EA004747B1 - Substituted 8-arylquinoline phosphodiesterase-4 inhibitors - Google Patents

Abstract

1. A compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein: S1, S2, and S3 are H; R1 is C1-C6alkyl group optionally substituted with -CN group or -SO2-C1-C6alkyl; A is CH; R2 is di(C1-C6)amino C1-C6alkyl; phenyl, optionally substituted with halogen or -SO2-C1-C6alkyl; -C(O)OH; carbamoyl optionally substituted with -C1-C6alkyl or C3-C6cycloalkyl; pyrrolidinocarbamoyl; or heteroaryl selected from the group comprising imidazolyl, thiazolyl, oxadiazolyl or pyridyl, each of them is optionally substituted with C1-C6alkyl, hydroxy-C1-C6alkyl or C1-C6alkoxyphenoxy-C1-C6alkyl. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is heteroaryl selected from the group comprising imidazolyl, thiazolyl, oxadiazolyl or pyridyl, each of them is optionally substituted with C1-C6alkyl, hydroxy-C1-C6alkyl or C1-C6alkoxyphenoxy-C1-C6alkyl. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with halogen or -SO2-C1-C6alkyl. 4. The compound according to claim 1 comprising or a pharmaceutically acceptable salt thereof. 5. 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{E/Z)-2-(3-methyl-1,2,4-oxa-diazol-5-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline of the formula 6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula(I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 7. The pharmaceutical composition according to claim 6, further comprising a Leukotriene receptor antagonist, a Leukotriene biosynthesis inhibitor, anM2/M3 antagonist, a corticosteroid, an HI receptor antagonist or a beta 2 adrenoceptor agonist. 8. The pharmaceutical composition according to claim 20, further comprising a COX-2 selective inhibitor, a statin, or an NSAID. 9. A method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crolm's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 10. A method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of forming in vivo a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1. 11. A compound of formula (I), according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use as phosphodiesterase inhibitors. 12. Use of a compound of formula (I), according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusiori injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 13. A phosphodiesterase-4 inhibitor pharmaceutical composition comprising an acceptable phosphodiesterase-4-inhibiting amount of a compound of formula (I), as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

Description

Field of Invention

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

BACKGROUND OF THE INVENTION

Hormones are compounds that act in different ways on cellular activity. In many ways, hormones act as messengers for specific trigger responses and cell activity. However, the many effects caused by hormones are not the result of the exclusive action of the hormone alone. On the contrary, the hormone first binds to the receptor, thus initiating the release of the secondary compound, which then acts on cellular activity. According to this scheme, the hormone is known as the primary messenger, while the secondary connection is called the secondary messenger. Cyclic adenosine monophosphate (adenosine 3 ', 5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a secondary messenger of hormones, including epinephrine, glucagon, calcitonin, corticotropin, lipotropin, luteinizing hormone, norethyreminide, thyrethyremin vasopressin. Thus, cAMP mediates cellular responses to the action of hormones. Cyclic AMP also mediates cellular responses to the action of various neutro-mediators.

Phosphodiesterases (“PDEs”) belong to a family of enzymes that metabolize 3 ′, 5′-cyclic nucleotides to 5′-nucleoside monophosphates, thus limiting the activity of the cAMP secondary messenger. Specific phosphodiesterase, phosphodiesterase-4 ("PDE4", also known as "PDE-ΐν"), which is a high affinity, cAMP-specific PDE of type ΐν, is of interest as a possible object for the development of new anti-asthma and anti-inflammatory compounds. PDE4 is known to exist in at least four isoenzymes, each of which is encoded by a specific gene. Each of the four known PDE4 gene products probably plays different roles in allergic and / or inflammatory responses. Thus, it is believed that the inhibition of PDE4, in particular specific PDE4 isoforms that cause harmful reactions, can successfully influence the symptoms of allergies and inflammation. It would be desirable to develop new compounds and compositions that would inhibit PDE4 activity.

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. Wigpoig e! A1., (“VigpoiG”), App. Ver. ΐη Meb. See, 33: 91-109 (1998). B. Nope! A1., Br. 1. Pappaso1., 118: 1183-1191 (1996); M. 1. Reggu e! A1., Ce11 Vuset. Würk., 29: 113-132 (1998); 8. B. Cn51n5ep e! A1., 1. Meb. Sc. 41: 821-835 (1998); and VigpoiG describe a wide variety of serious undesirable side effects exhibited by some compounds. As described by M. Ό. Noik1au e! A1., Α6ν. 1n Pbacto1., 44: 225-342 (1998) and Ό. 8 rsha e! A1., Α6ν. 1n Pbactaco1., 44: 33-89 (1998), there is great interest in the search for therapeutic PDE4 inhibitors.

International Patent Publication No. νϋ 9422852 describes quinolines as PDE4 inhibitors.

A.N. Sook, e! A1., 1. Eat. 8os, 413-417 (1943) described gamma-pyridylquinolines. Other quinoline compounds are described by Ke1 Mapae e! A1., 1. Og§. Sib., 58 (24): 6692-6700 (1993); Ke1 Mapae e! A1., 1. At. Eat. 8oc., 115 (12): 5324-5325 (1993); and Ke1 Mapa e! A1., 1. At. Eat. 8os, 114 (17): 6940-6941 (1992).

Compounds that include ring systems have been described by various researchers as being effective for various therapeutic and practical uses. For example, International Patent Publication No. νθ 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and US Patent Nos. 5679712, 5693672 and 5747541 describe substituted benzoylguanidines blocking sodium channels, US Pat. No. 5,736,297 describes a ring system used as a photosensitive composition.

U.S. Patents 5,491,147, 5,608,070,

5622977, 5739144, 5776958, 5780477, 5786354, 5798373, 5849770, 5859034, 5866593, 5891896 and the international patent publication νθ 95/35283 describes PDE4 inhibitors that are trisubstituted aryl or heteroarylphenyl derivatives. US Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. In US patent No. 5550137 described PDE4 inhibitors, which are phenylaminocarbonyl derivatives. US Pat. No. 5,340,827 describes PDE4 inhibitors, which are phenyl carboxamide compounds. US Pat. No. 5,780,478 describes PDE4 inhibitors, which are tetra-substituted phenyl derivatives. International patent publication νθ 96/00215 describes substituted oxime derivatives used as PDE4 inhibitors. US Pat. No. 5,633,257 describes PDE4 inhibitors, which are cyclo (alkyl and alkenyl) phenylalkenyl (aryl and heteroaryl) compounds.

However, there remains a need for new compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention relates to new substituted 8-arylquinolines, which are PDE4 inhibitors, where the aryl group at the 8-position contains a substituted alkenyl group as a substituent. The present invention also relates to a pharmaceutical composition which comprises an effective amount of a new substituted 8-arylquinoline and a pharmaceutically acceptable carrier. The invention further relates to a method for treating mammals, for example, asthma, chronic 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, ulcerative colitis, Crohn's disease, reperfusion injuries of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis ita, atopic 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, inflammatory pain ankylosing spondylitis, graft rejection and the graft versus host reaction, hypersecretion of gastric juice, sepsis or septic eye caused by a bacterial, fungal and viral infection, inflammation and cytokine-associated 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 injuries, head bruising, multiple sclerosis, tumor growth and cancer invasion into normal tissues by introducing an effective amount of new substituted 8-arylquinoline if the precursor compound which forms ίη νίνο new substituted 8-arilhinolin.

Brief Description of Drawings

In FIG. 1 is a schematic diagram of a chemical image of the general structure of the compounds of the present invention.

In FIG. Figure 2 shows a graph of the values relative to ° T11c1a for X-ray powder diffraction of the polymorph of Form A of the benzenesulfonic acid salt of 6- [1-methyl-1 (methylsulfonyl) ethyl] -8- [3- [(E) -2- [3-methyl-1 , 2, 4-oxadiazol-5-yl] -2- [4- (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline.

In FIG. Figure 3 shows a graph of the values relative to ° T11c1a for X-ray powder diffraction of the polymorph of Form B of the benzenesulfonic acid salt of 6- [1-methyl-1 (methylsulfonyl) ethyl] -8- [3 - [(E) -2- [3-methyl1,2 , 4-oxadiazol-5-yl] -2- [4- (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline.

In FIG. 4 shows a comparison of X-ray powder diffraction of polymorph Form A (bottom line) and Form B (top line) of benzenesulfonic acid salt 6- [1-methyl-1- (methylsulfonyl) ethyl] -8 [3 - [(E) -2- [3-methyl-1,2,4-oxadiazol-5-yl] -2- [4 (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline.

In fig. 5 is a graph of differential characteristic peaks of X-ray powder diffraction of a polymorph of Form B of a benzenesulfonic acid salt of 6- [1methyl-1 - (methylsulfonyl) ethyl] -8- [3 - [(E) -2- [3methyl-1,2,4- oxadiazol-5-yl] -2- [4- (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline.

In fig. 6 is a graph of differential characteristic peaks of X-ray powder diffraction of a polymorph of Form B of a benzenesulfonic acid salt of 6- [1methyl-1 - (methylsulfonyl) ethyl] -8- [3 - [(E) -2- [3methyl-1,2,4- oxadiazol-5-yl] -2- [4- (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline.

DETAILED DESCRIPTION OF THE INVENTION

The compound of this invention is represented by formula (I)

or a pharmaceutically acceptable salt thereof, wherein 81, 8 ₂ and 8 _{3 are} independently H, —OH, halogen, —C ₁ -C ₆ alkyl, —ΝΟ ₂ , —CY or —C 1 -C ₆ alkoxy, where alkyl and alkoxy groups optionally substituted with 1-5 substituents; where each substituent independently is halogen or OH;

TO-! represents H, OH, halogen, carbonyl, or -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -CY, -heterocycloC ₃ -C ₆ alkyl, amino, _-C1-C6 alkylamino, - (C1-C6 alkyl) (C1-C6alkyl) amino, _-C1-C6 alkyl (hydroxy) _-C1-C6 alkyl, -C (O) NH (aryl)

-C (O) NH (heteroaryl), -8O _n NH (aryl), -δΟ ,, ΝΗ (heteroaryl) -8O _n NH _(C1-C6 alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -Ν H-8O _|| - (C ₁ -C ₆ alkyl) -8O _n - _(C1-C6 alkyl), - _(C1-C6 alkyl) -O-C (CN) dialkylamino or a group - _(C1-C6 alkyl) -8O _p (C1-C6 alkyl), wherein any of the groups is optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CH, —C ₁ -C ₆ alkyl, —cycloC ₃ -C ₆ alkyl,

-C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) -O- (C ₀ -C ₆ alkyl), -C (O) aryloxy, -C ₁ -C ₆ alkoxy, - (C ₀ -C ₆ alkyl) (C0-C6 alkyl) amino, cycloalkyloxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _p - (C ₁ -C ₆ alkyl);

A represents CH, C-ester, or C-H;

K ₂ and K ₃ independently represent aryl, heteroaryl, H, halogen, —CH — C ₁ -C ₆ alkyl, heterocyclo-C _3-6 alkyl, —C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, —C (O) OH, - (C ₁ -C ₆ alkyl) -8O _p - (C ₁ -C ₆ alkyl), -C (O) H (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C ₁ -C ₆ alkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, -ΝΟ ₂ , -C (O) OH, carbonyl, -CH-C ₁ -C ₆ alkyl , -8O _p - (С ₁ С ₆ alkyl), -8О _p - (aryl), aryloxy, -heteroaryloxy, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycle C ₃ -C ₆ alkyl , -HH-cycloC ₃ -C ₆ alkyl l, amino, —OH or - (C0-C6 alkyl) (C0-C6 alkyl) amino group, a substituent group —C (O) -H (C ₀ -C ₆ alkyl) (C ₀ C ₆ alkyl), where each substituent is independently optional substituted by —OH, C ₁ -C ₆ alkoxy, —C ₁ C6 alkyl, cycloC3-C6 alkyl, aryloxy, —C (O) OH, —C (O) O (C ₁ -C ₆ alkyl), halogen, —HO ₂ , -CH, -8O _p - (C ₁ -C ₆ alkyl) or -C (O) -H (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

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

when K ₂ and K _{3 are} both aryl or heteroaryl, then K ₂ and K ₃ may optionally be connected via a thio, oxy or (C ₁ C ₄ alkyl) bridge to form a fused tri-ring system;

K ₄ represents aryl, -C ₁ -C ₆ alkyl, heteroaryl, -CH, carbonyl, carbamoyl, - (C ₁ -C ₆ alkyl) -8O _p - (C ₁ -C ₆ alkyl), -C (O) H (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or a C ₁ -C ₆ alkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently is carbonyl, -CH, halogen, -C (O) (C0-C6 alkyl), -C (O) O (C0-C6 alkyl), C ₁ -C ₆ alkyl, -8O _p - (C ₁ -C ₆ alkyl), -OH, C ₁ - A C ₆ alkoxy or - (C0-C6 alkyl) (C0-C6 alkyl) amino group;

n is independently 0, 1 or 2; and

K ₂ or K ₃ may optionally be attached to a K ₄ bond to form a ring.

In a first aspect, the compound of this invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —HO ₂ , —CH or —C ₁ -C ₆ alkoxy, where the alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently represents halogen or OH;

K ₁ represents H, OH, halogen, carbonyl, or -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C2-C6 alkenyl, -C1-C6 alkoxy, aryl, heteroaryl, -CH, -heterocycloC ₃ -C ₆ alkyl, -amino, -C ₁ -C ₆ alkylamino, - (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) amino, -C ₁ C ₆ alkyl (oxy) C ₁ -C ₆ alkyl, - C (O) HH (aryl), -C (O) HH (heteroaryl), -8O _p HH (aryl), -8O _p HH (heteroaryl), -8O _p HH (C ₁ -C ₆ alkyl), -C (O) H (C ₀ C ₆ alkyl) (C ₀ -C ₆ alkyl), -HH-8O _p - (C ₁ -C ₆ alkyl), -8O _p - (C ₁ -C ₆ alkyl), - ( C ₁ -C ₆ alkyl) -O-C (CH) dialkylamino or a group - (C ₁ -C ₆ alkyl) -8O _p (C ₁ -C ₆ alkyl), wherein any of the groups is optionally substituted with 1-5 substituents; where each substituent independently represents halogen, —OH, —CH, —C ₁ -C ₆ alkyl, —cycloC ₃ -C ₆ alkyl, —C (O) (heterocycloC3-C6 alkyl), —C (O) -O- (C0 -C6 alkyl), -C (O) aryloxy, -C1-C6 alkoxy, - (C0-C6 alkyl) (C0-C6 alkyl) amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl carbamoyl or -8O _p - (C ₁ -C ₆ alkyl);

A represents CH;

K ₂ and K ₃ independently represent aryl, heteroaryl, H, halogen, —CH, —C ₁ -C ₆ alkyl, heterocyclo-C _3-6 alkyl, —C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, —C (O ) OH, - (C ₁ -C ₆ alkyl) -8O _p - (C ₁ -C ₆ alkyl), -C (O) H (C1-C6 alkyl) (C1-C6 alkyl) or a group-C1-C6 alkylacylamino, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —HO2, —C (O) OH, carbonyl, —CH, —C ₁ —C ₆ alkyl, —8O _p - (C ₁ C ₆ alkyl), -8O _p - (aryl), -aryloxy, -heteroaryloxy, C ₁ -C ₆ alkoxy, H-oxide, -C (O) heterocycloC1-C6 alkyl, -HH-cycloC3-C6 alkyl, amino, - OH or Rupp - (C0-C6alkyl) (C0-C6alkyl) amino, -C (O) -H (C0-C6alkyl) (C0-C6alkyl), wherein each substituent is independently optionally substituted by -OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC3-C6 alkyl, -aryloxy, -C (O) OH, -C (O) O (C1-C6 alkyl), halogen, -NO2, -CH, -8O _p - (C ₁ -C ₆ alkyl) or —C (O) —H (C ₀ -C ₆ alkyl) (C ₀ C ₆ alkyl);

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

when K ₂ and K _{3 are} both aryl or heteroaryl, then K ₂ and K ₃ may optionally be connected via a thio, oxy or (C ₁ -C ₄ alkyl) bridge to form a fused tri-ring system; and n is independently 0, 1 or 2.

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

8 ₁ , 8 ₂ , and 8 ₃ independently represent H, —OH, halogen, —C ₁ —C ₆ alkyl, —HO ₂ , —CH, or —C ₁ —C ₆ alkoxy, where the alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently represents halogen or OH;

Ί

IN! is _-C1-C6 alkyl optionally substituted with 1-5 substituents; where each substituent independently represents halogen, —OH, —CY, —C (O) (heterocycloC ₃ —C ₆ alkyl), —C (O) —O— (C ₀ —C ₆ alkyl), —C (O) - O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cyclo C3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _p - (C ₁ C ₆ alkyl), - (C ₀ -C ₆ alkyl ) (C ₀ -C ₆ alkyl) amino; A represents CH; B ₂ and B ₃ independently represent aryl, heteroaryl, H, halogen, —CY, —C ₁ -C ₆ alkyl, heterocycloC _3-6 alkyl, —C1-C6 alkoxy, carbonyl, carbamoyl, —C (O) OH, - (C ₁ -C ₆ alkyl) -8O _p - (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or -C ₁ -C ₆ alkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, —CY, —C ₁ -C ₆ alkyl, -8O _P - (C ₁ -C ₆ alkyl), -8O _p - (aryl), -Oaryl, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl , -YN-tsikloS ₃ -C ₆ alkyl amine , -OH or - (C0-C6alkyl) (C0-C6alkyl) amino, -C (O) -N (C0-C6alkyl) (C0-C6alkyl), wherein each substituent is independently optionally substituted by -OH, C ₁ -C _{6 alkoxy,} , -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -ΝΟ ₂ , -СЫ, -8O _p - (C ₁ -C ₆ alkyl) or -C (O) -Y (C ₀ -C ₆ alkyl) (C ₀ C ₆ alkyl);

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

when B2 and B3 are both aryl or heteroaryl, then B2 and B3 may optionally be connected via a thio, hydroxy or (C ₁ C ₄ alkyl) bridge to form a fused tri-ring system;

n is independently 0, 1 or 2.

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

8), 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —O ₂ , —CY or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substitutes; where each substituent independently is halogen or OH;

B ₁ is a-cycloC ₃ -C ₆ alkyl optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CY, —C (O) (heterocycloC3-C6 alkyl), —C (O) -O- (C0-C6 alkyl), —C (O) -Oaryl, alkoxy, cycloalkyl hydroxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _p - (C ₁ -C ₆ alkyl);

A represents CH;

B ₂ and B ₃ are independently aryl, heteroaryl group, H, halogen, -SY, -C ₁ -C ₆ alkyl, geterotsikloS ₃ - ₆ alkyl, -C ₁ -C ₆ alkoxy carbonyl, carbamoyl, -C (O) OH, - (C ₁ -C ₆ alkyl) -8O _p - (C ₁

C6 alkyl), -C (O) N (C0-C6 alkyl) (C0-C6 alkyl) or -C1-C6 alkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, -O ₂ , -C (O) OH, carbonyl, -CY, -C ₁ -C ₆ alkyl, -8O _p - (C ₁ C ₆ alkyl), -8O _p - (aryl), -O-aryl, -O- heteroaryl, C ₁ -C ₆ alkoxy, Y-oxide, —C (O) -heterocycloC ₃ C6 alkyl, —YN-cycloC3-C6 alkyl, amino, —OH or - (C0-C6 alkyl) (C0-C6 alkyl) amino group, -C (O) -Y (C0-C6 alkyl) (C0-C6 alkyl), where each substituent is independently optionally substituted with -OH, C1-C6 alkoxy, -C1-C6 alkyl, -cycloC3-C6 alkyl ohm, aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -YO2, -SY, -8Op- (C1-C6alkyl), or -C (O) -N (C0-C6 alkyl) (C0-C6 alkyl);

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

when B2 and B3 are both aryl or heteroaryl, then B2 and B3 may optionally be connected via a thio, hydroxy or (C1C4 alkyl) bridge to form a fused three-ring system; and n is independently 0, 1 or 2.

