Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
View Patent ↗This invention concerns N—(2-arylamino) aryl sulfonamides, which are inhibitors of MEK and are useful in treatment of cancer and other hyperproliferative diseases.
1. A compound of formula I or a pharmaceutically acceptable salt, ester, or tautomer thereof:
wherein
Z is H or F;
X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF 3 ;
Y is I, Br, Cl, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, cyclopropyl, O-Methyl, O-Ethyl, S-Methyl or phenyl; where
said phenyl group is optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO 2 , CO 2 H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl-C(═O)—, C 1 -C 3 alkyl-C(═S)—, C 1 -C 3 alkoxy-C(═S)—, C 1 -C 3 alkyl-C(═O)O—, C 1 -C 3 alkyl-O—(C═O)—, C 1 -C 3 alkyl-C(═O)NH—, C 1 -C 3 alkyl-C(═NH)NH—, C 1 -C 3 alkyl-NH—(C═O)—, di-C 1 -C 3 alkyl-N—(C═O)—, C 1 -C 3 alkyl-C(═O)N(C 1 -C 3 alkyl)-, C 1 -C 3 alkyl-S(═O) 2 NH— or trifluoromethyl;
all said methyl, ethyl, C 1 -C 3 alkyl, and cyclopropyl groups are optionally substituted with OH;
all said methyl groups are optionally substituted with one, two, or three F atoms;
R 0 is H, F, Cl, Br, I, CH 3 NH—, (CH 3 ) 2 N—, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, monosubstituted phenyl, O(C 1 -C 4 alkyl), O—C(═O)(C 1 -C 4 alkyl) or C(═O)O(C 1 -C 4 alkyl); where
said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C 1 -C 6 alkyl and C 1 -C 4 alkoxy groups are also optionally substituted with OCH 3 or OCH 2 CH 3 ;
G is G 1 , G 2 , R 1a , R 1b , R 1c , R 1d , R 1e , Ar 1 , Ar 2 or Ar 3 ; where
G 1 is C 1 -C 6 alkyl optionally substituted with one amino, or is a C 3 -C 8 diamino alkyl group;
G 2 is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms independently selected from the group consisting of O, and S, optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, OH, O(C 1 -C 3 alkyl), OCH 3 , OCH 2 CH 3 , CH 3 C(═O)NH, CH 3 C(═O)O, CN, CF 3 , and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms independently selected from the group consisting of N, O , and S;
R 1a is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C 1 -C 3 alkoxy, where said cyclopropoxy group or the C 1 -C 3 alkyl moieties of said C 1 -C 3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 -alkyl groups within said C 1 -C 3 alkoxy are optionally further substituted with a second OH group;
R 1b is CH(CH 3 )—C 1-3 alkyl or C 3 -C 6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , and CN;
R 1c is (CH 2 ) n O m R′; where
m is 0 or 1; and where
when m is 0, n is 1 or 2;
when m is 1, n is 2 or 3;
R′ is C 1 -C 6 alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6 cycloalkyl;
R 1d is C(A)(A′)(B)—; where
B is H or C 1-4 alkyl, optionally substituted with one or two OH groups;
A and A′ are independently H or C 1-4 alkyl, optionally substituted with one or two OH groups; or
A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring;
R 1e is
where
q is 1 or 2;
R 2 and R 3 are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
R 4 is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl , isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H—tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl or N—pyrrolidinylcarbonylamino;
R 5 is H, F, Cl or methyl;
R 6 is H, F, Cl or methyl;
Ar 1 is
where
U and V are, independently, N, CR 2 or CR 3 ;
R 2 , R 3 and R 4 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert -butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N—pyrrolidinylcarbonylamino, or methylsulfonyl;
R 5 and R 6 are, independently, H, F, Cl or methyl;
Ar 2 is
where
the dashed line represents alternative formal locations for the second ring double bond;
U is —S—, —O— or —N═, and where
when U is —O— or —S—, V is —CH═, —CCl═ or —N═;
when U is —N═, V is —CH═, —CCl═, or —N═;
R 7 is H or methyl;
R 8 is H, acetamido, methyl, F or Cl;
Ar 3 is
where
U is —NH—, —NCH 3 — or —O—; and
R 7 and R 8 are, independently, H, F, Cl, or methyl.
2. The compound of claim 1 , or its pharmaceutically acceptable salt.
3. The compound of claim 1 , where
G is G 1 or G 2 ;
X is F, Cl, or CH 3 ;
Y is I, Br, Cl, CF 3 , C 1 -C 3 alkyl, phenyl, which phenyl group is optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO 2 , CO 2 H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl-C(═O)—, C 1 -C 3 alkyl-C(═S)—, C 1 -C 3 alkoxy-C(═S)—, C 1 -C 3 alkyl-C(═O)O—, C 1 -C 3 alkyl-O—(C═O)—, C 1 -C 3 alkyl-C (═O)NH—, C 1 -C 3 alkyl-C(═NH)NH—, C 1 -C 3 alkyl-NH—(C═O)—, di-C 1 -C 3 alkyl-N—(C═O)—, C 1 -C 3 alkyl-C(═O)N(C 1 -C 3 alkyl)-, C 1 -C 3 alkyl-S(═O) 2 NH— or trifluoromethyl; and
Z is H or F.
