RU2001111034A - 4-aminopyrrolopyrimidines as kinase inhibitors - Google Patents

Claims (45)

1. The compound represented by the following structural formula:

to which ring A is a six-membered aromatic ring or a five- or six-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of a substituted or unsubstituted aliphatic group, halogen, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or not -substituted heteroaralkyl, cyano, nitro, -NR ₄ R _5, -C (C) ₂ C, -OH, substituted or unsubstituted alkoxycarbonyl, -C (O) ₂ -haloalkyl, a substituted or unsubstituted alkyl thioesters, substituted or unsubstituted alkilsulfoksida, substituted or unsubstituted alkyl sulfone, substituted or unsubstituted arylthioether, substituted or unsubstituted aryl sulfoxide, substituted or unsubstituted arylsulfone, substituted or unsubstituted alkylcarbonyl, -C (O) -haloalkyl, substituted or unsubstituted aliphatic ester, substituted or not ameschennogo aromatic ester, substituted or unsubstituted carboxamido, tetrazolyl, triftormetilsulfonamido, triftormetilkarbonilamino, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamido or alkylcarboxamido, substituted or unsubstituted arylamido arylcarboxamide or substituted or unsubstituted styryl and a substituted or unsubstituted aralkilamido or aralkilkarboksamido; L represents —O—; -S-; -S (O) -; -S (O) ₂ -; -N (R) -; -N (C (O) OR) -; -N (C (O) R) -; -N (SO ₂ R) -; -CH ₂ O-; -CH ₂ S-; -CH ₂ N (R) -; -CH (NR) -; -CH ₂ N (C (O) R) -; -CH ₂ N (C (O) OR) -; -CH ₂ N (SO ₂ R) -; -CH (NHR) -; -CH (NHC (O) R) -; -CH (NHSO ₂ R) -; -CH (NHC (O) OR) -; -CH (OC (O) R) -; -CH (OC (O) NHR) -; -CH = CH-; -C (= NOR); -C (O) -; -CH (OR) -; -C (O) N (R) -; -N (R) C (O) -; -N (R) S (O) -; -N (R) S (O) ₂ -; -OC (O) N (R) -; -N (R) C (O) N (R) -; -NRC (O) O-; -S (O) N (R) -; -S (O ₂ ) N (R) -; -N (C (O) R) S (O) -; -N (C (O) R) S (O) ₂ -; -N (R) S (O) N (R) -; -N (R) S (O) ₂ N (R) -; -C (O) N (R) C (O) -; -S (O) N (R) C (O) -; -S (O) ₂ N (R) C (O) -; -OS (O) N (R) -; -OS (O) ₂ N (R) -; -N (R) S (O) O-; -N (R) S (O) ₂ O-; -N (R) S (O) C (O) -; -N (R) S (O) ₂ C (O) -; -SON (C (O) R) -; -SO ₂ N (C (O) R) -; -N (R) SON (R) -; -N (R) SO ₂ N (R) -; -C (O) O-; -N (R) P (OR ') O-; -N (R) P (OR ') -; -N (R) P (O) (OR ') O-; -N (R) P (O) (OR ') -; -N (C (O) R) P (OR ') O-; -N (C (O) R) P (OR ') -; —N (C (O) R) P (O) (OR ′) O— or —N (C (O) R) P (OR ′) -, where R and R ′ are each independently H, an acyl group substituted or an unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted cycloalkyl group, or L is —R _b N (R) S (O) ₂ -; —R _b N (R) P (O) - or —R _b N (R) P (O) O—, where R _b is a radical alkylene group, which, when taken together with a sulfonamide, phosphinamide or phosphonamide group, with by which it is connected, forms a five- or six-membered ring condensed with ring A, or L is represented by one of the following structural formulas:

in which R ₈₅ taken together with phosphinamide or phosphonamide is a 5-, 6- or 7-membered aromatic, heteroaromatic or heterocycloalkyl ring system; R ₁ represents H, 2-phenyl-1,3-dioxan-5-yl, a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₅ -C ₇ cycloalkenyl group or an optionally substituted phen (C ₁ - C ₆ alkyl group), wherein the alkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more groups of the formula —OR ^a , with the proviso that —OR ^{a is} not located on carbon bound to nitrogen; R ^a is H or a C ₁ -C ₆ alkyl group or a C ₃ -C ₆ cycloalkyl; R ₂ is H, substituted or unsubstituted aliphatic group, substituted or unsubstituted cycloalkyl, halogen, —OH, cyano, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroara -NR ₄ R ₅ or -C (O) NR ₄ R ₅ ; R ₃ represents a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocycloalkyl; or L represents -NRSO ₂ -, -NRC (O) -, -NRC (O) O-, -S (O) ₂ NR-, -C (O) NR- or -OC (O) NR-, and R ₃ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aralkyl; with the proviso that j = 0 when L is —CH ₂ NR—, —C (O) NR— or —NRC (O) - and R ₃ is azacycloalkyl or azaheteroaryl; and provided that j = 0 when L is —O and R ₃ is phenyl; R ₄ , R ₅ and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic group, or R ₄ and R ₅ each independently represents H, azabicycloalkyl, a substituted or unsubstituted alkyl group or YZ; Y is selected from the group consisting of —C (O) -; - (CH ₂ ) _p -; -S (O) ₂ ; -C (O) O-; -SO ₂ NH-; -CONH-; - (CH ₂ ) _p O-; - (CH ₂ ) _P NH-; - (CH ₂ ) _P S-; - (CH ₂ ) _P S (O) - and - (CH ₂ ) _p S (O) ₂ -; p is 0-6; Z is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocycloalkyl group; j = 0 - 6, and its pharmaceutically acceptable salts. 