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

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —O ₂ , —CY or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently represents halogen or OH;

B ₁ is —C ₂ -C ₆ alkenyl optionally substituted with 1-5 substituents; where each substituent independently represents halogen, —OH, —CY, —C (O) (heterocycloC3C6 alkyl), —C (O) —O- (C0-C6 alkyl), —C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _p - (C ₁ -C ₆ alkyl);

A represents CH;

B2 and B3 independently represent aryl, heteroaryl, H, halogen, -SY, -C ₁ -C ₆ alkyl, geterotsikloS ₃ - ₆ alkyl, -C ₁ -C ₆ alkoxy carbonyl, carbamoyl, -C (O) OH, - (C1-C6 alkyl) -8Op- (C1-C6 alkyl), -C (O) L (C0-C6 alkyl) (C0-C6 alkyl) or -C1-C6 alkyl acyl amino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —YO2, —C (O) OH, carbonyl, —CY, C ₁ -C ₆ alkyl, —8O _p - (C ₁ C6) alkyl, -8Op- (aryl), - O-aryl, -O-heteroaryl, C1-C6 alkoxy, Y-oxide, -C (O) -heterocycloC3C6 alkyl, -YN-cycloC3-C6 alkyl, amino, -OH or - (C0-C6 group alkyl) (C0-C6 alkyl) amino, -C (O) N (C0-C6 alkyl) (C0-C6 alkyl), where each substituent is independently optionally substituted with -OH, C1-C6 alkoxy, -C1-C6 alkyl, -cycloC3-C6 alkyl, aryloxy, -C (O) OH, -C (O) O (C1-C6alkyl), halogen, -ΝΟ _2, -ΟΝ, -8Ο _η - _(C1-C6 alkyl), or -C (O) -H ( C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

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

when K ₂ and K _{3 are} both aryl or heteroaryl, then K ₂ and K ₃ may optionally be connected via a thio, hydroxy or (C ₁ C ₄ alkyl) bridge to form a fused tri-ring system;

η is independently 0, 1, or 2.

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

8 _b 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ —C ₆ alkyl, —ΝΟ ₂ , —ΟΝ or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently represents halogen or OH;

Cd is heteroaryl, optionally substituted with 1-5 substituents; where each substituent independently represents halogen, —OH, —CH — C (O) (heterocycloC ₃ -C ₆ alkyl), —C (O) —O— (C ₀ —C ₆ alkyl), —C (O) —O -aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _P - (C ₁ -C ₆ alkyl); A represents CH; K ₂ and K ₃ independently represent aryl, heteroaryl, H, halogen, —CH, —C ₁ -C ₆ alkyl, heterocycloC _3-6 alkyl, —C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, —C (O) OH, - (C ₁ -C ₆ alkyl) -8O _P - (C ₁ -C ₆ alkyl), -C (O) H (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) or a -C1 group -C6 alkylacylamino, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, -ΝΟ2, -C (O) OH, carbonyl, -CH, -C ₁ -C ₆ alkyl, -8O _P - (C ₁ -C ₆ alkyl), -8O _p - (aryl), -aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, окс-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl , -Ν -cyclo C3-C6 alkyl, amino, -OH or a group - (S0S ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -and (C ₀ -C ₆ alkyl) (C0-C6 alkyl), wherein each substituent is independently optionally substituted with —OH, C ₁ -C ₆ alkoxy, -C1-C6 alkyl, -cycloC3-C6 alkyl, aryloxy, -C (O) OH, -C (O) O (C1-C6 alkyl), halogen, -O ₂ , -ΟΝ, -8O _P - (C ₁ -C ₆ alkyl) or-C (O) MS ₀ -C ₆ alkylXC ₀ -C ₆ alkyl);

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

when K ₂ and K _{3 are} both aryl or heteroaryl, then K ₂ and K ₃ may optionally be connected via a thio, hydroxy or (C ₁ C ₄ alkyl) bridge to form a fused tri-ring system;

η independently represents 0, 1 or 2.

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

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —IO ₂ , —ΟΝ or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently represents halogen or OH;

K represents an amino, -C ₁ -C ₆ alkylamino or - (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) amino group, wherein any of the groups is optionally substituted with 1-5 substituents; where each substituent independently represents halogen, —OH, —ΟΝ, —C (O) (heterocycloC ₃ -C ₆ alkyl), —C (O) —O (C0-C6 alkyl), —C (O) —O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _P - (C ₁ -C ₆ alkyl);

A represents CH;

K ₂ and K ₃ independently represent aryl, heteroaryl, H, halogen, -ΟΝ, -C ₁ -C ₆ alkyl, heterocycloC _3-6 alkyl, -C ₁ -C ₆ alkoxy, carbonyl, carbamoyl, -C (O) OH, - (C ₁ -C ₆ alkyl) -8O _P - (C ₁ -C ₆ alkyl), -C ^ HO-OalkylHO-Oalkyl) or

-C1-C6 alkylacylamino group, where any of the groups is optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, —ΟΝ, —C ₁ -C ₆ alkyl, 8O _P - (C ₁ C ₆ alkyl), -8O _p - (aryl), -aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ C ₆ alkyl, - # H-cycloC ₃ -C ₆ alkyl, amino, -OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) HO-OalkylXO-Oalkyl), where each substituent is independently optionally substituted -OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, -tsikloS ₃ -C ₆ alkyl, aryloxy, -C (O) OH, -C (O) O (C ₁ - ₆ alkyl), halogen, -YO _2, -ΟΝ, -8O _n - (C ₁ -C ₆ alkyl), or -C (O) -and (C ₀ -C ₆ -alkyl) (C ₀ -C ₆ alkyl);

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

when K ₂ and K _{3 are} both aryl or heteroaryl, then K ₂ and K ₃ may optionally be connected via a thio, oxy or (C ₁ -C ₄ alkyl) bridge to form a fused three-ring system;

η is independently 0, 1, or 2.

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

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —IO ₂ , —ΟΝ or C ₁ C6 alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently is halogen or OH;

To | represents -C ₁ -C ₆ alkyl, -cyclo C ₃ -C ₆ alkyl, -C ₁ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -ΟΝ, -heterocycloC ₃ -C ₆ alkyl, -amino, -C ₁ -C ₆ alkylamino, - (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) amino, -C ₁ -C ₆ alkyl (hydroxy) -C ₁ -C ₆ alkyl, -C (O) XN (aryl ), -C (O) NΗ (heteroaryl), -8O, CN (aryl), -8O, CN (heteroaryl), -8O _P IN (C ₁ -C ₆ alkyl), -C (O) M (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -ΝΗ8O _p - (C ₁ -C ₆ alkyl), -8O _p - (C ₁ -C ₆ alkyl), -carbamoyl, - (C1-C ₆ alkyl) —O — C (C№) dialkylamino or a group - (C ₁ -C ₆ alkyl) -8O _P - (C ₁ -C ₆ alkyl), wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent independently is halogen, —OH, —C ^ alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _P - ( C ₁ -C ₆ alkyl);

A represents CH;

K ₂ represents aryl, optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, ^ O ₂ . -C (O) OH, carbonyl, -C ^ -C ₁ -C ₆ alkyl, -8O _P - (C ₁ -C ₆ alkyl), -8O _P (aryl), aryloxy, -O-heteroaryl, C1- C6 alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -ΝΗ-cycloC3-C6 alkyl, amino, -OH or - (C0-C6 alkyl) (C ₀ -C ₆ alkyl) amino, -C (O ) -Y (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), where each substituent is independently optionally substituted with -OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, - aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -O ₂ , -ΟΝ, -8O _P - (C ₁ -C ₆ alkyl) or -C (O ) -Y- (C ₀ C6 alkyl) (C0-C6 alkyl);

K ₃ is heteroaryl, optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, —CO ₂ , —C (O) OH, carbonyl, —C ^ —C ₁ -C ₆ alkyl, - 8O _P - (C ₁ -C ₆ alkyl), 8O _p - (aryl), -aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl , -HH-cycloC ₃ -C ₆ alkyl, amino, -OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) ^ C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl ), where each substituent is independently optionally substituted with —OH, C1-C6 alkoxy, —C1-C6 alkyl, cycloC3-C6 alkyl, aryloxy, —C (O) OH, —C (O) O (C ₁ -C ₆ alkyl), g halogen, —O ₂ , —CH — 8O _p - (C ₁ -C ₆ alkyl) or —C (O) -Y- (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl); and n is independently 0, 1 or 2.

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

81, 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —ΝΘ ₂ , ^ Ν, or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently represents halogen or OH;

K ₁ represents halogen, carbonyl, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -C ^ -heterocycloC3- C6alkyl, -amino, -C1-C6alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, -C1-C6 alkyl (oxy) C ₁ -C ₆ alkyl, -C (O) HH (aryl), -C (O) XN (heteroaryl), -8O _p XH (aryl), -8O _p HH (heteroaryl), ^ OiNH ^ Cr ^ alkyl), ^ (O ^ Co-C ^ alkylXOxC alkyl), -HH ^ OiXCg ^ alkyl), -8O _p - (C ₁ -C ₆ alkyl), carbamoyl, - (C ₁ -C ₆ alkyl) -O-C (CN) dialkylamino or a group - (C1-C6 alkyl) -8Op (C1-C6 alkyl), where any of the groups is optionally substituted with 1-5 substituents ; where each substituent independently represents halogen, —OH, ^ Ν, —C (O) (heterocycloC ₃ -C ₆ alkyl), —C (O) —O (C0-C6 alkyl), —C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8Op- (C1-C6 alkyl);

A represents CH;

E ₂ represents aryl, optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, —C ^ -C ₁ -C ₆ alkyl, -8O _p - (C ₁ -C ₆ alkyl), -8O _p (aryl), aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -№NtsikloS3-C6alkyl, amino, -OH or a group - (S0S ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -N (C ₀ -C ₆ alkyl) (C0-C6alkyl), wherein each substituent is independently optionally substituted with —OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C1- C6alkyl), halo ene, -YO _2, -C ^ -8O _n - (C ₁ -C ₆ alkyl), or -C (O) C ^ ^^ ^ C ^ alkilHS lkil);

K ₃ represents aryl, optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, —C ^ —C ₁ -C ₆ alkyl, - 8O _p - (C ₁ -C ₆ alkyl), -8O _p - (aryl), aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -MH-cycloC ₃ -C ₆ alkyl, amino, -OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) ^ C ^^ alkylXC ^ C ^ lkyl), where each substituent independently optionally substituted with —OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen m, -YO _2, -C ^ -8O _n - (C ₁ -C ₆ alkyl), or -C (O) -N (C ₀ -C ₆ alkyl) (C0-C6 alkyl); and n is independently 0, 1 or 2.

And in another embodiment of this aspect, the compound of this invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —ΝΘ ₂ , ^ Ν or —C ₂ C6 alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

K ₁ is halogen, carbonyl, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₁ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -C ^ -heterocycloC3- C6alkyl, -amino, -C1-C6alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, -C1-C6 alkyl (oxy) C ₁ -C ₆ alkyl, -C (O) XH- (aryl), -C (O) YAN (heteroaryl), -8O _p NN (aryl), -8O _p NN (heteroaryl), ^ O ^ H ^ -Salkyl), -CHO) MS ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -XH-8O _p - (C ₁ -C ₆ alkyl), -8O _p - (C ₁ 13

C ₆ alkyl), carbamoyl, - (C ₁ -C ₆ alkyl) -O-C (CH) dialkylamino or a group - (C ₁ -C ₆ alkyl) -8O _p (C ₁ -C ₆ alkyl), where any from groups optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CY, —C (O) (heterocycloC ₃ -C ₆ alkyl),

-C (O) -O- (C ₀ -C ₆ alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl carbamoyl or -8O _p - (C ₁ -C ₆ alkyl);

A represents CH;

K ₂ is carbonyl optionally substituted with 1 substituent, where the substituent is aryl, heteroaryl, —C (O) OH, carbonyl, —C ₁ -C ₆ alkyl, —O-aryl, —heteroaryl, —O- (C1- C6 alkyl), -heterocycloC3-C6 alkyl, -YN-cycloC ₃ -C ₆ alkyl, amino, -OH or - (C0-C6 alkyl) (C0-C6 alkyl) amino group, where each substituent is independently optionally substituted with -OH, -O (C ₁ -C ₆ alkyl), -C ₁ -C ₆ alkyl, -cycloC3-C6 alkyl, -O (aryl), -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -O ₂ , -CY, -8O _p - (C ₁ C ₆ alkyl), -cycloC ₃ -C ₆ alkyl or -C (O) -O (C ₀ C6 alkyl) (C0-C6 alkyl);

K ₃ is aryl, optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, —CY, —C ₁ -C ₆ alkyl, - 8O _p - (C ₁ -C ₆ alkyl), -8O _p - (aryl), aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -YN-cycloC ₃ -C ₆ alkyl, amino, -OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) N (C0-C6 alkyl) (C0-C6 alkyl), where each the substituent is independently optionally substituted with —OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C1-C6 alkyl ), halo ene, -YO ₂ -SY, -8O _n - (C ₁ -C ₆ alkyl), or -C (O) -N (C0-C6alkyl) (C0-C6 alkyl); and n is independently 0, 1 or 2.

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

81, 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —O ₂ , —CY or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1- 5 substitutes; where each substituent independently is halogen or OH;

Βι is halogen, carbonyl, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C1-C6 alkoxy, aryl, heteroaryl, -CY, -heterocycloC3-C6 alkyl, amino , -C1-C6 alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, C1-C6 alkyl (oxy) C1-C6 alkyl, C (O) ON (aryl), -C (O) ON (heteroaryl), -8O _p ON (aryl) , -8O _p YN (heteroaryl),

-8O _p YN (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -YN-8O _p - (C ₁ -C ₆ alkyl) , -8О _p - (С ₁ -С ₆ alkyl), -carbamoyl, - (С ₁ -С ₆ alkyl) -О-С (СЫ) dialkylamino or a group - (С1-С6 alkyl) -8Оп- (С1

C6 alkyl), wherein any of the groups is optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CY, —C (O) (heterocycloC3-C6 alkyl), —C (O) O- (C0-C6 alkyl), —C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8Op- (C1-C6 alkyl);

A represents CH;

B ₂ is carbamoyl, optionally substituted with 1-2 substituents, where each substituent independently is carbonyl, —CY, —C ₁ -C ₆ alkyl, —8O _p - (C ₁ -C ₆ alkyl), —O-aryl, —O-heteroaryl, —C (O) -heterocycloC ₃ -C ₆ alkyl, —YN-cycloC ₃ -C ₆ alkyl, amino, —OH, or —C ₁ -C ₆ alkyl (amino) group, wherein each substituent is independently optional substituted by —OH, —O (C ₁ –C ₆ alkyl), —O (aryl), —COOH, —COO (C1 – C6 alkyl), halogen, —YO2, —CY or —C (O) —Y (C0- C6 alkyl) (C0-C6 alkyl);

B ₃ represents aryl, optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —O 2, —C (O) OH, carbonyl, —CY, —C ₁ -C ₆ alkyl, -8O _p - (C ₁ -C ₆ alkyl), -8Op- (aryl), aryloxy, -O-heteroaryl, C1-C6 alkoxy, Y-oxide, -C (O) -heterocycloC3-C6 alkyl, -YN-cycloC ₃ —C ₆ alkyl, amino, —OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, —C (O) S (C0-C6 alkyl) (C0-C6 alkyl), where each substituent is independently optionally substituted with —OH, C1-C6 alkoxy, -C1-C6 alkyl, cycloC3-C6 alkyl, aryloxy, -C (O) OH, -C (O) O (C1-C6 alkyl), halogen, -O2, -C , -8Op- (C1-C6alkyl), or -C (O) -N (C0-C6alkyl) (C0-C6 alkyl); and n independently represents 0, 1 or 2.

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

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ —C ₆ alkyl, —O ₂ , —CY or —C ₁ -C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents ; where each substituent independently is halogen or OH;

B ₁ represents halogen, carbonyl, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C1-C6 alkoxy, aryl, heteroaryl, -CY, -heterocycloC3-C6 alkyl, - amino, C1-C6 alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, C1-C6 alkyl (oxy) C1-C6 alkyl, -C (O) ON- (aryl), -C (O) ON (heteroaryl), -8 OPN (aryl) , -8 OPYN (heteroaryl), -8 OPYN (C1-C6 alkyl), -C (O) N (C0-C6 alkyl) (C ₀ -C ₆ alkyl), -NH-8O _p - (C ₁ -C ₆ alkyl), -8O _p (C1-C6 alkyl), -carbamoyl, - (C1-C6 alkyl) -O-C (CH) -dialkylamino or a group - (C1-C6 alkyl) 8Op- (C1-C6 alkyl), where any of the groups is optionally substituted 1 -5 substituents; where each substituent independently represents halogen, OH, —CY, —C (O) (heterocycloC3-C6 alkyl), —C (O) -O- (C0-C6 alkyl), —C (O) -O-aryl, alkoxy, cycloalkyloxy , acyl, acyloxy, -cycloC ₃ -C ₆ alkyl, heterocycloC ₃ -C ₆ alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _p - (C ₁ -C ₆ alkyl);

A represents CH;

1 ₂ and 1 ₃ each independently represent an optionally substituted aryl, linked by a thio, hydroxy or (C ₁ -C ₄ alkyl) bridged bridge to form a condensed three-ring system; and η is independently 0, 1, or 2.

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

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —ΝΟ ₂ , —ΟΝ or —C ₁ C6 alkoxy;

1 ₁ represents halogen, carbonyl,

-C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, -ΟΝ, -heterocycloC3-C6 alkyl, -amino, -C1- C6 alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, -C1-C6 alkyl (oxy) C ₁ -C ₆ alkyl, -C (O) YAN (aryl), -C (O) ΝΗ (heteroaryl), -8O _m NN (aryl). -8О _m НН (get-eroaryl), -8О _П ХН (С1-Сalkyl), -С (О) НС ₀ -С ₆ alkyl) (С ₀ -С ₆ alkyl), -№Н-8О _П - (С1 -C ₆ alkyl), -8O _P - (C ₁ -C ₆ alkyl), -carbamoyl, - (C ₁ -C ₆ alkyl) -O-C (SC) dialkylamino or a group - (C ₁ -C ₆ alkyl) -8 _{O P} (C1-C6 alkyl), wherein any of the groups is optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CH — C (O) (heterocycloC ₃ -C ₆ alkyl), —C (O) O- (C0-C6 alkyl), —C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or -8O _P - (C ₁ -C ₆ alkyl);

A represents CH;

1 ₂ represents - (C ₁ -C ₆ alkyl) -8O _P - (C ₁ -C ₆ alkyl), optionally substituted with 1-5 substituents, where each substituent is independently halogen, —O ₂ , —COOH, carbonyl, -CH, -C ₁ -C ₆ alkyl, -8O _P - (C ₁ -C ₆ alkyl), O-aryl, -O-heteroaryl, -C (O) -heterocycloC3C ₆ alkyl, -HH-cycloC ₃ -C ₆ alkyl, amino, —OH or a group —C ₁ -C ₆ alkyl (amino), where each substituent is independently optionally substituted with —OH, —O (C ₁ -C ₆ alkyl), —O (aryl), —COOH, - COO (C ₁ -C ₆ alkyl), halogen, —O ₂ , —CH or C (O) —I (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

1 to ₃ is aryl, optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, —CH, —C ₁ -C ₆ alkyl, - 8O _P - (C ₁ -C ₆ alkyl), -8O _p - (aryl), aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, -KH-cycloC ₃ -C ₆ alkyl, amino, -OH or a group (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) -I (C0-C6 alkyl) (C0 -C6 alkyl), where each substituent is independently optionally substituted with -OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O ) O (C1-C6 alkyl), halogen, —O ₂ , —CH — 8O _p - (C ₁ -C ₆ alkyl) or —C (O) -M (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl); and η is independently 0, 1, or 2.

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

81, 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —IO ₂ , Ν Ν or C ₁ C6 alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

1 ₁ represents halogen, carbonyl,

-C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₁ -C ₆ alkoxy, aryl, heteroaryl, ^ Ν, -heterocycloC3-C6 alkyl, -amino, -C1- C6 alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, -C1-C6 alkyl (oxy) C ₁ -C ₆ alkyl, -C (O) OH (aryl), -C (O) YAN (heteroaryl), -8O _p YAN (aryl), -8O _p YAN (heteroaryl), -8O _p KN (C ₁ -C ₆ alkyl), -C (O) HC ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -KH- 8O _p - (C ₁ -C ₆ alkyl), -8O _p - (C ₁ -C ₆ alkyl), carbamoyl, - (CrC ^ lkylGO-C ^ Ndialkylamino or a group - (C1-C6 alkyl) -8Op (C1- C6 alkyl), where any of the groups is optionally substituted with 1-5 substituents; where each substituent independently is halogen, -OH, ^ Ν, -C (O) (heterocycloC ₃ -C ₆ alkyl), -C (O) O- ( C0-C6 alkyl), -C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6 alkyl, heterocycloC3 -C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or 8O _p - (C ₁ -C ₆ alkyl);

A represents CH;

1 ₂ represents —C (O) / (C ₀ –C ₆ alkyl) (C ₀ –C ₆ alkyl) optionally substituted with 15 substituents, where each substituent independently is halogen, —O ₂ , —COOH, carbonyl, ^ Ν, - C ₁ -C ₆ alkyl, -8O _p - (C ₁ C6 alkyl), aryloxy, -heteroaryloxy, -C (O) heterocycloC ₃ -C ₆ alkyl, -KH-cycloC ₃ -C ₆ alkyl, amino, -OH or a group -C1-C6 alkyl (amino), where each substituent is independently optionally substituted -OH, -O (C ₁ -C ₆ alkyl), -O (aryl), -COOH, -COO (C ₁ -C ₆ alkyl), halogen, -O ₂ , ^ Ν or C (O) -M (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl);

1 to ₃ is aryl, optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, —O ₂ , —C (O) OH, carbonyl, ^ Ν, —C ₁ -C ₆ alkyl, - 8O _p - (C ₁ -C ₆ alkyl), -8Op- (aryl), aryloxy, -O-heteroaryl, C1-C6 alkoxy, Ν-oxide, -C (O) -heterocycloC ₃ -C ₆ alkyl, - KH-cycloC ₃ -C ₆ alkyl, amino, -OH or a group (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl) amino, -C (O) HCO-C ₆ alkyl) (Co-Salkyl), where each substituent is independently optionally substituted with —OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C1 -C6alkyl), gal fire, -O ₂ , ^ Ν, -8O _p - (C ₁ -C ₆ alkyl) or -C (O) -M (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl); and n is independently 0, 1 or 2.

