US2013150358A1PendingUtilityA1
Theramutein modulators
Assignee: HMI MEDICAL INNOVATIONS LLCPriority: May 23, 2004Filed: Feb 4, 2013Published: Jun 13, 2013
Est. expiryMay 23, 2024(expired)· nominal 20-yr term from priority
Inventors:Gerard M. Housey
A61P 35/00A61P 43/00A61P 31/00A61P 31/18G01N 33/575G01N 33/5041C07D 239/48C07D 401/12G01N 33/5011A61K 31/53C07D 253/065A61K 31/175C07D 409/12A61K 31/44A61K 31/495A61K 31/4709C07D 215/50G01N 33/502A61K 31/517C07D 213/81C07D 213/77A61K 31/166A61K 31/4436C07D 239/84A61K 31/506C07D 253/075C07D 405/12A61K 31/195G01N 2500/00C07D 239/42C07D 213/87G01N 2500/10C07D 403/12C07D 215/38C07D 213/86G01N 33/573A61K 31/415C12Q 1/485A61K 31/444A61K 31/4196A61K 31/5377C07C 243/38A61K 31/505G01N 2333/91215A61K 31/27G01N 2333/912A61K 31/47C07D 231/14
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Claims
Abstract
This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a neoplastic disease or a proliferative disorder in a human comprising administering a therapeutically effective amount of a compound having the formula I
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 2 is selected from —CR 21 a —, —NR 22 b —, and —(C═R 23 )—;
each R 21 is independently selected from H, halo, —NH 2 , —N(H)(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —O—(C 1-3 alkyl), OH and C 1-3 alkyl;
each R 22 is independently selected from H and C 1-3 alkyl;
R 23 is selected from O, S, N—R 0 , and N—OR 0 ;
R 3 is selected from —CR 31 c —, —NR 32 d —, and —(C═R 33 )—;
each R 31 group is selected from H, halo, —NH 2 , —N(H)(R 0 ), —N(R 0 ) 2 , —O—R 0 , OH and C 1-3 alkyl;
each R 32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
R 33 is selected from O, S, N—R 34 , and N—OR 0 ;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 4 is selected from —CR 41 e —, —NR 42 f —, —(C═R 43 )—, and —O—;
each R 41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
each R 42 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
each R 43 is selected from O, S, N—R 0 , and N—OR 0 ;
with the provisos that when R 2 is —NR 22 b — and R 4 is —NR 42 f —, then R 3 is not —NR 32 d —; and that both R 3 and R 4 are not simultaneously selected from —(C═R 33 )— and —(C═R 43 )—, respectively;
R 5 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, NR 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
a is 1 or 2;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
e is 1 or 2; and
f is 0 or 1.
2 . The method of claim 1 wherein X 1 is N.
3 . The method of claim 2 wherein X 2 is N.
4 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula I a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
each R 22 is independently selected from H and C 1-3 alkyl;
R 3 is selected from —CR 31 c —, —NR 32 d —, and —(C═R 33 )—;
each R 31 group is selected from H, halo, —NH 2 , —N(H)(R 0 ), —N(R 0 ) 2 , —O—R 0 , OH and C 1-3 alkyl;
each R 32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
R 33 is selected from O, S, N—R 34 , and N—OR 0 ;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 4 is selected from —CR 41 e —, —NR 42 f —, —(C═R 43 )—, and —O—;
each R 41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
each R 42 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
each R 43 is selected from O, S, N—R 0 , and N—OR 0 ;
with the provisos that when R 4 is —NR 42 f —, then R 3 is not —NR 32 d —; and that both R 3 and R 4 are not simultaneously selected from —(C═R 33 )— and —(C═R 43 )—, respectively;
R 5 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, N—R 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
a is 1 or 2;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
e is 1 or 2; and
f is 0 or 1.
5 . The method of claim 4 wherein X 1 is N.
6 . The method of claim 5 wherein X 2 is N.
7 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula I b
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
each R 22 is independently selected from H and C 1-3 alkyl;
each R 32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
R 4 is selected from —CR 41 e —, —(C═R 43 )—, and —O—;
each R 41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
each R 43 is selected from O, S, N—R 0 , and N—OR 0 ;
R 5 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, N—R 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
a is 1 or 2;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
e is 1 or 2; and
f is 0 or 1.
8 . The method of claim 7 wherein X 1 is N.
9 . The method of claim 8 wherein X 2 is N.
10 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula II
wherein
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
R 9 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, N—R 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
11 . The method of claim 10 wherein X 1 is N.
12 . The method of claim 11 wherein X 2 is N.