2. The compound according to claim 1, wherein R _{3 is} selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazole, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dioxane, substituted or unsubstituted dioxolane, substituted or unsubstituted quinoline, substituted or unsubstituted thiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted cyclopentanil, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzisothiazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted or substituted substituted or unsubstituted benzothiadiazole, substituted or unsubstituted isoquinoline, for substituted or unsubstituted quinoxaline, substituted or unsubstituted indole and substituted or unsubstituted pyrazole. 3. The compound according to claim 2, to which R _{3 is} substituted by one or more substituents selected from the group consisting of F, C1, Br, I, CH ₃ , NO ₂ , OCF ₃ , OCH ₃ , CN, CO ₂ CH ₃ , CF ₃ , tert-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, S- (substituted or unsubstituted aryl), -S- (substituted or non-substituted substituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, —C (O) NR _f R _g , R _c and CH ₂ OR _c ; R _f , R _g and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic group, R _f and R _g each independently represent H a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group; and R _c represents hydrogen or substituted or unsubstituted alkyl or substituted or unsubstituted aryl, -W- (CH ₂ ) _t -NR _d R _e , -W- (CH ₂ ) _t -O-alkyl, -W- (CH ₂ ) _t -S-alkyl or -W- (CH ₂ ) _t- OH; t = 0 - 6; W represents a bond or —O—, —S—, —S (O) -, —S (O) ₂ -, or —NR _k -; R _k represents H or alkyl; R _d , R _e and the nitrogen atom to which they are bonded together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterobicyclic group; or R _d and R _e each independently represents H, alkyl, alkanoyl or —KD; K represents —S (O) ₂ -, —C (O) -, —C (O) NH—, —C (O) _2, or a direct bond; D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted amino, or unsubstituted aminocycloalkyl, COOR _i or substituted or unsubstituted alkyl; and R _i is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. 4. The compound according to claim 3, in which R ₃ is substituted or unsubstituted phenyl or training, benzoxadiazolyl or benzothiadiazolyl. 5. The compound according to claim 1, in which ring A is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted indole. 6. The compound according to claim 5, in which ring A is substituted by one or more substituents selected from the group consisting of F, C1, Br, I, CH ₃ , NO ₂ , OCF ₃ , OCH ₃ , CN, CO ₂ CH ₃ , CF ₃ , tert-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, S- (substituted or unsubstituted aryl), -S- (substituted and whether unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, —C (O) NR _f R _g , R _c and CH ₂ OR _c ; R _f , R _g and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or a substituted or unsubstituted heteroaromatic group; or R _f and R _g each independently is H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aromatic group; and R _c is hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted aryl, -W- (CH ₂ ) _t -NR _d R _e , -W- (CH ₂ ) _t -O-alkyl, -W- (CH ₂ ) _t -S-alkyl; -W- (CH ₂ ) _t- OH; t = 0 - 6; W represents a bond or —O—, —S—, —S (O) -, —S (O) ₂ -, or —NR _k -; R _k is H or alkyl; and R _d , R _e and the nitrogen atom to which they are bonded together form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or a substituted or unsubstituted heteroaromatic group; or R _d and R _e each independently is H, alkyl, alkanoyl or —KD; K represents —S (O) ₂ -, —C (O) -, —C (O) NH—, —C (O) ₂ or a direct bond; D is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted amino, or unsubstituted aminocycloalkyl, COOR _i or substituted or unsubstituted alkyl; and R _i is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. 7. The compound according to claim 6, in which ring A is substituted or unsubstituted phenyl. 8. The compound according to claim 1, in which R ¹ is cyclopentyl, hydroxycyclopentyl or isopropyl. 