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

81, 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C ₁ -C ₆ alkyl, —O ₂ , —CY or C _g C ₆ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently is halogen or OH;

R1 represents halogen, carbonyl, _-C1-C6 alkyl, -tsikloS ₃ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -SY, -geterotsikloS3-C6alkyl, -amino, C1-C6 alkylamino,

- (C1-C6 alkyl) (C1-C6 alkyl) amino, -C1-C6 alkyl (hydroxy) C1-C6 alkyl, -C (O) ON (aryl), -C (O) ON (heteroaryl), -8 OPN (aryl), -8 OPYN (heteroaryl), -8O _p NO (C ₁ -C ₆ alkyl), -C (O) N (C ₀ -C ₆ alkyl) (C ₀ -C ₆ alkyl), -N-8O _p - (C ₁ -C ₆ alkyl), -8О _p - (С ₁ -С ₆ alkyl), -carbamoyl, - (С ₁ -С ₆ alkyl) -О-С (СЫ) dialkylamino or a group - (С1-С6 alkyl) -8Оп (C1-C6 alkyl), wherein any of the groups is optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CY, —C (O) (heterocycloC3-C6 alkyl), —C (O) O- (C0-C6 alkyl), —C (O) -O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or 8Op- (C1-C6 alkyl);

A represents CH;

K ₂ is —CO;

K ₃ is aryl, optionally substituted with 1-5 substituents, where each substituent independently is aryl, heteroaryl, halogen, —O2, —C (O) OH, carbonyl, —CY, —C ₁ -C ₆ alkyl, -8O _p - (C ₁ -C ₆ alkyl), -8O _p - (aryl), -aryloxy, -O-heteroaryl, C ₁ -C ₆ alkoxy, Y-oxide, -C (O) -heterocycloC3-C6 alkyl, -YN -cycloC ₃ -C ₆ alkyl, amino, -OH or a group (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) -Y (C0-C6 alkyl) (C0-C6 alkyl), where each substituent is independently optionally substituted -OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, -aryloxy, -C (O) OH, -C (O) O (C1-C6 alkyl), halogen ohm, -O2, -CY, -8Op- (C1-C6 alkyl) or -C (O) -Y (C0-C6 alkyl) (C0-C6 alkyl); and n is independently 0, 1 or 2.

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

8 ₁ , 8 ₂ and 8 ₃ independently represent H, —OH, halogen, —C 1 -C 6 alkyl, —O 2, —CY or C 1 –C 6 alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; where each substituent independently represents halogen or OH;

K ₁ is —C ₁ -C ₆ alkyl optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CY, —C1 – C6 alkyl, —cycloC3C ₆ alkyl, —C (O) (heterocycloC ₁ –C ₆ alkyl), —C (O)

O- (C0-C6 alkyl), -C (O) aryloxy, -C1-C6 alkoxy, - (C0-C6 alkyl) (C0-C6 alkyl) amino, cycloalkyloxy, acyl, acyloxy, -cyclo C3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or 8Op- (C1-C6 alkyl);

A represents CH,

K ₂ and K ₃ each independently represents aryl or heteroaryl, where each is optionally substituted with 1-5 substituents, where each Deputy independently represents aryl, heteroaryl, halogen, —YO2, —C (O) OH, carbonyl, —CY, - C ₁ -C ₆ alkyl, -8O _p - (C ₁ -C ₆ alkyl), 8Op- (aryl), aryloxy, heteroaryloxy, C1C6 alkoxy, Y-oxide, -C (O) heterocycloC3-C6 alkyl, -НН -cycloC ₃ -C ₆ alkyl, amino, -OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) L (C0-C6 alkyl) (C0-C6 alkyl), where each substituent is independently optionally substituted -OH, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl m, aryloxy, -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), halogen, -O ₂ , -CY, -8O _p - (C ₁ -C ₆ alkyl) or -C (O) -O (C0-C6 alkyl) (C0-C6 alkyl);

K ₂ and K ₃ can optionally be connected by a thio, hydroxy or (C ₁ -C ₄ alkyl) bridge to form a condensed three-ring system; and n is independently 0, 1 or 2;

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

81, 82 and 83 are each H;

K ₁ are —C ₁ -C ₆ alkyl optionally substituted with 1-5 substituents; where each substituent independently is halogen, —OH, —CY, —C ₁ -C ₆ alkyl, —cycloC3-C6 alkyl, —C (O) (heterocycloC3-C6 alkyl), —C (O) -O- (C0-C6 alkyl ), -C (O) -aryloxy,

-C1-C6 alkoxy, - (C0-C6 alkyl) (C0-C6 alkyl) amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6 alkyl, heterocycloC3-C6 alkyl, aryl, heteroaryl, carbonyl, carbamoyl or 8Op- (C1-C6;

A represents CH,

K ₂ and K ₃ each independently represents aryl or heteroaryl, where each is optionally substituted with 1-5 substituents, where each substituent independently represents aryl, heteroaryl, halogen, —YO2, —C (O) OH, carbonyl, —CY, —C ₁ -C ₆ alkyl, -8O _p - (C ₁ -C ₆ alkyl), 8Op- (aryl), aryloxy, heteroaryloxy, C1-C6 alkoxy, Y-oxide, -C (O) -heterocycloC3-C6 alkyl, - CN-cycloC3-C6 alkyl, amino, -OH or a group - (C0-C6 alkyl) (C0-C6 alkyl) amino, -C (O) N (C0-C6 alkyl) (C0-C6 alkyl), where each substituent is independently optionally substituted with -OH , C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl, -cycloC ₃ -C ₆ alkyl, and Ryloxy, —C (O) OH, —C (O) O (C ₁ -C ₆ alkyl), halogen, —O 2, —CY, —8Op- (C ₁ –C ₆ alkyl), or —C (O) —Y (C 0 -C6 alkyl) (C0-C6 alkyl);

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

As used herein, “alkyl” as well as other groups having the prefix “alk”, such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, mean carbon chains that 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 CC bond.

The term “cycloalkyl” means carbocycles not containing heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems may include a single ring that is partially or completely unsaturated, such as a benzene ring, to form fused ring systems, such as benzofused carbocycles. Cycloalkyl includes fused ring systems such as spiro condensed ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like. Similarly, “cycloalkenyl” means carbocycles containing no heteroatoms and containing at least one non-aromatic CC double bond, and includes mono-, bi- and tricyclic partially saturated carbocycles, as well as benzocondensed cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl and the like.

The term “cycloalkyloxy,” unless specifically defined otherwise, includes a cycloalkyl group attached to an oxy binding atom.

The term "alkoxy", unless specifically defined otherwise, includes an alkyl group attached to an oxy binding atom.

The term “aryl”, unless specifically defined otherwise, includes poly ring systems as well as mono ring systems, such as, for example, phenyl or naphthyl.

The term “aryloxy,” unless specifically defined otherwise, includes poly ring systems as well as mono ring systems, such as, for example, phenyl or naphthyl, attached via an oxy bonding atom to the point of attachment.

The term “C ₀ -C ₆ alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1 or not containing carbon atoms. Carbon-free alkyl is a substituent hydrogen atom or a direct bond, depending on whether the alkyl is a terminal or a bridging group.

The term “hetero”, unless specifically defined otherwise, includes one or more O, 8 or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, 8 or N atoms in a ring, including mixtures of such atoms. Hetero atoms replace the carbon atoms of the ring. Thus, for example, heterocyclo-C ₅ alkyl is a five-membered ring containing from 5 to 0 carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazyl isolazole, aziazole, aziazole, aziazole, aziazole, aziazole, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

The term “heteroaryloxy,” unless specifically defined otherwise, describes a heteroaryl group attached via an oxy linking atom to the attachment site.

Examples of heteroaryl (C ₁ -C ₆₎ alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pirazolilmetil, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazoliletil, benzimidazolylmethyl, oksadiazolilmetil, oksadiazoliletil, tiadiazolilmetil, tiadiazoliletil, trizolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

GeterotsikloS Examples ₃ - ₇ alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pirolidin2-one, piperidin-2-one, and thiomorpholinyl.

Examples of aryl (C _1-6 ) alkyl include, for example, phenyl (C _1-6 ) alkyl and naphthyl (C _1-6 ) alkyl.

Examples of heterocycloC3-7alkylcarbonyl ( _C1-6 ) alkyl include, for example, azetidinylcarbonyl ( _C1-6 ) alkyl, pyrrolidinylcarbonyl ( _C1-6 ) alkyl, piperidinylcarbonyl ( _C1-6 ) alkyl, piperazinylcarbonyl ( _C1-6) ) alkyl, morpholinylcarbonyl (C1-6) alkyl and thiomorpholinylcarbonyl (C1-6) alkyl.

The term “amine,” unless specifically defined otherwise, includes primary, secondary, and tertiary amines.

Unless specified otherwise, the term "carbamoyl" includes -INS (O) _C1-C4 alkyl, and -OC (O) INS ₁ -C ₄ alkyl.

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

The term “optionally substituted” is intended to mean both substituted and unsubstituted. Thus, for example, optionally substituted aryl may be a pentafluorophenyl or phenyl ring. In addition, substitution can be carried out in any group. For example, substituted aryl (C _{! -6} ) alkyl includes substitution in the aryl group as well as substitution in the alkyl group.

The compounds described herein contain one or more double bonds, and this may be the reason for the existence of cis / trans 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 herein 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 substantially pure separated enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts. The above formula ΐ is presented without indicating sterochemistry at certain positions. The present invention includes all steroisomers of formula ΐ and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. In the process of synthetic methods used to prepare such compounds, or when using the racemization or epimerization processes known to those skilled in the art, the products of such processes may be in the form of a mixture of stereoisomers.

The term "pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt may suitably be prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ΐ and ΐΐ), iron (ΐΐ), iron (ΐΐΐ), lithium, magnesium, manganese (ΐΐ and ΐν), potassium, sodium, zinc and things like that. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. 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 synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be obtained include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, Ν, Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, Ν-ethylmorpholine, Ν-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, triamine things like that.

When the compound of the present invention is a base, its corresponding salt may suitably be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, e.g. phosphoric, succinic, sulfuric, tartaric, ptoluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

The pharmaceutical compositions of the present invention include, as an active substance, a compound represented by the formula ΐ (or its pharmaceutically acceptable salts), a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, ί) leukotriene receptor antagonists, ίί) leukotriene biosynthesis inhibitors, ίίί) corticosteroids, ίν) H1 receptor antagonists, ν) beta 2 adrenoreceptor agonists, νί) selective COX-2 inhibitors, νίί) ) non-steroidal anti-inflammatory drugs (NSAIDs) and ίχ) antagonists of M2 / M3. Compositions include compositions suitable for oral, rectal, local 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 disease condition in which the active substance is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any method well known in the pharmaceutical art.

For topical use, creams, ointments, jellies, solutions or suspensions containing a compound of formula I can be used. Rinses for the mouth and throat are included in the scope of local use of this invention.

Dose levels of about 0.001 mg / kg to 140 mg / mg body weight per day can be used to treat conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis, and other benign or malignant proliferative skin diseases. , endotoxic shock (and related conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain damage associated with 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 conjunctivitis, spring conjunctivitis, arterial restenosis, atherosclerosis, pain, neurogenesis rheumatoid arthritis, ankylosing spondylitis, graft rejection and the graft versus host reaction, gastric juice hypersecretion, sepsis or septic shock, causing caused by bacterial, fungal and viral infections, inflammation and cytokine-associated 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 cancer invasion of normal tissue that are sensitive to inhibition of PDE4, or alternatively, from about 0.05 mg to about 7 g per patient NTA per day. For example, inflammation can be effectively treated by administering from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day or, alternatively, from about 0.5 mg to about 2.5 g per patient per day. In addition, it is understood that the PDE4 inhibiting compounds of the present invention can be administered at prophylactically effective dose levels for the prophylaxis of the above conditions.

The amount of active substance that can be combined with the substance of the carrier to obtain a unit dosage form may vary depending on the subject being treated and the particular route of administration. For example, a composition intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of the active substance, 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 0.01 mg to about 1000 mg of the active substance, usually 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

However, it is clear that the specific dose level for an individual patient will depend on various factors, including age, body weight, general condition, gender, nutrition, time of administration, route of administration, excretion rate, combination with another drug and the severity of the disease being treated .

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

The carrier may be selected from a wide variety of forms, depending on the type of drug desired for administration, for example, oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules, porridge or tablets, each containing a predetermined amount 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-water emulsion or in the form of a water-in-oil emulsion. In addition to the usual dosage forms indicated above, the compound represented by formula I, or pharmaceutically acceptable salts thereof, can also be administered by methods that control the release and / or delivery. Compositions can be obtained by any of the pharmaceutical methods. Typically, such methods include the step of entering into an association of the active substance and the carrier, which consists of one or more necessary ingredients. Typically, compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both. The product can then be appropriately shaped to the desired shape. Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of Formula I. Compounds of Formula I or their pharmaceutically acceptable salts may also be formulated in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used may 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.

In preparing the compositions for the oral dosage form, any conventional pharmaceutical medium may be used. For example, for oral liquid medicaments, such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavors, preservatives, colorants and the like can be used; whereas solid carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used to prepare solid oral forms of medicaments, such as powders, capsules and tablets. Preferred oral dosage unit forms are tablets and capsules, since they are easy to administer, and solid pharmaceutical carriers are thus employed. Optionally, tablets may be coated using standard aqueous or non-aqueous methods.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more additional ingredients or adjuvants. Compressed tablets may be prepared by compressing, in an appropriate machine, the active substance in granular form, such as powder or granules, optionally mixed with a binding agent, a lubricant, an inert diluent, a surface-active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of a powder of a compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active substance, and each cereal or capsule preferably contains from about 0.1 mg to about 500 mg of the active substance.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant, such as, for example, hydroxypropyl cellulose, may be included. Dispersions can also be obtained in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, a preservative may be included to prevent the harmful growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for use as an injection include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for preparation before direct use of such sterile solutions and dispersions for injection. In any case, the final injection form must be sterile and liquid enough for easy administration through a syringe. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably, microorganisms such as bacteria and fungi should be protected from the harmful effects. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g. glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils and their corresponding mixtures.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, powder in the form of a powder or the like. In addition, the compositions can be obtained in a form suitable for use in devices for transdermal administration. These preparations can be made using the compound represented by Formula I of the present invention, or pharmaceutically acceptable salts thereof, by conventional techniques. As an example, a cream or ointment is obtained by mixing a hydrophilic substance and water together with from about 5 wt.% To about 10 wt.% Of the compound to obtain a cream or ointment having the desired consistency.

The pharmaceutical compositions of this invention may be in a form suitable for rectal administration, wherein the carrier is a solid. Suppositories are preferably made from the mixture in unit dosage form. Suitable carriers include cocoa butter and other substances commonly used in the art. Suppositories can be conveniently prepared by first mixing the composition with a softener or molten carrier (s), and then cooling and shaping in the molds.

In addition to the above carrier ingredients, the pharmaceutical compounds described above may include, if appropriate, one or more additional carrier ingredients, such as solvents, buffers, flavoring agents, binding agents, surfactants, thickeners, lubricants, preservatives ( including antioxidants) and the like. In addition, other adjuvants may be included to make the composition isotonic with blood and the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in the form of a powder or liquid concentrate.

It was found that the compounds and pharmaceutical compositions of this invention are biologically active as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment in mammals, for example, of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and 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, damage to the myocardium and brain associated with blood supply, inflammatory arthritis, osteoporosis, chronic glom erulonephritis, atopic 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, pain, neurogenitis, arthritis, ankylosing spondylitis, graft rejection and the graft versus host reaction, hypersecretion of gastric juice, sepsis or sep shock caused by bacterial, fungal and viral infections, inflammation and cytokine-associated 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, disease Alzheimer's, spinal cord injuries, head bruising, multiple sclerosis, tumor growth and cancer invasion of normal tissue, diseases that could be alleviated by inhibiting isofer PDE4 and as a result of a decrease in cAMP levels with the administration of effective amounts of the compounds of this invention. The term “mammals” includes humans as well as animals, such as, for example, dogs, cats, horses, pigs and cattle. Accordingly, it is understood that the treatment of mammals, excluding humans, is the treatment of diseases clinically correlated with the above examples of human diseases.

Further, as described above, the compound of this invention can be used in combination with other therapeutic compounds. In particular, combinations of the PDE4 inhibiting compound of this invention can be suitably used in combination with ί) leukotriene receptor antagonists, ίί) leukotriene biosynthesis inhibitors, ίίί) COX-2 selective inhibitors, ίν) statins, ν) NSAIDs and νί) antagonists of M2 / M3, νί) corticosteroids, νίίί) antagonists of the H1 receptor (histamine) and ίχ) agonists of beta 2 adrenergic receptors.

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

which is a PDE4 inhibitor, is formed as the metabolite ίπ νίνο when the compound of Example 14 is administered:

Accordingly, the present invention includes prodrugs that sh ν шνο form PDE4 inhibitors as a metabolite after administration of such prodrugs to a mammal. In addition, this invention includes a method of treatment by introducing a prodrug with the formation of w ν νο an effective amount of a PDE4 inhibitor described by formula I.

The abbreviations used in this description have the following meanings presented in the table.

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

Ac = Acetyl Bp = Benzyl cAMP cyclic adenosine-3 ', 5'-monophosphate DBU = 1,8-diaaabicyclo [5.4.0] undec-7-ene E1BAB = diisobutylaluminum hydride DMAP = 4- (dimethylamino) pyridine DMF = Ν, Ν-dimethylformamide ΕΕ ₃ Ν = triethylamine NWT glutathione transferaa NMbZ hexamethyldisilazide LEA = lithium diisopropylamide m-CPBC = metachloroperbenzoic acid MIRR = monoperoxyphthalic acid MPPM = monoperoxyphthalic acid, magnesium salt 6Η ₂ 0 From = methanesulfonyl = mesyl = ZO ₂ Me MLO = methanesulfonate = mesylate ngtvs non-steroidal anti-inflammatory drug o-To1 ortho-tolyl ΟΧΟΝΕ® = 2KNZO ₅ · KNZO ₄ · K ₂ ZO ₄ RCC = pyridine chlorochromate ROS = pyridine dichromate PDE phosphodiesterase Pb = phenyl Pb = benzenediyl PMB = para-megoxybenzyl Rue = pyridinediyl com pace. room temperature You. = racemic ZAM = aminosulfonyl or sulfonamide or 8Ο2ΝΗ2 EARTH = 2- (trimethylsilyl) ethoxymethoxy ZRA = proximity analysis TBAE = tetra-n-butylammonium fluoride TA = 2- or 3-thienyl Tfu = trifluoroacetic acid

ATFU = trifluoroacetic acid anhydride THF = tetrahydrofuran YOU = thiopendiyl TLC = thin layer chromatography tmz-cm = trime tilsilschschianid ΤΜ5Ι trimethylsilyl iodide Τζ = 1H (or 2H) -tetrazol-5-yl SAM cerium ammonium nitrate C3H5 = -. allyl

Abbreviations for alkyl groups

Me = Methyl Fuck = ethyl P-Rg = normal cut ί-Rg = isopropyl p-vi = normal butyl ί-vi = Isobutyl 5-Vi = secondary butyl ΐ-vi = tertiary butyl s-Pr = cyclopropyl s-vi = cyclobutyl c-rep = cyclopentyl s-Neh = cyclohexyl

Studies showing biological activity

Quantitative analysis of LB8 and PMBP-induced L-L and LBB4 in human blood. Whole blood supplies a protein and cell rich medium suitable for studying the biochemical effectiveness of anti-inflammatory compounds such as PEE4-selective inhibitors. Normal, unstimulated human blood does not contain detectable levels of β-α and βB4. When stimulated with Lb8, activated monocytes are expressed and β-α is secreted up to 8 hours, and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of β-α by increasing intracellular cAMP by inhibiting PDE4 and / or enhancing adenylcyclase activity occurs at the transcription level. The synthesis of LBB4 is also sensitive to intracellular cAMP levels and can be completely inhibited by POE4 selective inhibitors. Since LBB4 slightly stimulates LB8 in whole blood for 24 hours, additional LB8 stimulation after stimulation [MEP of human whole blood is necessary for the synthesis of LBB4 activated by neutrophils. Thus, using the same blood sample, it is possible to evaluate the effect of the compound on the activity of two substitute marker PDE4 genes in whole blood in accordance with the following method.

