosphonium bromide (10.2g, 19.9mmol) in THF (200ml) and SNZSM (5Oml) at 25,900 drops was added tert-VOOK (100M in THF, 19.Oml, 19.9mmol) and the resulting red the solution was stirred at room temperature for 20 minutes. To the obtained product was then added at 2590 KZ ketone? (4.4 g, 18.9 mmol). The resulting mixture was stirred at 602C for 2 days and quenched with MNACI (sat.). 70 Then the mixture was diluted with E(Ac. The organic phase was washed with Manso uz (saturated), saturated saline solution, dried over Ma 5 ZO), filtered and concentrated, and used directly in the next stage 2.

Stage 2: (E)-2-(3-Bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-1-(4-(methylsulfonyl)phenyl|ethene

To a solution of crude sulfide, that is, (E/2)-2-(3-bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-1-(4-(methylthio)phenyl|ethene, with of stage 1 (18O9mmol) in 75 THF/MeOon/NiO (200/100/100ml) was added oxone (23.2g, 37.8mmol). The mixture was stirred at room temperature for 4 hours, quenched with Manso)" (sat.) and diluted E(Ac. The organic phase was washed with Manso»z (saturated), saturated saline solution, dried over Ma»5O), filtered and concentrated.

Flash chromatography (9590 EUAc/590 EE 3M) gave (E)-2-(3-bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-1-(4-(methylsulfonyl)phenyl) |ethene (single isomer) in the form of foam.

Stage 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-I(4-(methylsulfonyl)phenyl|ethene) from stage 2 (2 .0g; 4 mmol), pinacol diboron (1.5g; 5.mmol), COAc (1.65g; 16.6mmol) and Rasi" (arr) (0.2g; 0.24mmol) in bOml.0 SU

DMF was stirred at 902 for 4 hours. The resulting mixture was cooled to room temperature, diluted with E(Ac, washed with H 20 (Zh), saturated saline solution, dried over Ma»5ZO»4, filtered and concentrated. Flash chromatography (95956 EAs/595 EizM) gave boronate B1 in in the form of foam

Boronate 82

Pinacol. 3-(E/2)-2-(1,3-thiazol-2-yl)-2-(4-(methylsulfonyl)phenyl|ethenyl)uphenylboronate IF)

Boronate B2 was obtained in the following way. -

Stage 1: (E/27)-2-(3-bromophenyl)-1-(1,3-thiazol-2-yl)-1-(4-(methylthio)phenyl|ethene

To a solution of (3-bromobenzyl)triphenyl)phosphonium bromide (44.5g, 86.9mmol) in THF (500ml) and DMF (200ml) (ee) at 02 was added dropwise GINMO5 (1.00M in THF, 86b, Uml, 86b, 9 mmol), and the resulting red solution was stirred at room temperature for 20 minutes. It was then added to the obtained product at 02С

From ketone KA (18.6g, 79, Ommol). The mixture was stirred until the completion of the reaction according to TLC data and quenched with MN SI in (saturated). Then the mixture was diluted with EAs. The organic phase was washed with Manso uz (saturated), saturated saline solution, dried over MazoO), filtered and concentrated. Flash chromatography (CH 25Si) gave (E/2)-2-(3-bromophenyl)-1-(1,3-thiazol-2-yl)-1-I4-(methylthio)phenyl|ethene (a mixture of isomers 1 .5 to 1). "

Stage 2: (E/2)-2-(3-Bromophenyl)-1-(1,3-thiazol-2-yl)-1-(4-(methylsulfonyl)phenyl|ethene

To a solution of sulfide, i.e. /(E/2)-2-(3-bromophenyl)-1-(1,3-thiazol-2-yl)-1-(4--(methylthio)phenyl|ethene, with o) oxone (78.5 g, 128 mmol) was added from stage 1 (24.8 g, 63 9 µmol) to THF/MeOn/NiO (600/300/300 ml). The resulting "» reaction mixture was stirred at room temperature overnight. The resulting mixture was quenched with Manso with "(sat.) and diluted with EAs. The organic phase was washed with Manso with (saturated) saturated saline solution, dried over M2O, filtered and concentrated to give (BIGD-2-(3-bromophenyl)-1-(1,3-thiazol-2-yl) -1-(4--methylsulfonyl)phenyl|ethene (a mixture of isomers C to 2) - Stage 3: Pinacol 3-(E/2)-2-(1,3-thiazol-2-yl)-2-I4 -(methylsulfonyl)phenyl ethenyl)phenylboronate suspension of bromide (E/2)-2-(3-bromophenyl)-1-(1,3-thiazol-2-yl)-1-I(4--methylsulfonyl)phenyl| ethene from stage 2 (150g, C35.7mmol), pinacol diborane (10.9g, 42.8mmol), COAc (12.3g, 125mmol) and Rasi" (arr) (1.46g, bo 1.7vmmol) in ZbOml DMF was stirred at 902C for 4 hours. The resulting mixture was cooled to room temperature -sh 20, diluted with EAs, washed with HO (3x), saturated saline solution, dried over. Ma»5Ou, filtered and concentrated. Flash chromatography (ToI/acetone, 9/1) gave boronate B2 (a mixture of isomers C to 1) in the form of a foam.

Boronat VZ

Pinacol 3-(E)-2-(5-methyl-2-pyridinyl)-2-(4--(methylsulfonyl)phenyl|ethenyl/phenylboronate

Boronate VZ was obtained in the following way.

HF) Stage 1: (E)-2-(3-Bromophenyl)-1-(5-methyl-2-pyridinyl)-1-I(4--"methylsulfonyl)phenyl|ethylene

According to the method described for stage 1 of obtaining boronate B1, but using ketone K8 instead of ketone K2 as the starting product, and after separation of isomers using flash chromatography, (E)-2-(3-bromophenyl)-1-(5 -methyl-2-pyridinyl)-1-(4-(methylsulfonyl)phenyl|ethylene. 60 Stage 2: Pinacol 3-(E)-2-(5-methyl-2-pyridinyl)-2-(4--methylsulfonyl) ) phenyl)| ethenyl) phenylboronate

Boronate BZ was prepared according to the method described for stage C of obtaining boronate VI, but using as starting product instead of (E)-2-(3-bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)- 1-(4--methylsulfonyl)phenyl|ethylene bromide (E)-2-(3-bromophenyl)-1-(5-methyl-2-pyridinyl)-1-(4--(methylsulfonyl)phenyl)ethylene from stage 1. b5 Boronat VA

Pinacol 3-(E)-2-(5-(1-hydroxy-1-methylethyl)-2-pyridinyl)-2-(4--"methylsulfonyl)phenyl| ethenyl) phenylboronate

Boronate B4 was obtained in the following way.

Stage 1: (E)-2-(3-bromophenyl)-1-(5-(1-hydroxy-1-methylethyl)-2-pyridinylI-1-I(4-methylsulfonyl)phenyl|ethene

According to the method described for stage 1 of obtaining boronate VI, but substituting ketone as the starting product

K?2 to K1 ketone, and after separation of isomers using flash chromatography, (E)-2-(3-bromophenyl)-1-(5-(1-hydroxy-1-methylethyl)-2-pyridinyl) was obtained -1-(4--(methylsulfonyl)phenyl|ethene.

Stage 2: Pinacol 3-(E)-2-(5-(1-hydroxy-1-methylethyl)-2-pyridinyl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenylboronate 70 Boronate BA was obtained according to by the method described for stage C of obtaining boronate VI, but substituting as the starting product (E)-2-(3-bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-1-I4--methylsulfonyl) -phenyl|iethene to bromide (E)-2-(3-bromophenyl)-1-(5-(1-hydroxy-1-methylethyl)-2-pyridinyl|-1-(4--(methylsulfoyl)phenyliethene) from stage 1.

The aryl bromide compounds used to prepare the compounds of the present invention can be prepared according to Schemes C and 4 below:

SCHEME Z

Synthesis of oxadiazole with В MeORNYUM SI3,OM ----k- p-MEORNYUM OM

Ha s mov o

J Me"

HU m... zo (U

In Mn Meb,e - « 35 . Cha

In Oxadiazole (XM) "antibodies of idiots iniy vann ooo or HB threads -

Meox « - с ОохХ2 sh p-meORPOSNO " According to Scheme 3 presented above, the nitrile intermediate Xa can be prepared by alkylation of 4-methoxyphenol with chloroacetonitrile in the presence of a base such as potassium carbonate in a solvent such as acetone. sh- The amide oxime XM can be prepared by treating the nitrile XII with a hydroxyl amine in a solvent such as their methanol in the presence of a base such as sodium acetate.The formation of the oxadiazole XM! can be achieved by activating the arylacetic acid XM with a carbonyldiimidazole in a solvent such as DMF, and then adding co-amidoxime KHM and then heating the reaction mixture - 50 ml

F) name) 60 b5

SCHEME 4

Synthesis of aryl bromide in HG V sym y h vyin ny ny ny sno Z boon 15 son ve

HM Meo"Z Meb"

HUSHA (AV) HMNY

Oh yav id (X . V Arylbromide. (ХМИЙІ)

ВИ І пін пінни нни пони інд віпін не ін ні н н І фі і Рг АвВ2 сч (8)

Y m. Snu fi 2 nn Nn AVZ

Me od

IS)

Nn Vy Ava z HUNs (AV) -

According to Scheme 4, condensation of the aldehyde HMII by heating with arylacetic acid XM in the presence of a base such as piperidine in a solvent such as toluene afforded the unsaturated acid HMIPA. After the formation of the anhydride of the acid HMISH by treatment with thionyl chloride and a base such as triethylamine in a solvent such as toluene, an amine was added to the reaction mixture to obtain the amide HMIPH. Oxadiazole-ethene

HMShs can be prepared by heating OX1 from HMI in the presence of a base such as piperidine in a solvent such as toluene.

Scheme 4 (appendix) "Synthesis of aryl bromide" -I sh" (ee) - 50 sl

F) name) 60 b5

You Wu in ! now! now it is in so and tosome (i

Mo Mao MeO ON, uyu HchSha (AV) HU HUSHe

Vg about fi

MeOo MMez p

Khmin (AV) Fr

According to Scheme 4 presented above, treatment of HMIPA acid with diazomethane in a solvent such as THF afforded the methyl ester of HMIPA. Reduction of the HMPa ether with OIVAIH-N in a solvent such as THF afforded the allylic alcohol HMISHe. Conversion of the alcohol group in HMSe to a leaving group, such as a mesylate, IS o) using agents such as methanesulfonyl chloride and triethylamine in a solvent such as THF, followed by substitution with a nucleophile such as dimethylamine in a solvent such as DMF, gave the compound XM.

Aryl bromide AB 1 (E)-3-(3-Bromophenyl)-2-I4--(methylsulfonyl)phenyl|-2-propenoic acid (ee)

Aryl bromide АВИ1 was obtained by the following method. 4-(methylsulfonyl)phenylacetic acid (15g, 7Omol) and piperidine (2mL) were added to a solution of 3Z-bromobenzaldehyde (12.9g, 7Omol) in toluene (100ml). After refluxing overnight, the mixture was cooled to room temperature. Toluene (1 Oml) was added to the thus obtained suspension. Filtration gave (E)-3-(3-bromophenyl)-2-(4-(methylsulfonyl)phenyl|-2-propenoic acid as a white solid.

Aryl bromide AB2 (E)-M-Isopropyl-3-(3-bromophenyl)-2-I4-(methylsulfonyl)phenyl|-2-propenamide

Aryl bromide AB2 was obtained by the following method. Thionyl chloride (14.3 ml, 196 mmol) and triethylamine (34 ml, 245 mmol) were added to a solution of AVI (24.9 g, bbmmol) in toluene (250 ml). After stirring at room temperature for 0.5 hours, isopropylamine (28 mL, 327 mmol) was added. After additional 2 hours. at room "" temperature, the mixture was cooled to 09C and neutralized with a saturated solution of MNACI, then extracted

EUAs. The organic extracts were washed (NaOH, saturated saline solution), dried (MaSO), filtered and concentrated. Purification by flash chromatography (HexEthAc, 1:1-pure EAc) gave - and (E)-N-isopropyl-3-(3-bromophenyl)-2-(4-methylsulfonyl). phenyl|-2-propenamide. their Aryl bromide ABZ (E)-3-(3-Bromophenyl)-2-(4-(methylsulfonyl)phenyl|-2-propenamide (ee) Aryl bromide ABZ was prepared according to the method described for aryl bromide AB2, but using as -l 20 the starting product instead of isopropylamine is ammonium hydroxide.

Aryl bromide ABA sl (E)-M-(tert-Butyl)-3-(3-bromophenyl)-2-(I4-(methylsulfonyl).phenyl|-2-propenamide

Aryl bromide ABA was prepared according to the method described for aryl bromide AB2, but using tert-butylamine as the starting product instead of isopropylamine.

Aryl bromide AB5 o (E)-1-(3-Bromophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-methylsulfonyl)phenyl|ethene

Aryl bromide AB5 was obtained by the following method. co Stage 1 (scheme 3, oxadiazole ОХ1): (3-methyl-1,2,4-oxadiazol-5-yl)(4-(methylsulfonyl)phenyl|methane

Carbonyldiimidazole (12.5 g, 77 mmol) was added to a solution of 4-(methylsulfonyl)phenylacetic acid (15 g, 7 mmol) in DMF (30 mmol) at room temperature. After O,bBh. acetamide oxime (5.7 g, 77 mmol) was added at room temperature. After stirring the resulting mixture overnight at room temperature, the mixture was heated to 1202C for 6 hours. After cooling to room temperature, the mixture was quenched with HO and extracted with E(OAc. The organic extracts were washed with (HO, saturated saline), dried (MazO), filtered and concentrated. Purification by flash chromatography (NexEOAc, 11) gave 65 (3-methyl -1,2,4-oxadiazol-5-yl)(4-(methylsulfonyl)phenyl|methane.

Stage 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 (2.2g, 11.9mmol) in toluene (30ml) was added the product of stage 1 (OX1) (3.0g, 11.9mmol) and piperidine (0.4ml). After refluxing overnight, the mixture was cooled to room temperature. MeonH (ZOml) was added to the resulting suspension. After additional reflux and cooling to (0) F, filtration gave (E)-1-(3-bromophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2 -(4--methylsulfonyl)phenyl ether as a white solid.

The bromoquinolines used to prepare the compounds of the present invention can be prepared according to Scheme 5 below: then SCHEME 5

Production of bromoquinolines

And SN

- Sho 1

Woo vi A Z d! nshnn Cha

M Fri M M

G g

Vg (8)

IS) "- s " and -

Us SN» yo 1

And n "

M - s I ;"

XXe

According to Scheme 5 above and the table for Scheme 5 below, treatment of the bromomethyl compound XIX with a nucleophile such as sodium methanesulfinate or potassium cyanide in a solvent such as DMF or a mixture of DMF and water can be used to provide compounds XXa. Compound XX can be prepared by treating XXa with a base such as potassium tert-butoxide (1.1 eq.) in a solvent such as THF, followed by (ee) addition of the resulting mixture to a solution of methyl iodide in a solvent such as THF. Compound XXc shu 20 can be prepared by treating XXb with a base such as potassium tert-butoxide (1.1 eq.) in a solvent such as

THF, followed by addition of the resulting mixture to a solution of methyl iodide in a solvent such as THF. The compound cl XXse (where, B! - CM) can also be obtained by treating XXXa with a base such as potassium tert-butoxide (2.2 eq.) and methyl iodide in a solvent such as THF. Compound XXc (where B! - 5O»oMe) can also be obtained by processing

XxXa with a base such as potassium tert-butoxide (1.Eq.) and methyl iodide (1.Eq.) in a solvent such as TG/F, followed by an additional amount of methyl iodide (1.Eq.) and an additional amount of that same base (1, Eq.).