9. A compound selected from the group consisting of: N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2- (trifluoromethoxy) -1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -2-chloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -2-fluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-chloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -3-fluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-nitrophenyl) -1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -3- (trifluoromethyl) -1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -4-chloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-chlorophenyl) -2-cyano-1-beneolsulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-nitro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,6-difluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl) -1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,3,4-trifluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -4-bromo-2-fluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2, 5-difluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -3,4-difluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-bromo-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,6-dichloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,4,6-trichloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,4-dichloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-chloro-4-fluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,4-difluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-iodo-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,3-dichloro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -4-bromo-2,5-difluoro-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-chloro-4-cyano-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2-chloro-6-methyl-1-benzenesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -3-chloro-2-methyl-1-benzenesulfonamide, N2- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -4,5-dibromo-2-thiophenesulfonamide, N2- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -5-bromo-2-thiophenesulfonamide, N2- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -3-bromo-5-chloro-2-thiophenesulfonamide, N3- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,5-dichloro-3-thiophenesulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,1,3-benzothiadiazole-4-sulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,1,3-benzoxadiazole-4-sulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -7-chloro-2,1,3-benzoxadiazole-4- sulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -7-methyl-2,1,3-benzothiadiazole-4- sulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -5-methyl-2,1,3-benzothiadiazole-4- sulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -5-chloro-2,1,3-benzothiadiazole-4- sulfonamide, N4- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) - (2-nitrophenyl) methanesulfonamide, N1- (4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-fluorophenyl) -2,5-dibromo-3,6-difluoro-1- benzenesulfonamide,  and their pharmaceutically acceptable salts. 10. The compound according to claim 1, in which R ₂ is N. 11. The compound according to claim 1, in which L is —O—, —NHSO ₂ R—, —NHC (O) O— or —NHC (O) R—. 12. A method of inhibiting protein kinase activity, comprising administering a compound according to claim 1 or a physiologically acceptable salt, prodrug or biologically active metabolite thereof. 13. The method of claim 12, wherein said protein kinase relates to a group consisting of KDR, FGFR-1, PDGFRβ, PDGFRα, IGF-1R, c-Met, Flt-1, TIE-2, Lck, Src, fyn, Lyn, Bik and yes. 14. The method of claim 12, wherein the activity of said protein kinase acts on hyperproliferative disorders. 15. The method according to item 12, in which the activity of the specified protein kinase affects angiogenesis, vascular permeability, immune responses or inflammation. 16. A method of treating a patient having a condition mediated by protein kinase activity, comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined in claim 1, or a physiologically acceptable salt, prodrug or biologically active metabolite thereof. 17. The method according to clause 16, wherein said protein kinase relates to a group consisting of KDR, Fit-1, PDGFRβ, PDGFRα, IGF-1R, c-Met, TIE-2, Lck, Src, fyn, Lyn, Bik and yes. 18. The method of claim 16, wherein said condition mediated by protein kinase activity is a hyperproliferative disorder. 19. The method according to clause 16, in which the activity of the specified protein kinase affects angiogenesis, vascular permeability, immune responses or inflammation. 20. The method according to clause 16, in which the activity of the specified protein kinase affects angiogenesis or vascular permeability. 21. The method according to clause 16, in which the protein kinase is a protein-serine / threonine kinase or protein tyrosine kinase. 