Protein kinase inhibitors
View Patent ↗Disclosed are compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions containing such compounds. The disclosed compound contain two or more ligand moieties covalently linked together by one or more linking groups. Such compounds are useful for treating diseases or medical disorders mediated by protein kinases.
1. A compound of formula II:
L-X-L II
and pharmaceutically acceptable salts thereof; wherein:
one L is a moiety of formula V:
wherein
each R g is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R h is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R i is a covalent bond linking the moiety to the linker;
Q 1 is NR j′ , O, S, alkylene or a covalent bond, where R i′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
and the other L is a ligand selected from:
(i) a moiety of formula III:
wherein
each R a is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
each R b is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
R c is selected from the group consisting of aryl, alkaryl, heteroaryl and heterocycle;
provided one and only one of R a and R b comprises a covalent bond linking the moiety to the linker;
(ii) a moiety of formula IV:
wherein
R d is selected from the group consisting of aryl, alkaryl, heteroaryl and heterocycle;
R e is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
each R f is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
provided one and only one of R e or R f comprises a covalent bond linking the moiety to the linker;
(iii) a moiety of formula V:
(iv) a moiety of formula VI:
wherein
each R j is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
R k is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, hydroxy, halogen and —CHO;
each Q 2 is independently NR j′ , O and S, where R j′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
provided one and only one of R j comprises a covalent bond linking the moiety to the linker;
(v) a moiety of formula VII:
wherein
each R l and R m is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R n is a covalent bond linking the moiety to the linker;
Q 3 is NR n′ , O, S or alkylene;
Q 4 is NR n′ , O, S, alkylene or a covalent bond, where each R n′ in Q 3 and Q 4 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
(vi) a moiety of formula VIII:
wherein
each R o is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R p is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with —OZ′ where Z′ is a covalent bond linking the moiety to the linker;
Z is 2H or O;
m is an integer from 1 to 3;
(vii) a moiety of formula IX:
wherein
each R q is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocyclic and a covalent bond linking the moiety to the linker;
each R q′ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R s is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R r is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker;
provided one and only one of R q or R r comprises a covalent bond linking the moiety to the linker;
(viii) a moiety of formula X:
wherein
each R t is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
each R u is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy and a covalent bond linking the moiety to the linker;
Q 5 is NR t′ , O, S or alkylene, where R t′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
provided one and only one of R u comprises a covalent bond linking the moiety to the linker;
(ix) a moiety of formula XI:
wherein
each R v is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R v′ is a covalent bond linking the moiety to the linker;
each R w is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Q 6 is NR w′ , O, S or alkylene, where R w′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
Q 6′ is NR ″ , O, S or alkylene, where R v″ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
(x) a moiety of formula XII:
wherein
each R x is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
R y is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R z is a covalent bond linking the moiety to the linker;
E is CH or N; and
(xi) a moiety of formula XIII:
wherein
each R aa is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
R ab is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, thioalkoxy, substituted thioalkoxy, wherein the alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, thioalkoxy or substituted thioalkoxy group is substituted with a covalent bond linking the moiety to the linker;
D is a covalent bond, NR ab′ , O or S, where R ab′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
E is CH or N;
(xii) a moiety of formula XIV:
wherein
R ac is a covalent bond linking the moiety to the linker;
R ad is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
R ae is aryl or heteroaryl;
(xiii) a moiety of formula XV:
wherein
R af is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
each R ag is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R ah is aryl or heteroaryl;
R ai is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker;
Q 7 is NR af′ , O, S or alkylene, where R af is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
m′ is 1 or2;
(xiv) a moiety of formula XVI:
wherein
each R aj is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R al is aryl or heteroaryl;
each R ak is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocyclic, and a covalent bond linking the moiety to the linker;
Q 8 is NR al′ , O, S or alkylene, where R al′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
m is an integer from 1 to 3;
provided one and only one of R ak comprises a covalent bond linking the moiety to the linker;
(xvii) a moiety of formula XIX:
wherein
R as is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
R at is selected from the group consisting of 4-phosphonomethylphenyl, 4-phosphonodifluoromethylphenyl, 3-carboxy-4-carboxymethoxyphenyl and 3,4-dihydroxyphenyl;
R au is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with —OZ′, where Z′ is a covalent bond linking the moiety to the linker;
R av is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and alkaryl;
provided one and only one of R as and R au comprises a covalent bond linking the moiety to the linker;
(xviii) a moiety of formula XX:
wherein
each R aw is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
each R ax is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy, a covalent bond linking the moiety to the linker and —OZ′, where Z′ is a covalent bond linking the moiety to the linker;