F) name) 60 b5

Scheme 5 (table)

E. I

Bromoquinolines de do - 1 : Sogya g s o i v A Bromoquinoline (XX)

IS) dra pony poch ikru OO, rYUTLKO DNA UN UN UN captives Anonymous no matter how many "-

Z0oMe N their s y " vZOzMe Me Me 03 " shi - S N n 6 ;"

With Me Me. Bromoquinoline 1, 6-(methylsulfonyl)methyl-8-bromoquinoline, and Bromoquinoline 01 were obtained by the following method. DMF-20 (BOOML) was added to b-bromomethyl-8-bromoquinoline (b0Og, 200 mmol) (described in the international patent publication MUO 94/22852) and sodium methanesulfinate (27.6 g, 270 mmol). sp After stirring overnight at room temperature, the mixture was quenched with H 250 (2000 ml), stirred for one hour, isolated by filtration and washed with EE 20 to give 6-(methylsulfonyl)methyl-8-bromoquinoline. Bromoquinoline 02 6-/1-(methylsulfonyl)ethyl|-8-bromoquinoline

GF) Bromoquinoline 02 was obtained in the following way. To a solution of bromoquinoline 91 (16.1 g, 54 mmol) in THF (500 ml) 7 at -782C, potassium tert-butoxide (59 ml, yin in THF) was added. After 0.5 hours at -7892C, the resulting mixture was stirred at 02C for 45 minutes and then transferred dropwise via a cannula into a solution of Meiwo (16.7ml, 268.3mmol) in THF (160ml). After stirring overnight at room temperature, the mixture was neutralized with a saturated solution of MNACI and extracted with EtOAc. Organic extracts were washed (Neo), (saturated saline solution), dried (MazO)), filtered and concentrated. Stirring in ether followed by isolation by filtration gave 6-(1-methylsulfonyl)ethyl-8-bromoquinoline.

Bromoquinoline OZ 65 6-/1-methyl-1-(methylsulfonyl)ethyl|-8-bromoquinoline

Bromoquinoline OZ was obtained in the following way. In a solution of bromoquinoline 02 (15.7 g, HOmmol) in THF (500 ml)

at -78C, potassium tert-butoxide (5b5ml, yin in THF) was added. After stirring for 0.5 hours. at -78 "С, the resulting mixture was stirred at 02С for 45 minutes and then transferred dropwise into Mei's solution! (15.bml, 250mmol) in THF (40ml) at 02. After stirring overnight at room temperature, the mixture was neutralized with a saturated solution of MNACI and extracted with E(OAc. The organic extracts were washed with NaO, saturated saline), dried (Ma5O)), filtered and concentrated. Stirring in ether followed by isolation by filtration gave 6-|(/1-methyl-1-(methylsulfonyl)ethyl-8-bromoquinoline.

Bromoquinoline 04 b-cyanomethyl-8-bromoquinoline

Bromoquinoline 04 was obtained in the following way. To b-bromomethyl-8-bromoquinoline (Zg, TOmmol) (described in the international patent publication UUO 94/22852) and potassium cyanide (1.6g, 25mmol) were added DMF (1Oml) and NO (5ml).

After heating at 100 °C for 1 hour, the resulting mixture was quenched with HO (10 mL) and extracted with EtOAc.

The organic extracts were washed (H2O, saturated saline solution), dried (M9504), filtered and concentrated. Purification by flash chromatography (Nex:EOAc, 3:1) gave 6-cyanomethyl-8-bromoquinoline.

Bromoquinoline 05 6-/1-methyl-1-cyanoethyl|-8-bromoquinoline

Bromoquinoline 25 was obtained by the following method. To a solution of bromoquinoline 04 (Zg, 12.1 mmol) in THF (100 ml) at -78e2C was added Mei (1.7 ml, 27 mmol), and then potassium tert-butoxide (27 ml, 27 mmol). After 2 hours at -1892C, the mixture was heated to 09 and neutralized with a saturated solution of MNACI, then extracted with EUAs.

The organic extracts were washed (NiO, saturated saline solution), dried (Mo5O)), filtered and concentrated. Purification by flash chromatography (NexEOAc, 3:1) to give 6-P1-methyl-1-cyanoethyl|-8-bromoquinoline.

The benzyl phosphate reagents used to prepare the compounds of the present invention can be prepared according to Scheme 6, presented below: c

SCHEME 6 o

Production of benzyl phosphorous reagents with siv) ns Sn Na and Na CH - z! . че че че 1 с в! (He) o: ro. co

AND! - nin nn now "I

M t on ii FI ON fi xX - xx XX XXI XX (Xe B)

ХХИМ (Х « ОБОоМе) « shi - p

N

;" On Z su

M

-I и Z ve (o) ХХУ - 50 ' ; sp. Kk Kk Benz. phosph reaction (ХХУМ) well tynu ti ччч7ТТТntzhnТtytin тн чаатнаниныштин n SNOR(RYU VI RI

Н СНоРИОХОЕО» p2

F) yu SM SNRIOHOEYU" RZ

Arylquinolines of formula XXI! can be obtained by the addition reaction of bromoquinoline XX and boronic acid in XXI by heating in the presence of a catalyst such as РОА(ПРА 3)4 and a base such as sodium carbonate (aqueous) in a solvent such as DMF. Alcohol XXI! can be converted to XXIII bromide by treatment of NHHg (aq.) in a solvent such as acetic acid. Alcohol XXI! can be converted to methyl sulfonate ester XXIM with methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane. Benzyl phosphate reagents XXM can be obtained either by heating XXI! in the presence of PRNase in a solvent such as acetonitrile, or by heating XXIII or XXIM 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 obtained by the following method.

Stage 1: Isopropyl-8-13-(hydroxymethyl)phenyl|)quinoline

A mixture of b6-isopropyl-8-bromoquinoline (11.1 g, 44 4 mmol) (described in the international patent application UUO 94/22852),

3-(Hydroxymethyl)phenylboronic acid (8.70g, 57.2mmol), NaClCO3 (2M, 71ml, 142mmol) and RYAA(PPH3)4 (2.51mg, 2.17mmol) in 280ml DME was stirred at 802 for 5 hours The resulting mixture was cooled to room temperature, diluted with EtOAc, washed with a saturated saline solution, dried over Ma 550.4, filtered and concentrated. Flash chromatography (Nex/E(Ac, 1/1) and stirring in CH 525Cl/hexane (1/9) gave b-isopropyl-8-IZ-'(hydroxymethyl)phenylquinoline as a white solid.

Stage 2: 6-Isopropyl-8-IZ-"bromomethyl)phenylquinoline

A suspension of the hydroxymethyl product of the compound of this stage 1 (7.40 g, 26.7 mmol) in AcOH (5 mL) and NHg (5 mL, 4895 aq.) was stirred for 12 hours at 1002C. The mixture was cooled to room temperature, 75 was poured into NaOH (2N) in ice, the pH was adjusted to 8 and the mixture was diluted with ether. The organic phase was washed with saturated saline, dried over NaCl), filtered and concentrated to yield b-isoprotyl-8-13-bromomethyl)phenylquinoline as a yellow solid product.

Stage 3: I3-(6-isopropyl-8-quinolinyl)benzyl|-(triphenyl)phosphonium bromide

Triphenylphosphine (3.22g, 12.3mmol) was added to a solution of the bromomethyl product of the compound of this stage 2 (3.807g, 11.1mmol) in 40ml of SNZUSM. The mixture was stirred at 6°C for 12 hours, cooled to room temperature, diluted with ether, filtered and washed with ether to give the bromide

3-(6-isopropyl-8-quinolinyl)benzyl|(triphenyl)phosphonium.

Benzylphosphonate P2

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

Benzylphosphonate P2 was obtained by the following method. at

The bromomethyl compound of stage 2, presented above, of the synthesis of P1 (11.34 g, Eq.) was dissolved in THF (17 Oml).

Diethyl phosphite (3.87 ml, 1.0 beq.) was added and the solution was cooled to 02C. After that, tert-HCHOC (3.87 mL, yin in THF) was slowly added. The reaction mixture was stirred for 2 hours and quenched by adding MH/C1 (sat.), water, and EtOAc. The organic phase was separated and washed with a saturated saline solution, dried over Mo5O; and M were concentrated. Purification by flash chromatography on silica gel (hexane:E1OAc, 1/9) gave diethyl 3-(6-isopropyl-3-quinolinyl) benzylphosphonate as a clear oil.

Benzylphosphonate RZ (ee)

Diethyl 3-I6-(1-cyano-1-methylethyl)-8-quinolinyl|Ibenzylphosphonate «

Benzylphosphonate RZ was obtained by the following method. Stage 1: 6-(1-cyano-1-methylethyl)-8-3-(hydroxymethyl)-phenylquinoline -

According to stage 1 of the method described above for benzylphosphonium bromide P11, but replacing b-isopropyl-8-bromoquinoline with bromoquinoline O5 as the starting product, 6-(1-cyano-1-methylethyl)-8-3-(hydroxymethyl)phenyl) was obtained quinoline Stage 2: Methanesulfonate of 3-16-(1-cyano-1-methylethyl)-8-quinolinyl|IbGSenzil In an alcoholic solution of 6-(1-cyano-1-methylethyl)-8-3-(hydroxymethyl)phenyl| quinoline of this stage 1 (5.15 g, 1/mmol) in CHClCl (1500 ml) at - 18-2C was added EBM (3.3 bml, 2 bmmol) and methanesulfonyl chloride ("Me2Cl") (1.b6ml, 2t1mmol) . After 0.5 h at -782C, the mixture was neutralized with a saturated solution of MNACI, diluted with water and extracted with ether. The organic extracts were washed with NaOH, saturated saline), dried (M9504), filtered and concentrated to obtain 3-I(6-(1-cyano-1-methylethyl)-8-quinolinyl|bSensyl methanesulfonate in the form of a white foam. - Stage C: Diethyl 3-I6-(1-cyano-1-methylethyl)-8-quinolinyl| benzylphosphonate them To a solution of diethyl phosphite (2.5 ml, 18 mmol) in THF (100 ml) at -782C was added potassium tert-butoxide (1M, THF . and 12 hours at room temperature, the obtained mixture -k 70 was neutralized with a saturated solution of MH/ACI, diluted with water and extracted with ether. The organic extracts were washed (H2O, saturated saline solution), dried (MazO)), filtered and concentrated. sl Flash purification -chromatography (NexEOAc, 14 to 110) gave diethyl 3-I6-(1-cyano-1-methylethyl)-8-quinolinyl)|IsSensylphosphonate as an oil.

F) name) 60 b5

SCHEME 7; The reaction of the addition of a benznylphosphoric compound to a ketone is not ЕНе

WITH

Not with B! "I and

AND

Mi My s U e (fr

Ma

Bviz. phos reaction (hmm) xxM

M. p

On Sn o - 1

In Fu;

IS) with" F her

And forever

Example (Her) her-

Compounds of formula I can be prepared using the reaction pathways shown in Scheme 7 above. The compound ХМИ can be obtained by adding a solution of ketone MI! in a solvent such as THF to a mixture of benzylphosphorus reagent XXM and a base such as potassium tert-butoxide in a solvent such as THF. Compounds corresponding to formula I can then be obtained by treating ХХМИ with oxone in a mixture of solvents such as

THF/MeOH/water. Alternatively, compounds of the formula | can be obtained by the interaction of ketone MI with XHM in ptv) in the presence of a base such as potassium tert-butoxide in a solvent such as THF. . According to Scheme 7, presented above, and Table 1, presented below, the ketone addition reaction and of benzylphosphorus reagents gave the compounds of the examples presented in the table. -1 from so - slt 1777 in 17777618 from ni i ns VAN o t wo bo

SCHEME 8

Aryloromid-bromoquinoline addition reaction

H No Na ne ve z CH 4 Z 7 , water di Snv g Bromoquinoline M

TSO 0-8 | ! drink and

FI in; faculty

Meb»5 MeO MeO»

Aryl bromide (HMIII) Boronate (used as an example) Example (I)

According to scheme 8, compounds corresponding to formula I can be obtained by the conversion of aryl bromide

XM to the corresponding boronate ether on heating with pinacol diboronate, a catalyst such as 1,1"-bisbidiphenylphosphino)ferrocene|dichloropalladium(I), and a base such as potassium acetate in a solvent such as DMF, followed by the addition of bromoquinoline XX , an additional amount of catalyst, an additional amount of base such as sodium carbonate (aqueous) and with additional heating time.

According to Scheme 8 presented above, Table 2 and Table 2 (Appendix) presented below, the reaction of the addition of aryl bromide with bromoquinoline gave the compounds of the examples presented in the form of the table. (8) y zo - s - z si « z s Compounds according to the present invention can be obtained according to scheme 9 presented below. with -I sh" (ee) - 50 sl

F) name) 60 b5

SCHEME 9 a! (He) and: ' and; pool in M sno y

M HU p now xx h chik sno vva mes. what?

XXI

5 A reMeorv (Example 18)

HU Zh

Wang ch v! with di! (Example 19) sch with Zh and o

M M

A Z yu ptn nal ninachn na zo | Nooma - 1 sleep fi o so

Meb»8 Mebo8 « and -

HM (Example (I) "shi

With magic;" nya navy i zp p Pd o in pn nnyy

Example 27 - I sh» (ee) shchi mn- Example 28 " CH

With

Мн сн Example 29 сн З о З 7 Scheme 9 schematically presents the preparation of compounds of formula I, where the aldehyde XXMII can be obtained by heating bromoquinoline XX, 3-formylbenzeneboronic acid, a catalyst such as РА(ПРА 3)4 and a base such as sodium carbonate (aqueous) in a solvent such as DMF. Aldehyde XXMII can be converted to compounds of example 18 by heating with XMI in the presence of a base such as piperidine in a solvent such as toluene. The compound of example 19 can be obtained by treating the compound of example 18 with cerium-ammonium nitrate ("CAM") in a mixture of solvents such as acetonitrile/water. Alternatively, the aldehyde XXMIII can be converted to the unsaturated acid XXMIII by heating with XM and a base such as piperidine in a solvent such as toluene.

The CHMIII acid can then be converted to the amide I (example 27, 28 and 29) by treatment with a coupling system, for example, EOSI, NOVI and amine, in a solvent such as DMF.

The compounds of the present invention can be prepared by coupling bromoquinoline compounds and boronate compounds according to Scheme 10 below.

SCHEME 10

Reaction of addition of bromoquinoline - boronate.

N

70 SN V

Naota-sn I

Z o Z iy in V" m -E from the axis t FI p

Beh! fi Ag fi Ag

Maybe

I ,

Bromoquinoline (XX) Boronate Compound (I)

I) sch

Scheme 10 shows how compounds of formula I! can be obtained during the addition reaction of bromoquinoline d)

XX with the boronate ester XII in the presence of a catalyst such as РОА(ОАс)», РРИЗ and a base such as sodium carbonate (aqueous) in a solvent such as n-propanol. Referring to Table 3, the addition reaction of bromoquinoline and borate gave the products of the examples presented in the form of a table.

IS) from e-so "zv v"

Examples 1 and 2 - b-isopropyl-8(3-2/E)-2-(A4-methylsulfonyl)phenyl|-2-phenylethenylphenyl)quinoline;» -I sh" (ee) - 50 sl

F) name) 60 b5 yy

M

Ff

Mao. se sch

IS) "-

Example 1 with sn Yes n! m.

SN. « r shi - M z -I i j (ee) - 50 sl 8- SNU in 5 bo

IF) Example 2 ime) The products of examples 1 and 2 were obtained according to the following method. Potassium tert-butoxide 60 (1M, THF, 0.8µml, 0.8µmol) was added to a mixture of benzyl phosphonate P2 (30mg, 0.8µmmol) and ketone KZ (200µg, 0.77mmol) in THF (bml) at room temperature. Through the year at room temperature, the mixture was diluted with water and extracted

ESCO, organic extracts were washed (H2O), (saturated saline solution), dried (MaSO"), filtered and concentrated. Purification by flash chromatography (NexEOAc, 7:3) gave the products of examples 1 and 2 as a white foam, where one product was less polar than the other product. The product of example 1 was the less polar 2-isomer, and the product of example 2 was the more polar E-isomer. 65 Example 1: NMR "H (400 MHz, Acetone-dv) 5 8.79 (sq., 1H), 8.28 (sq., 1H), 7.94 (d, 2H), 7.73 (d, 1H), 7.6-7.1 (m, 14H), 3.14 (m, 1H), 2.97 (s, ЗН), 1.34 (d, 6H).

Example 2: NMR "H (400 MHz, Acetone-dv) 5 8.78 (sq., 1H), 8.25 (sq., 1H), 7.89 (d, 2H), 7.71 (d, 1H ), 7.6 (m, ЗН), 7.45 (m, ЗН), 7.39-7.2 (m, 8Н), 3.11 (m, 4Н), 1.34 (d, 6Н) .