13 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula II a
wherein
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
X 3 is N, CH or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
14 . The method of claim 13 wherein X 1 is N.
15 . The method of claim 14 wherein X 2 is N.
16 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula II b
wherein:
R 14 is selected from H and F;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
X 3 is N, CH or C—R 60 ;
each R 60 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 0 , halo, aryl, and a heterocyclic ring;
R 61 is selected from aryl and a heterocyclic ring;
Q is selected from a chemical bond or a group having the formula —O—, —(CH 2 ) i —, —(CH 2 ) i C(O)(CH 2 ) j —, —(CH 2 ) i —N(R 62 )—(CH 2 ) j —, —(CH 2 ) i C(O)—N(R 62 )—(CH 2 ) j —, —(CH 2 ) i C(O)O(CH 2 ) j —, —(CH 2 ) i —N(R 62 )C(O)—(CH 2 ) j —, —(CH 2 ) i OC(O)N(R 62 )—(CH 2 ) j —, and —O—(CH 2 ) i —C(O)N(R 62 )—(CH 2 ) j —;
R 62 is selected from aryl, and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
h is 0 to 4;
i is 0 to 4; and
j is 0 to 4.
17 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula III
wherein
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 10 is selected from —Y′—R 18 ;
Y′ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 18 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
18 . The method of claim 17 wherein X 1 is N.
19 . The compound of claim 18 wherein X 2 is N.
20 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula III a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
X 3 is N, CH or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
21 . The method of claim 20 wherein X 1 is N.
22 . The method of claim 21 wherein X 2 is N.
23 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula IV
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 22 is selected from H and C 1-3 alkyl;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 44 is selected from H, alkyl, cycloalkyl, —(C═O)R 0 , alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 45 is selected from —Y″—R 19 ;
Y″ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 ) 2 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
24 . The method of claim 23 wherein X 1 is N.
25 . The method of claim 24 wherein X 2 is N.
26 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula V
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 22 is selected from H and C 1-3 alkyl;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 56 is selected from —Y″—R 19 ;
Y″ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
27 . The method of claim 26 wherein X 1 is N.
28 . The method of claim 27 wherein X 2 is N.
29 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula V a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
X 3 is N or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
30 . The method of claim 29 wherein X 1 is N.
31 . The method of claim 30 wherein X 2 is N.
32 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula VI
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 56 is selected from —Y″—R 19 ;
Y″ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
33 . The method of claim 32 wherein X 1 is N.
34 . The method of claim 33 wherein X 2 is N.
35 . The method of claim 1 , comprising administering a therapeutically effective amount of a compound having the formula VI a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
X 3 is N or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
36 . The compound of claim 35 wherein X 1 is N.
37 . The compound of claim 36 wherein X 2 is N.
38 . A method of inhibiting P210 BCR-ABL-T315I theramutein comprising administering to a human a compound having the formula I
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) p R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 2 is selected from —CR 21 a —, —NR 22 b —, and —(C═R 23 )—;
each R 21 is independently selected from H, halo, —NH 2 , —N(H)(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —O—(C 1-3 alkyl), OH and C 1-3 alkyl;
each R 22 is independently selected from H and C 1-3 alkyl;
R 23 is selected from O, S, N—R 0 , and N—OR 0 ;
R 3 is selected from —CR 31 c —, —NR 32 d —, and —(C═R 33 )—;
each R 31 group is selected from H, halo, —NH 2 , —N(H)(R 0 ), —N(R 0 ) 2 , —O—R 0 , OH and C 1-3 alkyl;
each R 32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
R 33 is selected from O, S, N—R 34 , and N—OR 0 ;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 4 is selected from —CR 41 e —, —NR 42 f —, —(C═R 43 )—, and —O—;
each R 41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
each R 42 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
each R 43 is selected from O, S, N—R 0 , and N—OR 0 ;
with the provisos that when R 2 is —NR 22 b — and R 4 is —NR 42 f —, then R 3 is not —NR 32 d —; and that both R 3 and R 4 are not simultaneously selected from —(C═R 33 )— and —(C═R 43 )—, respectively;
R 5 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, NR 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
a is 1 or 2;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
e is 1 or 2; and
f is 0 or 1.
