Novel 4-Arylamino Pyridone Derivatives as Mek Inhibitors for the Treatment of Hyper-Proliferative Disorders

1 - 12 . (canceled)

13 . A compound of formula (I),

a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R 1 , R 2 , R 9 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —C(O)R 3 ,—C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , —S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, —S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 4 R 5 ) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl, —NR 4 (CR 4 R 5 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) substituted with 1 to 5 fluorines, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

R 10 is selected from: hydrogen, —OR 3 , —C(O)R 3 ,—C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 ; —S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl, —NR 4 (CR 4 R 5 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) substituted with 1 to 5 flourines, wherein each aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

L is selected from: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each group is optionally and independently substituted;

or L and R 10 are together hydrogen;

R 3 is selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2-10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which is optionally and independently substituted;

R 4 is selected from: hydrogen and C 1 -C 6 alkyl, wherein the alkyl may be optionally substituted; or

R 3 and R 4 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is optionally and independently substituted;

R 5 is selected from: hydrogen and C 1 -C 6 alkyl, wherein the alkyl may be optionally substituted; or

R 4 and R 5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally and independently substituted;

R 6 is selected from: trifluoromethyl,C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4 heteroatoms, each of which is optionally substituted by 1 to 5 substituents ZR 15 ; and 2) —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 2 -C 10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), S(O) j NR 4 R 15 , S(O) j NR 4 OR 15 , —S(O) j NR 4 C(O)R 15 , or —C(O)NR 4 S(O) j R 6 , whereby R 4 and R 15 are as defined herein, or taken together may form a 3 to 7 membered ring with 1 or 2 nitrogen atoms and optionally an oxygen atom;

Z is a bond, NR 16 , O, NR 16 SO 2 or S;

R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and indepdently substituted;

R 16 is selected from: hydrogen and C 1 -C 10 alkyl;

or R 15 and R 16 taken together form a 4 to 10 membered cyclic ring with 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being optionally substituted;

m is an integer from 0 to 5; and

j is 1 or 2.

14 . The compound according to claim 13 wherein:

R 1 , R 2 , R 9 , R 11 are independently selected from: hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cyano, nitro, OR 3 and NR 3 R 4 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl is optionally and independently substituted with one to five halogens;

R 10 is selected from: hydrogen, —OR 3 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , and —NR 3 R 4 ;

L is C 1 -C 5 alkyl;

or L and R 10 are together hydrogen;

R 12 is selected from: hydrogen, halo, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, cyano, nitro, azido, NR 4 SO 2 R 6 , SO 2 NR 3 R 4 , SO 2 R 6 , C(O)NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , OR 3 , NR 3 R 4 and —S(C 1 -C 2 alkyl) substituted with 1 to 5 fluorines, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

R 13 and R 14 are independently selected from: H, F, Cl, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl, wherein each alkyl, alkenyl, cycloalkyl, alkynyl is optionally and independently substituted with one to five halogens;

W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4 heteroatoms, each of which is optionally substituted by 1 to 3 substituents ZR 15 ; or 2) —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 2 -C 10 alkyl), —S(O) j NR 4 C(O)R 15 , —C(O)NR 4 S(O) j R 6 , —S(O) j NR 4 R 15 or S(O) j NR 4 OR 15 ;

Z is selected from: NR 16 , NR 16 SO 2 and O;

R 15 is selected from: hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, and C 4 -C 6 cycloalkylalkyl, wherein each alkyl or alkenyl is optionally and independently substituted by 1 or 2 -OH, —O—C 1 -C 4 alkyl or —NR′R″ groups;

R 16 is selected from: hydrogen and C 1 -C 4 alkyl; and

R′ and R″ are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl.

15 . The compound according to claim 13 wherein:

R 1 is selected from: H and F;

R 2 is selected from: F, Cl, Me, wherein the methyl group is optionally substituted with one to three fluorines;

R 9 is selected from: H, F, and Cl;

R 10 is selected from: hydrogen, —OR 3 , and —NR 3 R 4 ;

L is selected from: ethylene, n-propylene and n-butylene;

or L and R 10 together are methyl;

R 11 is selected from: H, F, Cl, Br, Me, and OMe, wherein the methyl groups are optionally substituted with one to three fluorines;

R 12 is selected from: H, F, Cl, Br, I, nitro, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, —SCF 3 , —SCHF 2 , —SCH 2 F, —SO 2 NR 3 R 4 , —C(O)NR 3 R 4 or —OMe, wherein the methyl groups are optionally substituted with one to three fluorines;

wherein R 3 and R 4 are each independently: 1) C 1 -C 6 alkyl, optionally substituted by 1 or 2 alkyl amino; or O-alkyl; or

R 3 and R 4 form together a cyclic ring with 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being optionally substituted by 1 or 2 alkyl amino or O-alkyl groups;

R 13 and R 14 are independently selected from H and F;

W is selected from —C(O)NR 4 OR 15 or SO 2 NR 4 OR 15 ; or W is:

wherein

Z is NR 16 ;

R 15 is C 1 -C 4 alkyl or C 1 -C 4 alkenyl optionally substituted with 1 to 3 substituents selected from: OH, O-Me, NH 2 , N(methyl) 2 and N(ethyl) 2 ;

R 16 is hydrogen or C 1 -C 4 alkyl; or R 16 and R 15 taken together form a 4 to 10 membered cyclic ring with 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl groups; and

Y is O, S or NR′.