Example C b-isopropyl-8-13-KE/2)-2-(4-(methylsulfonyl)phenyl|-2-(1,3-thiazol-2-yl)vinyl|phenyl)quinoline 70

SN

Mlk 5 M i ( s a SN (o) ke

The product of example C was obtained according to the following method. Tert-VIOK (1.0M in THF, 0.55ml, 0.55mmol) was added dropwise to a suspension of benzylphosphonium bromide P1 (320mg, 0.531mmol) in 2.50ml of THF at -782С, and - the resulting red solution was stirred for 30 minutes. at 02C. K5 ketone (122mg, 0455mmol) in 2ml of THF was then added dropwise to this obtained product at -182С. The mixture was heated at room temperature, then stirred for 1 hour, quenched with MHCl (saturated) and diluted with E(SO. The organic phase was washed with saturated saline, dried with NaCl5O), filtered and concentrated.

Flash chromatography (cartridge silica gel, Nex/E(OAc from 10 to 10095 in 20 minutes) gave the product of example 3. (mixture of isomers 1.5 to 1).

H NMR (500 MHz, Acetone-iv) 5 8.79-8.78 (w, 7), 8.26-8.23 (m, 1H), 8.01-7.92 (m, ЗН), 7.84 (d, 04Н, secondary), 7.78 (d, 0О,6Н, primary), 7.73-7.47 (m, TON), 7.43 (dd, 1Н), 7.34 ( t, 0, 6H, primary), 7.27 « (t, 04H, secondary), 7.18 (d, 0, 6H, primary), 7.09 (d, 04H, secondary), 3.12 (m , 1H), 3.11 (c, 1.8H, C primary), 2.99 (c, 1.2H, secondary), 1.36-1.33 (m, 6H). c Example 4: with b-isopropyl-8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4--("methylsulfonyl)phenyl|vinylphenyl)quinoline -I sh" (ee ) - 50 sl

F) name) 60 b5

And y: F sn i

M

M o y

B M i -5 e sch - m Ye ns i9)

The product of example 4 was obtained by the following method. C)

Stage 1: b-isopropyl-8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-((methylthio)phenyl|vinylphenyl)quinoline - b-isopropyl-8- (3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4-(methylthio)phenyl|vinylphenyl)quinoline was obtained according to the preparation method of example 3, replacing K5 as the starting product with K2. (ee)

Stage 2: 6-isopropyl-8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl|vinylphenyl)quinoline «

The product of example 4 was obtained according to the method of obtaining borate B1 (stage 2 of scheme 2), but substituting as the starting product /(E/2)-2-(3-bromophenyl)-1-(1-methyl-1H-imidazole-2- yl)-1-(4-methylthio)phenyl|uethylene - on y- sulfide obtained in this stage 1.

H NMR (500 MHz, Acetone-dv) 5 8.77 (5d, 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, ЗН), 3.10 (m, 1H), 2.99 (c, ZN), 1.32 (d, 6H).

MV: (that?); 5094, o) c Examples 5 and 6 "» b-isopropyl-8-(3-(2/E)-2-(4-fluorophenyl)-2-(4--methylsulfonyl)phenyl|vinyl)phenyl)quinoline p -I sh" (ee) - 50 sl

F) ime) 60 b5 y: sne to

M

From 75 В E s o (o)

Example 5

SNa «- che so

SN her -

M

"- with - I t" (ee) - I is in de;

In! I and O

Example 6

F) Examples 5 and 6 were obtained in the following way. The products of examples 5 and 6 were prepared according to the method of preparation of example 1, but replacing ketone KZ with CL as the starting product, and using flash chromatography purification (5090 EtOAc/5095 hexane). in H NMR (500 MHC, Acetone-dv) Example 5: Major (7) isomer: 5 8.78 (dd, 1H), 8.25 (dd, 1H), 7.93 (d, 2H), 7.712 (d , 71), 7.55-7.40 (m, 6H), 7.35 (m, 2H), 7.25 (t, 1H), 7.23 (s, 1), 7.11 (t, 2H), 7.05 (d, 1H), 3.12 (m, 1H), 2.96 (s, ЗН), 1.34 (d, 6H).

NMR NN (500MHz, Acetone-dv) Example 6: Secondary (E) isomer: δ 8.78 (dd, 1H), 8.35 (dd, 1H), 7.93 (d, 2H), 7.72 ( d, 1H), 7.65-7.55 (m, ЗН), 7.45 (dd, 1H), 7.35-7.15 (m, 9H), 3.12 (m, 4H), 1 ,34 (d, 6H). 65 Example 7 2-(2-CE/2)-2-I3-(6-isopropyl-8-quinolinyl)phenyl|-1-(4--methylsulfonyl)phenyl|vinyl)-1,3-thiazol-5- yl)-2-propanol and | y: SN r ON

M. 8

Fo with vo

I I I I . with

The product of example 7 was obtained according to the method of example 1, but replacing ketone KZ with Kb as the starting product. Purification by flash chromatography (10095 E(OAc) gave the product of example 7 in the form of a mixture of isomers. i)

H NMR (400 MHz, Acetone-iv) 5 8.80 (nm, 1H), 8.30 (m, 1H), 8.05 (d(main), 1.44H), 7.93 (d(secondary ), 0.55Н), 7.85 (s(primary), 0.72Н), 7.77 (s, (secondary), 0.28Н), 7.75-7.45 (m, 7Н) 7 .35 (t(secondary), 0.28Н), 7.28 (t, (main), 0.72Н), 7.21 (d(secondary), 0.28Н), 7.10 (d (main) . 16H), 1.60 (m, 6H), 1.35 (m, 6H).

M8 (item 1): 569.6 -

Example 8 (ee) 2-I8-(3-KE/2)-2-(5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl|-2-(4--( methylsulfonyl)phenyl|vinylphenyl)-6-hy« nolinyl|-2-methylpropanenitrile

M and -

Neither do I

She « o | Snu SN" from the same page.

And" (M sh--

M chai 5 -I sh» so d- - 50 sl - SN» th Me o

ГФ) The product of example 8 was obtained according to the method of obtaining example 1, but substituting ketone КЗ with Кб and benzyl phosphonate P2 with РЗ as the starting product. Purification by flash chromatography (2095 CH»CI»8096 EAs) gave the product of example 8 in the form of a mixture of isomers. in H NMR (400 MHz, Acetone-dv) 5 8.92 (n, 71Н), 8.45 (m, 1Н), 8.10 (m, 1Н), 8.05 (t, 1Н), 7, 93 (m, tn), 7.85 (m, 2Н), 7.77-755 (m, ХН), 7.40 (t (secondary), 0.43Н), 7.28 (t, (main) , 0.57Н), 7.21 (а (secondary), 0.43Н), 7.10 (а (main), 0.57Н), 4.67 (с, (main), 0.57Н), 4 .63 |(с(secondary), 0.43Н), 3.15 (с(secondary), 1, ЗН), 2.99 (с(primary), 1.7Н), 1.90 (m, b6Н) , 1.65 (s(primary), 3.4H), 1.45 (s(secondary), 2.6H). 65 M5 (thia1): 594.6

Example 9

2-methyl-2-I8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4-(methylsulfonyl)phenylvinyl)phenyl)-6-quinolinyl|propanenitrile; Mao Yang" is dishonest

Ж ше т и при с 0 / о у /М 2? Us

IS) » NS to her

Example 9 was obtained in the following way. (uh)

Stage 1: "2-methyl-2-I8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4-(methylthio)phenyl|vinyl)uphenyl)- 6b-quinolinyl|Ipropanenitrile was obtained according to the method of preparation of example 1, but replacing ketone KZ with K2 and benzyl phosphonate P2 with RZ as starting products.

Stage 2: 2-methyl-2-I8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-I(4-(methylsulfonyl)phenyl|vinylphenyl)-6 -quinolinyl|-propane « ytril, the product of example 9, was obtained according to the method used for the preparation of boronate B1 (step 2 of scheme 2), but substituting as the starting product - c (E/2)-2-(3-bromophenyl) -1-(1-methyl-1H-imidazol-2-yl)-1-(4--(methylthio)-phenyl|ethylene on the sulfide obtained in a presented stage 1. The product of example 9 was obtained after purification by flash chromatography ( 9796 EUAs "» EVBM/Z39).

NMR "NN (400MHz, Acetone-iv) 5 8.92 (5d, 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, 1), 7.19 (m, 1H), 7.10 ( m, 1H), 6.95 (m, 1H), 3.55 (s, ЗН), 3.00 ш- (s, ЗН), 1.85 (s, 6Н). their M5 (thia1): 533 ,3

Example 10 bo 6-(1-(methylsulfonyl)ethyl|-8-13-KE)-2-(4-(methyl-sulfonyl)phenyl|)|-2-(1,3-thiazol-2-yl)vinyl |phenyl)quinoline - 50 ml

F) name) 60 b5

OS

7 | at

F s with 9 Sh, o sh (and 5 o?

IS) "-

The product of example 10 was obtained according to the following method. A mixture of bromoquinoline 22 (105 mg, 0.3 mmol), boronate B2 (236 mg, 0.51 mmol), Ma»CO3 (2M, 0.65 ml, 1.3 mmol), RI(OAc)» (6.3 mg 0.028 mmol) and PPAz (28 mg, 0.11 mmol) in 4 ml of n-propanol was stirred at 902C for 2 hours. The mixture was cooled at room temperature, diluted with EtOAc, washed with saturated saline, dried over Ma»5O»;, filtered and M concentrated. Flash chromatography (toluene/acetone; 4/1) and stirring in hexane/E(OAc) gave the product of example 10 (single isomer) as a white solid.

H NMR (400 MHz, Acetone-dv) 5 8.89 (5d, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7.94 (c, 1H), 7.86 (d, 1), 7.71-7.68 (m, ЗН) 7.62-7.60 (m, 2H), 7.55 (dd, 1H), 7 ... c, ЗН) 1.88 (с, ЗН). z с М (М) 576. Example 11 a 6-P1-methyl-1-(methylsulfonyl)ethyl|-8-13-KE)-2-(4 -(methylsulfonyl)phenyl|/|-2-(1,3-thiazol-2-yl)vinyl|phenyl)quinoline -I sh» (ee) - 50 ml

F) name) 60 b5

Oh SN"

M

F

Fi, s » o M o x 5 os?

IS) not "-

Example 11 was prepared according to the method described in example 10, but replacing bromoquinoline 22 with OZ and co using boronate B2. Flash chromatography (toluene/acetone; 9/1) and stirring in EtOAc/Nex afforded the product of Example 11 (single isomer) as a white solid. "AND

H NMR (400 MHz, Acetone-dv) 5 8.90 (5d, 1H), 8.41 (dd, 1H), 8.23 (s, 1H), 8.02-7.99 (d, ЗН) , 7.95 (s, 1H), M 7.86 (d, 1H), 7.70 (d, 2H), 7.60-7.54 (m, 4H), 7.32 (t, 1H) , 7.13 (d, 1Н), 3.00 (с, ЗН), 2.69 (с, ЗН), 1.96 (с, 6Н).

M (M) 523.

Example 12 8-(3-(2)-2-(1-methyl-1H-imidazol-2-yl)-2-I(4-methylsulfonyl)-phenylvinylphenyl)-6-(I1--"methylsulfonyl)ethyl /) quinoline 2 s o

M

-i eh ko SNz (sg) nt ayu M dn sl M M shchi SN she

F) ke - 60 - ze;

Example 12 was prepared according to the method described in example 10, using bromoquinoline 02, but replacing boronate B2 with B1. Flash chromatography (9595 CH»bSiI»/5956 EN) gave the compound of example 12. b5 NMR "H (400 MHz, Acetone-dv) 5 8.92 (5d, 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, 1), 7.26 (s, 1H), 7.18 (s, 1H), 7.05 (m, 2H), 4.70 (sq ., 1H), 3.40 (s, ЗН), 3.13 (s,

ZN), 2.93 (c, ZN), 1.87 (d, ZN).

M (Ma): 572.4

Example 13 8-(3-(2)-2-(1-methyl-1H-imidazol-2-yl)-2-(4--methyl-sulfonyl)phenyl|vinylphenyl)-6-(/1-methyl- 1--"methylsulfonyl)-ethylquinoline

AND

70 Oh Sleep : | CH,

M r s ( o 5- СН o h gre ch- o so

Example 13 was prepared according to the method described in example 10, but replacing bromoquinoline 22 with OZ and replacing boronate B2 with B1. Flash chromatography (9595 EOAc/5 90Ei 3M) gave the product of example 13 (single isomer) as a foam. uh-

H NMR (400 MHz, Acetone-dv) 5 8.92 (5d, 1H), 8.45 (dd, 1H), 8.37 (d, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.76 (d, 71), 7.69 (d, 2H), 7.65 (d, 71H), 7.59 (dd, 71H), 7.38 (t, 71H) , 7.31 (s, 1H), 7.18 (s, 1H), 7.05 (m, 2H), 3.40 (s, ЗН), 3.13 (s, ЗН), 2.70 ( s, ZN), 1.95 (s, 6H). "

M (M): 586.2

Examples 14 and 15 o, c 6-P1-methyl-1-(methylsulfonyl)ethyl|-8-(3-(E/27)-2-(3-methyl-1,2,4-oxadiazol-5-yl) )-2-I(4-(methylsulfonyl)phenyl)-phenyl)quinoline and? -I sh" (ee) - 50 sl

F) name) 60 b5

With

And piece; 5-OH,

It is about 170 M | M p o /- ОН» x - p

KK: oh M o h m o g h s e

IC) p z report 14

OO. SNU - ed. so no x « o i - r F «

M Nas - s ke M "z i M y F o -I

Shan sh" (ee) - 50 sl

OT and oh

F)

Example 15 where Examples 14 and 15 were obtained according to the following method. A solution of aryl AB5 bromide (249mg, 0.57mmol), pinacol diboronic ester (167mg, 0.bbmmol), (1,1!-bis(idiphenylphosphino)ferrocene|dichloropalladium bo (I) (12mg, 0.015mmol) and potassium acetate (17 mg, 1.9 mmol) in DMF (M,M-dimethylformamide) (1 mL) was degassed and stirred at 802 C for 3 hours. Bromoquinoline was then added to the mixture thus obtained at 2523

OZ (15O0mg, 0.4bmmol), (1,1!-bis(diphenylphosphino)ferrocene|dichloropalladium (II) (12mg, 0.015mmol) and sodium carbonate (0O.bml, 2M). After degassing, the mixture was heated at 802C for overnight. Then the mixture was cooled to room temperature, quenched with H2O and extracted with E(SO4). The organic extracts were washed (H2O, saturated saline solution), dried (Ma95045), filtered and concentrated. Purification by flash chromatography

(Hexane:EuAcSEBM, 22:68:10, then hexane:E(OAc, 3:1) gave both isomers (Example 14 and Example 15).

H NMR (500 MHz, Acetone-dv) Major (E) isomer (Example 14): δ 8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d, 1H), 8, 12 (s, 1H), 8.02 (d, 1), 8.00 (d, 2H), 7.70 (m, ЗН), 7.64 (s, 1H), 7.55 (dd, 1H ), 7.38 (t, 1H), 7.23 (d, 1H), 3.03 (s, ЗН), 2.69 (s, ЗН), 2.33 (s, ЗН), 1.96 (c, 6H).

M5 (M): 588.2

Secondary (7) isomer (Example 15): 5 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, ЗН), 7.62 (s, 1H), 7.58 (q., 1H), 7.48 (t, 1H ), 7.24 (d, 71Н), 3.16 (с, ЗН), 2.70 (с, ЗН), 2.38 (с, ЗН), 2.00 (с, 6Н).

M5 (M): 588.2

Alternatively, the product of example 14 can be obtained according to the following method: glycerin vo, y

Me5OON x AVM Be Verya ini Yani

Ve Bbama cm MV5 M st5Ozha

Where is she?

MO" (n p. 7 and 5OoMe o

M Am U | ZOzMe SNO,

KVoOMa kerosene

Ve M u bg "- . (ee) and: 502Ma « 4 M. and 50oMe 4

M, o piperidine F « tension and

MeO, - I am a

I" sno I. ERSNOVI and Y

M on Mao: we i them | And Example 14 of them 2 with RVOZON on Oshchi and sl ch

Meb, J

Salt of benzosulfonic acid

Stage 1. Scroup's reaction (5 Kgashr) (F. ko) bo b5 glycerol t-MORNZO" Ma to Su M

MA; g /5 Sodium m-nitrobesol sulfonate (0.6-0.equiv.), and then ferrous sulfate heptahydrate (0.01-0.05 equiv.) were added to methanesulfonic acid (8-1 eq.) at 209. 2-bromo-4-methylaniline (Tech.) was added to the resulting mixture.