4. The compound of claim 1 , where
G is G 1 or G 2 , and R 0 is F, Cl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl group and the C 1 -C 4 alkyl moiety of said C 1 -C 4 alkoxy group is optionally substituted with F, Cl, OCH 3 , or OCH 2 CH 3 .
5. The compound of claim 3 , where R 0 is H, F, Cl, C 1 -C 4 alkyl, methoxy, ethoxy, or 2-methoxy-ethoxy.
6. The compound of claim 5 , where G is G 1 .
7. The compound of claim 6 , where G 1 is N-methyl-2-aminoethyl.
8. The compound of claim 6 , where
G 1 is (CH 3 ) 2 N—CH 2 CH 2 —NH—(CH 2 ) n —, where n is 1, 2, or 3;
X is F and
Z is F.
9. The compound of claim 5 , where G is G 2 .
10. The compound of claim 9 , where G 2 is morpholyl.
11. The compound of claim 1 , where G is R 1a , R 1b , R 1c , R 1d , R 1e , Ar 1 , Ar 2 or Ar 3 .
12. The compound of claim 11 , where
X is F, Cl, or CH 3 ;
Y is I, Br, Cl, CF 3 , or C 1 -C 3 alkyl; and
Z is H or F.
13. The compound of claim 11 , where
R 0 is F, Cl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl group and the C 1 -C 4 alkyl moiety of said C 1 -C 4 alkoxy group is optionally substituted with F, Cl, OCH 3 , or OCH 2 CH 3 .
14. The compound of claim 12 , where R 0 is H, F, Cl, C 1 -C 4 alkyl, methoxy, ethoxy, or 2-methoxy-ethoxy.
15. The compound of claim 14 , where
G is R 1a ; and
Z is F.
16. The compound of claim 15 , where
G is CH 3 ;
R 0 is H; and
Y is Br, I, CF 3 , or CH 3 .
17. The compound of claim 1 , where G is R 1b .
18. The compound of claim 14 , where
G is R 1b and
Z is F.
19. The compound of claim 18 , where
R 0 is H, F, or OCH 3 ,
X is F or CH 3 , and
Y is Br, I or CH 3 .
20. The compound of claim 19 , where G is unsubstituted C 3 -C 6 cycloalkyl.
21. The compound of claim 20 , where R 0 is H.
22. The compound of claim 19 , where G is isopropyl or cyclopropyl.
23. The compound of claim 11 , where G is R 1c .
24. The compound of claim 14 , where
G is R 1c ;
Y is I, Br, CH 3 , or CF 3 ; and
Z is F.
25. The compound of claim 14 , where m is zero.
26. The compound of claim 11 , where G is R 1d .
27. The compound of claim 26 , where R 0 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino;
X is F, Cl, CH 3 , or mono-, di- or tri-fluoromethyl;
Y is I, Br, Cl, or mono-, di- or tri-fluoromethyl; and
Z is H or F.
28. The compound of claim 26 , where R 0 is F, Cl, methyl, ethyl, methoxy, ethoxy, or 2-methoxy-ethoxy;
X is F, Cl, or CH 3 ;
Y is I, Br, Cl, or mono-, di- or tri-fluoromethyl; and
Z is H or F.
29. The compound of claim 26 , where
R 0 is H; X is F, Cl, CH 3 , or mono-, di- or tri-fluoromethyl;
Y is I, Br, Cl, or mono-, di- or tri-fluoromethyl; and
Z is H or F.
30. The compound of claim 27 , where C(A)(A′) is C 3 -C 6 cycloalkyl.
31. The compound of claim 30 , where B is H.
32. The compound of claim 31 , where C(A)(A′) is cyclopropyl.
33. The compound of claim 30 , where B is methyl, optionally substituted with one OH group, or C 2 -C 4 alkyl, optionally substituted with one or two OH groups.
34. The compound of claim 33 , where C(A)(A′) is cyclopropyl.
35. The compound of claim 34 , where B is methyl, ethyl, 2-hydroxyethyl, n-propyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 1-methyl-2-hydroxy ethyl, n-butyl, sec-butyl, isobutyl, or 2-hydroxymethyl-3-hydroxy propyl.