16 . The compound according to claim 13 wherein:

W is selected from —C(O)NR 4 OR 15 and SO 2 NR 4 OR 15 , or W is:

wherein

R 4 is hydrogen;

Z is NH;

R 15 is selected from: C 1 -C 4 alkyl and C 1 -C 4 alkenyl, each of which may be further substituted by 1 or 2 groups selected from: OH, O—C 1 -C 4 alkyl and NR′R″;

R′ and R″ are independently hydrogen, methyl or ethyl; and

Y is O.

17 . The compound according to claim 13 wherein L and R 10 together are methyl.

18 . A method for treating a mammal with a hyperproliferative disease or a disorder mediated by aberrant proliferation comprising administering to the mammal a therapeutically effective amount of a compound according to Formula I:

a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R 1 , R 2 , R 9 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , —S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, —S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 4 R 5 ) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl, —NR 4 (CR 4 R 5 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) substituted with 1 to 5 fluorines, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

R 10 is selected from: hydrogen, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 ; —S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl, —NR 4 (CR 4 R 5 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) substituted with 1 to 5 flourines, wherein each aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

L is selected from: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each group is optionally and independently substituted;

or L and R 10 are together hydrogen;

R 3 is selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 - 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which is optionally and independently substituted;

R 4 is selected from: hydrogen and C 1 -C 6 alkyl, wherein the alkyl may be optionally substituted; or

R 3 and R 4 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is optionally and independently substituted;

R 5 is selected from: hydrogen and C 1 -C 6 alkyl, wherein the alkyl may be optionally substituted; or

R 4 and R 5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally and independently substituted;

R 6 is selected from: trifluoromethyl,C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4 heteroatoms, each of which is optionally substituted by 1 to 5 substituents ZR 15 ; and 2) —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 2 -C 10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), S(O) j NR 4 R 15 , S(O) j NR 4 OR 15 , —S(O) j NR 4 C(O)R 15 , or —C(O)NR 4 S(O) j R 6 , whereby R 4 and R 15 are as defined herein, or taken together may form a 3 to 7 membered ring with 1 or 2 nitrogen atoms and optionally an oxygen atom;

Z is a bond, NR 26 , O, NR 16 SO 2 or S;

R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and indepdently substituted;

R 16 is selected from: hydrogen and C 1 -C 10 alkyl;

or R 15 and R 16 taken together form a 4 to 10 membered cyclic ring with 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being optionally substituted;

m is an integer from 0 to 5; and

j is 1 or 2.

19 . A method of treating a mammal with a hyperproliferative disease related to the hyperactivity of MEK or diseases modulated by the MEK cascade in mammals, comprising administering to the mammal a therapeutically effective amount of a compound according to Formula I:

a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R 1 , R 2 , R 9 , R 11 , R 12 , R 13 and R 14 are independently selected from: hydrogen, halogen, cyano, nitro, azido, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , —S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, —S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 4 R 5 ) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl, —NR 4 (CR 4 R 5 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) substituted with 1 to 5 fluorines, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

R 10 is selected from: hydrogen, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 S(O) j R 6 , —S(O) j NR 3 R 4 , —S(O) j NR 4 C(O)R 3 , —C(O)NR 4 S(O) j R 6 , S(O) j R 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 ;

—S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl, —NR 4 (CR 4 R 5 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) substituted with 1 to 5 flourines, wherein each aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

L is selected from: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each group is optionally and independently substituted;

or L and R 10 are together hydrogen;

R 3 is selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 - 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which is optionally and independently substituted;

R 4 is selected from: hydrogen and C 1 -C 6 alkyl, wherein the alkyl may be optionally substituted; or

R 3 and R 4 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is optionally and independently substituted;

R 5 is selected from: hydrogen and C 1 -C 6 alkyl, wherein the alkyl may be optionally substituted; or

R 4 and R 5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally and independently substituted;

R 6 is selected from: trifluoromethyl,C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted;

W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4 heteroatoms, each of which is optionally substituted by 1 to 5 substituents ZR 15 ; and 2) —C(O)OR 15 , —C(O)NR 4 R 15 , —C(O)NR 4 OR 15 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 2 -C 10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), S(O) j NR 4 R 15 , S(O) j NR 4 OR 15 , —S(O) j NR 4 C(O)R 15 , or —C(O)NR 4 S(O) j R 6 , whereby R 4 and R 15 are as defined herein, or taken together may form a 3 to 7 membered ring with 1 or 2 nitrogen atoms and optionally an oxygen atom;

Z is a bond, NR 16 , O, NR 16 SO 2 or S;

R 15 is independently selected from: hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and indepdently substituted;

R 16 is selected from: hydrogen and C 1 -C 10 alkyl;

or R 15 and R 16 taken together form a 4 to 10 membered cyclic ring with 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being optionally substituted;

m is an integer from 0 to 5; and

j is 1 or 2.

20 . The method of claim 19 wherein the disease is selected from: cancer, inflammation, pancreatitis or kidney disease, pain, benign hyperplasia of the skin, restenosis, prostate, diseases related to vasculogenesis or angiogenesis, tumor angiogenesis, psoriasis, eczema, sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma and Kaposi's sarcoma.

21 . The method of claim 20 wherein the disease is cancer or inflammation.

22 . The method of claim 21 wherein the type of cancer is selected from: ovarian, breast, lung, pancreatic, prostate, colon and epidermoid.

23 . The method of claim 21 wherein the type of inflammation is selected from: rheumatoid arthritis, inflammatory bowel disease, and atherosclerosis.

24 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.