Glycerin (2-Zeq.) was added and the resulting solution was heated at 120-1402C and left until the reaction was complete.

The mixture was cooled to 70-90 and diluted with water. Then the solution was cooled to about 20C and neutralized with aqueous Mahon and sodium bicarbonate. MTBE (methyl tert-butyl ether) was added and the mixture was filtered, and the phases were separated (the product was in the MTBE layer).

Stage 2. Bromination of AIVM Zk si 2 Be z | at

m)

Ve Vg -

The MTBE solution from stage 1 was dissolved by switching to chlorobenzene. After filtration through silica gel and partial concentration, M-bromosuccinimide (МВ5, 0.6-0, eq.) and 2.2! - azobisisobutylnitrile (AIVM, "Ж 0.01-0.1 eq.). The degassed mixture was heated at 55-8592C. The resulting mixture was dissolved in cyclohexane. An additional amount of MV (0.3-0.Eq.) and AIVM (0.01-0.05 Eq.) was added. The degassed mixture was heated to approximately 55-8592C until the reaction was complete. The mixture was cooled to 10-402C and diluted with cyclohexane and allowed to settle.

The solid was isolated by filtration.

Stage 3. Formation of sulfone "

Z - s Ve i y: 5OMe z y polo pr orinerro

М СВо5ОоМа - g г Вг (ee) To a solution of bromomethyl-bromoquinoline (product of the previous stage, Teq.) in DMF was added powdered -l 20 sodium methanesulfinate (1.0-1.5 equiv.) at 10-602С. The mixture was heated at about 50-70 for 30 minutes.

The mixture was diluted with water, maintaining the temperature at about 50-702C, with vigorous stirring, then cooled to about 10-20 and allowed to settle. The mixture was filtered and the solid was washed successively with 1:4 DMF/water and then dried with water.

Stage 4. Methylation

HF) 8O»SNU 0 Mao Osn 0 MebiVy osn ko M, OME Ma, OME i T :y 60 A solution of the sulfone (product of the previous stage, Tekv.) in DMF was cooled to approximately -10 to 020.

Sodium tert-butoxide (-Teq.) was added. A solution of methyl iodide/DMF (Mei's solution) was added slowly, maintaining the temperature at about -10 to 0°C.

A second portion of solid sodium tert-butoxide (-Teq.) was added, followed by a solution of methyl iodide/DMF (-Teq.), 65 maintaining the temperature from -5 to 1023 (if the reaction does not proceed completely, an additional amount of base can be added and Mei). The reaction was quenched by adding water, and the isolated product was crystallized and dried. -BO0-

Stage 5. The Zygiki joining reaction

He) with

SN"? roses and pvOosne

RICE I clean - 2 I I no 0 KoSOUOME I vs Fo y: what

RYAAMS (5 or 1Omas.9o, 0.005-0.1 eq.), potassium carbonate (2-Eq.) and 3-formylphenylboronic acid (1-2 eq.) were added to the sulfone solution from the previous stage (1 eq.). The degassed reaction mixture was heated to 60-1202C until the reaction was complete. The mixture was filtered and the filtrate was diluted with water. The product was crystallized, isolated by filtration and dried.

Stage 6. Oxadiazole ono 1. EOSTOV in o

BUT Sh;

Mey8 2. HC Meabz8 ny

To a mixture of benzotriazole hydroxy hydrate ("NEW") (1-1.5 equiv.), 4-methylsulfonylphenylacetic acid (Teq.) in acetonitrile was added EOS hydrochloride (1-1. equiv.). The suspension was left to settle at approximately 20-302C for 30 minutes. (at)

Other M-OH compounds, such as M-hydroxyphthalimide, 2-hydroxypyridine, M-oxide, M-hydroxysuccinimide, can also be used instead of NOVA. Instead of EOS hydrochloride (ethyl dimethylaminopropylcarbodiimide hydrochloride), other carbodiimides can be used, such as iso dicyclohexylcarbodiimide and diisopropylcarbodiimide.

Acetamide oxime (1-1.5 eq.) was added to the suspension. The resulting mixture was then boiled under reflux until the reaction was complete. The resulting solution was concentrated and diluted with ethyl acetate. The resulting mixture was washed with aqueous sodium bicarbonate. The solution was dissolved, replacing with 2-propanol, and after cooling, the isolated product was crystallized and dried. "AND

Stage 7. Condensation to obtain the product of example 14

M shi s 50Me.

M shlperilyn

And" - my 0 UAH in my meod - And in the spring. Also, (ee) - 50

To the suspension of the aldehyde of stage 5 presented above (according to Eq.) in 2-propanol was added oxadiazole of stage 6, c presented above (according to 1-1 equiv.), and then piperidine (0.2-1.5 equiv.).

Instead of 2-propanol, other solvents can be used, such as, for example, DMF, acetonitrile, 1-propanol, toluene, ether and other alcohols. Piperidine serves as the main initiator. Instead of piperidine

Other amino bases can be used, especially secondary amines.

The resulting mixture was refluxed over molecular sieves until the reaction was complete. o After cooling, the product was isolated by filtration and dried. Examples 16 and 17 (E/2)-3-13-(6-(1-cyano-1-methylethyl)-8-quinolinylphenyl)-M-isopropyl-2-(4-methylsulfonyl)phenyl| propenamide 60 b5

In zm

Sho

IR! with I SN

Z o o sn sia - Z o ne x she;

Example 16 IS o) "-

NS -ZM (ee) chh chE

M

SN them and Fr. In with M. in"

F shk SN -I t" (ee) shu 20 57 ОН" -

Example 17 55 . . . . b- . .

The products of examples 16 and 17 were obtained in accordance with the method described earlier for examples 14 and 15,

HF) replacing the starting substances aryl bromide AB5 with AB2 and bromoquinoline OZ with 05. Examples 16 and 17 were obtained in the 7th form of a 4:1 mixture.

NMR NN (500 MHz, Acetone-dv5) Major (E) isomer (Example 16): 5 8.89 (dd, 1H), 8.43 (dd, 1H), 8.09 (d, in 1), 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 (width, d, 1H), 4.13 (m, 1H) 2.92 (s, 3H), 1.87 (s, 6H), 1.12 (d, bN).

M (Ma): 538.3

Secondary (72) isomer (Example 17): 5 8.93 (dd, 1H), 8.48 (dd, 1H), 8.14 (d, 1H), 7.94 (m, 4H), 7.85 (d, 2H), 7.70 (dd, 2H), 7.59 (sq., 1H), 7.50 (m, 2H), 7.28 (s, 1H), 4.15 (m, 1H) 3.13 (c, ЗН), 1.91 (c, 6H), 1.04 (d, 6H). 65 M (Ma): 538.3

Example 18

8-(3-(KE)-2-13-(4-methoxyphenoxy)methyl)-1,2,4-oxadiazol-5-yl)-2-I(4-(methylsulfonyl)phenyl|ethenylphenyl)-b -(P1-methyl-1-(methylsulfonyl)ethyl)quinoline; But about --SN v

In the 5th CH,

F o, shih: sch r/ o nesu, o Fyu "- s " i -

The product of example 18 was obtained by the following method. in c Stage 1 (scheme 3): (4-methoxyphenoxy)acetonitrile. A mixture of 4-methoxyphenol (10g, 10mmol), chloroacetonitrile (7.00ml, 111mmol) and K»CO3 (26g, 188mmol) in acetone (15 Oml) was stirred at room temperature for 18 hours. The mixture was filtered, concentrated and purified by flash chromatography (Nex: EtOAc, 4:11) to give (4-methoxyphenoxy)acetonitrile as a clear oil. -I Stage 2 (scheme 3): (4-methoxyphenoxy)acetamide oxime

A mixture of the product (4-methoxyphenoxy)acetonitrile (5.0g, Zimmol) of stage 1, hydroxylamine hydrochloride ve (4.3g, b2mmol) and sodium acetate (5.1g, b2mmol) in Meon (100ml) was stirred at room temperature

Go! within 2 hours. The resulting mixture was filtered through Siebt, concentrated, stirred in NaCl for 18 hours and filtered. The resulting solution was concentrated to obtain oxime (4-methoxyphenoxy)acetamide in the form of wax. sp Stage C (scheme C, oxadiazole OX): 3-(4-Methoxyphenoxy)methyl|)-5-(4-(methylsulfonyl)benzyl|)-1,2,4-oxadiazole 3-(4-Methoxyphenoxy)methylide- 5-I(4-(methylsulfonyl)benzyl/|-1,2,4-oxadiazole was prepared according to the following method presented in scheme C for AB5 stage 1 (ОХ1), but replacing the acetamide oxime with (4-methoxyphenoxy)acetamide oxime of step 2 above and heating the reaction mixture at 902C for 6 hours.(iF) Purification by flash chromatography (NexEAc, 3:2 to 1:4) afforded the desired material as a tan solid.

Stage 4: 3-16-((/1-methyl-1-(methylsulfonyl)ethyl)-8-quinolinyl) benzaldehyde to Bromoquinoline 03 (10.1g, 30.0mol), 3-formylbenzeneboronic acid (5.8g, 38 .7mmol), tetrakis(triphenylphosphine)palladium (0) (2.1g, 1.8bmmol) and sodium carbonate (30ml, 2M) were added to OME (330ml).

After degassing, the mixture was heated at 80 C overnight. After cooling to room temperature, the resulting mixture was quenched with NaO and extracted with EtOAc. The organic extracts were washed (NoO, saturated saline solution), dried (MaSO), filtered and concentrated. Stirring in ether and subsequent isolation of 65 by filtration gave 3-(6-|1-methyl-1-(methylsulfonyl)-ethyl|-8-quinolinyl)/benzaldehyde.

Stage 5:

8-(3-(KE)-2-13-(4-methoxyphenoxy)methyl/-1,2,4-oxadiazol-5-yl)-2-I(4-(methylsulfonyl)phenyl|ethenylphenyl)-6- (1-methyl-1-(methylsulfonyl)ethyl) quinoline

A mixture of the product of step 4 (150mg, 042mmol), oxadiazole OX2 of step 3 described above (175mg, 0.47mmol) and piperidine (0.1ml, 1.0mmol) in toluene (0.bml) was heated at 12023 for

From hours The mixture was purified by flash chromatography (NexEUAc, 3:2 to 1:4) to give the product of example 18 as a foam.

H NMR (400 MHz, Acetone-dv) 5 8.90 (sq., 1H), 8.42 (sq., 1H), 8.24 (d, 1H), 8.20 (s, 1H), 8 .02 (m, ЗН), 7.75-7.66 (m, 4Н), 7.55 (sq., 1Н), 7.39 (t, 1Н), 7.25 (d, 1Н), 7 .00 (d, 2H), 6.87 (d, 2H), 5.17 (s, 2H), 3.73 70 (s, ЗН), 3.03 (s, ЗН), 2.80 (s , ЗН), 1.96 (с, 6Н).

Example 19 (5-(E)-2-(3-6-/1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-1-(4--methylsulfonyl)phenyl|ethenyl)-1,2 "4-oxadiazol-3-yl)umethanol i ns o e-CH"z tah M » | at

M Sn, p 25 - (8)

IS) 30 - o her « 35 o | pH -

Te M and "

The product of example 19 was obtained according to the following method. To a solution of the compound of example 18 (25 Ωg, 0.6 mmol) in acetonitrile: water (41 L, vml) was added SAM (3 3 Ω, 0.6 0.2 mmol) in two portions at room temperature. After 3 hours at room temperature, the mixture was diluted with a saturated Manso solution, diluted with water and extracted with EtOAc. Organic extracts were washed (H2C), (saturated saline solution), - dried (Ma5zO)), filtered and concentrated. Purification by flash chromatography (Nex, EtOAc, 3:7) gave (5-(E)-2-(3-6-/1-methyl-1-(methylsulfonyl)ethyl)|-8-quinoliniluphenyl)-1-( 4--methylsulfonyl)phenyl|ethenyl)-1,2,4-0 and xadiazol-3-yl)umethanol in the form of a light-yellow foam. co NMR "H (400MHC, Acetone-dv) 5 8.90 (sq. , 1H), 8.42 (sq., 1H), 8.25 (d, 1H), 8.15 (s, 1H), 8.02 (m, ЗН), 7.73-7.65 (m, 4H ), 7.55 (sq., 1H), 7.38 (t, 1H), 7.23 (d, 1H), 4.67 (m, ЗН), 3.04 (s, ЗН), 2, 82 (c, ZN), 1.96 (c, 6H). - Example 20 with (E)-M-isopropyl-3-(3-16-(/1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-2-(4-(methylsulfonyl)phenyl)| -2- propenamide

F) ime) 60 b5 -B4-

Neo and

ZONE

| What is it?

F No | your: chu f o

From zo v

The product of example 20 was obtained according to the following method described above for examples 14 and 15, but replacing the aryl bromide AB5 with AB, and using bromoquinoline 3 as the starting product.

H NMR (Z00MHC, Acetone-dv) 5 8.89 (5d, 1H), 8.41 (dd, 1H), 8.22 (d, 1H), 7.99 (d, 1H), 7.88 (d, 2H), 7.67 (s, 1), 7.53 (m, 4H), 7.43 (s, 1H), 7.28 (t, 1H), 7.05 (d, 1H) . (M 1): 591.3

Example 21 "- (E)-3-13-I6-(1-cyano-1-methylethyl)-8-quinolinyl|phenyl)-2-I(4--(methylsulfonyl)phenyl|-2-propenoic acid with

NS SNa Z' m.

M « 4 shi s with -I sh» y - he sl

However, the product of example 21 was prepared according to the following method described above for examples 14 and 15, but replacing the starting products of aryl bromide AB5 with AB and bromoquinoline OZ with O5.

H NMR (500 MHz, Acetone-dv) 5 8.8 (5d, 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, Н) , 1.88 (c, 6H).

M (M-CO"): 451.4 (negative ion). 65 Example 22 2-methyl-2-I8-(3-(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-I(4-(methylsulfonyl)phenyl) ethenylphenyl)-b-quinolini l|-propanenitrile chx М 70 M

And F

In, in the village

I m- (5)

These

Mass in SN,

IS)

The product of example 22 was obtained according to the following method described above for examples 14 and 15i - using as starting products aryl bromide AB 5 and replacing bromoquinoline OZ with O5.

H NMR (500 MHz, Acetone-dv) 5 8.90 (5d, 1H), 8.43 (dd, 1H), 8.1 (d, 2H), 8.01 (d, 2H), 7.83 (d, 1H), 7.71. ...00 (t, ZH), 7.66 (s, 1H), 7.56 (sq., 1H), 7.55 (dd, 1H), 7, 38 (t, 1H), 7.22 (d, 1H), 3.03 (s, ЗН), 2.33 (s, ЗН), 1.87 (s, 6Н).

M (M): 535.2

From Example 23 o (E)-3-13-I6-(1-cyano-1-methylethyl)-8-quinoline|phenyl)-2-(4--(methylsulfonyl)phenyl|-2-propenamide

NO dream « - with che -ch

And" | M that

M

-I sh" (ee) - 50 sl a MNH --

From what

Not U

The product of example 23 was obtained according to the following method described above for examples 14 and 15, but replacing 65 as starting products the aryl bromide AB5 with ABZ and the bromoquinoline OZ with O5, obtaining the compound indicated in -58c-

header

H NMR (500 MHz, Acetone-iv) 5 8.89 (bd, 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 (width, 1H), 6.7 (width s, 1H), 2.93 (s, ЗН), 1.87 (s, 6H).

Example 24 (E)-M-(tert-butyl)-3-13-I(I6-(1-cyano-1-methylethyl)-8-quinolinylphenyl)-2-(4--"methylsulfonyl)phenyl)|- 2-propenamide and CH, ! Sh- t and F sh o Na yu xx o SNne "-

Crust

With o; co

The product of example 24 was obtained according to the following method described above for examples 14 and 15, but replacing as starting products aryl bromide AB5 with ABA and bromoquinoline OZ with O5. them

H NMR (500 MHz, Acetone-iv) 5 8.89 (5d, 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 (width, 1H), 2.93 (s, ЗН), 1.87 (s, 6H), 1.36 (s, 9H). M (M-0553.