Fresh blood was collected in heparin-containing tubes by venipuncture of healthy volunteers (men and women). These objects did not have any obvious inflammatory conditions and did not take any NSAIDs (Ν8ΑΙΌ8) for at least 4 days before taking the blood. Aliquots of blood of 500 μl were pre-incubated either with 2 μl of the carrier (DMSO) or with 2 μl of the test compound at various concentrations for 15 min at 37 ° C. After that, either 10 μl of the carrier (PB8) was added as a control, or 10 μl of LR8 (final concentration 1 μg / ml; # L-2630, 8% CHST1ca1 Co., 8L. Roche8, MO) from E. soi, serotype 0111: B4 ; dilution in 0.1% wt./about. B8A (in PB8)). After 24 h of incubation at 37 ° C, another 10 μl of PB8 (control) or 10 μl of LB8 (final concentration of 1 μg / ml) was added to the blood and incubated for 30 min at 37 ° C. Blood was then stimulated with either 10 μl of PB8 (control) or 10 μl of EMP (final concentration of 1 μM; # Ρ-3506 (81 dtA); dilution in 1% w / v B8A (in PB8)) for 15 min at 37 ° C. Blood samples were centrifuged at 1500 x d for 10 min at 4 ° C to obtain plasma. A 50 μl aliquot of the plasma was mixed with 200 μl of methanol to precipitate the protein and centrifuged as described above. The supernatant was analyzed on LBB4 using a set of immunoassay enzymes (# 520111 from Southap Syetka Co., App Arbog, ΜΙ) in accordance with the technological method. TKR-a was analyzed in diluted plasma (in PB8) using an E18A kit (C181gop Vy1ss11po1od. Rshe Vgook, N1) in accordance with the technological method. Values 1C _{50 of} examples 1-42 were usually in the range from 0.04 mm to 8.71 mm.

Antiallergic activity ίη νίνο

The compounds of the invention were tested for an effect on allergic pneumonia caused by 1de, induced by inhalation of antigen in sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin with mild immunosuppression caused by cyclophosphamine by intraperitoneal injection of antigen in combination with alumina and pertussis vaccine. Stimulating doses of antigen were administered after two and four weeks. At week six, animals were stimulated with aerosolized ovalbumin at the same time as the intraperitoneal administration of an antihistamine agent (mepiramine). After another 48 hours, bronchial alveolar lavage (BAB) was performed and the number of eosinophils and other leukocytes in BAB fluids was counted. The lungs were also removed for histological examination for inflammatory damage. The introduction of the compounds of the examples (0.001-10 mg / kg ί.ρ. or p.o.) up to three times within 48 hours after antigenic stimulation led to a significant decrease in eosinophils and the accumulation of other inflammatory white blood cells. Also, in animals that were administered the compounds of the examples, inflammatory damage to the lungs was less.

Study Protocol 8PA Based RBE Activity

Compounds that inhibit cAMP hydrolysis to AMP using cAMP-specific type IV phosphodiesterase were tested on a 96-well plate as follows.

96 luchnochnuyu-plate at 30 ° C was applied to the test compound (dissolved in 2 L DMSO), 188 ml of substrate buffer containing [2,8 ³ H] adenosine 3 ', 5'-cyclic phosphate (cAMP, 100 nM to 50 μM), 10 mM MDS1 ₂ , 1 mM EDTA, 50 mM Tp8, pH 7.5. The reaction was initiated by the addition of 10 ml of human recombinant ΡΌΕ4 (the amount was controlled so that ~ 10% of the product formed within 10 minutes).

The reaction was stopped after 10 min by adding 1 mg of glass beads (Ateshyat Ryatta Da Vu! Esy, 1ps., P | 5ca1a \ yau. N1). The resulting AMP product was quantitatively determined on a \ X11ac Mugo! E® counter in a 96-well plate (EC & C \ Xaacas ', Sayyesht, ΜΌ). The signal in the presence of the enzyme was determined as background. 100% activity was defined as a detectable signal in the presence of an enzyme and DMSO by subtracting the background. The percent inhibition was calculated accordingly. The value of 1C _{50 was} approximated to nonlinear regression using the equation of a standard 4-parameter / multiplet binding site of ten titration points.

The 1C ₅₀ value in Examples 1-42 was determined with 100 nM cAMP using purified C8T-bound human recombinant Scha phosphodiesterase protein (te! -248) obtained from the baculovirus / 8 £ -9 express system. The 1Cg0 value in Examples 1-42 is typically in the range of 0.14 nM to 10.24 nM, although in one example there was a 1C ₅₀ value of 109 nM.

The following examples are given to illustrate certain preferred embodiments of the invention and are not intended to limit the invention.

Unless specifically defined otherwise, experimental methods were carried out under the following conditions. All operations were carried out at room temperature or at ambient temperature, namely: at a temperature in the region of 18-25 ° C. The solvent was evaporated using a rotary evaporator under reduced pressure (6004000 pascals: 4.5-30 mm Hg) at a bath temperature of up to 60 ° C. After the reaction, thin-layer chromatography (TLC) was carried out, and the reaction time is indicated for illustration only. Melting points are given in the range and 'ά' stands for decomposition. The given melting points are obtained for substances obtained in such a way as described. In some preparations, polymorphism can lead to the release of substances with different melting points. The structure and degree of purification of all final products was confirmed by at least one of the following methods: TLC, mass spectroscopy, nuclear magnetic resonance spectrum (NMR), or microanalytical data. The output is for illustration only. If indicated, NMR data are presented as delta (δ) values for the main diagnostic protons, are given in parts per million (ppm) relative to tetramethylsilane (TM8) as an internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicator solvent. For signal peaks, the usual abbreviations are given: p. singlet; d. doublet; T. triplet; m. multiplet; broad. broadened; etc. In addition, “Ar” denotes an aromatic signal. Chemical symbols have their usual meanings; The following abbreviations were also used: vol. (volume), wt. (mass), t.kip. (boiling point), so pl. (melting point), l (liter (s)), ml (milliliters), g (gram (s)), mg (milligrams), mol (moth), mol (millimole), equiv. (equivalent (s)).

Synthesis Methods

Compounds of the present invention can be obtained in accordance with the following methods. The substituents are the same as in formula I, unless otherwise specified.

Scheme 1

where X = halogen, H;

Υ = halogen, N;

A = 4- (methylthio) benzaldehyde;

E = electrophile;

Ar = aryl or heteroaryl.

According to Scheme 1 above and the table of Scheme 1 below, an intermediate alcohol compound II can be prepared by reacting a metal derivative of aryl or heteroaryl ΐΐΐ, such as an organomagnesium halide, with 4- (methylthio) benzaldehyde (A) in an organic solvent such as THF. Intermediate alcohol compound II can also be obtained by treating aryl or heteroaryl hydride or bromide IV with a base or organometallic compound such as n-butyllithium in an organic solvent such as THF and then with 4 (methylthio) benzaldehyde. Alternatively, the intermediate alcohol compound II can also be obtained by the following chemical transformations:

1) treating the aryl or heteroaryl dihydride, halide or dihalide of compound V with a base or 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) sequential treatment with a base or organometallic compound, such as n-butyl lithium, in an organic solvent, such as THF, then with an electrophile, such as acetone or 4- (methylthio) benzaldehyde, where 4- (methylthio) should be used in the first or second conversion benzaldehyde as an electrophile. Sulfone alcohol VI can be obtained by oxidizing sulfide alcohol II with an oxidizing agent such as oxone in a solvent such as a mixture of THF / MEOH / H ₂ O. Ketones VII and VIII can be obtained by oxidizing alcohols,

II and VI, respectively, using an oxidizing agent such as MnO ₂ in a solvent such as CH ₂ Cl ₂ . The sulfone ketone VIII can also be prepared by oxidizing a sulfide ketone VII with an oxidizing agent such as oxone in a solvent such as a THF / MEOH / H ₂ O mixture.

Table. Patterns: Ketones

7I (n = 0) CS (n = 2)

Ketone K1. (4-Fluorophenyl) [4- (methylsulfonyl)] phenylketone.

Ketone K1 was prepared as follows.

Stage 1. (4-Fluorophenyl) [4- (methylthio) phenyl] ketone. To a solution of 4- (methylthio) benzaldehyde (2.5 g, 16.4 mmol) in THF (100 ml), 4-fluorophenyl magnesium bromide (1.0 M in THF, 19.7 ml) was added dropwise at -78 ° C. 19.7 mmol). The resulting solution was stirred at -78 ° C for 3 hours and quenched with a saturated aqueous KNdCl solution. Then the mixture was diluted with EJAc and 10% HCl, extracted and washed (No. 11CO ₃ (sat.), Brine). The organic phase was dried over MgSO ₄ and concentrated. Then the precipitate was treated with MnOg (28.6 g, 330 mmol) in CH ₂ Cl ₂ (150 ml) and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of silica gel (EyAc) to give 2.6 g of (4-fluorophenyl) [4- (methylthio) phenyl] ketone compound.

Stage 2. (4-Fluorophenyl) [4- (methylsulfonyl) phenyl] ketone.

To a solution of sulfide, specifically (4-fluorophenyl) [4- (methylthio) phenyl] ketone, from step 1 (2.0 g, 8.1 mmol) in THF / MeOH / H2O (80/40/40 ml) was added oxone (7.5 g, 12.2 mmol). The mixture was stirred at room temperature for 4 hours, quenched with NaHCO ₃ (sat.) And diluted with EuAc. The organic phase was washed with NaHCO ₃ (sat.), Brine, dried over No. ₂ 8O. |. filtered and concentrated. Crystallization (CH ₂ Cl ₂ / hexane) afforded (4-fluorophenyl) [4- (methylsulphonyl) phenyl] ketone, ketone compound K1, as a white solid.

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

Ketone K2 was prepared as follows.

Stage 1. (1-Methyl-1H-imidazol-2-yl) [4 (methylthio) phenyl] methanol.

To a solution of Y-methylimidazole (10.0 g, 122 mmol) in 500 ml of THF at -78 ° C, n-butyllithium (2.5 M in hexane, 48.7 ml, 118 mmol) was added dropwise and the resulting solution was stirred at -78 ° C for 30 minutes Then 4- (methylthio) benzaldehyde (14.73 ml, 110 mmol) was added at -78 ° C, and the mixture was stirred until completion of the reaction according to TLC and quenched with ON ₄ Cl (sat.). Then the mixture was diluted with EuAc, extracted and washed (NaHCO ₃ (sat.), Brine). The organic phase was dried over MgSO ₄ , filtered and concentrated. Crystallization (EJAc / Hexane) afforded (1-methyl-1H-imidazol-2-yl) [4- (methylthio) phenyl] methanol.

Step 2. (1-Methyl-1H-imidazol-2-yl) [4 (methylthio) phenyl] ketone.

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

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

Ketone K3 was prepared as follows.

Stage 1. (4-Methylthio) (phenyl) methanol.

Phenylmagnesium chloride (2M, THF, 3.5 ml, 7.0 mmol) was added to a solution of 4- (methylthio) benzaldehyde (1.0 g, 6.5 mmol) in THF (20 ml) at 0 ° C. After the mixture was kept for 0.5 h at room temperature, it was neutralized with a saturated LH4C1 solution, diluted with water, and extracted with EtO. The organic extracts were washed (H ₂ O) (brine), dried (Md ₈ O ₄ ), filtered and concentrated. Purification by vigorous stirring in hexane / E! ₂ O and filtration gave (4-methylthio) (phenyl) methanol as a white solid.

Stage 2. (4-Methylthio) (phenyl) ketone.

(4-Methylthio) (phenyl) ketone was obtained by treating (4-methylthio) (phenyl) methanol from step 1 with MnO ₂ as described for step 2 of the process for producing K4 below.

Stage 3. (4-Methylsulfonyl) (phenyl) ketone.

To a solution of (4-methylthio) (phenyl) ketone from step 2 (0.98 g, 4.3 mmol) in CHCl ₃ (10 ml) at 0 ° C was added mCBCA (m-chloroperbenzoic acid) (1.7 g, 10 mmol). After keeping the mixture for 0.5 h at room temperature, Ca (OH) ₂ (1.7 g, 23 mmol) was added to the mixture and stirred for 1 h. Filtration through celite (Ce1e®) and concentration gave K3 ketone as white solid product.

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

Ketone K4 was prepared as follows.

Stage 1. (1,3-Thiazol-2-yl) [4- (methylthio) phenyl] methanol.

To a solution of thiazole (5.0 g, 58.7 mmol) in THF (250 ml) at −78 ° C., n-butyllithium (2.5 M in hexane, 23.5 ml, 58.7 mmol) was added dropwise and the resulting solution stirred at -78 ° C for 10 minutes Then 4 (methylthio) benzaldehyde (7.1 ml, 53.4 mmol) was added at -78 ° C. The resulting mixture was stirred until completion of the reaction and quenched with a saturated aqueous solution of YN ₄ Cl. Then the mixture was diluted with EuAc and 10% HCl, extracted and washed (NaHCO ₃ (sat.), Brine). The organic phase was dried over MgSO ₄ and concentrated. Then the precipitate was purified using flash chromatography (80%

CH ₂ Cl ₂ /20% ENAc) to give (1,3-thiazol-2yl) [4- (methylthio) phenyl] methanol.

Stage 2. (1,3-Thiazol-2-yl) [4- (methylthio) phenyl] ketone.

MnOg (70 g, 843 mmol) was added to a solution of (1,3-thiazol-2-yl) [4- (methylthio) phenyl] methanol from step 1 (10.0 g, 42.1 mmol) in ESAc (250 ml) ), and the reaction mixture was stirred at 25 ° C. overnight. The mixture was filtered through a pad of silica gel (EYAc) to give the K4 ketone compound.

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

Ketone K5 was prepared as follows. To a solution of K4 (1,3-thiazol-2-yl) [4- (methylthio) phenyl] ketone (8.2 g, 34.7 mmol) in THF / MeOH / H ₂ O (350/175/175 ml) oxon (42.6 g, 69.4 mmol) was added. The reaction mixture was stirred at 25 ° C. for 3 hours and quenched with a saturated aqueous NaHCO ₃ solution. The resulting mixture was then diluted with EuAc, extracted and washed (NaHCO ₃ (sat.), Brine). The organic phase was dried over MgSO ₄ and concentrated. Then, the precipitate was purified by crystallization (ЕУАс / hexane) to obtain (1,3-thiazol-2-yl) [4- (methylsulfonyl) phenyl] ketone.

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

Ketone K6 was prepared as follows.

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

To a solution of thiazole (1.0 g, 12.0 mmol) in THF (100 ml) at −78 ° C., n-butyllithium (2.3 M in hexane, 5.3 ml, 12.3 mmol) was added dropwise and the resulting solution was stirred at -78 ° C for 10 minutes Then 4- (methylthio) benzaldehyde (7.1 ml, 53.4 mmol) was added at -78 ° C. The resulting mixture was stirred at room temperature for 10 minutes and cooled at -78 ° C.

Then n-butyllithium (2.3 M in hexane, 5.3 ml, 12.3 mmol) was added dropwise, and the resulting solution was stirred at 25 ° C. for 10 min and quenched with acetone (3.0 ml). Then, the mixture was diluted with EJAc and 10% HCl, extracted and washed (NaHCO ₃ (sat.), Brine). The organic phase was dried over MgSO ₄ and concentrated. Then, the precipitate was treated with MnO ₂ (20.4 g, 235 mmol) in CH2C12 (250 ml), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then filtered through a pad of silica gel (EYAc). Flash chromatography (90% CH ₂ Cl ₂ /10% ENAc) afforded [5- (1-hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4 (methylthio) phenyl] ketone.

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

Into a sulfide solution, ie [5- (1hydroxy-1-methylethyl) -1,3-thiazol-2-yl] [4- (methylthio) phenyl] ketone, from step 1 (1.7 g, 5.8 mmol ) in TTF / MeOH / H ₂ O (100/50/50 ml) was added oxone (7.1 g, 11.5 mmol). The reaction mixture was stirred at 25 ° C for 3 hours and quenched with saturated aqueous NaHCO ₃ . Then the mixture was diluted with EAAc, extracted and washed (NaHCO ₃ (sat.), Brine). The organic phase was dried over MgSO ₄ and concentrated. Then, the precipitate was purified by crystallization (EJAc / Hexane) to give K6 ketone.

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

Ketone K7 was prepared as follows.

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

To a solution of 3-bromo-6-methylpyridine (760 mg, 1 equiv.) In THF (20 ml) at -78 ° C, n-butyllithium in hexane (1.1 equiv.) Was slowly added. Then the solution was stirred for 30 minutes. After this, 4- (thiomethyl) benzaldehyde (738 mg, 1.1 eq.) Was slowly added. The solution was warmed to room temperature, HH4C1 (sat.) Was added, then water and ЕУАс. The organic phase was separated, dried over MgSO ₄ and concentrated. (6-Methyl-3-pyridinyl) [4- (methylthio) phenyl] methanol was obtained by precipitation with ether / hexane and was used in the next step without further purification.

Stage 2. (6-Methyl-3-pyridinyl) [4- (methylsulfonyl) phenyl] methanol.

Following the method described above from step 2 for the preparation of ketone K1, but using (4-methyl-3-pyridinyl) [4- (methylthio) phenyl] methanol sulfide instead of (4-fluorophenyl) [4- (methylthio) phenyl] ketone stage 1, received (6-methyl-3pyridinyl) [4- (methylsulfonyl) phenyl] methanol.

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

Following the method described above from step 2 for the preparation of K2 ketone, but using (4-(methylthio) phenyl] methanol (6methyl-3-pyridinyl) [4- (methylsulfonyl) as the starting product instead of (1-methyl-1Nimidazol-2-yl) [4- (methylsulfonyl) ) phenyl] methanol from step 2, received K7 ketone.

Ketone K8. (5-Methyl-2-pyridinyl) [4- (methylsulfonyl) phenyl] ketone. K8 ketone was obtained according to the method described for K7 ketone, but replacing 3-bromo-6-methylpyridine with 2-bromo-5methylpyridine.

Ketone K9. Bis - [(4-methylsulfonyl) phenyl] ketone.

Ketone K9 was obtained according to the method described for ketone K7, but replacing 3-bromo6-methylpyridine with 4-bromothioanisole and using a double amount of oxone in the sulfide oxidation step.

Ketone K10. (2-Pyridinyl) [4- (methylsulfonyl) phenyl] ketone. Ketone K10 was obtained according to the method described for ketone K7, but replacing 3-bromo-6-methylpyridine with 2bromopyridine.

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

Ketone K11 was prepared as follows.

Stage 1. [5- (1-Hydroxy-1-methylethyl) -2pyridinyl] [4- (methylthio) phenyl] methanol.

To a suspension of 2,5-dibromopyridine (5.12 g, 1 eq.) In ether at -78 ° C, nbutyl lithium in hexane (1.05 eq.) Was slowly added. The resulting yellow-orange precipitate was stirred for 30 minutes. Then acetone (1.54 ml, 1.05 equiv.) Was added. The solution was kept at -78 ° C for another 30 minutes. The resulting orange suspension was slowly injected with a syringe of nbutyl lithium in hexane (1.1 eq.). Then the suspension was stirred for 1 h at -78 ° C. After that, 4- (methylthio) benzaldehyde (2.85 ml, 1.1 eq.) Was added. The resulting suspension was heated to -35 ° C and quenched with a solution of HH4C1 (sat.). Water and EJAc were added and the organic layer was dried over MgSO ₄ , evaporated and purified by flash chromatography (EJAc) to give [5 (1-hydroxy-1-methylethyl) -2-pyridinyl] [4 (methylthio) phenyl] methanol.

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

[5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] methanol was obtained according to the method described above for stage 2 of the preparation of ketone K1, but instead of using (4- fluorophenyl) [4 (methylthio) phenyl] -4-fluorophenylketone sulfide, i.e., [5- (1-hydroxy-1-methylethyl) -2-pyridinyl] [4- (methylthio) phenyl] methanol, from step 1.