39 . The method of claim 38 comprising administering a compound having the formula I a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
each R 22 is independently selected from H and C 1-3 alkyl;
R 3 is selected from —CR 31 c —, —NR 32 d —, and —(C═R 33 )—;
each R 31 group is selected from H, halo, —NH 2 , —N(H)(R 0 ), —N(R 0 ) 2 , —O—R 0 , OH and C 1-3 alkyl;
each R 32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
R 33 is selected from O, S, N—R 34 , and N—OR 0 ;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 4 is selected from —CR 41 e —, —NR 42 f —, —(C═R 43 )—, and —O—;
each R 41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
each R 42 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
each R 43 is selected from O, S, N—R 0 , and N—OR 0 ;
with the provisos that when R 4 is —NR 43 f —, then R 3 is not —NR 32 d —; and that both R 3 and R 4 are not simultaneously selected from —(C═R 33 )— and —(C═R 43 )—, respectively;
R 5 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, N—R 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
a is 1 or 2;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
e is 1 or 2; and
f is 0 or 1.
40 . The method of claim 38 comprising administering a compound having the formula I b
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
each R 22 is independently selected from H and C 1-3 alkyl;
each R 32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , aryl, and a heterocyclic ring;
R 4 is selected from —CR 41 e —, —(C═R 43 )—, and —O—;
each R 41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
each R 43 is selected from O, S, N—R 0 , and N—OR 0 ;
R 5 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, N—R 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 ), N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
a is 1 or 2;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
e is 1 or 2; and
f is 0 or 1.
41 . The method of claim 38 comprising administering a compound having the formula II
wherein
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
R 9 is selected from —Y—R 6 and —Z—R 7 ;
Y is selected from a chemical bond, O, N—R 0 ,
R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
Z is a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 ), N(R 0 ) 2 , NO 2 , and OR 0 ;
R 7 is H or is selected from aryl and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
42 . The method of claim 38 comprising administering a compound having the formula II a
wherein
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
X 3 is N, CH or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
43 . The method of claim 38 comprising administering a compound having the formula II b
wherein:
R 14 is selected from H and F;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
X 3 is N, CH or C—R 60 ;
each R 60 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 0 , halo, aryl, and a heterocyclic ring;
R 61 is selected from aryl and a heterocyclic ring;
Q is selected from a chemical bond or a group having the formula —O—, —(CH 2 ) i —, —(CH 2 ) i C(O)(CH 2 ) j —, —(CH 2 ) i —N(R 62 )—(CH 2 ) j —, —(CH 2 ) i C(O)—N(R 62 )—(CH 2 ) j —, —(CH 2 ) i C(O)O(CH 2 ) j —, —(CH 2 ) i N(R 62 )C(O)—(CH 2 ) j —, —(CH 2 ) i OC(O)N(R 62 )—(CH 2 ) j —, and —O—(CH 2 ) i —C(O)N(R 62 )—(CH 2 ) j —;
R 62 is selected from aryl, and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
h is 0 to 4;
i is 0 to 4; and
j is 0 to 4.
44 . The method of claim 38 comprising administering a compound having the formula III
wherein
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 10 is selected from —Y′—R 18 ;
Y′ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 18 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
45 . The method of claim 38 comprising administering a compound having the formula III a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
X 3 is N, CH or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
46 . The method of claim 38 comprising administering a compound having the formula IV
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 22 is selected from H and C 1-3 alkyl;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 44 is selected from H, alkyl, cycloalkyl, —(C═O)R 0 , alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 45 is selected from —Y″—R 19 ;
Y″ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
47 . The method of claim 38 comprising administering a compound having the formula V
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 22 is selected from H and C 1-3 alkyl;
R 34 is selected from H, NO 2 , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 56 is selected from —Y″—R 19 ;
Y″ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
48 . The method of claim 38 comprising administering a compound having the formula V a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
X 3 is N or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
49 . The method of claim 38 comprising administering a compound having the formula VI
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 56 is selected from —Y″—R 19 ;
Y″ is selected from a chemical bond, O, NR 0 —, and a hydrocarbon chain having from 1 to 4 carbon atoms, and optionally substituted with one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0 , C(O)R 0 , C(O)N(R 0 ) 2 , CN, CF 3 , N(R 0 ) 2 , NO 2 , and OR 0 ;
R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3 , aryl, and a heterocyclic ring; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
50 . The method of claim 38 comprising administering a compound having the formula VI a
wherein:
ring A is a 5-, 6-, or 7-membered ring or a 7- to 12-membered fused bicyclic ring;
X 1 is selected from N, N—R 0 or C—R 1 ;
X 2 is selected from N, N—R 0 or C—R 1 ;
the dotted lines represent optional double bonds;
each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 11 , —(CH 2 ) p C(O)(CH 2 ) q R 11 , —(CH 2 ) p C(O)N(R 12 )(R 13 ), —(CH 2 ) p C(O)O(CH 2 ) q R 11 , —(CH 2 ) p N(R 11 )C(O)R 11 , —(CH 2 ) p N(R 12 )(R 13 ), —N(R 11 )SO 2 R 11 , —OC(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
n is 0 to 6,
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
p is 0 to 4;
q is 0 to 4;
R 55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
X 3 is N or C—R 50 ;
each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 51 , —(CH 2 ) r C(O)(CH 2 ) s R 51 , —(CH 2 ) r C(O)N(R 52 )(R 53 ), —(CH 2 ) r C(O)O(CH 2 ) s R 51 , —(CH 2 ) r N(R 51 )C(O)R 51 , —(CH 2 ) r N(R 52 )(R 53 ), —N(R 51 )SO 2 R 51 , —OC(O)N(R 52 )(R 53 ), —SO 2 N(R 52 )(R 53 ), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 50 groups on adjacent ring atoms form a 5- or 6-membered fused ring which contains from 0 to 3 heteroatoms;
R 51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring;
R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
r is 0 to 4;
s is 0 to 4;
m is 0 to 4; and
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.