Example 25 "(E)-3-IZ3-(6-isopropyl-8-quinolinyl)phenyl|-2-I(4-(methylsulfonyl)phenyl|-2-propenoic acid shi - СНа . » p s СН» ) - I -y7 schi IM (ee) - 50 7 Ff schi yu on y o; t 0: t a -- us b5

The product of example 25 was obtained according to the following method described above for examples 14 and 15, but replacing as starting products aryl bromide AB5 with AB and OZ with 5-isopropyl-8-bromoquinoline (described in international patent publication MU09422852).

H NMR (500 MHz, Acetone-iv) 5 8.69 (5d, 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), 7.96 (dd, 71H), 7.31 (t, 1H), 7.20 (s, 7H) , 7.13 (d, 1H), 31 (m, 1H), 2.93 (s, ЗН), 1.36 (d, 6H). M (Mn) 472.

Example 26 b-isopropyl-8-(3-(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4--"methylsulfonyl)phenyl|ethenylphenyl)quinoline CH"

M -

I F s | o me o I y o ne-8 y y tyy

With "

The product of example 26 was obtained according to the following method described above for examples 14 and 15, but in using as starting products aryl bromide AB5 and replacing OZ with 5-isopropyl-8-bromoquinoline (described in the international patent publication UUO9422852).

H NMR (500 MHz, Acetone-iv) 5 8.80 (5d, 1H), 8.29 (dd, 1H), 8.12 (s, 1H), 8.03 (d, 2H), 7.76 (s, 1H), 7.73 « (m, ЗН), 7.59 (s, 1H), 7.53 (d, 71H), 7.47 (sq., 1H), 7.36 (t, 1H), 7.22 (d, 1H), 3.1 (m, 1H), 2.93 (s, Н), - 70 2.33 (s, Н) 1.36 (d, 6Н). (Me) 510. c Example 27; c" (E)-3-(3-(6-(/1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-2-(4--(methylsulfonyl) )phenyl|-1-(1-pyrrolidin yl)-2-propen-1-one -I sh» (ee) - 50 ml

F) name) 60 b5

; with v7OHz x o 2 o 10 U 20 o o, s g ny Y

Us scha; at

The product of example 27 was obtained according to the following method.

Stage 1: IC o) (E)-3-(3-46-/1-methyl-1-(methylsulfonyl)ethyl/|-8-quinolinylphenyl)-2-I(4--methylsulfonyl)phenyl|-2- propenoic acid

A mixture of /3-6-(/1-methyl-1--"methylsulfonyl)ethyl|)|-8-quinolinyl)-"benzaldehyde of stage 4 of example 18 (2.33 g,; 00 6.bOmmol), 4-(methylsulfonyl ) of phenylacetic acid (1.71 g, 7.98 mmol) and piperidine (0.20 ml, 1.98 mmol) in 1 Oml of toluene was refluxed for 2 days. The mixture was cooled to room temperature, diluted with СНоСі, subjected to flash chromatography (CHClSO/EUAc/AsonH, 50/50/1) and finally mixed with them (EBO/CH»oCl») and isolated to obtain (E)-3-(3-16-(/1-methyl-1 -(methylsulfonyl)ethyl|-8-quinolinylphenyl)-2-(4--methylsulfonyl)phenyl|-2-propenoic acid (single isomer) as a white solid.

H NMR (400 MHz, Acetone-dv) 5 8.89 (5d, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7.94 (c, 1H), 7.86 (d, 1), 7.71-7.68 (m, ЗН) 7.62-7.60 (m, 2H), 7.55 (dd, 1H), 7 ... (с, ЗН) 1.88 (с, ЗН). "» M (М) 576. " Stage 2: (E)-3-(3-16-(/1-methyl-1-(methylsulfonyl)ethyl| -8-quinolinylphenyl)-2-(4-("methylsulfonyl)phenyl|-1-(1-pyrrolidinyl)-2-propene-Thone - A mixture of (E)-3-(3-16-(/1-methyl) -1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-2-(4--methylsulfonyl)phenyl|-2-propenoic acid (104mg, 0.19mmol) presented in step 1 above, pyrrolidine (24µl, 0.29mmol) . 12 hours The mixture was diluted

EUAs, washed with MNACI (sat.), NiO (Zh), saturated saline solution, dried over Na»53O»), filtered and concentrated. Stirring in EtOAc/Nex afforded the product of Example 27 as a white solid.

H NMR (400 MHz, Acetone-dv) 5 8.88 (5d, 1H), 8.40 (dd, 1H), 8.22 (d, 1H), 8.98 (d, 1H), 7.88 (d, 2H), 7.67 (d, 2H), 7.60 (d, 1H) 7.55-7.52 (m, 2H) 7.34 (t, 1H), 7.18 (d, 1H), 7.03 (width s, MN) 3.58 (width s, 2H), 3.44 99 (width s, 2H), 3.02 (s, ЗН), 2.69 (s , ЗН) 1.95 (s, 6H), 1.88 (width s, 4H). M5 (Mt) 603.

HF) Example 28 (E)-M-cyclopropyl-3-(3-16-(/1-methyl-1-(methylsulfonyl)-ethyl)-8-quinolinylphenyl)-2-(4--methylsulfonyl)-phenyl 12-propenamide 60 b5

More -- at 170 M

And F

| M.S.F.S.S.N

The product of example 28 was prepared according to the following method described for step 2 of example 27, but replacing pyrrolidine with cyclopropylamine, thus obtaining a solid product. IC o)

H NMR (400 MHz, Acetone-dv) 5 8.89 (5d, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.87 (d, 2H), 7.68 "- (c, 7), 7.59-7.53 (m, 4H), 7.43 (c, 1H), 7.29 (t, 71H), 7, 04 (d, 1H), 6.94 (width, s, 1H), 2.89 (s, ЗН), 2.84-2.80 (m, 1H), 2.69 (s, ЗН), 1 .96 (c, 6H), 0.67-0.63 (m, 2H), 0.49-0.45 (m, 2H).

M (Mt) 589. "

Example 29

Zo (E)-M-(tert-butyl)-3-(3-16-(1-methyl-1-(methylsulfonyl)ethyl/|-8-quinolinyl)uphenyl)-2-(4--methylsulfonyl)phenyl in. -2-propenamide

NIS CH 4th. "With what; - o

M'. -I sh» (ee) - 50 sl i | "M N (F, che Z and that about St

But about

The product of example 29 was prepared as a white solid by following the procedure of step 2 of example 27, but substituting tert-butylamine for pyrrolidine. bo NMR "H (400 MHz, Acetone-dv) 5 8.89 (5d, 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, 7H), 7.05 (d, 71H), 6.43 (width, 1H) , 2.94 (с, ЗН), 2.69 (с, ЗН), 1.96 (с, 6Н), 1.36 (с, 9Н). M5 (M--1) 606.

Example 30 8-13-(2,2-bis(4-chlorophenyl)vinyl|Ifenyl)-6b-isopropylquinoline from the SNU

M

F s o si si o

The product of example 3 was obtained according to the following method. Potassium tert-butoxide (1 M, THF, 0.35 ml, 0, 35 mmol). After 1 hour at room temperature, the mixture was diluted (ee) with water/MNACI and extracted with E(Ac. The organic extracts were washed (H2O), (saturated saline solution), "dried (Ma53O)), filtered and concentrated. Purification by flash chromatography (Nex, EtOAc, 8:2) gave the product of example 30 in the form of a foam.

H NMR (300 MgCl, Acetone-iv) 5 8.79 (5d, 1), 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 31 132 « b-isopropyl-8-(3-(E/2)-X2-(6-methyl-3-pyridinyl)-2-(4--methylsulfonyl)phenyl|ethenyl)phenyl)quinoline Z c z - And sh" (ee) - 50 sl

F) name) 60 b5

SN xx SN y

M hu with NO 4 k! - o o yuyu zo Example 31 - sne and "I | xx SNe - y

M « - s z -I ї (ee) che - 70 | M sl sdee CH and o Сn, o Example 32

The products of examples 31 and 32 were prepared according to the following method described for example 30, but 60 replacing 4,4"-dichlorobenzophenone with K7 and using benzylphosphonate Ra as starting products.

NMR NN (ZOOMHC, Acetone-dv) (E) isomer (Example 31): 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, ЗН), 7.10 (d, 1H), 3 .15 (hept., 1H), 2.98 (s, ЗН), 1.34 (d, 6H). (24) isomer (Example 32): δ 8.79 (dd, 1H), 8.35 (d, 7H), 8.28 (dd, 1H), 7.92 (d, 2H), 7.74 ( d, 1H), 7.61-7.30 (m, TON), 7.19 (d, 1H), 3.13 (s, ЗН), 3.11 (hept., 1H), 1.35 ( d, 6H). b5.

Examples 33 and 34 b-isopropyl-8-(3-(E/2)-2-(5-methyl-2-pyridinyl)-2-I(4-(methylsulfonyl)phenyl|ethenyl)phenyl)quinoline

M F y F y 7 M y s o. EE o o SN.

From iv)

Example 33 - « ah SN ge --

M "shi s;" - I t so M - 50 Shk 7 o tka sh2 and this; about the dream)

Example 34 The products of examples 33 and 34 were prepared according to the following method described for example 30, but substituting 4.4! -dichlorobenzophenone to ketone KV and using benzylphosphonate Ra as starting products.

NMR "H (300 MgCz, Acetone-yve) (E) isomer (Example 33): δ 8.80 (dd, 71H), 8.48 (c, 1), 8.28 (dd, 1H), 7.99 -7.96 (m, ЗН), 7.97 (m, 1), 7.74 (d, 1Н), 7.61-7.44 (m, 6Н), 7.27 (t, 1Н), 7.07 (d, 1H), 6.97 (d, 1nH), 3.15 (hept., 1H), 2.96 (s, ЗН), 1.36 (d, 6H). 65 NMR NN ( ZOOMHC, Acetone-adv) (2) isomer (Example 34): 5 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 (c, ЗН), 3.12

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

Example 35 8-(3-42,2-bis(4-(methylsulfonyl)phenyl|vinyl)phenyl)-6-isopropylquinoline

SN

M s (8)

Oh x

Also to her from SNU Z -

The product of example 35 was obtained according to the following method described for example 30, but replacing 4,4-dichlorobenzophenone with CO ketone and using benzyl phosphonate Ra as starting products. "Mr

H NMR (500 MHz, Acetone-dv) 5 8.80 (5d, 1H), 8.29 (dd, 1H), 7.98 (d, 2H), 7.93 (d, 2H), 7.75 (d, 1Н), 7.61 (d, 2Н), 759-756 (m, ЗН), 7.50 (d, IN), 748-744 (m, ЗН) 7.30 (t, 1Н), 7.12 (d, IN), 314 (hept., 1H), 3.13 (s, ЗН), 2.97(s, ЗН), 1.35 (Д, 6Н).

Examples C6 and 37 2-methyl-2-I8-(3-(E/2)-2-(5-methyl-2-pyridinyl)-2-I(4-methylsulfonyl)phenyl|ethenyl)phenyl)-6 -quinolinyl|propane « nitrile to shi s ;» -I sh" (ee) - 50 sl

F) name) 60 b5 x cha z M

M

M

In I VT - wo o ren (o) sleep from Example 36 "-

MN SA; so "I chad na, - zm

M ikh - s z -I t (ee) a tyu ch sl u I Z o SNa ko

Example 37 in The products of examples 36 and 37 were obtained according to the following method described for example 30, but as starting products replacing 4,4"-dichlorobenzophenone with ketone K8 and replacing benzyl phosphonate P2 with Р3.

NMR NN (400 MHz, Acetone-adv) (E) isomer (Example 36): δ 8.90 (dd, 1H), 8.47 (s, 1H), 8.43 (dd, 1H), 8.08 ( d, 1H), 8.00 (s, 1H), 7.97 (d, 2H), 7.83 (d, 1H) 7.57-7.53 (m, 5H), 7.50 (s, 1H), 7.28 (t, 71H), 7.06 (d, 1H), 6.96 (d, 1H), 2.96 (s, ЗН), 2.33 (s, ЗН), 1, 88 (p. 6H). 65 NMR NN (400 MHz, Acetone-adv) (2) isomer (Example 37): δ 8.89 (dd, 1H), 8.51 (s, 1H), 8.45 (dd, 1H), 8.09 (d, 7), 7.89 (d, 2H), 7.72 (d, 1), 7.62-7.56 (m, 5H), 7.43-7.42 (m, 2H) 7 .30 (t, 1), 7.25 (d, 1H), 7.10

(d, 1Н), 3.11 (с, ЗН), 2.34 (с, ЗН), 1.87 (с, 6Н).

Example 38 2-18-(3-2,2-bis(4--"methylsulfonyl)phenylvinyl)uphenyl)-6-quinolinyl|-2-methylpropanenitrile

On OUN 70 | y: zm

We

F s o 079 them, o

SN 09 - p

The product of example C 8 was obtained according to the following method described for example 30, but as starting products, replacing 4,4"-dichlorobenzophenone with ketone KO and replacing benzyl phosphonate P2 with P3.

H NMR (500 MHz, Acetone-iv) 5 8.90 (5d, 1H), 8.44 (dd, 1H), 8.09 (d, 1H), 7.97 (d, 2H), 7.92 (d, 2H), 7.81. 44 (s, 1H), 7.32 (t, 71H), 7.13 (d, 71H), 6.96 (d, 1H), 3.13 (s, ЗН), 2.97 (s, ЗН ), 1.86 (c, 6H).

Example 39 "2-methyl-2-(8-13-KE)-2-(4-(methylsulfonyl)phenyl|-2-(2-pyridinyl)ethenyl|phenyl)-6-quinolinyl)propanenitrile and Us 7 s Ex - b and chh | - -i nt r i» Not M (ee) - 50 and F 55 . o yu x.

She 60 5-5) where b5

St»

The product of example 39 was obtained according to the following method described for example 30, but as starting products replacing 4,4"-dichlorobenzophenone with ketone K10 and replacing benzylphosphonate P2 with P3.

NMR "NN (300 MHz, Acetone-dv) 5 8.90 (5d, 1H), 8.45 (dd, 1H), 8.11-8.09 (m, 2H), 7.84-7.80 ( m, ЗН), 50007.12-7.69 (m, 1Н), 7.63-7.52 (m, 5Н), 7.43-7.38 (m, 2Н), 7.33 (t, 1H) 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, ЗН), 1.86 (s, 6H).

Examples 40 and 41 6-P1-methyl-1-(methylsulfonyl)ethyl|-8-(3-(E/2)-2-(5-methyl-2-pyridinyl)-2-I(4--(methylsulfonyl )phenyl|ethenyl)f enyl)quinoline o us sn and -o r

M 9 en

I Ff se o yu z r r Sh

H 5 so no te and o Sn. hE m.

Example 40

SN, "

The same t s | 8 p.m

IR Z

-I t» so . - 50 sp 25 She o o o) Gu ni 8 SN 60 us o

Example 41

The products of examples 41 and 42 were prepared according to the following method described for example 10, but replacing bromoquinoline 02 with OZ and replacing boronate B2 with boronate B3. 65 NMR NN (400 MHz, Acetone-dv) (E) isomer (Example 40): δ 8.91 (dd, 1H), 8.45 (s, 1H), 8.41 (dd, 1H), 8.23 (d, 7), 8.01-8.00 (m, 2H), 7.95 (d, 2H), 7.57-7.54 (m, 4H), 7.51 (d, 1H) 7 .49 (c, 1), 7.28 (t, 1H), 7.07

(d, 1H), 6.96 (d, 1H), 2.94 (s, ЗН), 2.69 (s, ЗН), 2.33 (s, ЗН), 1.97 (s, 6Н) .

H NMR (400 MHz, Acetone-dv) (7) isomer (Example 41): δ 8.88 (dd, 1H), 8.49 (s, 1H), 8.42 (dd, 1H), 8.24 (dd, 1H), 7.94 (d, 1H), 7.88 (d, 2H), 7.61-7.55 (m, 5H), 7.47 (s, 1H), 7.40 ( s, 1H), 7.29 (t, 1H), 7.24 (d, 1H), 7.06 (d, 1H), 3.12 (s, ЗН), 2.68 (s, ЗН), 2.33 (c, ZN), 1.96 (c, 6H).