each m is independently an integer from 1 to 3;
provided one and only one of R ax comprises a covalent bond linking the moiety to the linker;
(xxii) a moiety of formula XXIV:
wherein
R be is a covalent bond linking the moiety to the linker;
(xxiv) a moiety of formula XXVI:
wherein
R bi is a covalent bond linking the moiety to the linker;
(xxv) a moiety of formula XXVII:
wherein
each R bj is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
Q 11 is NR bj′ , O, S or alkylene, where R bj′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
provided one and only one of R bj comprises a covalent bond linking the moiety to the linker;
(xxvi) a moiety of formula XXVIII:
wherein
each R bk is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy, —SO—R bk′ and —SO 2 —R bk′ , where R bk′ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl or heterocyclic;
R bl is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with —(CH 2 ) u -Z′, where Z′ is a covalent bond linking the moiety to the linker and u is an integer from 1 to 3;
m is an integer from 1 to 3;
(xxvii) a moiety of formula XXIX:
wherein
R bn is selected from the group consisting of alkoxy, substituted alkoxy, hydroxy and —OZ′, where Z′ is a covalent bond linking the moiety to the linker;
R bo is aryl or heteroaryl;
R bp is acyl, alkoxycarbonyl and a covalent bond linking the moiety to the linker;
provided one and only one of R bn and R bp comprises a covalent bond linking the moiety to the linker;
and each X is a linker independently selected from a group of the formula:
—X a -Z-(Y a -Z) m′ -Y b -Z-X a —
wherein
m′ is an integer of from 0 to 20;
X a at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond;
Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Y a and Y b at each separate occurrence are selected from the group consisting of: —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(R)—NR′—, —P(O)(OR′)—O—, —S(O) n CR′R″—, —S(O) n —NR′—, —S—S— and a covalent bond; where n is 0, 1 or 2; and
R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.
2. The compound of claim 1 , wherein one L is a moiety of formula C:
wherein
R 3 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and —CH 2 CH 2 OCH 3 ;
R 4 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkylalkoxy;
R 5 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
and the other L is a ligand selected from:
(i) a moiety of formula A:
(ii) a moiety of formula B:
wherein, in formula A and B,
R 1 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and —(CH 2 ) v —NR 28 R 29 , where v is an integer from 2 to 4;
Ar 1 is selected from the group consisting of an aryl, alkaryl and heterocycle;
R 28 is selected from group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R 29 is selected from the group consisting of 4-pyrimidinyl, 2-methylaminopyrimidin-4-yl, 2-phenoxypyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 2-(4-fluorophenoxy)pyrimidin-4-yl, 2-(4-aminocarbonylphenoxy)pyrimidin-4-yl, 2-(4-ethylphenoxy)pyrimidin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 4-pyridinyl, 2-phenoxypyridin-4-yl, 2-(4-methoxyphenoxy)pyridin-4-yl, 2-(4-fluorophenoxy)pyridin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, and 2-(4-methoxyphenoxy)pyrimidin-4-yl;
(iii) a moiety of formula C;
(iv) a moiety of formula D:
wherein
R 6 is selected from the group consisting of substituted alkyl and —CHO;
R 7 is selected from the group consisting of hydrogen, alkyl and acyl;
(v) a moiety of formula E:
wherein
R 8 is selected from the group consisting of hydrogen, alkoxy and halogen;
V is selected from the group consisting of amino, alkyl of 1 to 6 carbon atoms, S and O;
R 9 is selected from the group consisting of hydrogen, alkoxy and halogen;
(vi) a moiety of formula F:
wherein
R 10 is selected from the group consisting of hydrogen, alkoxy, amino and substituted amino;
R 11 is selected from the group consisting of hydrogen, alkoxy, halogens, amino, substituted amino and nitro;
R 12 is selected from the group consisting of hydrogen, hydroxy, alkoxy and halogen;
R 13 is selected from the group consisting of hydrogen, hydroxy, alkoxy and halogen;
Z is selected from the group consisting of 2H and O;
(vii) a moiety of formula H:
wherein
R 17 and R 18 are independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R 19 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, —CH 2 C(O)OEt, —(CH 2 ) 3 OH, alkaryl, aryl and heteroaryl;
(viii) a moiety of formula N:
(ix) a moiety of formula O:
wherein
R 26 is selected from the group consisting of hydrogen and acyl;
Het 1 is heterocyclic or heteroaryl;
(x) a moiety of formula P:
wherein
R 27 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and substituted alkyl;
Ar 3 is aryl;
(xi) a moiety of formula S:
wherein
D is selected from the group consisting of a covalent bond, —NH—, —S— and —O—;
E is selected from the group consisting of CH and N;
Ar 3 is aryl;
(xii) a moiety of formula U:
wherein
R 29 is selected from the group consisting of 4-pyrimidinyl, 2-methylaminopyrimidin-4-yl, 2-phenoxypyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 2-(4-fluorophenoxy)pyrimidin-4-yl, 2-(4-aminocarbonylphenoxy)pyrimidin-4-yl, 2-(4-ethylphenoxy)pyrimidin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 4-pyridinyl, 2-phenoxypyridin-4-yl, 2-(4-methoxyphenoxy)pyridin-4-yl, 2-(4-fluorophenoxy)pyridin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, and 2-(4-methoxyphenoxy)pyrimidin-4-yl;
(xiii) a moiety of formula V:
wherein
R 30 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, halogen and alkoxy;
R 31 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy and Z v ;
R 32 is selected from the group consisting of hydrogen, amino, substituted amino, alkoxy, —NHCOCH 3 , and Z v , provided one and only one of R 31 and R 32 is Z v ; and
(xiv) a moiety of formula Z:
wherein
R 34 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, halogen and substituted alkyl;
R 35 is selected from the group consisting of hydrogen and halogen;
R 36 , R 37 , and R 38 are selected from the group consisting of hydrogen, —NO 2 , alkyl, substituted alkyl, amino, substituted amino, alkoxy, hydroxy and halogen;
and further wherein Z a , Z b , Z c , Z d , Z e , Z f , Z h , Z n , Z o , Z p , Z s , Z u , Z v , and Z z , are covalent bonds linking the moiety to the linker;
and stereoisomers thereof.