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

Ketone K11 was obtained according to the method described above for stage 2 of the preparation of ketone K2, but instead of using (1-methyl-1H-imidazol-2-yl) [4 (methylthio) phenyl] methanol [5- (1- hydroxy-1 methylethyl) -2-pyridinyl] [4- (methylsulfonyl) phenyl] methanol from step 2.

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

Aryl bromides IX and X can be obtained by treating benzylphosphonium bromide XI with a base such as t-ViOK or L1NME8 in an organic solvent such as THF, followed by adding ketone VII or VIII to the reaction mixture. The sulfide in IX can be converted to sulfone X by treatment with an oxone in a solvent, such as a mixture of THF / MeOH / H ₂ O. Boronate ester XII can be obtained by heating aryl bromide X with pinacoldiborane in the presence of a base such as KOAc and a catalyst such as RBC1 ₂ (brrG). in a solvent such as DMF.

Boronat B1. Pinacol 3 - {(E) -2- (1-methyl1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboranate.

Boronate B1 was prepared as follows.

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

To a solution of (3-bromobenzyl) (triphenyl) phosphonium bromide (10.2 g, 19.9 mmol) in THF (200 ml) and CH ₃ CU (50 ml) at 25 ° C was added dropwise tert-ViOK (1.0 M in THF, 19.9 ml, 19.9 mmol) and the resulting red solution was stirred at room temperature for 20 minutes. Ketone K2 (4.4 g, 18.9 mmol) was then added to the resulting product at 25 ° C. The resulting mixture was stirred at 60 ° C for 2 days and quenched with NH ₄ C1 (sat.). Then the mixture was diluted with EAAc. The organic phase was washed with NaHCO ₃ (sat.), Brine, dried over MgSO ₄ , filtered and concentrated, and used directly in the next step 2.

Stage 2. (E) -2- (3-Bromophenyl) -1- (1-methyl1H-imidazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene.

To a solution of crude sulfide, i.e. (E / Ζ) 2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) 1- [4- (methylthio) phenyl] ethene, from step 1 (18.9 mmol) in TTF / MeOH / H ₂ O (200/100/100 ml) was added oxone (23.2 g, 37.8 mmol). The mixture was stirred at room temperature for 4 hours, quenched with NaHCO ₃ (sat.) And diluted with EuAc. The organic phase was washed with NaHCO ₃ (sat.), Brine, dried over NaHCO, filtered and concentrated. Flash chromatography (95% E1OAc / 5% E1 ₃ S) afforded (E) -2- (3-bromophenyl) -1- (1-methyl1H-imidazol-2-yl) -1- [4- (methylsulfonyl) phenyl ] ethene (single isomer) in the form of a foam.

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

Suspension of bromide, i.e. (E) -2- (3bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) -1- [4 (methylsulfonyl) phenyl] ethene, from step 2 (2.0 g ; 4.8 mmol), pinacol diborone (1.5 g; 5.8 mmol), KOAc (1.65 g; 16.8 mmol) and PbC1 ₂ (brrH) (0.2 g; 0.24 mmol) in 50 ml of DMF was stirred at 90 ° C for 4 hours. The resulting mixture was cooled to room temperature, diluted with EuAc, washed with H ₂ O (3x), brine, dried over Na-28O4, filtered and concentrated. Flash chromatography (95% E1OAc / 5% E13Y) gave B1 boronate as a foam.

Boronat B2. Pinacol 3 - {(E ^) - 2- (1,3thiazol-2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate.

Boronate B2 was prepared as follows.

Stage 1. (E ^) - 2- (3-Bromophenyl) -1- (1,3thiazol-2-yl) -1- [4- (methylthio) phenyl] ethene.

To a solution of (3-bromobenzyl) (triphenyl) phosphonium bromide (44.5 g, 86.9 mmol) in THF (500 ml) and DMF (200 ml) at 0 ° C was added dropwise E1NMB8 (1.0 M in THF, 86.9 ml, 86.9 mmol), and the resulting red solution was stirred at room temperature for 20 minutes. Ketone K4 (18.6 g, 79.0 mmol) was then added to the resulting product at 0 ° C. The mixture was stirred until TLC the reaction was complete and quenched with NH ₄ C1 (sat.). Then the mixture was diluted with EAAc. The organic phase was washed with NaHCO ₃ (sat.), Brine, dried over MgSO ₄ , filtered and concentrated. Flash chromatography (CH ₂ Cl ₂ ) afforded (E ^) - 2- (3-bromophene 41 nyl) -1 - (1,3-thiazol-2-yl) -1- [4- (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 sulfide solution, i.e. (Ε / Ζ) -2- (3bromophenyl) -1 - (1,3-thiazol-2-yl) -1- [4- (methylthio) phenyl] ethene, from stage 1 (24, 8 g, 63.9 mmol) in TTF / MeOH / H ₂ O (600/300/300 ml) was added oxone (78.5 g, 128 mmol). The resulting reaction mixture was stirred at room temperature overnight. The resulting mixture was quenched with NaHCO3 (sat.) And diluted with EuAc. The organic phase was washed with NaHCO ₃ (sat.), Brine, dried over Na ₂ 8O ₄ , filtered and concentrated to give (E ^) - 2- (3-bromophenyl) -1- (1,3thiazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene (mixture of 3 to 2 isomers).

Step 3. Pinacol 3 - {(E ^) - 2- (1,3-thiazol2-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate.

Suspension of bromide (E ^) - 2- (3-bromophenyl) -1- (1,3-thiazol-2-yl) -1- [4- (methylsulfonyl) phenyl] ethene from stage 2 (15.0 g, 35 , 7 mmol), pinacol diborane (10.9 g, 42.8 mmol), KOAc (12.3 g, 125 mmol) and PbC1 ₂ (άρρί) (1.46 g, 1.78 mmol) in 350 ml of DMF stirred at 90 ° C for 4 hours. The resulting mixture was cooled to room temperature, diluted with EuAc. washed with H2O (3x), brine, dried over Na ₂ 8O ₄ , filtered and concentrated. Flash chromatography (To1 / acetone, 9/1) gave boronate B2 (a mixture of 3 to 1 isomers) as a foam.

Boronat B3. Pinacol 3 - {(E) -2- (5-methyl-2pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate. Boronate B3 was prepared as follows.

Stage 1. (E) -2- (3-Bromophenyl) -1- (5-methyl2-pyridinyl) -1- [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 material, and after the isomers were separated by flash chromatography, (E) -2- (3bromophenyl) -1- (5-methyl- 2-pyridinyl) -1- [4- (methylsulfonyl) phenyl] ethylene.

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

Boronate B3 was obtained according to the method described for stage 3 of obtaining boronate B1, but using, instead of (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) - as the starting material 1- [4- (methylsulfonyl) phenyl] ethene bromide (E) -2- (3-bromophenyl) -1- (5-methyl-2-pyridinyl) -1- [4- (methylsulfonyl) phenyl] ethylene from step 1 .

Boronat B4. Pinacol 3 - {(E) -2- (5- (1hydroxy-1-methylethyl) -2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenylboronate. Boronate B4 was prepared as follows.

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

According to the method described for stage 1 of obtaining boronate B1, but replacing ketone K2 with ketone K11 as a starting product, and after the isomers were separated by flash chromatography, (E) -2- (3-bromophenyl) 1- [5- (1 -hydroxy-1-methylethyl) -2-pyridinyl] -1 [4- (methylsulfonyl) phenyl] ethene.

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

Boronate B4 was prepared according to the method described for step 3 of producing boronate B1, but replacing (E) -2- (3-bromophenyl) -1- (1-methyl-1H-imidazole-2yl) -1- [ 4- (methylsulfonyl) phenyl] ethene on (E) -2- (3-bromophenyl) -1- [5- (1-hydroxy-1methylethyl) -2-pyridinyl] -1- [4- (methylsulfonyl) phenyl bromide ] ethene from stage 1.

Aryl bromide compounds that are used to obtain the compounds of this invention can be obtained according to schemes 3 and 4 below:

DIAGRAM 3

Synthesis of oxadiazole) -MeORION + ΟΙ- ^ ΟΝ ------ ►- ρ-Μ®ΟΡΚΟ <ΧΝ

XI On

40Ν

β Oxmtol (XVI)

Me OX1 r-MeOROS ^ OX2

According to Scheme 3 above, an XIII nitrile intermediate can be prepared by alkylating 4 methoxyphenol with chloroacetonitrile in the presence of a base such as potassium carbonate in a solvent such as acetone.

Amide oxime XIV can be prepared by treating nitrile XIII with an amine hydroxyl in a solvent such as methanol in the presence of a base such as sodium acetate. The formation of oxadisole XVI can be achieved by activating aryl acetic acid XV with carbonyldiimidazole in a solvent such as DMF, then adding amidoxime XIV and then heating the reaction mixture.

Scheme 4. Synthesis of aryl bromide

According to Scheme 4, condensation of the aldehyde XVII by heating with aryl acetic acid XV in the presence of a base such as piperidine in a solvent such as toluene gave the unsaturated acid ΧνΐΙΙη. After the formation of acid chloride, ΐΙΙνΐΙΙη ίη κίΐιι by treating thionyl chloride and a base such as triethylamine in a solvent such as toluene, an amine was added to the reaction mixture to give amide XVI11b. Oxadiazole-ethene XνΐΙΕ can be obtained by heating 0X1 with XVII in the presence of a base such as pipyridine in a solvent such as toluene.

Scheme 4 (appendix). Aryl bromide synthesis

ΧνΐΙΙβ (AB1) BUY χνιιΐβ

Vg

XVII "(AB6)

According to Scheme 4 above, treatment of XVIII acid with diazomethane in a solvent such as THF afforded methyl ester XVIII. Reduction of XVIII ester with BGVAB-H in a solvent such as THF afforded the allylic alcohol XVIII. Converting the alcohol group in XVIII to a removable group such as mesylate using agents such as methanesulfonyl chloride and triethylamine in a solvent such as THF, and then substitution with a nucleophile, such as dimethylamine, in a solvent such as DMF, gave compound XVIII £

Aryl bromide AB1. (E) -3- (3-Bromophenyl) -2 [4- (methylsulfonyl) phenyl] -2-propenyl acid.

Aryl bromide AB1 was prepared as follows. To a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in toluene (100 ml) was added 4 (methylsulfonyl) phenylacetic acid (15 g, 70 mmol) and piperidine (2 ml). After refluxing overnight, the mixture was cooled to room temperature. Toluene (10 ml) was added to the suspension thus obtained. Filtration afforded (E) -3- (3bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2propenoic acid as a white solid.

Aryl bromide AB2. (E) -Y-Isopropyl-3- (3bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2propenamide.

Aryl bromide AB2 was prepared as follows. Thionyl chloride (14.3 ml, 196 mmol) and triethylamine (34 ml, 245 mmol) were added to a solution of AB1 (24.9 g, 65 mmol) in toluene (250 ml). After stirring at room temperature for 0.5 h, isopropylamine (28 ml, 327 mmol) was added. After an additional 2 h at room temperature, the mixture was cooled to 0 ° С and neutralized with a saturated solution of ΝΗ ₄ 01, then extracted with ЕУАс. The organic extracts were washed (H ₂ O, brine), dried (Mg§ ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: EJAc, 1: 1 pure EJAc) afforded (E) -isopropyl-3- (3-bromophenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenamide.

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

Aryl bromide AB3 was obtained in accordance with the method described for aryl bromide AB2, but using ammonium hydroxide instead of isopropylamine as the starting material.

Aryl bromide AB4.

(E) -№ (tert-butyl) -3- (3-bromophenyl) -2- [4 (methylsulfonyl) phenyl] -2-propenamide.

Aryl bromide AB4 was obtained in accordance with the method described for aryl bromide AB2, but using tert-butylamine as the starting material instead of isopropylamine.

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

Aryl bromide AB5 was prepared as follows. Stage 1 (Scheme 3, Oxadiazole 0X1). (3-Methyl-1,2,4-oxadiazol-5-yl) [4- (methylsulfonyl) phenyl] methane.

To a solution of 4- (methylsulfonyl) phenylacetic acid (15 g, 70 mmol) in DMF (300 ml) was added carbonyldiimidazole (12.5 g, 77 mmol) at room temperature. After 0.5 hours at room temperature, acetamide oxime (5.7 g, 77 mmol) was added. After stirring the resulting mixture overnight at room temperature, the mixture was heated to 120 ° C. for 6 hours. After cooling to room temperature, the mixture was quenched with H ₂ O and extracted with EAAc. The organic extracts were washed (H2O, brine), dried (Mg ₄ 0), filtered and concentrated. Purification by flash chromatography (Hech: EJAc, 1: 1) afforded (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 (2.2 g, 11.9 mmol) in toluene (30 ml) was added the product of stage 1 (0X1) (3.0 g, 11.9 mmol) and piperidine (0.4 ml). After refluxing overnight, the mixture was cooled to room temperature. MeOH (30 ml) was added to the resulting suspension. After additional boiling under reflux and cooling to 0 ° C, filtration gave (E) -1 (3-bromophenyl) -2- (3-methyl-1,2,4-oxadiazole-5yl) -2- [4- ( methylsulfonyl) phenyl] ethene as a white solid.

Bromoquinolines that are used to prepare the compounds of this invention can be prepared according to Scheme 5 below.

Scheme 5. Obtaining bromquinolines.

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 prepare XXa compounds. Compound XXB can be prepared by treating XXa with a base such as potassium t-butoxide (1.1 eq.) In a solvent such as THF, followed by adding the resulting mixture to a solution of methyl iodide in a solvent such as THF. Compound XXC can be prepared by treating XXI with a base such as potassium tert-butoxide (1.1 eq.) In a solvent such as THF, followed by adding the resulting mixture to a solution of methyl iodide in a solvent such as THF. Compound XXC (where B ¹ = CH) can also be obtained by treating XXa with a base such as potassium tert-butoxide (2.2 equiv.) And methyl iodide in a solvent such as THF. Compound XXC (where B ¹ = 8O ₂ Me) can also be obtained by treating XXA with a base such as potassium tert-butoxide (1.3 equiv.) And methyl iodide (1.6 equiv.) In a solvent such as THF, and then an additional amount of methyl iodide (1.6 eq.) and an additional amount of the same base (1.0 eq.).

Scheme 5 (table). Bromoquinolines

Bromoquinoline 01. 6- (Methylsulfonyl) methyl-8-bromoquinoline.

Bromoquinoline 01 was prepared as follows. DMF (500 ml) was added to 6-bromomethyl-8-bromoquinoline (60 g, 200 mmol) (described in international patent publication AO 94/22852) and sodium methanesulfinate (27.6 g, 270 mmol). After stirring overnight at room temperature, the mixture was quenched with H2O (2000 ml), stirred for one hour, isolated by filtration and washed with E1 ₂ O to give 6- (methylsulfonyl) methyl-8-bromoquinoline.

Bromoquinoline 02. 6- [1- (Methylsulfonyl) ethyl] -8-bromoquinoline.

Bromoquinoline 02 was prepared as follows. To a solution of bromquinoline 01 (16.1 g, 54 mmol) in THF (500 ml) at -78 ° С, potassium tert-butoxide (59 ml, 1N in THF) was added. After 0.5 h at -78 ° C, the resulting mixture was stirred at 0 ° C for 45 min and then transferred via cannula dropwise into a solution of MeI (16.7 ml, 268.3 mmol) in THF (160 ml). After stirring overnight at room temperature, the mixture was neutralized with saturated NaH ₄ Cl solution and extracted with EuAc. The organic extracts were washed (H ₂ O), (brine), dried (MgO), filtered and concentrated. Stirring in ether, followed by isolation by filtration, gave 6- [1 (methylsulfonyl) ethyl] -8-bromoquinoline.

Bromoquinoline 03. 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8-bromoquinoline. Bromoquinoline 03 was prepared by the following method. Potassium tert-butoxide (55 ml, 1N in THF) was added to a solution of bromquinoline 02 (15.7 g, 50 mmol) in THF (500 ml) at -78 ° С. After stirring 0.5 h at -78 ° C, the resulting mixture was stirred at 0 ° C for 45 min and then transferred dropwise into a solution of MeI (15.6 ml, 250 mmol) in THF (40 ml) at 0 ° C. After stirring overnight at room temperature, the mixture was neutralized with saturated NaH ₄ Cl solution and extracted with EuAc. The organic extracts were washed (H 2 O, brine), dried (Md ₈ O ₄ ), filtered and concentrated. Stirring in ether followed by isolation by filtration gave

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

Bromoquinoline 04. 6-Cyanomethyl-8-bromoquinoline.

Bromoquinoline 04 was prepared as follows. To 6-bromomethyl-8-bromoquinoline (3 g, 10 mmol) (described in international patent publication AO 94/22852) and potassium cyanide (1.6 g, 25 mmol) were added DMF (10 ml) and H ₂ O (5 ml). After heating at 100 ° С for 1 h, the resulting mixture was quenched with Н2О (100 ml) and extracted with Е1ОАс. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (HEX: E1OAc, 3: 1) afforded 6-cyanomethyl-8 bromoquinoline.

Bromoquinoline 05. 6- [1-Methyl-1-cyanoethyl] -8-bromoquinoline.

Bromoquinoline 05 was prepared as follows. To a solution of bromquinoline 04 (3 g, 12.1 mmol) in THF (100 ml) at -78 ° C was added Me1 (1.7 ml, 27 mmol), followed by potassium tert-butoxide (27 ml, 27 mmol). After 2 hours at -78 ° C, the mixture was heated to 0 ° C and neutralized with a saturated solution of ΝΗ ₄ Ο 1, then extracted with Е1ОАс. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (HEX: E1OAc, 3: 1) to give 6- [1-methyl-1-cyanoethyl] -8 bromoquinoline.

Benzyl phosphorus reagents that were used to prepare the compounds of this invention can be prepared according to Scheme 6 below.

Scheme 6. Obtaining benzyl phosphorus reagents.

XX XXI

XXIII (X = Br)

XXIV (Χ = 0302Μθ)

XXV to ¹ to ² “N CH ₂ P (RI) ₃ * Vg '

H CH ₂ P (0) (0E1);

SI CH ₂ P (O) (OE1) ₂

Benz phosph. reaction. (Xxv)

P2

RZ

Arylquinolines of formula XXII can be prepared by the addition of bromoquinoline XX and boronic acid XXI by heating in the presence of a catalyst such as Pb (PPy ₃ ) ₄ and a base such as sodium carbonate (aqueous) in a solvent such as DMF. Alcohol XXII can be converted to bromide XXIII by treating HBr (aq.) In a solvent such as acetic acid. Alcohol XXII can be converted to methyl sulfonate ester XXIV with methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane. Benzyl phosphorus reagents XXV can be prepared either by heating XXIII in the presence of PPY ₃ in a solvent such as acetonitrile, or by heating XXIII or XXIV with diethyl phosphite and a base such as potassium tert-butoxide in a solvent such as THF.

Benzylphosphonium bromide P1. [3- (6-Isopropyl-8-quinolinyl) benzyl] (triphenyl) phosphonium bromide. Benzylphosphonium bromide P1 was obtained in the following manner. Stage 1. 6-Isopropyl8- [3- (hydroxymethyl) phenyl] quinoline. A mixture of 6isopropyl-8-bromoquinoline (11.1 g, 44.4 mmol) (described in international patent application AO 94/22852), 3- (hydroxymethyl) phenylboronic acid (8.70 g, 57.2 mmol), No. ₂ CO ₃ (2M, 71 ml, 142 mmol) and Pb (PP ₃ ) ₄ (2.51 mg, 2.17 mmol) in 280 ml of DME were stirred at 80 ° C for 5 hours. The resulting mixture was cooled to room temperature, diluted with EAAc, washed with brine, dried over No. ₂ 8O ₃ . filtered and concentrated. Flash chromatography (HEX / EJAc, 1/1) and stirring in CH ₂ Cl / hexane (1/9) afforded 6-isopropyl-8- [3- (hydroxymethyl) phenyl] quinoline as a white solid.

Stage 2. 6-Isopropyl-8- [3- (bromomethyl) phenyl] quinoline. A suspension of the hydroxymethyl product of the compound of this stage 1 (7.40 g, 26.7 mmol) in AcOH (50 ml) and HBg (50 ml, 48% water) was stirred for 12 h at 100 ° C. The mixture was cooled to room temperature, poured into No. 1OH (2N) in ice, the pH was adjusted to 8, and the mixture was diluted with ether. The organic phase was washed with brine, dried over MgSO ₄ , filtered and concentrated to yield 6-isopropyl-8- [3 (bromomethyl) phenyl] quinoline as a yellow solid.

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

Triphenylphosphine (3.22 g, 12.3 mmol) was added to a solution of the bromomethyl product of the compound of this stage 2 (3.807 g, 11.1 mmol) in 40 ml of ΟΠ ^ Ν. The mixture was stirred at 60 ° C. for 12 hours, cooled to room temperature, diluted with ether, filtered and washed with ether to give [3 (6-isopropyl-8-quinolinyl) benzyl] (triphenyl) phosphonium bromide.