Example 42 2-(6-(E)-2-(3-46-/1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-1-(4--methylsulfonyl)phenyl|ethenyl)-Z -pyridinyl)-2-propanol

On SN che iv | oh thai

And Ff p

M o) (i

On it from S Zh vyv - m

BUT ev about her with about "

The product of example 42 was prepared according to the following method described for example 10, but replacing the bromoquinoline 02 with OZ and replacing the boronate B2 with boronate B4.

H NMR (500 MHz, Acetone-dv) 5 8.91 (5d, 1H), 8.80 (d, 1H), 8.42 (dd, 1H), 8.23 (d, 1H), 8.03 -8.01 (m, 2H), 7.96 (d, 1), 7.82 (dd, 71H), 7.58-7.54 (m, 4H), 7.51 (s, 1H), 7.29 (t, 1H), 7.08 (d, 1H), 7.01 (d, 1H), 4.31 " (c, 1H), 2.96 (c, ЗН), 2.70 ( c, ZN), 1.96 (c, 6H), 1.56 (c, 6H).

Example 43 - p ;" -I sh" (ee) - 50 sl

F) ime) 60 b5 and SEM 7 M and F m s o

ИЙ ю » 0 - о ий

The product of example 43 was obtained according to the following method described above for examples 14 and 15, but as starting products replacing the aryl bromide AB5 with ABb and the bromoquinoline OZ with O5.

Additional examples follow: - "shi s z -I sh" (ee) - 50 sl

F) name) 60 b5 o

M dut- o | and: r, o

M pi

Ma. 8 sch

And | Also 57 3o /Y x her o t, iy « ich-

Ii «| ve 57 - s r / z

M sh 45 ih o so (F. yuyu Even 7 vo a

She oh oh

WITH

She

10 -

M o o o--Y 15 February 20 | J Phi zv Kt y

WHAT 6) o o, yu so o "I 35 | river a - y , - z : s M z scho s" (ee) t o, o;

From the wounds because Ot

; | and yah rya r Oh

M o)

M, F M o o yu so "I ich- ech v

Ah " - c) o - s M z sh 45 s" i slo i i vo U uh U

Shk v - dh yutM a and Fi fi o o

And m hu her her kh 7

F /x x s 40 still oo : s i Y

Ot. her Z

A V e nt U 70 M u, y o What M F o

Z ik yu she y - she t 57

Ah 5 s Ж oo 7 : С з 50 | sh

IN

(F) yuyu tod FI o) 6o b T ek rai /x ry oo

M

More o o r z o o v (ge)

I « m- sh r: d-o 4 rik o x shi s M

I" sh 45 s" (ee) s o oo A 5 bo Z ih 8)

x "4

THEIR r; eh

M

| | M sch tv - (a! o) mk

They have something

In heaven « db oh 5

M s z sh 45 s» y sp o o a M--4 tr i x i 9 c)

Y: p to r okh 70 M va

Y sh I o o o . x, o and ra im "- o (se) "I i- " and vF7 - s b Z

And" - o)

M

-1

Sg»' o s ryu SHCHI name) ra vo oo p r o

M i o J o o M hu o y zo Zh - o so « m- « y v - s y "" no o o.

IM

- so: F to rya 60 o shi o)

And r

M o i o m t h, Ge 9 o rai i y so "I zh i - o, r: " -d- o H o, s M z - 45 iz so sl r o o; yu Shk 4 60 o // She and o,

OO SsStu

She

-- o

M what! at

HU SCHI o and 7, I - "

Eh Hee shi ;" rya m /p

V. - 5 li (ee) of them: Ф и ю ФИ 577 m 60 У и и

Go with

M

WITH

ІЧ tin y F M iz 7 o ra oo y y "I yich- s xx 5 s M sh 45 s" ; lm

F) I " ve u bo r 07 o nev 70 -8O

In, with | o (o) 4 yu zol - o) so « y i - « re -- M Y sh s :" -

M o) - in . I am listening. in bo a o

Ou r 70 M iv) o Y sch o u fi Zm. d) yu (ee) "I і- " - s a -- ro 47 M v! so Sh-h 7 F 4 o Another 577 60 yad c)

M

! and 70 9) ---

IR

Y I F -sh- / o what m. Y 4 x yuyu o " them water o, I M OO sh 45 : t" M (ee) to i dO F o kt " 2 vo o o

M: M 70s

M. about | Ф ----оО сч р" (о) о о ю и "I

M

«| a pe M - s khz» pcs

M sh 45 them 5-M so . sl Y Ff rya

GF) - yu Still in bo a o shh IM 10 yr

M

15 -- M t F dO

In o o yu 30 o "- (ge) "I 35 de ich- eh " 40 | - with ;" M sh 45 s»

So k sl "and where where"

That 7170 rya

M

And se -/ 0/7 o s o

ХО, and

Y ich- p "

So - s et | m

MORE /t with Mo IM-. (ee) yuyu "7 well, I'm not

Su 70 t

M o 25 ry o r z o o i o o o « « 40 o - "» - sh 45 IC | I so i o i ov ZHK she o., | where M s -

M silk » -E hu o

And | --M - -7 -

And" and | CHDHY:. A and yu in what and r

M they | o -M yu tova 0 M in, y

And Va oh oh and oh new 70: --O

M

» g 7 g shk | AND

And and and "m-

With me;" Cha

Mts so FI a sl y zhd o v g And her o ? 07 pF current

M

M F r

F from ; iy | and so and | S y and t: s with the same shk. more sl I ka about these | ra and what yu -

IM

There is; Oh and | F - M

With x | r v y u M « y - Z s I y? And | o g OO tya dt-

And What (F;

then -

M still about | FI g

And A, - o h z y " 40 - what g" 45 t

In Moscow. at

Say what

| j 70 Ptya shi y ' F Zh s y Also y

M y : " im " eh 2 i :" r sh 45 YM y" her 50 o ryt o v: " bo t M pov y re

M and | o s Ma" nevOshny 25 | o lk yu her 6 OZ 5 i,

M and the chief - to | heh » de tv r, I

M i o i - In school with | | at

And 2-4 and her pi: F 5

AND

;" I fe IM and o o v. and | With ho shk

OS

And -

M

A. ge | in; oh ho and her her ek "hos;" rya "7 M in F rani o dO | Change to child

OS

And riy

M de o M

F - o y i y iy v : 40 - s r "» M y F kri y a sh o

M vo lo So

OS

And r and y

And about; about in

Si , l a: ; , | F)

And - and her "I IF : s ;" Ry

In k » F y r" ld- | s ya rya:

what

And r

M

I

2-4 M s | about her not "

KS g» nt with IR in ss

MORE d ; with

And -

M

S. with | oh oh

M I) : z s y vo : v r 7 :» M chi o DI

I F - and I | that's why -

M ss

Dt and with | | and r And her sh " "I F: I ro . 45 them. : oh oh

And re

S and p

M. and Oso Ma. Dow and with | | Oh, I love her and F 5 s;" Ry

M h- M

M g by M.M that F rya | Mo about

And ro

M M-M i Ga

And M and. 4 | y z » b y y ro 5

AND

;" -th

MORE M us-M and M y

Su, o u » r

| enter paradise F

M i o FI sho sho e Go)

From | and co

Thursday: 7 p.m. 45 p.m. " at 55 xx where is this | )- » dk ryh

M y o o M ikh re

What is M about her

Uh « s 40 m ry - y t 50 r F (F) o u bo o o

And Zh

" and

F; M

Frya Zh ts 2v | oh o sh « oo g» ryy and what else Ж | Z. in EM as well as r

M schorao rea 2v | F) j M u ;" r i» M va and about her sh F z | same o -M go and -E

M o ve . l: and zv | o » in her o and: F 5 e ;" NE 47 M z-M v y MU 0 o 55 F dya | same city

Y In tv and ry

M -- in i5 M h o .

FI r i I What about - her sh -

F « - Y M Ears and ears M -- o g» z y F - s yu Z t

M o 8)

Ff r -

Still at 7 o'clock in the evening "And them-

Eh F « | - and -

Muk - 45 M ich M j o (ee) sp - m F o of u -

M iv Me, and d- o.

I Be yu v y " " і" r o M M--M ikh / M s o" Ж у во t M

WITH

70 la

M M- Mr

M M

- And mine

In osh r; and

F - with them

Ex « 7 | r o,

M

M

- - 27 r oo zo | o she Z 70 roya

M

And | sch vh hi M ge) u

M zh M- m y (ge) "I ichvo: s y" ver y kosh g M "r (ee) . i r o o Still in? because Sh with

| check

M M- /

G H. M » | and

M well (U and her

Ex « s 40 m NE - sh 45 o

Y SCHI o o o rya bo - o r 70 i

M

Fry with E Even at 827 ry

And that to her (ee) « to them | t s y

I» IM sh 45 E i» i F i »:ch bo o u y

I

Msch o r y aka - « і- « і: - ;» le

M' - m. so sl ry yu -Zht 9 Another 47 because M

| xx yu re

M

What

More: 25. at)

AK zo o 'o, to her (ee) « и- чЧЧ«хх « | t s ry :» M Mem h X -I so I y r bo o o o i - /

M M-M

What is in

M

Fr

What's wrong with "y-7: s 40 r - y?" M. Va

M o M. so s r yu Sche vo bo Y z

J

-4O

M | 77

F o sh

ХК t

Schi vo s ru o o o

IS o) and « | ek ch- r «

M - s with sh 45 m. so she with

OD o SI "F bo xx

Mr

70 dO

M s o ve Si Is) // M - o o so "I m "

Eh - ;" -

M

- - them to her about sprya about and because and about 70 M of her. y 7 y -ya i х-/ y about her (ee) « them about : «7 hom t "» 2. 47 і" t

M she o Hv She shcha bo 6 Kho r

M

More about

What about 87

Zh ho "about her (he) "I i- ek " - - s M ;" sh 45 s" (ee) i

F more

GI She Phi

Because of them

| ek pe

IM

57 7

Ehhh

E U e vo so « h-

Eh y « rok - s M z sh 45 s» so t zIyy I FI Still E z /A 60 o IF; IS

IS

| ek and 70 M

WHAT? 0-eo r v) / » o vo her (ee) « them

HU and. x - - - M "" and sh 45 their (ee) i

F) Still in / xx o to

| In 70 t

M. and

What else is wrong with her?

In o « m « shi s eh v-- it v. M

Sg" (ee) o - yu o; because FI

| in. F h o and d h o

And d--k- | | o 0) o o yu and « | She -

J

IM shi s z g F

Sg" so with vd, go r. bo o sh-o -

M

KO s - 8 (8) rows of Chi o | to her about " yin with " | t - - M z sh 45

Fi (ee) t se bo b vo 10 i

M

SI sch o os Even with ve I Io) and . "I ich- " ek - : | F. R. le

M Phi SI i. (ee) " F y

F o co bo o o o o water "

And there is more » s o » about her her eh F « i | With i ra and with y

BUT oh oh ko Y oh

E xx is 70 | in; . - | high school

F); (o) o, IF) and « и- ek and s 40 | about tires from

M

- their so « : dn (F) yu o; 60 o

70 rya

M y More o y / o)

M 5 -/ | then to her about "im t s;" with

M ul sh 45 2 A (ee) : F dO bo r xx 07 ho d yu

M g- : ICH sh Eh r. F rya Fi rai y

With Fr

OH vya Be yu y "I y ' - in If i s 40 M shi z sh 45 ich . (ee) and ;

M te yu Sche t 5 y ry » oo de 70 y

M Fri

M 5

Fry:

FI at 507

ШТ I | oso and (ee) « them and | t s » pehyZ (ee) (F)

Y r vo o o y | at 70 Kc

M piece 9;

M 5 7 | Ff | r and | As early as 8217 AD

And 5 about her

With x « | - - S and M | And with Ma 8 sl t v. There are 57 more

IS

5. | about the year 7170 M | with o

S r iy

That's it

And them- (8) fo " "

I" rya

M --Sh- y Pn y Z dl (ee) chivFfe : A A 60 F sh o 70 rya

M. and o

Fr

What o o r , od o (ee) "I | and - | o - s - g» M va sh 45 o M ich .

F) yu 87 60 ol o nev and 70 i

Mche: sch

SU SCHI y FU yu "o y "I 35 . - y (I s ;» Bo sh 45 t so U z J yu v bo y y ho o

IFF: and 70 sh M

With | lowland school

M 4 and to o « and o pov

And eat" -

M

47 g "che (og) e a i -

F) name) in 6 o o . at

-sh.:

IS

- F E 70 o E rai

M E o o

More o o o o zo o - (ee) shchi. h

E i - in: i 5 s | oh, E x» r E

M - M

Kh. -1 with M o (ee) sl i (F) o tyu v7 because I o

Shlt

University of M

H

M. 0 rai o se o i

F) y ch o i - « pp - - M ukh sh 45 M cho o x F shi 20 rya o Shche "F7 i 4 o sho 70 rai .

M o o i | SHHI: 87 I am her sister

Om what about; o : Ff with 50 -

F) o -o t r 5 - 6 o o ch ry 70 M 5- at a. : zo Fo her s o « and in yoroshi: 2-7 M M

I" 47 F their (ee) t

Z as yu k 5-77 bo Fo

AND

And -

M m u o i v o high school

Her . (8) o yu o "

XX | in. in

M no) s with more them (og) 27 o; what, what, what, M, etc

| at 70 and-- o

M va o M

M - F r v se

M: paradise o o. oh oh

E E her

E i - t i : s 40 o SE shi z 4 E sh 45 t o M (ee) s -

F) Fr

I Zh. bo o o o r y 70 M o - o 7 in 9 IF) zo | and « - and | их и и ото З с 40 щ г» m п- щ 45 и / у (ee) я ря В

F, 5 and Uh wo o he

Yes

M

8) -

F rya r vF7 o o y

F. «- (ge) o; y sha F m : - ;» I'm still 45 / ot in her" My Z so . ; r o Shchi A r bo | in and also about ho

KO

IS

IS

Eh | Eh - Eh

M si o 5 y s SHHI r. her 5 che so voy y o « - s y y A y" em . t- so M - 5 sp w (F. Shch v | ruk b ho

Zh m

M U-

H

M o no yah.

SCHI paradise o o

WITH

54 and (o) (ge) " them-

What et, : p 40 r - » M it

M 5 M

Co. sp m! Even in MAK, oh dear

| Z r M 2 F dO fi y (o) u o x, her and "I -

That I - from 40 ru and M. t sh 45 in r M s" to her . sl - o Fe 577 ko as yu and x U

- M

SS

IN

M g, iv M Z

S r o z o o - dsch- | what is-

IM « et y 5 " t that M Z I F de F still o » 4 y o o y udo ' what Her

M 0) 20 C

F) ! from Fri, 7 o'clock

IS c) at « 35 same M c. ve 40 - | - with M z

Z F g» so t

OD; t Oh, M Y bo

! about | sh Y a r

M

F d- FI sch | oh ho r her a | so about; "r | what-

Seh -V--M their s 40 r g» M sh 45 o - s»

Y Still oh ra " oh bo oh

--

M y o) - s r o o o Io) o) (ge) h- : 0- « t 5 s 40

I" 2 - 45 these X i" M (ee) sl -b (F) Ge and i: bo o o

Higher education: 70 C

M 5 720 F YO ' o // y

Se Y, :

And "I

M M m « shi s | in: z t sh 45 M -m their so M o) sl -E ; g. co

With in o o o)

o o r

M

Ge 25 r. o 41 o o o "-- (ee) "I m. m --k : s ry ; ' ;z» M --M - 45 M b

Her xx. (ee) . and Shchi o v and i 60 o)

is,

Eh // -і- 70 ІМ Фі 29 Ф я о о о ч во " ра - с ІХ щ 45 о | M; F from 50 -

F) and Still From Heaven

I'm 4 o'clock)

nn OO rya 7170 M

Her o and o o o o sh I

IS o) shk - "I і- " yu p. Z;" Ry

And nannia them 5 M so ryy sl - o yuyu FI th with Mk v"

at

SA

- 70 M h.

