ERK inhibitors and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A method of inhibiting one or both of ERK1 and ERK2, or a mutant thereof, comprising the step of contacting the one or both of ERK1 and ERK2, or a mutant thereof, with a compound of formula VIII:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
Ring A is selected from
R 1 is a warhead group -L-Y, wherein R 1 is attached to an atom adjacent to where NH is attached, wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; or
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; or
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; and
Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; or
L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, or —SO 2 NH—, and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(ii) C 2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vi)
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(x)
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(xii)
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or
(xiv)
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or
(xvi)
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from the following (i) through (xvii):
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vi)
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(x)
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(xii)
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or
(xiv)
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or
(xvi)
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;
each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyloxy, or diazonium, wherein:
Q is a bivalent C 1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and
each Z is independently hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN;
each R 2 is independently hydrogen, an optionally substituted C 1-6 aliphatic, halogen, or —OR;
each R 3 is independently selected from —R, -Cy, halogen, —OR, —SR, —CN, —NO 2 , —SO 2 NR, —SO 2 R, —SOR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)N(R) 2 , —C(O)N(R) 2 , —C(O)N(R)—OR—C(O)C(O)R, —P(O)(R) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or two R 3 groups on the same carbon atom together form —C(O)—, —C(S)—, or —C(N—R)—;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Cy is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R y is hydrogen, optionally substituted C 1-6 aliphatic, halogen, haloalkyl, —CN, —C(O)R′, —C(O)N(R′) 2 , —C(═N—R″)R′ or —N(R′) 2 ;
each R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic;
R″ is hydrogen or —OR;
and m and p are each independently 0-4.
2. The method according to claim 1 , wherein R y is haloalkyl.
3. The method according to claim 2 , wherein R y is —CF 3 .
4. The method according claim 1 , wherein at least one R 3 is —OMe.
5. The method according to claim 1 , wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—.
6. The method according to claim 5 , wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and
Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
7. The method according to claim 6 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.
8. The method according to claim 6 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —, wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
9. The method according to claim 8 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, or —NHC(O)C(═CH 2 )CH 2 .
10. The method according to claim 1 wherein R 1 is selected from:
11. The method according to claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The method according to claim 1 , wherein said compound is of formula VIII-a:
or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12 , wherein R 1 is
14. The method according to claim 10 , wherein R 1 is
15. The method according to claim 1 , wherein the one or both of ERK1 and ERK2, or a mutant thereof, is inhibited irreversibly by covalently modifying Cys 183 of ERK1.
16. The method according to claim 1 , wherein the one or both of ERK1 and ERK2, or a mutant thereof, is inhibited irreversibly by covalently modifying Cys 166 of ERK2.
17. The method according to claim 1 , wherein the one or both of ERK1 and ERK2, or a mutant thereof, is inhibited irreversibly by covalently modifying Cys 183 of ERK1 and Cys 166 of ERK2.
18. A method for treating cancer in a patient in need thereof, comprising the step of administering to said patient a compound of formula VIII:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
Ring A is selected from
R 1 is a warhead group -L-Y, wherein le is attached to an atom adjacent to where NH is attached, wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; or
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; or
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; and
Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; or
L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, or —SO 2 NH—, and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(ii) C 2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vi)
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(x)
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(xii)
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or
(xiv)
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or
(xvi)
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from the following (i) through (xvii):
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vi)
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(x)
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(xii)
or
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or
(xiv)
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or
(xvi)
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;
each R e is independently selected from —Q-Z, oxo, NO 2 , halogen, CN, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyloxy, or diazonium, wherein:
Q is a bivalent C 1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and
each Z is independently hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN;
each R 2 is independently hydrogen, an optionally substituted C 1-6 aliphatic, halogen, or —OR;
each R 3 is independently selected from —R, -Cy, halogen, —OR, —SR, —CN, —NO 2 , —SO 2 NR, —SO 2 R, —SOR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)N(R) 2 , —C(O)N(R) 2 , —C(O)N(R)—OR, C(O)C(O)R, —P(O)(R) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or two R 3 groups on the same carbon atom together form —C(O)—, —C(S)—, or —C(N—R)—;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Cy is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R y is hydrogen, optionally substituted C 1-6 aliphatic, halogen, haloalkyl, —CN, —C(O)R′, —C(O)N(R′) 2 , —C(═N—R″)R′ or —N(R′) 2 ;
each R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic;
R″ is hydrogen or —OR;
and m and p are each independently 0-4.
19. The method according to claim 18 , wherein R y is haloalkyl.
20. The method according to claim 19 , wherein R y is —CF 3 .
21. The method according claim 18 , wherein at least one R 3 is —OMe.
22. The method according to claim 18 , wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—.
23. The method according to claim 22 , wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and
Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
24. The method according to claim 23 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.
25. The method according to claim 22 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —, wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
26. The method according to claim 25 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, or —NHC(O)C(═CH 2 )CH 2 —.
27. The method according to claim 18 wherein R 1 is selected from:
28. The method according to claim 18 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
29. The method according to claim 18 , wherein said compound is of formula VIII-a:
or a pharmaceutically acceptable salt thereof.
30. The method according to claim 29 , wherein R 1 is
31. The method according to claim 27 , wherein R 1 is
32. The method according to claim 18 , wherein the cancer is selected from bladder cancer, bone cancer, breast cancer, cancer of the central nervous system (CNS), cervical cancer, colorectal cancer (CRC), cancer of the head and neck, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, stomach cancer, thyroid cancer, and uterine cancer.
33. The method according to claim 32 , wherein the cancer is selected from colorectal cancer, lung cancer, melanoma, pancreatic cancer, and thyroid cancer.
34. The method according to claim 33 , wherein the cancer is colorectal cancer.
35. The method according to claim 33 , wherein the cancer is lung cancer.
36. The method according to claim 33 , wherein the skin cancer is melanoma.
37. The method according to claim 33 , wherein the cancer is pancreatic cancer.
38. The method according to claim 33 , wherein the cancer is thyroid cancer.
39. The method according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
40. The method according to claim 18 , wherein the compound is
or a pharmaceutically acceptable salt thereof.