Benzylphosphonate P2. Diethyl 3- (6-isopropyl-8-quinolinyl) benzylphosphonate. Benzylphosphonate P2 was prepared as follows.

The bromomethyl compound of step 2 above, synthesis of P1 (11.34 g, 1 equiv.) Was dissolved in THF (170 ml). Diethyl phosphite (3.87 ml, 1.05 equiv.) Was added and the solution was cooled to 0 ° C. After this, tert-ViOK (3.87 ml, 1N in THF) was slowly added. The reaction mixture was stirred for 2 hours and quenched by the addition of ΝΗ. · | Ί.Ί (sat.), Water, and YES. The organic phase was separated and washed with brine, dried over MgSO ₄ and concentrated. Purification by flash chromatography on silica gel (hexane: EULS, 1/9) afforded diethyl 3- (6-isopropyl-8-quinolinyl) benzyl phosphonate as a clear oil.

Benzyl phosphonate P3. Diethyl 3- [6- (1-cyano1-methylethyl) -8-quinolinyl] benzylphosphonate.

Benzyl phosphonate P3 was prepared by the following method.

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

In accordance with step 1 of the above process for benzylphosphonium bromide P1, but replacing 6isopropyl-8-bromoquinoline with bromquinoline 05 as the starting material, 6- (1-cyano-1-methylethyl) -8- [3- (hydroxymethyl) phenyl] was obtained quinoline.

Step 2: 3- [6- (1-Cyano1-methylethyl) -8-quinolinyl] benzyl methanesulfonate.

Into a solution of alcohol 6- (1-cyano-1-methylethyl) 8- [3- (hydroxymethyl) phenyl] quinoline of this stage 1 (5.15 g, 17 mmol) in CH ₂ Cl ₂ (150 ml) at -78 ° Εΐ ₃ Ν (3.6 ml, 26 mmol) and methanesulfonyl chloride (MkCl) (1.6 ml, 21 mmol) were added. After 0.5 h at -78 ° C, the mixture was neutralized with a saturated solution of ΝΗ ₄ ί.Ί. diluted with water and extracted with ether. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated to give 3- [6- (1-cyano-1-methylethyl) -8-quinolinyl] benzyl methanesulfonate as a white foam.

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

To a solution of diethyl phosphite (2.5 ml, 18 mmol) in THF (100 ml) at -78 ° С were added potassium tert-butoxide (1M, THF, 16 ml, 16 mmol) and the mesylate compound of methanesulfonate 3- [6 (1- cyano-1-methylethyl) -8-quinolinyl] benzyl from step 2 (5.1 g, 13.5 mmol). After 0.5 h at 78 ° C and 12 h at room temperature, the resulting mixture was neutralized with a saturated solution of ΝΗ ₄ Ο, diluted with water and extracted with ether. The organic extracts were washed (H ₂ O, brine), dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (Nech: JULS, 1: 4 to 1:10) afforded diethyl 3- [6- (1 cyano-1-methylethyl) -8-quinolinyl] benzyl phosphonate as an oil.

Scheme 7. The reaction of addition of benzylphosphoric compounds - ketones.

(Xxv) χχνι

Example (I)

Compounds corresponding to formula I can be obtained using the reaction paths indicated in scheme 7 above. Compound XXVI can be prepared by adding a solution of ketone VII in a solvent such as THF to a mixture of benzylphosphoric reagent XXV and a base such as potassium tert-butoxide in a solvent such as THF. Compounds of formula I can then be prepared by treating XXVI with an oxone in a solvent mixture such as THF / MeOH / water. Alternatively, compounds of formula I can be prepared by reacting a ketone VIII with XXV 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 reaction of addition of ketones and benzyl phosphorus reagents gave the compounds of the examples shown in the table.

Table 1 Benz phosph. reaction. Ketone Example P2 KZ one P2 KZ 2 P1 K5 3 P1 K2 4 P2 K1 5 P2 K1 6 P2 Kb 7 RZ Kb 8 RZ K2 nine P2 Commercially available thirty P2 K7 31 P2 K7 32 P2 K8 33 P2 K8 34 P2 K9 35 RZ K8 36 RZ K8 37 RZ K9 38 RZ K10 39

Scheme 8. The reaction of addition of aryl bromide - bromquinoline.

Aryl Bromide (XVIII) Thieves (using ΐη zKi) Example (I)

According to Scheme 8, compounds corresponding to Formula I can be prepared by converting shyi aryl bromide XVIII to the corresponding boronate ester by heating with pinacol diboronate ester, a catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), and a base such as potassium acetate in a solvent such as DMF, followed by the addition of bromquinoline XX, an additional amount of catalytic

XXVIII (Example (I) of a mash, an additional amount of a base, such as sodium carbonate (aqueous) and with an additional heating time.

According to scheme 8 presented above, table 2 and table. 2 (Appendix) below, the addition reaction of an aryl bromide with bromoquinoline afforded the compounds of the examples presented in table form.

The compounds of this invention can be obtained in accordance with scheme 9, below.

Scheme 9

Example

Example

Example

Scheme 9 schematically illustrates the preparation of compounds of formula I, where the aldehyde XXVII can be obtained by heating bromquinoline XX, 3-formylbenzeneboronic acid, a catalyst such as Pb (PPB ₃ ) ₄ and a base such as sodium carbonate (aqueous) in a solvent such as DMF. Aldehyde XXVII can be converted to the compound of Example 18 by heating with XVI in the presence of a base such as piperidine in a solvent such as toluene. The compound of example 19 can be obtained by treating the compound of example 18 with cerium ammonium nitrate (“ΟΑΝ”) in a mixture of solvents such as acetonitrile / water. Alternatively, aldehyde XXVII may be converted to the unsaturated acid XXVIII by heating with XV and a base such as piperidine in a solvent such as toluene. Acid XXVIII can then be converted to amide I (Example 27, 28 and 29) by treatment with a binding system, for example ΕΩΟΕ NEW! and amine, in a solvent such as DMF.

The compounds of this invention can be prepared by the addition of bromoquinoline compounds and boronate compounds in accordance with Scheme 10 below.

Scheme 10. Reaction of addition of bromquinoline - boronate.

Example 2. NMR ¹ N (400 MHz, acetone-b ₆ ) δ

8.78 (q, 1H), 8.25 (q, 1H), 7.89 (d, 2H), 7.71 (d,

1H), 7.6 (m, 3H), 7.45 (m, 3H), 7.39-7.2 (m, 8H),

3.11 (m, 4H); 1.34 (d, 6H).

Example 3. 6-Isopropyl-8- {3 - [(E ^) - 2- [4 (methylsulfonyl) phenyl] -2- (1,3-thiazol-2-yl) vinyl] phenyl} quinoline.

Scheme 10 shows how the compounds of formula I can be prepared by the addition of bromquinoline XX with boronate of ester XII in the presence of a catalyst such as Pb (OAc) ₂ , PP1c and a base such as sodium carbonate (aqueous) in a solvent such as n propanol. Referring to the table. 3, the addition reaction of bromquinoline and borate gave the products of the examples presented in table form.

Table 3 Bromquinoline Borate Example 02 AT 2 10 Oz AT 2 eleven 02 IN 1 12 Oz IN 1 thirteen Oz OT 40 Oz OT 41 Oz AT 4 42

Examples 1 and 2. 6-Isopropyl-8- (3 - {(2 / E) -2 [4- (methylsulfonyl) phenyl] -2-phenylethenyl} phenyl) quinoline.

Example 1

Example 2

The products of examples 1 and 2 were obtained in accordance with the following method. To a mixture of benzyl phosphonate P2 (330 mg, 0.83 mmol) and K3 ketone (200 mg, 0.77 mmol) in THF (6 ml), potassium tert-butoxide (1M, THF, 0.83 ml, 0) was added at room temperature. 83 mmol). After 1 h at room temperature, the mixture was diluted with water and extracted with EO. the organic extracts were washed (H ₂ O), (brine), dried (Md ₈ O ₄ ), filtered and concentrated. Purification by flash chromatography (Hech: EJAc, 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 Ζ-isomer, and the product of example 2 was the more polar E-isomer.

Example 1. NMR 'N (400 MHz, acetone-b ₆ ) δ

8.79 (q, 1H), 8.28 (q, 1H), 7.94 (d, 2H), 7.73 (d, 1H), 7.6-7.1 (m, 14H) 3.14 (m, 1H), 2.97 (s, 3H),

1.34 (d, 6H).

The product of example 3 was obtained in accordance with the following method. To a suspension of benzylphosphonium bromide P1 (320 mg, 0.531 mmol) in 2.5 ml of THF at -78 ° C, tert-ViOK (1.0 M in THF, 0.55 ml, 0.55 mmol) was added dropwise and the resulting solution of red the colors were mixed for 30 min at 0 ° C. To this obtained product at -78 ° C, K5 ketone (122 mg, 0.455 mmol) in 2 ml of THF was then added dropwise. The mixture was warmed at room temperature, then stirred for 1 h, quenched with HH ₄ Cl (saturated) and diluted with EuAc. The organic phase was washed with brine, dried On ₂ 8O ₄ , filtered and concentrated. Flash chromatography (cartridge silica gel, HEX / ENAc from 10 to 100% in 20 min) gave the product of example 3 (isomer mixture 1.5 to 1).

NMR Ή (500 MHz, acetone-b ₆ ) δ 8.79-8.78 (m, 1H), 8.26-8.23 (m, 1H), 8.01-7.92 (m, 3H) 7.84 (d, 0.4H, minor), 7.78 (d, 0.6H, basic), 7.73-7.47 (m, 10H), 7.43 (dd, 1H), 7 34 (t, 0.6H, main), 7.27 (t, 0.4H, secondary), 7.18 (d, 0.6H, main), 7.09 (d, 0.4H, secondary) 3.12 (m, 1H); 3.11 (s, 1.8H, basic); 2.99 (s, 1.2H; minor); 1.36-1.33 (m, 6H).

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

The product of example 4 was obtained in the following manner.

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

6-Isopropyl-8- (3 - {(E) -2- (1-methyl-1Nimidazol-2-yl) -2- [4- (methylthio) phenyl] vinyl} phenyl) quinoline was prepared according to the production method example 3, replacing as a starting product K5 to K2.

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

The product of example 4 was obtained in accordance with the method of obtaining borate B1 (stage 2 of scheme 2), but replacing (исходного / Ζ) -2- (3-bromophenyl) -1- (1-methyl-1-nimidazol-2-yl as the starting product ) -1- [4- (methylthio) phenyl] ethylene to the sulfide obtained in this step 1.

¹ H NMR (500 MHz, acetone-6 ₆ ) δ 8.77 (dd, 1H), 8.24 (dd, 1H), 7.88 (d, 2H), 7.71 (d, 1H), 7 59 (d, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.41 (dd, 1H),

7.28 (t, 1H), 7.23 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 3.51 (s , 3H), 3.10 (m, 1H),

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

M8: (t + 2): 509.4.

Examples 5 and 6. 6-Isopropyl-8- (3 - {^ / E) -2 (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] vinyl} phenyl) quinoline.

Example 5

Example 6

Examples 5 and 6 were obtained in the following manner.

The products of examples 5 and 6 were obtained in accordance with the method of obtaining example 1, but replacing K3 ketone with K1 as the starting product, and using flash chromatography (50% EJAc / 50% hexane).

¹ H NMR (500 MHz, acetone-6 ₆ ) Example 5: main (Ζ) isomer: δ 8.78 (dd, 1H), 8.25 (dd, 1H), 7.93 (d, 2H), 7 72 (d, 1H), 7.55-7.40 (m, 6H),

7.35 (m, 2H), 7.25 (t, 1H), 7.23 (s, 1H), 7.11 (t, 2H), 7.05 (d, 1H), 3.12 (m , 1H), 2.96 (s, 3H), 1.34 (D, 6H). _one

¹ H NMR (500 MHz, acetone-6 ₆ ) Example 6: minor (E) isomer: δ 8.78 (dd, 1H), 8.35 (dd, 1H), 7.93 (d, 2H), 7 72 (d, 1H), 7.65-7.55 (m, 3H), 7.45 (dd, 1H), 7.35-7.15 (m, 9H), 3.12 (m, 4H) ), 1.34 (d, 6H).

Example 7. 2- (2 - {(E ^) - 2- [3- (6-Isopropyl-8-quinolinyl) phenyl] -1- [4- (methylsulfonyl) phenyl] vinyl} -1,3-thiazole-5- il) -2-propanol.

The product of example 7 was obtained in accordance with the method of example 1, but replacing the ketone K3 with K6 as the starting product. Purification by flash chromatography (100% ENAc) afforded the product of Example 7 as a mixture of isomers.

¹ H NMR (400 MHz, acetone-6 ₆ ) δ 8.80 (m, 1H), 8.30 (m, 1H), 8.05 (d (basic), 1.44 N), 7.93 (d (minor), 0.55H), 7.85 (s (primary), 0.72H), 7.77 (s (secondary), 0.28H), 7.75-7.45 (m, 7H) 7 , 35 (t (secondary), 0.28H), 7.28 (t (primary), 0.72H), 7.21 (d (secondary), 0.28H), 7.10 (d (primary),

0.72H), 4.7 (m, 1H), 3.15 (m, 1H), 3.15 (s (minor), 0.84), 2.99 (q (main), 2.16H) 1.60 (m, 6H); 1.35 (m, 6H).

M8 (t + 1): 569.6.

Example 8. 2- [8- (3 - {(E ^) - 2- [5- (1-hydroxy1-methylethyl) -1,3-thiazol-2-yl] -2- [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6-quino linyl] -2methylpropanenitrile.

The product of example 8 was obtained in accordance with the method of obtaining example 1, but replacing ketone K3 with K6 and benzyl phosphonate P2 with P3 as the starting product. Purification by flash chromatography (20% CH ₂ Cl ₂ /80% ENAc) gave the product of Example 8 as a mixture of isomers.

¹ H NMR (400 MHz, acetone-6 ₆ ) δ 8.92 (m, 1H), 8.45 (m, 1H), 8.10 (m, 1H), 8.05 (t, 1H), 7 93 (m, 1H), 7.85 (m, 2H), 7.77-7.55 (m, XN), 7.40 (t (minor), 0.43H), 7.28 (t, (main), 0.57H), 7.21 (b (minor), 0.43H), 7.10 (6 (main), 0.57H), 4.67 (s, (main), 0.57H ), 4.63 (s (minor), 0.43H), 3.15 (s (secondary), 1.3H), 2.99 (s (main), 1.7H),

1.90 (m, 6H), 1.65 (s, (main), 3.4H), 1.45 (s (minor), 2.6H).

M8 (t + 1): 594.6.

Example 9. 2-Methyl-2- [8- (3 - {(E) -2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6-quinolinyl] propannitrile.

Example 9 was obtained by the following method.

Stage 1. 2-Methyl-2- [8- (3 - {(E) -2- (1-methyl1H-imidazol-2-yl) -2- [4- (methylthio) phenyl] vinyl} phenyl) -6 -quinolinyl] propannitrile was obtained in accordance with the production method of Example 1, but replacing K3 ketone with K2 and benzyl phosphonate P2 with P3 as starting materials.

Stage 2. 2-Methyl-2- [8- (3 - {(E) -2- (1-methyl1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6 -quinolinyl] propannitrile, the product of example 9, was obtained in accordance with the method that was used to obtain boronate B1 (stage 2 of scheme 2), but replacing (Ε / Ζ) -2- (3bromophenyl) -1- (1 methyl-1H-imidazol-2-yl) -1- [4 (methylthio) phenyl] ethylene on the sulfide obtained in the above step 1. The product of Example 9 was obtained after purification by flash chromatography (97% ЕУАс Εί ₃ Ν / 3%).

NMR 'H (400 MHz, acetone-b ₆ ) δ 8.92 (dd, 1H), 8.45 (dd, 1H), 8.10 (d, 1H), 7.93 (d, 2H), 7 76 (d, 1H), 7.60-7.50 (m, 5H), 7.38 (t, 1H), 7.35 (s, 1H), 7.19 (m, 1H), 7, 10 (m, 1H), 6.95 (m, 1H), 3.55 (s, 3H), 3.00 (s, 3H), 1.85 (s, 6H).

M8 (t + 1): 533.3.

Example 10. 6- [1- (Methylsulfonyl) ethyl] -8 {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (1,3thiazol-2-yl) vinyl] phenyl} quinoline .

O ^^ SN

The product of example 10 was obtained in accordance with the following method. A mixture of bromquinoline 02 (105 mg, 0.33 mmol), B2 boronate (236 mg, 0.51 mmol), NbCO ₃ , (2M, 0.65 ml, 1.3 mmol), RB (YuAc) ₃ ( 6.3 mg, 0.028 mmol) and PPy ₃ (28 mg, 0.11 mmol) in 4 ml of n-propanol were stirred at 90 ° C for 2 hours. The mixture was cooled at room temperature, diluted with EuAc, washed with brine, dried over No. ₂ 8O ₄ , filtered and concentrated. Flash chromatography (toluene / acetone; 4/1) and stirring in hexane / EJAc gave the product of Example 10 (single isomer) as a white solid.

NMR 'H (400 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7 94 (s, 1H), 7.86 (d, 1H), 7.71-7.68 (m, 3H) 7.62-7.60 (m, 2H), 7.55 (dd, 1H) 7.45 (s, 1H) 7.34 (t, 1H),

7.18 (d, 1H), 4.67 (q, 1H), 3.04 (s, 3H), 2.86 (s, 3H) 1.88 (s, 3H).

M8 (M + 1) 576.

Example 11. 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8- {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (1,3-thiazole-2- il) vinyl] phenyl} quinoline.

o ° ^ cn ₃ ..% cn ₃ GuM X BUT kA, p V O / N ₃ C

Example 11 was obtained in accordance with the method described in example 10, but replacing bromquinoline 02 with 03 and using boronate B2. Flash chromatography (toluene / acetone; 9/1) and stirring in EJAc / Hex gave the product of Example 11 (single isomer) as a white solid.

NMR 'H (400 MHz, acetone-b ₆ ) δ 8.90 (dd, 1H), 8.41 (dd, 1H), 8.23 (s, 1H), 8.02-7.99 (d, 3H)

7.95 (s, 1H), 7.86 (d, 1H), 7.70 (d, 2H), 7.60-7.54 (m, 4H), 7.32 (t, 1H), 7 13 (d, 1H), 3.00 (s, 3H),

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

M8 (M + 1) 523.

Example 12. 8- (3 - {^) - 2- (1-methyl-1H-imidazol-2-yl) -2- [4- (methyl-sulfonyl) phenyl] vinyl} phenyl) -6- [1- (methylsulfonyl) ethyl] quinoline.

o ° ^ cn ₃

Example 12 was obtained in accordance with the method described in example 10 using bromquinoline 02, but replacing boronate B2 n B1. Flash chromatography (95% CH ₂ Cl ₂ /5% EUN) gave the compound of example 12.

NMR 'H (400 MHz, acetone-b ₆ ) δ 8.92 (dd, 1H), 8.45 (dd, 1H) 8.10 (s, 1H), 7.93 (d, 2H), 7, 76-

7.65 (m, 4H), 7.59 (dd, 1H), 7.39 (t, 1H), 7.26 (s, 1H), 7.18 (s, 1H), 7.05 (m, 2H), 4.7 (q, 1H), 3.40 (s, 3H), 3.13 (s, 3H), 2.93 (s, 3H), 1.87 (d 3H).

M8 (M + 1): 572.4.

Example 13. 8- (3 - {^) - 2- (1-Methyl-1H-imidazol-2-yl) -2- [4- (methylsulfonyl) phenyl] vinyl} phenyl) -6- [1-methyl- 1 - (methylsulfonyl) ethyl] quinoline.

O ° ^ cn ₃

Example 13 was obtained in accordance with the method described in example 10, but replacing bromquinoline 02 with 03 and replacing boronate B2 with B1. Flash chromatography (95% EUAc / 5% E! ₃ S) gave the product of Example 13 (single isomer) as a foam.

¹ H NMR (400 MHz, acetone-b ₆ ) δ 8.92 (dd, 1H), 8.45 (dd, 1H), 8.37 (d, 1H), 8.05 (d, 1H), 7 93 (d, 2H), 7.76 (d, 1H), 7.69 (d, 2H), 7.65 (d, 1H), 7.59 (dd, 1H), 7.38 (t, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.05 (m, 2H), 3.40 (s, 3H), 3.13 (s, 3H), 2, 70 (s, 3H); 1.95 (s, 6H).

M8 (M + 1): 586.2.

Examples 14 and 15. 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8- (3 - {(E / 2) -2- (3-methyl-1,2,4oxadiazol-5-yl) - 2- [4- (methylsulfonyl) phenyl] vinyl} phenyl) quinoline.