With o

X 5 o o r o | to her (ee) about "I

Os i - eh F che « - | shi that M z" sh 45

Sg" (ee) . I am for (F) 60 and for

Eat water

Mi (o, o - » F ud . Fe v : s 3o s, her her her - -k y ra 4 so I! z s m o g" M re

M

- and M o s» t 50 - F y | 87 5-4 because | o yes, uch p00-

Zh ro o

Kk more

M "Is:

F dO school 57

MK with 9 her so o I « xh rya i- o- 4 s 40 | rek - z r, o sh 45 M ---- s» so "dk iV i . t v bo u

IN

THOSE

NOT

Y M --m

K is F fan | ry | o rai o o o o o her o y ekh ra s 40 M o o o, sh 45 o M . y Still d 55 r yu Z bo o o o o .

We are 0-5

She 70 | about

C, and:

In o ee y

SI so o "TOM h | v. louse: t zhd SI i M sh 45 them

WITH

; 5 OH SHIELD (0 in OH

SI o f M and M p

Exemplary Salts As discussed above, pharmaceutically acceptable salts are often preferred. Examples of such salts are provided below:

General method of obtaining salts

Salts of the compounds according to the present invention, which are basic, can be obtained in several ways: - a) The compound is dissolved in an acceptable solvent, such as ethyl acetate. An acceptable acid, such as hydrochloric acid, in an acceptable solvent, such as 1,4-dioxane, is then added. The resulting suspension of salts is allowed to settle and then the salt is separated by filtration. (b) The compound and a suitable acid such as benzenesulfonic acid are dissolved in a suitable solvent such as isopropyl acetate or a mixture of solvents such as isopropyl acetate and methanol. The salt can then be separated by concentration or by changing the solvent leading to precipitation and then by filtration. A more stable crystalline form can be obtained by equilibrating the resulting salt suspension by heating and settling before filtration. Crystals of the previous fraction can also be added to balance the suspended salt, to initiate the crystallization and balancing process. 59 Sulfuric acid salt of the compound of example 14

HF) The sulfuric acid salt of the compound of example 14 was obtained by dissolving the compound (1.00 eq.) under reflux with ethyl acetate. After cooling to room temperature, sulfuric acid (1.04 eq.) was slowly added while stirring. The obtained suspension was stirred for another 40 minutes and the solid product was separated by filtration and washed with ethyl acetate to obtain the sulfuric acid salt of compound 60 of example 14.

H NMR (500 MHz, Acetone-dv) 5 9.45 (d, 1H), 9.23 (d, 1H), 8.65 (d, 1H), 8.25 (d, 1H), 8.16 (dd, 1H), 8.10 (s, 1), 7.99 (d, 2H), 7.80 (d, 2H), 7.60 (d, 71H), 7.49 (s, 1H) , 7.45 (t, 71Н), 7.30 (d, 71Н), 5.09 (с, ЗН), 2.77 (с, ЗН), 2.33 (с, ЗН), 2.01 ( p, 6H).

The methanesulfonic acid salt of the compound of example 14 The methanesulfonic acid salt of the compound of example 14 was obtained by dissolving the compound (1.0 eq.) under reflux in ethyl acetate. After cooling to room temperature, methanesulfonic acid (1.1 eq.) was slowly added with stirring. The obtained suspension was stirred, left to concentrate by evaporation, and the solid product was separated by filtration and washed with ether to obtain the methanesulfonic acid salt of the compound of example 14.

H NMR (500 MHz, Acetone-dv) 5 9.45 (5, 1H), 9.32 (d, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 8.22 (t, 1H), 8.11 (s, 1), 7.99 (d, 2H), 7.78 (d, 2H), 7.61 (d, 71H), 7.49 (m, 2H) , 7.35 (d, 71Н), 3.09 (с, ЗН), 2.78 (с, ЗН), 2.33 (с, ЗН), 2.01 (с, 6Н).

The p-toluenesulfonic acid salt of the compound of example 14 70 The p-toluenesulfonic acid salt of the compound of example 14 was obtained by dissolving the compound (1.Eq.) under reflux in ethyl acetate. After cooling to room temperature, p-toluenesulfonic acid (1.1 eq.) in ethyl acetate was slowly added. The solvent was concentrated and the suspension was left with stirring and periodic sonication at room temperature for 3 days.

The solid product was then separated by filtration and washed with ethyl acetate to obtain 75 p-toluenesulfonic acid salt of the compound of example 14.

T.pl. 184-18526.

H NMR (500 MHz, Acetone-dv) 5 9.58 (5, 1H), 9.22 (d, 1H), 8.63 (s, 1H), 8.23 (d, 1H), 8.16 (m, 1Hn), 8.03 (s, 1), 7.94 (d, 2H), 7.73 (d, 2H), 7.55 (m, ЗН), 7.45 (s, 1H) , 7.40 (t, 1H), 7.27 (d, 1), 7.12 (d, 2H), 3.07 (s, ЗН), 2.75 (s, ЗН), 2.33 ( c, ZN), 2.29 (c, ZN), 2.01 (c, 6H).

Salt of 2-naphthalenesulonic acid of the compound of example 14

The 2-naphthalenesulfonic acid salt of the compound of example 14 was obtained by dissolving the compound (1.00 eq.) under reflux with ethyl acetate. After cooling to room temperature, 2-naphthalenesulfonic acid (1.1 eq) in ethyl acetate was slowly added to ethyl acetate followed by ethanol. Then toluene was added to the solution, and then it was concentrated. Then more toluene was added, and the suspension was left with CM stirring and periodically sonicating at room temperature for 24 hours. at

The solid product was then separated by filtration and washed with toluene to obtain the 2-naphthalenesulfonic acid salt of the compound of example 14.

T.pl. 202-20496.

H NMR (500 MHz, Acetone-dv) 5 9.64 (5, 1H), 9.30 (d, 1H), 8.67 (d, 1H), 8.25 (d, 1H), 8.23 (m, 1H), 8.16 o (s, 1), 7.99 (s, 1H), 7.91 (d, 2H), 7.87 (m, 2H), 7.82 (d, 1H ), 7.72 (dd, 1H), 7.68 (d, 2H), 7.54 (d, 1), "-- 7.52 (m, 2H), 7.43 (width, s, 1H ), 7.37 (t, 1H), 7.22 (d, 1H), 3.03 (s, ЗН), 2.76 (s, ЗН), 2.33 (s, ЗН), 2.02 (c, 6H).

Hydrochloric acid salt of the compound of example 43 so

The hydrochloric acid salt of the compound of example 43 was obtained by dissolving the compound (1.00 eq.) in ethyl acetate under reflux and sonication.

After cooling the solution to room temperature, NOSI in 1,4-dioxane (4M, - 1 Equiv.) was added with stirring.

The suspension was stirred for another 5 minutes and the solid product was separated by filtration to obtain the monohydrochloric acid salt of the compound of example 43.

The benzenesulfonic acid salt of the compound of example 14 of 70 The benzenesulfonic acid salt of the compound of example 14 exists in two crystalline forms ("form A" and "form B"). Forms are obtained in the following ways: :z» Obtaining a salt - what is Ethyl acetate ve. і n no-4 cherry I i in so 1 Methanolp di sl 5 Z o still with SO kak - or o Me; --

GF) Form A

Benzenesulfonic acid (1-1.2 eq.) was added to a suspension of the compound of example 14 (Equ.) in ethyl acetate. Instead of ethyl acetate, you can use another ester. Methanol was added and the resulting mixture was heated until the solid dissolved. Other alcohols such as ethanol or propanol can be used instead of methanol. 6o The resulting solution was filtered and concentrated. In the process of concentration, the product crystallized.

The resulting mixture was dissolved in ethyl acetate and allowed to settle. The yellow solid was collected by filtration.

HPLC showed that the molar ratio of 6-P1-methyl-1-(methylsulfonyl)ethyl-8-13-KE)-2-I(13-methyl-1,2,4-oxadiazol-5-yl|-2-( 4(methylsulfonyl)phenyl|ethene and li|phenyl quinoline and benzenesulfonic acid is 1:1.

T.pl. determined using Yu5C: 19396,

Spectrogram of X-ray powder diffraction (XRD) of form A is presented in Fig. 1.

Identification peaks are presented in the table below and shown in Fig.4.

Peaks identifying polymorphic form A (22TNeia) 10.0 19.5 214 224 30.5

Form B

Benzenesulfonic acid (1-1.2 eq.) was added to the suspension of the compound of example 14 (Teq.) in a mixture of isopropyl acetate (I-PrOAc) and methanol (1:11). Another ester can be used instead of PgOAc, and other alcohols such as ethanol or propanol can be used instead of methanol. The mixture was left at 20-50 90 to 75 dissolution of the solid. The resulting solution was filtered and distilled, maintaining the volume by adding a 9:1 (v/v) mixture of i-PrOAc/methanol. The product crystallized during the distillation process.

The resulting mixture was left at 20-702C for 2-10 hours to ensure complete formation of form B.

The resulting off-white solid was separated by filtration and dried.

HPLC showed that the molar ratio of 6-(1-methyl-1--"methylsulfonyl)ethyl|-8-IZ3-KE)-2-(3-methyl-1,2,4-oxadiazol-5-yl|-2 -(4--"methylsulfonyl)phenyl|ethenyl|phenylquinoline and benzenesulfonic acid is 1:1.

T.pl. determined using Yu5C: 21096,

The spectrogram of ХКРО for form B is presented in Fig. 2. The identification peaks are presented in the table below and shown in Fig.5. A comparison of the spectrum with the identification peaks marked by arrows is presented in Fig.3. with

Peaks identifying polymorphic form B (22TNeia) at 144 17.7 20.0 23.7 at 28.9 "-

Other variations or modifications that are obvious to those skilled in the art are within the scope and methods of this invention. This invention is not limited except as indicated in the attached claims. co

Claims (28)