22. The method of claim 16, wherein the condition mediated by protein kinase activity is one or more ulcers. 23. The method according to item 21, in which the ulcer or ulcers are caused by a bacterial or fungal infection, or the ulcer or ulcers are Murena ulcers, or the ulcer or ulcers are a symptom of ulcerative colitis. 24. The method of claim 16, wherein the condition mediated by protein kinase activity is Lyme disease, sepsis, or infection caused by herpes simplex, herpes zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis. 25. The method according to clause 16, in which the condition mediated by the activity of protein kinase is Hippel-Lindau disease, pemphigoid, psoriasis, Paget's disease or polycystic kidney disease. 26. The method of claim 16, wherein the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive lung disease, asthma, exudate, ascites, pleural effusions, exudative pericarditis, pulmonary edema, cerebral edema or edema after burns, trauma, radiation, hemorrhage, hypoxia or ischemia. 27. The method of claim 16, wherein the condition mediated by protein kinase activity is ovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, or endometriosis. 28. The method of claim 16, wherein the condition mediated by protein kinase activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis and osteoarthritis, multiple sclerosis, or transplant rejection. 29. The method according to clause 16, in which the condition mediated by the activity of protein kinase, is anemia of drepanocytes or sickle-shaped red blood cells. 30. The method of claim 16, wherein the condition mediated by protein kinase activity is ocular disease. 31. The method of claim 30, wherein the ocular disease is ocular or macular edema, ocular neovascular disease, scleritis, radical keratotomy, uveitis, vitritis, myopia, congenital fossae in the optic disc, chronic retinal detachment, complications after laser treatment, conjunctivitis , Stargardt’s disease, Ilse’s disease, retinopathy or macular macular degeneration. 32. The method of claim 16, wherein the condition mediated by protein kinase activity is a cardiovascular disorder. 33. The method of claim 32, wherein the condition mediated by protein kinase activity is atherosclerosis, restenosis, ischemic / reperfusion injury, vascular obstruction, venous defect, or carotid artery obstruction. 34. The method according to clause 16, in which the condition mediated by the activity of protein kinase is a malignant tumor. 35. The method according to clause 34, in which the malignant tumor is a solid tumor, sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, malignant diseases of the blood-forming organs and malignant ascites. 36. The method according to clause 34, in which the malignant tumor is Kaposi’s sarcoma, Hodgkin’s disease, lymphoma, myeloma or leukemia. 37. The method according to clause 16 in which the condition mediated by the activity of protein kinase is Crow-Fukas syndrome (POEMS) or a diabetic condition. 38. The method according to clause 36, in which the diabetic condition is insulin-dependent diabetic glaucoma, diabetic retinopathy or microangiopathy. 39. A method of reducing fertility in a patient, comprising administering to the patient an effective amount of a compound of formula I, as defined in claim 1, or a physiologically acceptable salt, prodrug or biologically active metabolite thereof. 40. The method according to clause 16, in which the compound of formula I or its physiologically acceptable salt, prodrug or biologically active metabolite is administered in an amount effective to enhance angiogenesis or vasculogenesis. 41. The method of claim 39, wherein the protein kinase is Tie-2. 42. The method according to § 39, in which the compound of formula I or its physiologically acceptable salt, prodrug or biologically active metabolite is administered in combination with a pro-angiogenic growth factor. 43. The method according to paragraph 41, wherein the pro-angiogenic growth factor is selected from the group consisting of VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, HGF, FGF-1, FGF-2, their derivatives and anti-iodotypic antibodies. 44. The method of claim 39, wherein the condition mediated by protein kinase activity is anemia, ischemia, heart attack, graft rejection, wounds, gangrene, or necrosis. 45. The method according to clause 16, in which the activity of protein kinase is involved in the activation of T cells, activation of B cells, mast cell degranulation, activation of monocytes, enhancing the inflammatory response or a combination thereof.