Example 14

Example 15

Examples 14 and 15 were obtained in accordance with the following method. Solution of aryl AB5 bromide (249 mg, 0.57 mmol), pinacol diborone ester (167 mg, 0.66 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (12 mg, 0.015 mmol ) and potassium acetate (17–6 mg, 1.8 mmol) in DMF (S, Udimethylformamide) (10 ml) were degassed and stirred at 80 ° С for 3 h. Bromoquinoline 03 was then added to the mixture thus obtained at 25 ° С 03 (150 mg, 0.46 mmol), [1,1'bis (diphenylphosphino) ferrocene] dichloropalladium (P) (12 mg, 0.015 mmol) and sodium carbonate (0.6 ml, 2 M). After degassing, the mixture was heated at 80 ° C. overnight. The mixture was then cooled to room temperature, quenched with H ₂ O and extracted with EAAc. The organic extracts were washed (H ₂ O, brine), dried (Md ₈ O ₄ ), filtered and concentrated. Purification by flash chromatography (hexane: EHAc: E! ₃ S, 22: 68: 10, then hexane: E!: OAc, 3: 1) gave both isomers (Example 14 and Example 15).

¹ H NMR (500 MHz, acetone-b ₆ ) main (E) isomer (Example 14): δ 8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 8.00 (d, 2H), 7.70 (m, 3H), 7.64 (s, 1H), 7.55 (dd , 1H),

7.38 (t, 1H), 7.23 (d, 1H), 3.03 (s, 3H), 2.69 (s, 3H), 2.33 (s, 3H), 1.96 (s , 6H).

M8 (M + 1): 588.2.

Minor ^) isomer (Example 15): δ

8.92 (dd, 1H), 8.45 (dd, 1H), 8.29 (d, 1H), 8.07 (d, 1H), 7.99 (d, 2H), 7.88 (s , 1H), 7.75 (m, 3H), 7.62 (s, 1H), 7.58 (q, 1H), 7.48 (t, 1H), 7.24 (d, 1H)

3.16 (s, 3H), 2.70 (s, 3H), 2.38 (s, 3H), 2.00 (s, 6H).

M8 (M + 1): 588.2.

Alternatively, the product of example 14 can be obtained in accordance with the following method.

νο ₂

Stage 1. Scrap reaction (8kgair)

Sodium m-nitrobesolsulfonate (0.6-0.8 equivalents), and then iron sulfate heptahydrate (0.01-0.05 equivalents) were added to methanesulfonic acid (8-10 equiv.) At 20 ° C. To the resulting mixture was added 2-bromo-4-methylaniline (1 equiv.).

Glycerin (2-3 equiv.) Was added and the resulting solution was heated at 120-140 ° C and left until the reaction was complete.

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

Stage 2. Bromination.

The MTBE solution from step 1 was dissolved by switching to chlorobenzene. After filtration through silica gel and partial concentration, L-bromosuccinimide (LB8, 0.6-0.8 equivalents) and 2,2'-azobisisobutyl nitrile (ASHY, 0.01-0.1 equivalents) were added.

The degassed mixture was heated at 5585 ° C. The resulting mixture was dissolved in cyclohexane. An additional amount of YB8 (0.3-0.5 equiv.) And ASHY (0.01-0.05 equiv.) Were added. The degassed mixture was heated to approximately 55-85 ° C until the reaction was complete. The mixture was cooled to 10-40 ° C and diluted with cyclohexane and allowed to settle. The solid was isolated by filtration.

Stage 3. The formation of sulfone.

To a solution of bromomethyl-bromoquinoline (product of the previous step, 1 equiv.) In DMF was added powdered sodium methanesulfinate (1.0-1.5 equiv.) At 10-60 ° C. The mixture was heated at approximately 50-70 ° C for 30 minutes. The mixture was diluted with water, maintaining the temperature at about 50-70 ° C, with vigorous stirring, then cooled to about 10-20 ° C 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.

A solution of sulfone (the product of the previous step, 1 equiv.) In DMF was cooled to about -10 to 0 ° C. Sodium tert-butoxide (~ 1 equiv.) Was added. A solution of methyl iodide / DMF (~ 1 equiv. McO was slowly added, maintaining the temperature at about -10 to 0 ° C.

A second part of solid sodium tert-butoxide was added (~ 1 equiv.), Followed by a solution of methyl iodide / DMF (~ 1 equiv.), Maintaining the temperature at -5 to 10 ° С (if the reaction does not go completely, you can add an additional amount of base and ms!).

The reaction was quenched by the addition of water, and the isolated product was crystallized and dried.

Stage 5. The reaction of accession 8i2ck1.

Pb / C (5 or 10 wt.%, 0.0050.1 equiv.), Potassium carbonate (2-3 equiv.) And 3 formyl phenylboronic acid (1-2 equiv.) Were added to the sulfone solution from the previous stage (1 equiv.) ) The degassed reaction mixture was heated to 60-120 ° C until completion of the reaction. The mixture was filtered and the filtrate was diluted with water. The product was crystallized, isolated by filtration and dried.

Stage 6. Oxadiazole.

EEC hydrochloride (1-1.5 equiv.) Was added to a mixture of benzotriazole hydroxy hydrate (NOV!) (1-1.5 equivalents), 4-methylsulfonylphenylacetic acid (1 equivalents) in acetonitrile. The suspension was allowed to settle at approximately 2030 ° C for 30 minutes.

Instead of NEW! other N-OH compounds, such as N-hydroxyphthalimide, 2-hydroxypyridine, N-oxide, N-hydroxysuccinimide, can also be used. Instead of EEC hydrochloride (ethyl dimethylaminopropylcarbodiimide hydrochloride), other carbodiimides, such as dicyclohexylcarbodiimide and diisopropylcarbodiimide, can be used.

Acetamide oxime (1-1.5 equiv.) Was added to the suspension. The resulting mixture was then refluxed until completion of the reaction. The resulting solution was concentrated and diluted with ethyl acetate. The resulting mixture was washed with aqueous sodium bicarbonate. The solution was dissolved by changing to 2-propanol, and after cooling, the isolated product was crystallized and dried.

Stage 7. Condensation to obtain the product of example 14.

To a suspension of the aldehyde of step 5 above (1 equiv.) In 2-propanol was added the oxadiazole of step 6 above (11.5 equiv.), And then piperidine (0.2-1.5 equiv.).

Instead of 2-propanol, other solvents may be used, such as, for example, DMF, acetonitrile, 1-propanol, toluene, esters and other alcohols. Piperidine is the main initiator. Other amino bases, especially secondary amines, can be used instead of piperidine. The resulting mixture was refluxed over molecular sieves until the reaction was completed. After cooling, the product was isolated by filtration and dried.

Examples 16 and 17. (E / 2) -3- {3- [6- (1-Cyano1-methylethyl) -8-quinolinyl] phenyl} -Y-isopropyl-2- [4- (methylsulfonyl) phenyl] -2 -propenamide.

Example 16

Example 17

The products of examples 16 and 17 were obtained in accordance with the method described previously for examples 14 and 15, replacing AB5 aryl bromide as AB2 and bromquinoline 03 as 05 starting materials. Examples 16 and 17 were obtained as a 4: 1 mixture.

¹ H NMR (500 MHz, acetone-b ₆ ) main (E) isomer (Example 16): δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.09 (d, 1H), 7.90 (d, 2H), 7.81 (d, 1H), 7.68 (s, 1H), 7.57 (m, 4H), 7.45 (s, 1H), 7.29 ( t, 1H), 7.04 (d, 1H), 6.71 (broad d, 1H), 4.13 (m, 1H) 2.92 (s, 3H), 1.87 (s, 6H) ), 1.12 (d, 6H).

M8 (M + 1): 538.3.

Minor (Ζ) isomer (Example 17): δ

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 (q, 1H),

7.50 (m, 2H), 7.28 (s, 1H), 4.15 (m, 1H) 3.13 (s, 3H), 1.91 (s, 6H), 1.04 (d , 6H).

M8 (M + 1): 538.3.

Example 18. 8- (3 - {(E) -2- {3 - [(4-Methoxyphenoxy) methyl] -1,2,4-oxadiazol-5-yl} -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6- [1methyl-1- (methylsulfonyl) ethyl] quinoline.

o-sn ₃

The product of example 18 was obtained in the following manner.

Stage 1 (Scheme 3). (4-Methoxyphenoxy) acetonitrile.

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

Stage 2 (Scheme 3). Oxime (4-methoxyphenoxy) acetamide.

A mixture of the product of (4-methoxyphenoxy) acetonitrile (5.0 g, 31 mmol) of stage 1, hydroxylamine hydrochloride (4.3 g, 62 mmol) and sodium acetate (5.1 g, 62 mmol) in MeOH (100 ml) was stirred at room temperature for 2 hours. The resulting mixture was filtered through CeCe®, concentrated, stirred in CHCl ₃ for 18 hours and filtered. The resulting solution was concentrated to obtain wax (4-methoxyphenoxy) acetamide oxime.

Stage 3 (Scheme 3, Oxadiazole OX2). 3 - [(4Metoxyphenoxy) methyl] -5- [4- (methylsulfonyl) benzyl] -1,2,4-oxadiazole.

3 - [(4-Methoxyphenoxy) methyl] -5- [4- (methylsulfonyl) benzyl] -1,2,4-oxadiazole was obtained in accordance with the following method shown in scheme 3 for AB5 stage 1 (OX1), but replacing acetamide oxime on the oxime of (4 methoxyphenoxy) acetamide of step 2 described above and heating the reaction mixture at 90 ° C for 6 hours. Purification by flash chromatography (Hex: EJAc, 3: 2 to 1: 4) gave the desired substance as a light brown solid.

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

To bromquinoline 03 (10.1 g, 30.9 mmol), 3formylbenzene boronic acid (5.8 g, 38.7 mmol), tetrakis (triphenylphosphine) palladium (0) (2.1 g, 1.86 mmol) and carbonate sodium (39 ml, 2 M) was added ΌΜΕ (330 ml). After degassing, the mixture was heated at 80 ° C. overnight. After cooling to room temperature, the resulting mixture was quenched with H ₂ O and extracted with EAAc. The organic extracts were washed (H ₂ O, brine), dried (Md ₈ O ₄ ), filtered and concentrated. Stirring in ether and subsequent isolation by filtration afforded 3- {6- [1methyl-1 - (methylsulfonyl) ethyl] -8-quinolinyl} benzaldehyde.

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

A mixture of the product of step 4 (150 mg, 0.42 mmol), oxadiazole OX2 of step 3 described above (175 mg, 0.4-7 mmol) and piperidine (0.1 ml, 1.0 mmol) in toluene (0 , 6 ml) was heated at 120 ° C for 3 hours. The mixture was purified by flash chromatography (Hex: E! OAc, 3: 2 to 1: 4) to give the product of Example 18 as a foam.

NMR 'P (400 MHz, acetone-b ₆ ) δ 8.90 (q, 1H), 8.42 (q, 1H), 8.24 (d, 1H), 8.20 (s, 1H) 8.02 (m, 3H), 7.75-7.66 (m, 4H), 7.55 (q, 1H), 7.39 (t, 1H), 7.25 (d, 1H) 7.00 (d, 2H), 6.87 (d, 2H), 5.17 (s, 2H), 3.73 (s, 3H), 3.03 (s, 3H), 2.80 ( s, 3H),

1.96 (s, 6H).

Example 19. (5 - {(E) -2- (3- {6- [1-Methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -1 [4- (methylsulfonyl) phenyl] ethenyl} - 1,2,4-oxadiazole-3-yl) methanol.

The product of example 19 was obtained in accordance with the following method. To a solution of the compound of Example 18 (250 mg, 0.35 mmol) in acetonitrile: water (4: 1, 8 ml) was added CΑN (330 mg, 0.62 mmol) in two portions at room temperature. After 3 h at room temperature, the mixture was diluted with saturated NaHCO3 solution, diluted with water and extracted with E! OAc. The organic extracts were washed (H ₂ O), (brine), dried (Md ₈ O ₄ ), filtered and concentrated. Purification by flash chromatography (Hex: E! OAc, 3: 7) gave (5 - {(E) -2- (3- {6- [1-methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -1 [4- (methylsulfonyl) phenyl] ethenyl} -1,2,4-oxadiazol-3-yl) methanol as a pale yellow foam.

NMR 'H (400 MHz, acetone-b ₆ ) δ 8.90 (q, 1H), 8.42 (q, 1H), 8.25 (d, 1H), 8.15 (s, 1H) 8.02 (m, 3H), 7.73-7.65 (m, 4H), 7.55 (q, 1H), 7.38 (t, 1H), 7.23 (d, 1H) 4.67 (m, 3H); 3.04 (s, 3H); 2.82 (s, 3H); 1.96 (s, 6H).

Example 20. (E) -Y-Isopropyl-3- (3- {6- [1methyl-1 - (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -2- propenamide.

The product of example 20 was obtained in accordance with the following method described above for examples 14 and 15, but replacing aryl bromide AB5 with AB2, and using bromquinoline 03 as a starting material.

NMR 'H (300 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.41 (dd, 1H), 8.22 (d, 1H), 7.99 (d, 1H), 7 88 (d, 2H), 7.67 (s, 1H), 7.53 (m, 4H), 7.43 (s, 1H),

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

M8 (M + 1): 591.3.

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

The product of example 21 was obtained in accordance with the following method described above for examples 14 and 15, but replacing AB5 aryl bromide with AB1 and bromquinoline 03 with 05 as starting materials.

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.8 (dd, 1H), 8.38 (dd, 1H), 8.04 (d, 2H), 7.88 (d, 2H), 7 66 (d, 1H), 7.55 (m, 4H), 7.36 (t, 1H), 7.29 (s, 1H),

7.18 (d, 1H), 2.93 (s, 3H), 1.88 (s, 6H).

M8 (M-CO ₂ ): 451.4 (negative ion).

Example 22. 2-Methyl-2- [8- (3 - {(E) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6-quinolinyl] propannitrile.

The product of example 22 was obtained in accordance with the following method described above for examples 14 and 15 and using AB5 aryl bromide as starting materials and replacing bromquinoline 03 with 05.

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.90 (dd, 1H), 8.43 (dd, 1H), 8.1 (d, 2H), 8.01 (d, 2H), 7 83 (d, 1H), 7.71 (t, 3H), 7.66 (s, 1H), 7.56 (q, 1H),

7.55 (dd, 1H), 7.38 (t, 1H), 7.22 (d, 1H), 3.03 (s, 3H), 2.33 (s, 3H), 1.87 (s , 6H).

Μδ (M + 1): 535.2.

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

The product of example 23 was obtained in accordance with the following method described above for examples 14 and 15, but replacing aryl bromide AB5 with AB3 and bromquinoline 03 with 05 as starting materials, to give the title compound.

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08 (d, 1H), 7.93 (d, 2H), 7 8 (d, 2H), 7.6 (m, 4H), 7.48 (s, 1H), 7.31 (t, 1H), 7.08 (d, 1H), 6.6 (br. s, 1H), 6.7 (br s, 1H), 2.93 (s, 3H), 1.87 (s, 6H).

Example 24. (E) -Y- (tert-Butyl) -3- {3- [6- (1 cyano -1-methylethyl) -8-quinolinyl] phenyl} -2- [4 (methylsulfonyl) phenyl] -2- propenamide.

^NZS \ _ ^SN s N || 1 | about ιΓΤ CHSh- ^ CHz | G + CH ₃ n ₃ s-% About SNZ

The product of example 24 was obtained in accordance with the following method described above for examples 14 and 15, but replacing AB5 aryl bromide with AB4 and bromquinoline 03 with 05 as starting materials.

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08 (d, 1H), 7.92 (d, 2H), 7 79 (d, 1H), 7.58 (m, 5H), 7.45 (s, 1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.4 (br. s, 1H), 2.93 (s, 3H), 1.87 (s, 6H), 1.36 (s, 9H). Μδ (M + 1) 553.

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

The product of example 25 was obtained in accordance with the following method described above for examples 14 and 15, but replacing aryl bromide AB5 with AB1 and 03 as 5-isopropyl-8-bromoquinoline as starting materials (described in international patent publication XV O 422852).

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.69 (dd, 1H), 8.26 (dd, 1H), 7.85 (s, 1H), 7.83 (d, 2H), 7 68 (s, 1H), 7.51 (d, 2H), 7.49 (m, 2H), 7.36 (dd, 1H), 7.31 (t, 1H), 7.20 (s, 1H), 7.13 (d, 1H), 3.1 (m, 1H),

2.93 (s, 3H); 1.36 (d, 6H).

Μδ (M + 1) 472.

Example 26. 6-Isopropyl-8- (3 - {(E) -2- (3methyl-1,2,4-oxadiazol-5-yl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline .

CH ₃

The product of example 26 was obtained in accordance with the following method described above for examples 14 and 15, but using AB5 aryl bromide as starting materials and replacing 03 with 5-isopropyl-8-bromoquinoline (described in international patent publication νθ 422852).

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.80 (dd, 1H), 8.29 (dd, 1H), 8.12 (s, 1H), 8.03 (d, 2H), 7 76 (s, 1H), 7.73 (m, 3H), 7.59 (s, 1H), 7.53 (d, 1H), 7.47 (q, 1H), 7.36 (t , 1H), 7.22 (d, 1H), 3.1 (m, 1H), 2.93 (s, 3H), 2.33 (s, 3H) 1.36 (d, 6H). Μδ (M + 1) 510.

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

The product of example 27 was obtained in accordance with the following method.

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

A mixture of 3 - {6- [1-methyl-1 - (methylsulfonyl) ethyl] -8-quinolinyl} benzaldehyde of step 4 of Example 18 (2.33 g, 6.60 mmol), 4- (methylsulfonyl) phenylacetic acid (1 , 71 g, 7.98 mmol) and piperidine (0.20 ml, 1.98 mmol) in 10 ml of toluene were refluxed for 2 days. The mixture was cooled to com69 (d, 2H), 7.68 (s, 1H), 7.59-7.53 (m, 4H), 7.43 (s,

1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.94 (br s, 1H),

2.89 (s, 3H), 2.84-2.80 (m, 1H), 2.69 (s, 3H), 1.96 (s, 6H), 0.67-0.63 (m, 2H), 0.49-0.45 (m, 2H).

M8 (M + 1) 589.

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

temperature, diluted with CH ₂ Cl ₂ , subjected to flash chromatography (CH ₂ Cl ₂ / EUAc / AcOH, 50/50/1) and finally mixed with (E _{1 2} O / CH ₂ Cl ₂ ) and isolated to obtain (E) -3 (3- {6- [1-methyl-1 - (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] 2-propenoic acid (single isomer) as a white solid product.

¹ H NMR (400 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7 94 (s, 1H), 7.86 (d, 1H), 7.71-7.68 (m, 3H) 7.62-7.60 (m, 2H), 7.55 (dd, 1H) 7.45 (s, 1H) 7.34 (t, 1H),

7.18 (d, 1H), 4.67 (q, 1H), 3.04 (s, 3H), 2.86 (s, 3H) 1.88 (s, 3H).

M8 (M + 1) 576.

Stage 2. (E) -3- (3- {6- [1-Methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -1- (1 -pyrrolidinyl) -2propen-1-one.

Mixture of (E) -3 - (3- {6- [1-methyl-1- (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -2- [4- (methylsulfonyl) phenyl] -2-propenoic acid (104 mg, 0.19 mmol) of the above Step 1, pyrrolidine (24 μl, 0.29 mmol), ΕΌΓΊ (hydrochloride (1 - (3-dimethylaminopropyl) -3 ethylcarbodiimide) (55 mg, 0.29 mmol) and NOV ! (1-hydroxybenzotriazole hydrate) (34 mg, 0.25 mmol) in 1 ml of DMF was stirred at room temperature for 12 hours. The mixture was diluted with EuAc, washed with. · | ΓΊ (sat.), H ₂ O (3x) , brine, dried over №1 ₂ 8o _4, filtered and concentrated. Stirring in EYuAs / Hex yes alo product of Example 27 as a white solid.

¹ H NMR (400 MHz, acetone-b ₆ ) δ 8.88 (dd, 1H), 8.40 (dd, 1H), 8.22 (d, 1H), 8.98 (d, 1H), 7 88 (d, 2H), 7.67 (d, 2H), 7.60 (d, 1H) 7.55-7.52 (m, 2H) 7.34 (t, 1H), 7.18 ( d, 1H), 7.03 (broad s, ΝΉ) 3.58 (broad s, 2H), 3.44 (broad s, 2H), 3.02 (s, 3H),

2.69 (s, 3H) 1.95 (s, 6H); 1.88 (br s, 4H). M8 (M + 1) 603.

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

The product of example 29 was obtained as a white solid, following the procedure of step 2 of example 27, but replacing pyrrolidine with tert-butylamine.