"The formula of the invention is 1. The compound represented by formula (1): -- c. (0) « zo Ya b - s M y s VZ 7 -I th c. (ee) or its pharmaceutically acceptable salt, where shu 20 51, Zo and Z3z independently represent H, -OH, halogen, -C 41-Svalkyl, -MO», -SM or -C.i-Svalkoxy, where alkyl and Alkoxy groups are optionally substituted with 1-5 substituents; where each substituent is independently sl halogen or OH; Ku represents H, OH, halogen, carbonyl, -C 1-Svalky group, -dicloC3-Svalky group, -C4-Svalkenyl group, -Ci-Svalkoxy group, aryl group, heteroaryl group, -CM, -heterocycloC3-Svalky group, -amino group, -C4-Salkylamino group, -(C4-Salkyl)uC4-Salkyl)amino group, -C4-Salkyl(oxy)C-Salkyl group, -СШ(О)МН(aryl) group, -С(О)МН( heteroaryl) group, -5O,MH(aryl) group, -ZO,MHi(heteroaryl) group, o -300MH(C.-Salkyl) group, -CHO)M(Co-SalkyluCo-Salkyl) group, -MH-5O -(C4-Salkyl) group, -504-(C1-Salkyl) group, -(C4-Salkyl)-0O-C(CM)-dialkylamino group or -(C.4-Salkyl)-5O-(C4- Svalkil) a group where any of the groups is optionally replaced by 1-5 substituents; 60 where each substituent is independently a halogen, -OH, -CM, -C 4-Salkyl, -cycloC3-Salkyl, -F(O)(heterocycloC3-Salkyl), -K0)-O-(Co-Salkyl), - C(O)-aryloxy, -C1-Salkyloxy, -(Co-Salkyl)xCo-Salkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -504- (C1-Svalkil); A is CH, C-complex ether or C-K,; 6E K» and Kz independently represent an aryl, heteroaryl group, H, halogen, -CM, -C /-Svalky group, heterocyclo-C3-Svalky group, -C1-Svalkoxy group, carbonyl, carbamoyl, -"FON, -(Ci-Salkyl)-50,-(C3-Salkyl) group, -CHOM(Co-SalkyluCo-Salkyl) group or -C.-Salkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent is independently an aryl, heteroaryl, halogen, -MO", -C(O)OH, carbonyl, -CM, -C4-Salkyl, -50,-(Ci-Salkyl), -50.-(aryl) . C(0)-M(Co-SalkylCo-Salkyl), where each substituent is independently optionally substituted by -OH, C 4-Salkyloxy, -Ci-Salkyl, -cycloC3-Salkyl, aryloxy, -C(O)OH, - ЧО)О(С 1-Svalkyl), halogen, -MO», -СМ, -50,-(С1-Svalkyl) or -С(0)-М(Со-SvalkyluСо-Svalkyl); one of K» and Kz must be aryl or heteroaryl, optionally substituted; 70 when Co and Kz are both aryl or heteroaryl, then Co and Kz may optionally be connected by means of a thio, oxy or (C.i-C;alkyl) bridge to form a fused three-ring system; Ku; represents an aryl, -C 1-Salkyl group, a heteroaryl group, -CM, a carbonyl group, a carbamoyl group, -"-C4-Salkyl)-5O4-(C1-Salkyl) group, -FKSOM(Co-SalkyluCo-Salkyl) group or -C1-Salkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent /5 Independently represents a carbonyl group, -CM, halogen, -KOH(C o -Salkyl), -CO)O (Co-Salkyl), -C--Salkyl, -504-(C4-Salkyl), -OH, C.-Salkyloxy or -""Co-Salkyl(Co-Salkyl) amino group; n is independently equal to 0, 1 or 2; and E" or Kz may optionally be bonded to C to form a ring where aryl is a mono- or polycyclic ring system such as, for example, phenyl or naphthyl, and heteroaryl is a ring system that contains in the ring one or more heteroatoms independently selected from 0, 5 or M. 2. The compound according to claim 1 or its pharmaceutically acceptable salt, where A is CH. 3. The compound according to claim 2 or its pharmaceutically acceptable salt, where Ku represents -C.4-Svalkyl, optionally substituted with 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -C(O)(heterocycloC 3-Salkyl), -4(0)-0-(Co-Salkyl), -C(0)-O-aryl . 4. The compound according to claim 2 or its pharmaceutically acceptable salt, where y zo Ku is -cycloC3-Svalkyl, optionally substituted with 1-5 substituents; where each substituent is independently halogen, -OH, -CM, -C(O)(heterocycloC. z-Salkyl), -C(O)-O-(Co-Salkyl), -C(O)-O-aryl . 5. The compound according to claim 2 or its pharmaceutically acceptable salt, where "Ku represents -C/-Svalkenyl, optionally substituted with 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -С(О)(heterocycloC 3-Salkyl), -С(0)-О-(Co-Salkyl), -С(0)-О- aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50-(C1-Salkyl). 6. The compound according to claim 2 or its pharmaceutically acceptable salt, where "Ku is a heteroaryl, optionally substituted with 1-5 substituents; where each substituent independently represents halogen, -OH, -CM, -C(O)XheterocycloC3-Salkyl), -C(O)-O-(Co-Salkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, ;" carbamoyl or -50-(C1-Svalkyl). 7. The compound according to claim 2 or its pharmaceutically acceptable salt, where Ku is an amino group, -C 4-Salkylamino group or -(C--Salkyl3/C1-Salkyl)amino group; where any of the -I groups is optionally substituted with 1-5 substituents; where each substituent is independently a halogen, -OH, -CM, -F(O)(heterocycloC3-Salkyl), -C(0)-O-(Co-Salkyl), -C(0)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, ve -cycloC3-Salkyl, heterocycloC3-Salkyl, aryl, heteroaryl, carbonyl, carbamoyl or -50,-(C1-Salkyl). Go! 8. The compound according to claim 2 or its pharmaceutically acceptable salt, where EC" represents aryl, optionally substituted with 1-5 substituents; and - Kz is a heteroaryl, optionally substituted with 1-5 substituents. Mr 9. The compound according to claim 2 or its pharmaceutically acceptable salt, where EC" represents aryl, optionally substituted with 1-5 substituents; and Kz is aryl optionally substituted with 1-5 substituents. 10. The compound according to claim 2 or its pharmaceutically acceptable salt, where EC" is a carbonyl, optionally substituted by 1 substituent; and F) Kz is aryl, optionally substituted with 1-5 substituents. ka 11. The compound according to claim 2 or its pharmaceutically acceptable salt, where Co-MHC(О0ООС 1-C;alkyl, -OC(O)MHC.-Sualalkyl, optionally substituted with 1-2 substituents; and in Kz is aryl, optionally substituted with 1-5 substituents. 12. The compound according to claim 2 or its pharmaceutically acceptable salt, where K» and Kz, each independently represents an aryl, optionally substituted, connected to each other by means of a thio, oxy or (Ci1-C; alkyl) bridge with the formation condensed three-ring system. 13. The compound according to claim 2 or its pharmaceutically acceptable salt, 65 where Co represents -(C1-Svalkyl)-5O,-(C1-Svalkyl), optionally substituted with 1-5 substituents, where each substituent independently represents a halogen . -O-aryl, -O-heteroaryl, -C(0)-heterocycloC3-Salkyl, -MH-cycloCa3-Salkyl, amino, -OH or -C1-Salkyl(amino) substituent, where each substituent is independently optionally substituted - OH, -0O-(C --Svalkyl), -O(aryl), -СООН, -СО0О (С.-Svalkyl), halogen, -MO», -СМ or С(О)-М(Со-SvalkylСо- Svalkil); and Kz is aryl optionally substituted with 1-5 substituents. 14. The compound according to claim 2 or its pharmaceutically acceptable salt, where EC" represents -C(O)M-(C o-Svalkyl/uCo-Svalkyl), optionally substituted by 1-5 substituents; and Kz is aryl optionally substituted with 1-5 substituents. 15. The compound according to claim 2 or its pharmaceutically acceptable salt, where 70 EC" represents -SM; and Kz is aryl optionally substituted with 1-5 substituents. 16. The compound according to claim 2 or its pharmaceutically acceptable salt, where Ku represents -S.-Svalkil, optionally substituted with 1-5 substituents; E" and Kz, each independently, represent aryl or heteroaryl, where each is optionally substituted with 1-5 substituents; and Co and Kz may optionally be linked by means of a thio, oxy or (C --C;alkyl) bridge to form a condensed three-ring system. 17. The compound according to claim 2 or its pharmaceutically acceptable salt, where 51, Z" and 33, each, represent H; Ku represents -S.-Svalkil, optionally substituted with 1-5 substituents; E" and Kz, each independently, represent aryl or heteroaryl, where each is optionally substituted with 1-5 substituents; and Co and Kz may optionally be linked by means of a thio, oxy or (C --C;alkyl) bridge to form a condensed three-ring system. high school 18. The compound according to claim 1, selected from the compounds represented by the formula: С Что н ю M s - sk | with Ж h зв | i-oh still ve shk -a - with SNU , . » p oo sen, - M to he - t. t | Z Go) soy and - 8-7, ik sl and not SN ; Sho She o | sn» sho nt ko M r- Z IC 60 th | 4 in - 8-- ik b5 oo Well; Me snu i M SCHI A IT o ov - y tv o) n.s not NN ; | She: Another dream, - m - dya | Ha shchi Ж i) is | ee | and stars 4 and o and - 9 (ge) H, ; « She She sn - -- M r - « sh | - - :z» sus E a v-o - Go i» SNU so us sn, - 50 | I I sleep an sl what I a -- n. as MV that re F) o ad-sNU oh vo o b5 And not g She Sho SNuz | On | осн ко З m - Sen y / M 8 ю p ШЕ 8-7, о а не сн , лен а Shk M r - F -- | cm a | o pa i o ne ne yu zo o ; o Sn" - (ge) Zshshcn Z SNU "t ЧУ -щ ич- ШЧХХ « | - with oh;" about zv | she iy o te -I o ; i» o Sn» so sleep - 70 | plarya SNU sl CHA -- where I S o ko | What about Shield 60 And where the 8th ge is not 65 Ge) ; Om SN grandfather Z | Xia Shen sn, MU - scho sho x Me sv, 70 shchi | r 5-7, MA y "v a O i sna sn, Zhan TE sn, m -o t she | She Me sv, zv s - sch (o) v-N, "V; o ta yu zo Nz o ' on, ch- Zhe ie so sn t Z M ch cha - « s de 2 S s o v | r 0-Y H, and go "" Nas a o ; ns whose -| », Zno OO n (ee) M still By pz mm sl | i: z dre v--SNU (F) aa ko vo 65 still sleep, , Zhe Zhe em - t I SHHI s 70 o a Shchi t75 Nose o Zene sleep shle shi she she I SN, I a - pe d- Nh sch d-SN, o o not 9 ; Io) zo KHAN, n chi: He her so Ж sv I "I kt v. -Ж « zho o, 2 in | | and; shi s td What mo with No a a -I i» 2--sn, (o) not 9 ; pub xx lien, she is sent M - o Z o to o, vba | | m and nie IR and n o b5 IV); It's not a matter of fact, I'm sorry for it. 15. Neyu a Ne bNz o: Jean ZHE srya m nt - r s 7 | an o U a z sh- (v; V, o zo Na o - NIS o SN" , so Znn E se "I: de cha M nii ХK ih p | - s s o ;" a | ! Y ta it o R New and Art -| . not SNU ' their p---- so | Sn TE seEee pz mya p « more / - (F) eh mn, ime) o. | še TV) 8 o'clock at NO 65 НС about ЕНз; sen hu Be h- se Ж N s 5 Son rya 9 sn, radi Ne o svo; She Shk SNU | is in J s (o) Y. on he K - Go) re that zon nyu To "- SNU ; so h- w- in "F | - s h i what ;z o | | m ke sh 45 NI o y; Nze sleep; s» so Za le VN | oo sl and Ye (F. s o to o hu she M vne for 57 65 At sleep; in -- 8-7" at. oo M still - ХХ 70 century She o, | y same ke Ge) Z Not for Na snu; --OSN still She V with | a o -- M -e A y s o Y V sn, I o, | I "E-sn, with V dt sn. o ns (v) - st; so "I Zhe in sn | і- MU « pe - s with Shk | ee Ho to 15 s si Sh- s; their S so | Zhene N, pz a sl shchi F! | z | --- eat) Zh - - ne m I Ve bo sn, 65 stv; Se sn, ; o I 70 | y shi o i s t5 OI y; st SN ; | shi sn, ee s About cancer y M schi ve IS o) not yet - st" (ge) sn: " vavy sn, - ra Y | - s s ;" M Shen | - Zh Ho still -8 - 07) Iv gch sleep so sleep: - vavy sn, s | ra (F) s t | m Shen | - 60 o'clock - 5 o'clock - 9 o'clock After sleep at 5 o'clock Us SNU; Zones | and m - 70 | ee g | ш- Ж, дн t ne Z. Ha SNU nas SNU | psy t» em m y s s (o) o XX, M. she vo zo o sn - SNU so Nas osn; " them Same and m and " | - с с хз» The same. | es still dev U -I ah y To their sleep (ee) Us ; z ju sn, z zhu sp | Y M M shle y F) sho yu M sh-x bo Y i 5 V-o a SNuz b5 s ; and; SNU M ke: vo al sn, -i M -sh | y: M is also Z, | dsh x Ko ne r. a ten, Ne ; sun, would 7 ve Ki F 9 sun, M o sch | o M Shk s - SN o cha zo NS a - no Well; so Zast yt VYN, Z I" | se y ay shchi - M sche « pe | shi s g" / -- ;" pi shle de SN" 45. BUT Mo -I Snu iz , pe SD - what Mi - sl i sho dk o SHHI and what o o o 6o or its pharmaceutically acceptable salts. 19. The compound according to claim 18, represented by the following formula: b5 neo ' z U ov Zhdy t U y | Sun M ШЕ 70 С Ш Ше дут Х- 7 ре и не ий 20. The compound according to claim 1, selected from b-isopropyl-8-(3-(2/E)-2-(4--(methylsulfonyl)phenyl|-2-phenylethenylphenyl)quinoline; b-isopropyl-8-13- KE/2)-2-(4-(methylsulfonyl)phenyl|-2-(1,3-thiazol-2-yl)ethenyl|phenyl)quinoline; b-isopropyl-8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4--(methylsulfonyl)phenyl|ethenylphenyl)quinoline; b-isopropyl-8- (3-(2/E)-2-(4-fluorophenyl)-2-(4--methylsulfonyl)phenyl|ethenylphenyl)quinoline; 2-(2-CE/2)-2-I3-(6-isopropyl- 8-quinolinyl)phenyl|-1-(4(methylsulfonyl)phenyl|ethenyl)-1,3-thiazol-5-yl)-2-propanol; 2-I8-(3-4E/2)-2-(5-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-ylI|-2-(4--methylsulfonyl)phenyl|ethenyl) phenyl)-6-inolinyl|-2-methylpropanenitrile; c 2-methyl-2-I8-(3-(E)-2-(1-methyl-1H-imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl|ethenylphenyl)-6b-quinolinyl|pro o pannitrile; 6-1-(methylsulfonyl)ethyl|-8-13-KE)-2-(4-(methylsulfonyl)phenyl|-2-(1,3-thiazol-2-yl)ethenyl|phenyl/quinoline; 6-P1-methyl-1-(methylsulfonyl)ethyl|-8-13-KE)-2-(4-(methylsulfonyl)phenyl|-2(1,3-thiazol-2-yl)ethenyl|phenyl)quinoline ; iv) 8-(3-(2)-2-(1-methyl-1H-imidazol-2-yl)-2-(4--methylsulfonyl)phenyl|ethenyl)uphenyl)-6-(I1--"methylsulfonyl) )ethyl|"- quinoline; 8-(3-(2)-2-(1-methyl-1H-imidazol-2-yl)-2-(4(methylsulfonyl)phenyl|ethenylphenyl)-6-(1-methyl -1 c -(methylsulfonyl)ethylquinoline; "6-P1-methyl-1-(methylsulfonyl)ethyl|-8-(3-(E/27)-2-(3-methyl-1,2,4-oxadiazole- 5-yl)-2-I(4-(methylsulfonyl)phenyl)phenyl)quinoline; - (E/2)-3-13-(6-(1-cyano-1-methylethyl)-8-quinolinyl)phenyl )-M-isopropyl-2-(4-methylsulfonyl)phenyl|-2-propenamide; 8-(3-(KE)-2-13-(4-methoxyphenoxy)methyl)-1,2,4-oxadiazole -5-yl)-2-I(4-(methylsulfonyl)phenyl|ethenylphenyl)-b -(P1-methyl-1-(methylsulfonyl)ethylquinoline; " (5-(E)-2-(3-6-/ 1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-1-((methylsulfonyl)phenyl|ethenyl)-1,2, 4-oxadiazol-3-yl)methanol; - c (E)-M- isopropyl-3-(3-16-(/1-methyl-1--(methylsulfonyl)ethyl|-8-quinolinyl)phenyl)-2-(4--("methylsulfonyl)phenyl|-2- h propenamide; » (E)-3-13-I6-(1-cyano-1-methylethyl)-8-quinolinyl|phenyl)-2-I(4-(methylsulfonyl)phenyl|- 2- propenoic acid; 2-methyl-2-I8-(3-(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-I(4-(methylsulfonyl)phenyl|ethenylphenyl)- - (E)-3-13-16-(1-cyano-1-methylethyl)-8-quinolinyl|phenyl)-2-(4-methylsulfonyl)phenyl|-2-propenamide; (E)-M-(tert-butyl)-3-13-16-(1-cyano-1-methylethyl)-8-quinolinylphenyl)-2-(4-(methylsulfonyl)phenyl|-2-propene IDU; (E)-3-IZ3-(6-isopropyl-8-quinolinyl)phenyl|-2-I(4-(methylsulfonyl)phenyl|-2-propenoic acid; -oUu 70 b-isopropyl-8-(3- (E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4--methylsulfonyl)phenyl|ethenylphenyl)quinoline; (E)-3-(3-16-( (1-methyl-1-(methylsulfonyl)ethyl)-8-quinolinylphenyl)-2-(4-(methylsulfonyl)phenyl)-1-(1-pyrrolidinyl)-2-propen-1-one; (E )-M-cyclopropyl-3-(3-16-(/1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-2-(4-(methylsulfonyl)phenyl|-2-propenamide; 22 (E )-M-(tert-butyl)-3-(3-16-(1-methyl-1-(methylsulfonyl)ethyl/|-8-quinolinyl)phenyl)-2-(4--methylsulfonyl)phenyl He!- 2-propanamide; 8-13-(2,2-bis(4-chlorophenyl)vinyl|phenyl)-6b-isopropylquinoline; where b-isopropyl-8-(3-(E/2)-2-(6-methyl -3-pyridinyl)-2-(4-(methylsulfonyl)phenyl|ethenyl).phenyl)quinoline; b-isopropyl-(3-(E/2)-2-(5-methyl-2-pyridinyl)-2- (4--methylsulfonyl)phenyl|ethenyl)y.phenyl)quinoline; 60 8-(3-42,2-bis(4--(methylsu lphenyl)phenyl|vinyl)phenyl)-6-isopropylquinoline; 2-methyl-2-I8-(3-(E/2)-2-(5-methyl-2-pyridinyl)-2-(4(methylsulfonyl)phenyl|ethenylphenyl)-6-quinolinyl|propanenitrile; 2- 18-(3-2,2-bis(4-methylsulfonyl)phenylvinyl)uphenyl)-6-quinolinyl|-2-methylpropanenitrile; 2-methyl-2-(8-13-KE)-2-(4-(methylsulfonyl)phenyl|-2-(2-pyridinyl)ethenyl|phenyl)-b-quinolinyl)propanenitrile; 65 6-P1-methyl-1-(methylsulfonyl)ethyl|-8-(3-(E/2)-2-(5-methyl-2-pyridinyl)-2-I(4-(methylsulfonyl)phenyl)| ethenyl)f enyl)quinoline; 2-(6-(E)-2-(3-46-/1-methyl-1-(methylsulfonyl)ethyl|-8-quinolinylphenyl)-1-(4--methylsulfonyl)phenyl|ethenyl)-3-pyridinyl )-2-propanol, or its pharmaceutically acceptable salt. 21. The compound of formula (I) according to any one of claims 1-20 or its pharmaceutically acceptable salt for use as phosphodiesterase inhibitors. 22. The compound of formula (I) according to any of claims 1-20 or its pharmaceutically acceptable salt as an active ingredient of a medicinal product for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or 7/0 malignant proliferative lung disease, endotoxic shock (and related conditions such as equine laminitis and colic), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain damage related to blood supply, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive disease in animals, diabetes insipidus, allergic rhinitis, allergic /5 conjunctivitis, spring conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, etc graft rejection and graft-versus-host reactions, hypersecretion of gastric juice, sepsis or septic shock caused by bacterial, fungal and viral infection, inflammation and cytokine-related chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle weakness, depression, deterioration memory, monopolar depression, acute and chronic neurodegenerative diseases with an inflammatory component, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancerous invasion of normal tissues. 23. A pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) according to any of claims 1-20 or its pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier. and) 24. The pharmaceutical composition according to claim 23, which additionally contains an antagonist of leukotriene receptors, an inhibitor of leukotriene biosynthesis, a corticosteroid, an H1 receptor antagonist or an agonist of beta 2 adrenoceptors. 25. Pharmaceutical composition according to claim 23, which additionally contains a selective inhibitor of COX-2, a statin or the drug "MAYU". 26. Method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative lung diseases, endotoxic shock (and related conditions, such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, damage to the myocardium and brain related to blood supply, - from5 inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atonic dermatitis, urticaria, r. respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, graft rejection and "graft versus host" reactions , hypersecretion of gastric juice, sepsis or septa chronic shock caused by bacterial, fungal and viral infection, inflammation and cytokine-related chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle weakness, depression, memory impairment, monopolar depression, acute and chronic;" neurodegenerative diseases with an inflammatory component, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth and cancerous invasion of normal tissues, which includes the step of administering a therapeutically effective amount or a prophylactically effective amount of the compound according to claim 1 or its pharmaceutically acceptable salt. 27. Method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative diseases. lung diseases, endotoxic shock (and related conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain damage related to the blood supply - inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atonic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, of rheumatoid arthritis, ankylosing spondylitis, graft rejection and "graft versus host" reactions, hypersecretion of gastric juice, sepsis or septic shock caused by bacterial, fungal and F) viral infection, inflammation and cytokine-related chronic tissue degeneration, osteoarthritis, cancer, etc. cachexia, muscle weakness, depression, memory impairment, mo nonpolar depression, acute and chronic neurodegenerative diseases with an inflammatory component, Parkinson's disease, Alzheimer's disease, because of spinal cord injury, head injury, multiple sclerosis, tumor growth and cancerous invasion of normal tissues, which includes the step of administering a therapeutically effective amount or a prophylactically effective amount of the compound for claim 1. 28. A pharmaceutical composition that inhibits phosphodiesterase 4, containing a phosphodiesterase 4 inhibitory amount of a compound of formula (I) specified in any of claims 1-20, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.