36. The compound of claim 35 , where B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl.
37. The compound of claim 36 , in which the chiral carbon in B is in the R configuration.
38. The compound of claim 36 , in which the chiral carbon in B is in the S configuration.
39. A composition comprising a compound according to claim 37 , which is substantially free of the S isomer.
40. A composition comprising a compound according to claim 37 , which is substantially free of the R isomer.
41. The compound of claim 1 , where G is R 1e .
42. The compound of claim 1 , where n is 1.
43. The compound of claim 42 , where
R 0 is H,
R 4 - 6 are H;
R 2 and R 3 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 , O CH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, or methylsulfonyl;
X is F and
Y is I.
44. The compound of claim 1 , where G is Ar 1 .
45. The compound of claim 44 , where
G is phenyl,
optionally substituted with one group selected from the group consisting of acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4- thiadiazolyl, 1H-tetrazolyl, N—morpholylcarbonylamino, N-morpholylsulfonyl, N— pyrrolidinylcarbonylamino, and methylsulfonyl;
optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, and CH 3 ;
R 0 is H;
X is F, Cl, or methyl;
Y is Br, I, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, cyclopropyl, O CH 3 , OCH 2 CH 3 or SCH 3 .
46. The compound of claim 44 , where G is
where
R 2 and R 3 are, independently, H, F, Cl, CH 3 , CF 3 , or OCH 3 ;
X is F or CH 3 ;
Y is I, Br, or Cl; and
Z is F.
47. The compound of claim 44 , where
G is phenyl or mono-substituted phenyl;
X is F or CH 3 ;
Y is I, Br, or Cl;
Z is F; and
R 0 is F, methyl, ethyl, methoxy, or 2-methoxy-ethoxy.
48. The compound of claim 44 , where
U is N or CR 2 and
V is N.
49. The compound of claim 44 , where
U is N or CR 2 ;
V is CR 3 ;
R 0 is H,
X is F, Cl, or methyl; and
Y is Br, I, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, cyclopropyl, OCH 3 , OCH 2 CH 3 or SCH 3 .
50. The compound of claim 1 , where G is Ar 2 .
51. The compound of claim 50 , where G is
in which
R 7 is H or methyl,
R 8 is H, acetamido, methyl, F or Cl;
R 0 is H;
X is F, Cl, or methyl;
Y is Br, I, CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, cyclopropyl, OCH 3 , OCH 2 CH 3 or SCH 3 ; and
Z is F.
52. The compound of claim 51 , where
U is S or O;
V is CH═; and
R 8 is H or CH 3 .
53. The compound of claim 52 , where R 0 is H.
54. The compound of claim 53 , where
X is F or Cl and
Y is Br, I, CH 2 CH 3 or SCH 3 .
55. The compound of claim 1 , where G is Ar 3 .
56. The compound of claim 55 , where U is —O—.
57. A compound which is selected from the group consisting of:
58. A compound selected from the group consisting of
where the 2—OH carbon is in the R configuration.
59. A compound selected from the group consisting of
where the 2—OH carbon is in the S configuration.
60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of
where the 2—OH carbon is in the R configuration, substantially free of the S-isomer.
61. A pharmaceutical composition comprising a compound selected from the group consisting of
where the 2—OH carbon is in the S configuration, substantially free of the R-isomer.
62. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, or tautomer thereof according to claim 1 and a pharmaceutically acceptable carrier.
63. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from the group consisting of
and a pharmaceutically acceptable salt, and ester thereof, and a pharmaceutically acceptable carrier.
64. The pharmaceutical composition of claim 63 , where the compound is in the R configuration.
65. The pharmaceutical composition of claim 63 , where the compound is in the S configuration.
66. A method for inhibiting an MEK enzyme comprising contacting said MEK enzyme with a compound according to claim 1 sufficient to inhibit said enzyme, whereby said enzyme is inhibited.
67. The method of claim 66 , wherein said MEK enzyme is MEK kinase.
68. The method of claim 66 , wherein said contacting occurs within a cell.
69. A method of treatment of a MEK mediated disorder in an individual suffering from said disorder, which disorder is breast cancer, comprising administering to said individual an effective amount of a composition comprising a compound according to claim 1 .
70. The method of claim 69 , in combination with an additional therapy.
71. The method of claim 70 , wherein said additional therapy is radiation therapy, chemotherapy or a combination of both.
72. The method of claim 69 , further comprising administering at least one additional therapeutic agent.
73. A method of treatment of a MEK mediated disorder in an individual suffering from said disorder, which disorder is breast cancer, comprising administering to said individual an effective amount of a composition comprising a compound according to claim 57 .
74. A method of treatment of a MEK mediated disorder in an individual suffering from said disorder, which disorder is breast cancer, comprising administering to said individual an effective amount of a composition comprising a compound according to claim 58 .
75. A method of treatment of a MEK mediated disorder in an individual suffering from said disorder, which disorder is breast cancer, comprising administering to said individual an effective amount of a composition comprising a compound according to claim 59 .
76. The method of claim 69 , wherein said individual is a mammal.
77. The method of claim 76 , wherein said mammal is human.