Tyrosine kinase inhibitors
Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein X, Y and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.
1. A compound having the structure formula (I):
or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvate or hydrate thereof, wherein
X is hydrogen, Cak(C 0 -C 6 alkyl), Hca(C 0 -C 6 alkyl), Ar(C 0 -C 6 alkyl), Het(C 0 -C 6 alkyl), halogen or Hca(C 1 -C 6 alkyl)-O—, wherein Ar, Het, Cak, Hca and the alkyl group is optionally substituted by one to four —R X1 groups, wherein each —R X1 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, OP(O)(OR) 2 , —CH 2 —OP(O)(OR), Ar(C 0 -C 6 alkyl), Het(C 0 -C 6 alkyl), Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), or two —R X1 groups taken together, when attached to adjacent atoms, form a Cak, Hca or Het, wherein the Cak Hca and the Het comprise a 3-8 membered ring optionally substituted with one or two —R X2 groups,
or two —R X1 groups taken together, when attached to the same carbon atom, form a Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —R X2 groups,
or two —R X1 groups taken together, when attached to non-adjacent atoms, and combined with X, form a bridged Hca optionally substituted with one or two —R X2 groups,
wherein each —R X2 is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR 2 , —C(O)OR, —C(O)NR 2 , —C(O)R, —S(O)R, —S(O) 2 R, —S(O)OR, —S(O) 2 OR, —S(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O)R, —N(R)S(O) 2 R, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
Y is Cak(C 0 -C 8 alkyl) or Hca(C 0 -C 6 alkyl), each optionally substituted by one or two —R Y1 groups;
wherein each —R Y1 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , N(R)C(NR 2 )NR 2 , —C(O)R, —C(O)OR, C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR);
Z is C 1 -C 6 alkyl substituted by one to three —R Z1 groups, or Z is Cak(C 0 -C 6 alkyl), optionally substituted by one to three —R Z1 groups;
wherein each —R Z1 is independently halogen, cyano, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR); and
each R is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, Hca(C 0 -C 6 alkyl), Cak(C 0 -C 8 alkyl), C 1 -C 6 alkyl-CN, —CH 2 C(O)NH 2 , C 1 -C 6 alkyl-OH, wherein
Hca is a 3-15 membered ring or ring system comprising at least one ring, 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Het is a 5-15 membered aromatic ring or ring system comprising at least one ring and 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Cak is a 3-8 membered non-aromatic carbocyclic ring or ring system, which may be saturated or partially unsaturated; and
Ar is a 6-16 membered aromatic ring or ring system having at least one carbocyclic aromatic ring optionally fused one or more aromatic or non-aromatic rings.
2. The compound of claim 1 , having the structure of formula (Ie):
3. The compound of claim 2 , wherein R Y1 is —OR.
4. The compound of claim 3 , wherein X is hydrogen, Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein each Cak, Hca and alkyl group is optionally substituted by one to three —R X1 groups.
5. The compound of claim 4 , wherein X is hydrogen or Hca(C 0 -C 6 alkyl), wherein each Hca and alkyl group is optionally substituted by one to three —R X1 groups.
6. The compound of claim 5 , having the structure of formula (If):
7. The compound of claim 5 , having the structure of formula (II):
or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvate or hydrate thereof, wherein
ring A is Hca;
a is 0 or 1; and
p is 1, 2, 3 or 4; and
each —R X1 is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 , —CH 2 —OP(O)(OR), Ar(C 0 -C 6 alkyl), Het(C 0 -C 6 alkyl), Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl).
8. The compound of claim 7 , wherein
(a) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X 1 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
X 2 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—; and
X 3 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(b) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X 2 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(c) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2; and
ring B is Hca or Het, each comprising a 3-8 membered ring optionally substituted with one or two —R X2 groups;
(d) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2;
n is 0, 1 or 2;
m is 0, 1 or 2; and
X 4 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(e) ring A is
wherein
X 6 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—; and
X 7 is —CR—, —C(R X1 )— or —N—;
p is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2; and
s is 0, 1 or 2.
9. The compound of claim 1 , wherein
(a) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X 1 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
X 2 is —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—; and
X 3 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(b) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X 2 is —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(c) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2; and
ring B is Hca or Het, each comprising a 3-8 membered ring optionally
substituted with one or two —R X2 groups;
(d) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2;
n is 0, 1 or 2;
m is 0, 1 or 2; and
X 4 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
(e) ring A is
wherein
X 6 is —O—, —S—, —S(O)—, —S(O) 2 —, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or
—N(R X1 )—; and
X 7 is —CR—, —C(R X1 )— or —N—;
p is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2; and
s is 0, 1 or 2.
10. The compound of claim 7 , wherein a is 0.
11. The compound of claim 7 , wherein a is 1.
12. The compound of claim 1 , wherein
Z is Cak(C 0 -C 6 alkyl) substituted by one to three —R Z1 groups;
wherein each —R 2 is independently halogen, cyano, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR) or Z is Cak(C 0 -C 6 alkyl) optionally substituted by one to three —R Z1 groups;
wherein each —R Z1 is independently halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
13. The compound of claim 1 , wherein
Z is Cak substituted by one to three —R Z1 groups;
wherein each —R 2 is independently halogen, cyano, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR);
or Z is Cak optionally substituted by one to three —R Z1 groups;
wherein each —R 2 is independently halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
14. The compound of any of claim 13 , wherein
Z is Cak(C 1 -C 6 alkyl) substituted by one to three —R Z1 groups;
wherein each —R Z1 is independently halogen or C 1 -C 6 haloalkyl.
15. The compound of claim 1 , having the structure of formula (III):
or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof, wherein
a is 0 or 1;
ring A is
wherein
p is 0, 1, 2 or 3;
X 2 is —O—, —S—, —CR 2 —, —C(R)(R X1 )—, —C(R X1 ) 2 —, —N(R)— or —N(R X1 )—;
wherein
p is 0, 1 or 2;
ring B is 5-membered Hca or Het; or
each —R X1 is independently hydrogen, C 1 -C 6 alkyl, —C(O)OR, Cak(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl);
—R Y1 is hydrogen or C 1 -C 6 alkyl;
Z is Cak; and
each R is independently hydrogen or C 1 -C 6 alkyl.
16. The compound of claim 1 , having the structure of formula (IV):
or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof, wherein
a is 0 or 1;
each —R X1 is independently hydrogen or C 1 -C 6 alkyl; and
—R Y1 is hydrogen or C 1 -C 6 alkyl.
17. A method of inhibiting a cellular TAM receptor, the method comprising contacting a cell comprising a TAM receptor with a compound according to claim 1 .
18. A method for treating a disease or condition mediated by or involving the TAM receptor family in a subject in need thereof, comprising administering an effective TAM receptor inhibiting amount of a compound of claim 1 , wherein the disease or condition is a hematological neoplasm.
19. The method of claim 18 , wherein the hematological neoplasm is acute myeloid leukemia AML.
20. The method of claim 17 , wherein contacting comprises administering the compound to a human subject.