3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .
4. A method of treating a disease or medical disorder mediated by a protein kinase, wherein the disease or medical disorder mediated by a protein kinase is selected from the group consisting of recurrent ocular herpetic keratitis, diabetic retinopathy, VEGF-induced angiogenesis, macular degeneration, ischemia, atherosclerosis, and psoriasis; the method comprising administering to a mammal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a thereaputically effective amount of a compound of claim 1 .
5. The compound of claim 1 , wherein one L is a moiety of formula (V); and the other L is a ligand selected from the group consisting of:
(iv) a moiety of formula L:
(v) a moiety of formula M:
wherein, in formula L and M,
R 22 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and substituted alkyl;
R 23 is
R 24 is selected from the group consisting of hydrogen and acyl;
R 25 is selected from the group consisting of alkyl and cycloalkyl;
R 39 is selected from the group consisting of
Ar 2 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, substituted alkyl and aryl;
and further wherein Z i , Z j , Z k , Z l , and Z m are covalent bonds linking the moiety to the linker;
and stereoisomers thereof.
6. The compound of claim 1 , wherein one L is a moiety of formula V; and the other L is a moiety of formula Q:
wherein
Z q is a covalent bond linking the moiety to the linker;
and stereoisomers thereof.
7. The compound of claim 1 , wherein one one L is a moiety of formula V; and the other L is a moiety of formula AA:
and further wherein Z r , Z t and Z aa , are covalent bonds linking the moiety to the linker;
and stereoisomers thereof.
8. The compound of claim 1 , wherein one L is a moiety of formula V; and the other L is selected from the group consisting of:
(i) a moiety of formula X:
and
(ii) a moiety of formula Y:
and further wherein Z w , Z x and Z y are covalent bonds linking the moiety to the linker; and stereoisomers thereof.
9. The compound of claim 1 , wherein one L is a moiety of formula V; and the other L is selected from the group consisting of:
(i) a moiety of formula AB:
(ii) a moiety of formula AC:
(iii) a moiety of formula AD:
(iv) a moiety of formula AE:
(v) a moiety of formula AH:
(vi) a moiety of formula AI:
wherein
R 41 is independently selected from the group consisting of hydrogen, 4-CH 3 , 5-CH 3 and 4,5-di-CH 3 ;
R 42 is independently selected from the group consisting of hydrogen, CH 3 , —F, —Cl and —NO 2 ;
R 43 is independently selected from the group consisting of -Z ac , hydrogen, —(CH 2 ) v —NR 45 Z ac and —(CH 2 ) v —NR 45 R 46 ;
R 44 is independently selected from the group consisting of -Z ad , hydrogen, —CH 3 , —CH 2 CH 3 and t-butyl;
R 45 is independently selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 and —CH 2 CH 2 NMe;
R 46 is independently selected from the group consisting of hydrogen, —CH 3 and ethyl;
R 49 is independently selected from the group consisting of acetyl, t-BOC, -Cbz, and —C(O)Ph;
R 50 is independently selected from the group consisting of C 1-5 alkyl (preferably mdthyl, ethyl and propyl);
Ar 4 is independently selected from the group consisting of 4-Cl-3-F—C 6 H 3 , 3-Br-C 6 H 4 , 3-Cl—C 6 H 4 , 3-F—C 6 H 4 , 4-Br—C 6 H 4 , 4-Cl—C 6 H 4 , and 3,4-dihalophenyl;
Ar 5 is independently selected from the group consisting of C 6 H 5 , p-C 6 H 4 OH, and other substituted phenyl groups;
u is an integer from 1 to 3,
v is an integer from 2 to 4,
and further wherein Z ab , Z ac , Z ad , Z ae , Z ah , and Z ai are covalent bonds linking the moiety to the linker;
and stereoisomers thereof.