51 . The compound having the formula II b
wherein:
R 14 is selected from H and F;
R 8 is selected from the group consisting of is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0 , C(O)R 0 , aralkyl, aryl, and a heterocyclic ring;
X 3 is N, CH or C—R 60 ;
each R 60 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3 , NO 2 , OR 0 , halo, aryl, and a heterocyclic ring;
R 61 is selected from aryl and a heterocyclic ring;
Q is selected from a chemical bond or a group having the formula —O—, —(CH 2 ) i —, —(CH 2 ) i C(O)(CH 2 ) j —, —(CH 2 ) i —N(R 62 )—(CH 2 ) j —, —(CH 2 ) i C(O)—N(R 62 )—(CH 2 ) j —, —(CH 2 ) i C(O)O(CH 2 ) j —, —(CH 2 ) i N(R 62 )C(O)—(CH 2 ) j —, —(CH 2 ) i OC(O)N(R 62 )—(CH 2 ) j —, and —O—(CH 2 ) i —C(O)N(R 62 )—(CH 2 ) j —;
R 62 is selected from aryl, and a heterocyclic ring;
each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;
h is 0 to 4;
i is 0 to 4; and
j is 0 to 4.
52 . A method for determining whether a substance is an inhibitor or an activator of a theramutein which is capable of eliciting a detectable phenoresponse, which comprises:
a) incubating a first cell which expresses the theramutein at a substantially constant level with the substance; b) incubating a second cell which expresses a corresponding prototheramutein at a substantially constant level with a known inhibitor or activator of the prototheramutein; c) comparing a phenoresponse of the second cell to the known inhibitor or activator of the prototheramutein to the phenoresponse of the first cell to the substance; and d) determining that the phenoresponse of the first cell is inhibited or activated to at least the same degree as the phenoresponse of the second cell is inhibited or activated by the known inhibitor or activator of the prototheramutein, thereby identifying the substance as an inhibitor or an activator of the theramutein.
53 . The method of claim 52 , wherein the phenoresponse of the cell expressing the theramutein to the substance is greater than the phenoresponse of the cell expressing the prototheramutein to the known inhibitor or activator of the theramutein.
54 . A method for determining whether a substance is a specific inhibitor or specific activator of a theramutein, which comprises:
a) providing a test cell which expresses the theramutein and which gives rise to a detectable phenoresponse; b) treating the test cell with the substance; c) examining the treated cell to determine whether the phenoresponse is modulated by treatment with the substance.
55 . The method of claim 52 or 54 , wherein the theramutein or prototheramutein is a component of a signal transduction cascade.
56 . The method of claim 52 or 54 , wherein the theramutein or prototheramutein is an enzyme.
57 . The method of claim 52 or 54 , wherein the theramutein or prototheramutein is a protein kinase.
58 . The method of claim 52 or 54 , wherein the theramutein or prototheramutein is a tyrosine kinase.
59 . The method of claim 52 or 54 , wherein the theramutein or prototheramutein is a receptor tyrosine kinase.
60 . The method of claim 52 or 54 , wherein the or prototheramutein is p210 Bcr-Abl .
61 . The method of claim 52 or 54 , wherein the or prototheramutein is the T315I mutant of p210 Bcr-Abl .
62 . The method of claim 52 or 54 , wherein the phenoresponse is a change in a cultural, morphological, or transient characteristic of the cell.
63 . The method of claim 52 or 54 , wherein the phenoresponse includes phosphorylation of an intracellular substrate of the theramutein.
64 . The method of claim 52 or 54 , wherein the phenoresponse is detected on a subcellular fraction of the cell.Join the waitlist — get patent alerts
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