NMR 'H (400 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7 90 (d, 2H), 7.59-7.53 (m, 5H), 7.43 (s, 1H), 7.30 (t, 1H), 7.05 (d, 1H), 6, 43 (br s, 1H), 2.94 (s, 3H),

2.69 (s, 3H), 1.96 (s, 6H), 1.36 (s, 9H).

M8 (M + 1) 606.

Example 30. 8- {3- [2,2-bis (4-Chlorophenyl) vinyl] phenyl} -6-isopropylquinoline.

The product of example 30 was obtained in accordance with the following method. To a mixture of benzylphosphonate P2 (100 mg, 0.25 mmol), 4,4'-dichlorobenzophenone (63 mg, 0.25 mmol), in THF (2 ml) at room temperature was added potassium tert-butoxide (1M, THF, 0, 35 ml, 0.35 mmol). After 1 h at room temperature, the mixture was diluted with water / HH ₄ Cl and extracted with EuAc. The organic extracts were washed (H 2 O), (brine), dried (Md ₈ O ₄ ), filtered and concentrated. Purification by flash chromatography (Hech: EJAc, 8: 2) gave the product of Example 30 as a foam.

NMR ¹ H (300 MHz, acetone-b ₆ ) δ 8.79 (dd,

1H), 8.28 (dd, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.487.25 (m, 12H), 7.20-7.16 (m, 2H) ), 3.13 (hept., 1H),

1.36 (d, 6H).

Examples 31 and 32. 6-Isopropyl-8- (3 {(E / 2) -2- (6-methyl-3-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline.

The product of example 28 was obtained in accordance with the following method described for stage 2 of example 27, but replacing pyrrolidine with cyclopropylamine, thereby obtaining a solid product.

¹ H NMR (400 MHz, acetone-b ₆ ) δ 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7 , 87

EXAMPLE 31

EXAMPLE 32

The products of examples 31 and 32 were obtained in accordance with the following method described for example 30, but replacing 4,4'-dichlorobenzophenone with K7 and using benzyl phosphonate P2 as starting materials.

NMR 'H (300 MHz, acetone-b ₆ ) (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, 3H), 7.10 (d, 1H) ), 3.15 (hept., 1H), 2.98 (s, 3H), 1.34 (d, 6H).

(Ζ) isomer (Example 32): δ 8.79 (dd, 1H),

8.35 (d, 1H), 8.28 (dd, 1H), 7.92 (d, 2H), 7.74 (d, 1H), 7.67-7.30 (m, 10H), 7 19 (d, 1H), 3.13 (s, 3H),

3.11 (hept., 1H); 1.35 (d, 6H).

Examples 33 and 34. 6-Isopropyl-8- (3 {(E ^) - 2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline.

EXAMPLE 33 benzylphosphonate P2 as starting materials.

NMR 'H (300 MHz, acetone-b ₆ ) (E) isomer (Example 33): δ 8.80 (dd, 1H), 8.48 (s, 1H), 8.28 (dd, 1H), 7 99-7.96 (m, 3H), 7.97 (m, 1H), 7.74 (d, 1H), 7.61-7.44 (m, 6H), 7.27 (t, 1H) ), 7.07 (d, 1H),

6.97 (d, 1H), 3.15 (hept., 1H), 2.96 (s, 3H), 1.36 (d, 6H).

NMR 'H (300 MHz, acetone-b ₆ ) (Ζ) isomer (Example 34): δ 8.79 (dd, 1H), 8.52 (s, 1H), 8.29 (dd, 1H), 7 89 (d, 2H), 7.75 (d, 1H), 7.65-7.54 (m, 4H), 7.47 (dd, 1H), 7.42-7.23, (m, 5H), 7.11 (d, 1H), 3.12 (s, 3H), 3.12 (hept., 1H), 1.36 (d, 6H).

Example 35. 8- (3- {2,2-bis [4- (Methylsulfonyl) phenyl] vinyl} phenyl) -6-isopropylquinoline.

The product of example 35 was obtained in accordance with the following method described for example 30, but replacing 4,4'-dichlorobenzophenone with K9 ketone and using benzylphosphonate P2 as starting materials.

NMR 'H (500 MHz, acetone-b ₆ ) δ 8.80 (dd, 1H), 8.29 (dd, 1H), 7.98 (d, 2H), 7.93 (d, 2H), 7 75 (d, 1H), 7.61 (d, 2H), 7.59-7.56 (m, 3H), 7.50 (d, 1H), 7.48-7.44 (m, 3H ) 7.30 (t, 1H), 7.12 (d, 1H),

3.14 (hept., 1H), 3.13 (s, 3H), 2.97 (s, 3H), 1.35 (d, 6H).

Examples 36 and 37. 2-Methyl-2- [8- (3 - {(E ^) 2- (5-methyl-2-pyridinyl) -2- [4- (methylsulfonyl) phenyl] ethenyl} phenyl) -6 -quinolinyl] about pannitrile.

EXAMPLE 36

EXAMPLE 34

The products of examples 33 and 34 were obtained in accordance with the following method described for example 30, but replacing 4,4 ′ dichlorobenzophenone with K8 ketone and using

EXAMPLE 37

The products of examples 36 and 37 were obtained in accordance with the following method described for example 30, but as starting materials, replacing 4,4'-dichlorobenzophenone with K8 ketone and replacing P2 benzylphosphonate with P3.

NMR 'H (400 MHz, acetone-b ₆ ) (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, 1H), 7.06 (d, 1H), 6 96 (d, 1H), 2.96 (s, 3H), 2.33 (s, 3H), 1.88 (s, 6H).

NMR 'H (400 MHz, acetone-b ₆ ) (Ζ) isomer (Example 37): δ 8.89 (dd, 1H), 8.51 (s, 1H), 8.45 (dd, 1H), 8 09 (d, 1H), 7.89 (d, 2H), 7.72 (d, 1H), 7.62-7.56 (m, 5H), 7.43-7.42 (m, 2H) ) 7.30 (t, 1H),

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

Example 38. 2- [8- (3- {2,2-bis- [4- (Methylsulfonyl) phenyl] vinyl} phenyl) -6-quinolinyl] 2-methylpropannitrile.

The product of example 38 was obtained in accordance with the following method described for example 30, but as starting materials, replacing 4,4'-dichlorobenzophenone with ketone K9 and replacing benzylphosphonate P2 with P3.

¹ H NMR (500 MHz, acetone-b ₆ ) δ 8.90 (dd, 1H), 8.44 (dd, 1H), 8.09 (d, 1H), 7.97 (d, 2H), 7 92 (d, 2H), 7.81 (d, 1H), 7.61 (d, 2H) 7.58-7.55 (m, 3H), 7.53 (s, 1H), 7.44 (s, 1H), 7.32 (t, 1H), 7.13 (d, 1H), 6.96 (d, 1H), 3.13 (s, 3H), 2.97 (s, 3H) ,

1.86 (s, 6H).

Example 39. 2-Methyl-2- (8- {3 - [(E) -2- [4- (methylsulfonyl) phenyl] -2- (2-pyridinyl) ethenyl] phenyl} -6-quinolinyl) propannitrile.

The product of example 39 was obtained in accordance with the following method described for example 30, but as starting materials, replacing 4,4'-dichlorobenzophenone with ketone K10 and replacing benzylphosphonate P2 with P3.

NMR 'H (300 MHz, acetone-b ₆ ) δ 8.90 (dd, 1H), 8.45 (dd, 1H), 8.11-8.09 (m, 2H), 7.84-7, 80 (m, 3H), 7.72-7.69 (m, 1H), 7.63-7.52 (m, 5H), 7.43-

7.38 (m, 2H), 7.33 (t, 1H), 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, 3H), 1.86 (s) , 6H).

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

EXAMPLE 40

about

EXAMPLE 41

The products of examples 41 and 42 were obtained in accordance with the following method described for example 10, but replacing bromquinoline 02 with 03 and replacing boronate B2 with boronate B3.

NMR 'H (400 MHz, acetone-b ₆ ) (E) isomer (Example 40): δ 8.91 (dd, 1H), 8.45 (s, 1H), 8.41 (dd, 1H), 8 23 (d, 1H), 8.01-8.00 (m, 2H), 7.95 (d, 2H), 7.57-7.54 (m, 4H), 7.51 (d, 1H) ) 7.49 (s, 1H),

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

NMR 'H (400 MHz, acetone-b ₆ ) (Ζ) 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, 3H), 2.68 (s, 3H) ), 2.33 (s, 3H), 1.96 (s, 6H).

Example 42. 2- (6 - {(E) -2- (3- {6- [1-Methyl-1 (methylsulfonyl) ethyl] -8-quinolinyl} phenyl) -1 [4- (methylsulfonyl) phenyl] ethenyl } -3-pyridinyl) -2-propanol.

The product of example 42 was obtained in accordance with the following method described for example 10, but replacing bromquinoline 02 with 03 and replacing boronate B2 with boronate B4.

¹ H NMR (500 MHz, acetone-b ₆ ) δ 8.91 (dd, 1H), 8.80 (d, 1H), 8.42 (dd, 1H), 8.23 (d, 1H), 8.038 01 (m, 2H), 7.96 (d, 1H), 7.82 (dd, 1H), 7.58-7.54 (m, 4H), 7.51 (s, 1H), 7, 29 (t, 1H), 7.08 (d, 1H),

7.01 (d, 1H), 4.31 (s, 1H), 2.96 (s, 3H), 2.70 (s,

3H), 1.96 (s, 6H), 1.56 (s, 6H).

Example 43

The product of example 43 was obtained in accordance with the following method described above for examples 14 and 15, but as starting materials, replacing aryl bromide AB5 with AB6 and bromquinoline 03 with 05.

The following are additional examples.

^ζ

'0'

one hundred

101

102

Salts of Examples

As discussed above, pharmaceutically acceptable salts are often desirable. Examples of such salts are given below: General Method for the Preparation of Salts

Salts of the compounds of this invention, which are basic, can be prepared in several ways.

a) The compound is dissolved in a suitable solvent, such as ethyl acetate. A suitable acid, such as hydrochloric acid, is then added in an acceptable solvent, such as 1,4-dioxane. Received

103

104 suspensions of salt are allowed to settle and then the salt is separated by filtration.

B) The compound and an acceptable acid, such as benzenesulfonic acid, are dissolved in an acceptable solvent, such as isopropyl acetate or in a mixture of solvents, such as isopropyl acetate and methanol. The salt can then be separated by concentration or by changing the solvent, which leads to precipitation, and then by filtration. A more stable crystalline form can be obtained by balancing the resulting suspension of salt by heating and settling before filtration. Crystals of the preceding fraction can also be added to balance the suspension of salt, to initiate the process of crystallization and balancing.

Sulfuric acid salt of the compound of example

14.

The sulfuric acid salt of the compound of Example 14 was obtained by dissolving the compound (1.00 equiv.) Under reflux with ethyl acetate. After cooling to room temperature, sulfuric acid (1.04 equiv.) Was slowly added with stirring. The resulting 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 the compound of example 14.

NMR 'H (500 MHz, acetone-b ₆ ) δ 9.45 (d, 1H), 9.23 (d, 1H), 8.65 (d, 1H), 8.25 (d, 1H), 8 16 (dd, 1H), 8.10 (s, 1H), 7.99 (d, 2H), 7.80 (d, 2H),

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

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 equiv.) Under reflux in ethyl acetate. After cooling to room temperature, methanesulfonic acid (1.1 eq.) Was slowly added with stirring. The resulting suspension was stirred, allowed to concentrate by evaporation, and the solid product was separated by filtration and washed with ether to give the methanesulfonic acid salt of the compound of Example 14.

NMR 'H (500 MHz, acetone-b ₆ ) δ 9.45 (d, 1H), 9.32 (d, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 8 22 (t, 1H), 8.11 (s, 1H), 7.99 (d, 2H), 7.78 (d, 2H),

7.61 (d, 1H), 7.49 (m, 2H), 7.35 (d, 1H), 3.09 (s, 3H), 2.78 (s, 3H), 2.33 (s, 3H) ), 2.01 (s, 6H).

The p-toluenesulfonic acid salt of the compound of Example 14.

The p-toluenesulfonic acid salt of the compound of Example 14 was prepared by dissolving the compound (1.0 eq.) Under reflux in ethyl acetate. After cooling to room temperature, p-toluenesulfonic acid (1.1 equiv.) In ethyl acetate was slowly added. The solvent was concentrated and the suspension was left with stirring and periodically performing sonication at room temperature for 3 days. The solid product was then separated by filtration and washed with ethyl acetate to obtain the p-toluenesulfonic acid salt of the compound of Example 14.

Mp 184-185 ° C.

NMR 'H (500 MHz, acetone-b ₆ ) δ 9.58 (d, 1H), 9.22 (d, 1H), 8.63 (s, 1H), 8.23 (d, 1H), 8 16 (m, 1H), 8.03 (s, 1H), 7.94 (d, 2H), 7.73 (d, 2H),

7.55 (m, 3H), 7.45 (s, 1H), 7.40 (t, 1H), 7.27 (d, 1H), 7.12 (d, 2H), 3.07 (s , 3H), 2.75 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.01 (s, 6H).

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

The 2-naphthalenesulfonic acid salt of the compound of Example 14 was prepared by dissolving the compound (1.0 eq.) Under reflux with ethyl acetate. After cooling to room temperature, 2-naphthalenesulfonic acid (1.1 equiv.) In ethyl acetate was slowly added to ethyl acetate, followed by ethanol. Then, toluene was added to the solution, and then concentrated. Further toluene was added and the suspension was left stirring and sonication was periodically performed at room temperature for 24 hours. The solid was then filtered off and washed with toluene to give the 2-naphthalenesulfonic acid salt of the compound of Example 14.

Mp 202-204 ° C.

NMR 'H (500 MHz, Acetone-be) δ 9.64 (d, 1H), 9.30 (d, 1H), 8.67 (d, 1H), 8.25 (d, 1H), 8, 23 (m, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.91 (d, 2H),

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

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

The hydrochloric acid salt of the compound of Example 43.

The hydrochloric acid salt of the compound of Example 43 was obtained by dissolving the compound (1.0 equiv.) In ethyl acetate at the boil under reflux and sonication.

After the solution was cooled to room temperature, HCl in 1,4-dioxane (4M, 1.0 equiv.) Was added with stirring.

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

The benzenesulfonic acid salt of the compound of Example 14.

The benzenesulfonic acid salt of the compound of Example 14 is in two crystals105

106 forms (“Form A” and “Form B”). Forms are obtained in the following ways:

Salt production

Form A

In suspension of the compound of Example 14 (1 eq.) In ethyl acetate, benzenesulfonic acid (1-1.2 eq.) Was added. Instead of ethyl acetate, other esters can be used. Methanol was added and the resulting mixture was heated to dissolve the solid. Instead of methanol, other alcohols, such as ethanol or propanol, can be used.

The resulting solution was filtered and concentrated. During the concentration process, the product crystallized. The resulting mixture was dissolved in ethyl acetate and allowed to stand. The yellow solid was collected by filtration.

HPLC showed that the molar ratio of 6- [1-methyl-1- (methylsulfonyl) ethyl] -8- [3 - [(E) -2 [3-methyl-1,2,4-oxadiazol-5-yl] - 2- [4 (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline and benzenesulfonic acid is 1: 1.

Mp determined using B8C: 193 ° C.

The X-ray powder diffraction spectrogram) of Form A is shown in FIG. 1. Identification peaks are presented in the table below and shown in FIG. 4.

In suspension of the compound of Example 14 (1 equiv.) In a mixture of isopropyl acetate (ί-PrOAc) and methanol (1: 1) benzenesulfonic acid (11.2 equiv.) Was added. Other esters can be used instead of ί-PrOAc, and other alcohols, such as ethanol or propanol, can be used instead of methanol. The mixture was left at 20-50 ° C. until the solid dissolved. The resulting solution was filtered and distilled, maintaining the volume by adding 9: 1 (vol./about.) A mixture of β-PrOAc / methanol. The product crystallized during distillation.

The resulting mixture was left at 20–70 ° С for 2–10 h in order to ensure the complete formation of Form B. The resulting not quite white solid was separated by filtration and dried.

HPLC showed that the molar ratio of 6- [1-methyl-1 - (methylsulfonyl) ethyl] -8- [3 - [(E) -2 [3-methyl-1,2,4-oxadiazol-5-yl] - 2- [4- (methylsulfonyl) phenyl] ethenyl] phenyl] quinoline and benzenesulfonic acid is 1: 1.

Mp determined using B8C: 210 ° C.

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

Other variations or modifications that are apparent 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.

Claims (13)

CLAIM 1. The compound represented by formula (I) 0) or its pharmaceutically acceptable salt, where 81, 82 and 83 are H; Κι represents _-C1-C6 alkilnuyu group optionally substituted by a group -8O2 -SY or C1-C6alkyl; A represents CH; K ₂ is phenyl substituted with halogen or -8O ₂ -C1-C ₆ alkyl; K ₃ represents a di (C1-C ₆ alkyl) amino-C1-C6 alkyl; phenyl, optionally substituted with halogen or -8O2-C1-C6 alkyl; -C (O) OH; carbamoyl, optionally substituted with -C1-C6 alkyl or C3-C6 cycloalkyl; pyrrolidinocarbonyl; or heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl or oxadiazolyl, each of which is optionally substituted with C1-C ₆ alkyl, 107 108 _{hydroxy-C1-C6} alkyl or _C1-C6 alkoksifenoksi C1-C6alkyl; 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ₃ represents a heteroaryl selected from the group consisting of imidazolyl, thiazolyl, pyridyl or oxadiazolyl, each of which is optionally substituted _C1-C6 alkyl, hydroxy _C1-C6 alkyl or C1-C6 alkoxyphenoxy-C1-C6 alkyl. 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein K ₃ is phenyl, optionally substituted with halogen or -8O ₂ -C ₁ -C ₆ alkyl. 4. The compound according to claim 1, selected from the group including 109 110 111 112 113 114 or its pharmaceutically acceptable salt. 5. 6- [1-Methyl-1- (methylsulfonyl) ethyl] -8 (3 - {(E ^) - 2- (3-methyl-1,2,4-oxadiazol-5-yl) -2 [4 - (methylsulfonyl) phenyl] ethenyl} phenyl) quinoline of the formula or its pharmaceutically acceptable salt. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 7. The pharmaceutical composition according to claim 6, further comprising a leukotriene receptor antagonist, a leukotriene biosynthesis inhibitor, an M2 / M3 antagonist, a corticosteroid, an H1 receptor antagonist or a beta 2 adrenoreceptor agonist. 8. The pharmaceutical composition according to claim 6, further comprising a selective COX-2 inhibitor, a statin or NSAID. 9. A method of treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related conditions such as laminitis and horse colic), septic shock , ulcerative colitis, Crohn's disease, myocardial and brain damage associated with blood supply, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, rep iratornogo distress syndrome, adult respiratory distress syndrome in infants, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis , transplant rejection and graft versus host reaction, hypersecretion of gastric juice, sepsis or septic shock caused by bacterial, c bacterial and viral infections, 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 cancer invasion in normal tissues, including the stage of administering a therapeutically effective amount or prophylactically effective amount a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 10. A method of treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related conditions such as laminitis and colic in horses), septic shock , 115 116 ulcerative colitis, Crohn's disease, myocardial and brain damage associated with blood supply, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, respiratory distress syndrome in infants, chronic obstructive pulmonary disease in animals, in animals, in adults diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatism idnogo arthritis, ankylosing spondylitis, transplant rejection and reaction of "graft versus host", hypersecretion of gastric acid, 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 injuries ozga, head contusion, multiple sclerosis, tumor growth and cancer invasion into normal tissues, including the stage of ίη νίνο forming a therapeutically effective amount or a prophylactically effective amount of a compound according to claim 1. 11. The compound of formula () according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as phosphodiesterase inhibitors. 12. The use of the compounds of formula (Ι) according to any one of claims 1 to 5 or its pharmaceutically acceptable salt for use in the manufacture 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 malignant proliferative skin diseases, endotoxic shock (and related conditions such as laminitis and horse colic), septic shock, ulcerative colitis, Crohn's disease, myocardial damage and the brain associated with blood supply, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in infants, chronic obstructive pulmonary disease in animals, insulin diabetes, allergic rhinitis, allergic rhinitis in children, insulin diabetes, allergic rhinitis, allergic rhinitis, obesity, allergic rhinitis, allergic rhinitis, allergic rhinitis, allergic rhinitis vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, rejection graft and graft versus host reactions, hypersecretion of gastric juice, sepsis or septic shock caused by bacterial, fungal and viral infections, 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 contusion, multiple sclerosis, tumor Ta and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount or prophylactically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition inhibiting phosphodiesterase 4, comprising an acceptable amount of the compound of formula (Ι) inhibiting phosphodiesterase 4 according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.