US2016310499A1PendingUtilityA1
Highly Active Anti-Neoplastic and Anti-Proliferative Agents
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
A61P 37/02A61P 43/00A61P 35/00A61P 35/02A61P 37/06C07D 487/20A61K 47/545A61K 47/6867A61P 17/02A61K 31/527A61P 17/06A61P 1/04A61K 31/5377A61K 31/529A61P 17/10A61P 19/02C07D 487/14A61K 51/0468A61K 51/0459A61K 47/4863A61K 47/6803
60
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Claims
Abstract
This invention is in the area of improved compounds and methods for treating selected cancers and hyperproliferative disorders.
Claims
exact text as granted — not AI-modified1 . A method for the treatment of abnormal B-cell proliferation that comprises administering an effective amount of a Compound of Formula I, II, III, IV, or V to a host in need thereof:
or a pharmaceutically acceptable salt thereof;
wherein:
Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;
each X is independently CH or N;
each X′ is independently, CH or N;
X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;
R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)m-C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(0)-NR 3 R 4 ; -(alkylene) m -0-R 5 , -(alkylene) m -S(0) n -R 5 , or -(alkylene) m -S(0)n-NR 3 R 4 any of which may be optionally independently substituted with one or more R groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
each R 1 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 1 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, 3 or 4;
R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 1 or 2;
R 3 and R 4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 5 and R 5 * at each occurrence is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance;
R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 )-(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:
said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)O R 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,
n is 0, 1 or 2, and
m is 0 or 1;
R 3 * and R 4 * at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance; and
R 6 is H or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(0)-NR 3 R 4 ; -(alkylene) m -0-R 5 , -(alkylene) m -S(0) n -R 5 , or -(alkylene) m -S(0) n -NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and
R 10 is (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A .
2 . The method of claim 1 , wherein the Compound is selected from the group consisting of
Structure Reference
Structure
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O
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AA
BB
CC
DD
EE
FF
GG
HH
II
JJ
KK
LL
MM
NN
OO
PP
QQ
RR
SS
TT
UU
VV
WW
XX
YY
ZZ
AAA
BBB
CCC
DDD
EEE
FFF
GGG
HHH
III
JJJ
KKK
LLL
MMM
NNN
OOO
PPP
QQQ
RRR
SSS
TTT
UUU
VVV
WWW
XXX
3 . The method of claim 2 , wherein the Compound is Compound Q or its pharmaceutically acceptable salt.
4 . The method of claim 2 , wherein the Compound is Compound T or its pharmaceutically acceptable salt.
5 . The method of claim 2 , wherein the Compound is Compound U or its pharmaceutically acceptable salt.
6 . The method of claim 2 , wherein the Compound is Compound GG or its pharmaceutically acceptable salt.
7 . The method of claim 2 , wherein the Compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.
8 . The method of claim 2 , wherein the Compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.
9 . The method of claim 2 , wherein the Compound is selected from the group consisting of Compound AAA through ZZZ, or its pharmaceutically acceptable salt.
10 . The method of claim 1 , wherein the abnormal B-cell proliferation is B-cell lymphoma.
11 . The method of claim 1 , wherein the abnormal B-cell proliferation is B-cell leukemia.
12 . The method of claim 1 , wherein the Compound is conjugated to a targeting agent.
13 . The method of claim 1 , wherein the targeting agent is an antibody or antibody fragment.
14 . The method of claim 1 , wherein the Compound is conjugated to a radioisotope.
15 . The method of claim 1 , wherein the host is a human.
16 . The method of claim 2 , wherein the host is a human.
17 . The method of claim 10 , wherein the host is a human.
18 . The method of claim 11 , wherein the host is a human.
19 . A method for the treatment of an autoimmune disease that comprises administering an effective amount of a Compound of Formula I, II, III, IV, or V to a host in need thereof:
or a pharmaceutically acceptable salt thereof;
wherein:
Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;
each X is independently CH or N;
each X′ is independently, CH or N;
X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;
R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)m-C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(0)-NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(0) n -R 5 , or -(alkylene) m -S(0) n -NR 3 R 4 any of which may be optionally independently substituted with one or more R groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
each R 1 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 1 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, 3 or 4;
R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n -NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 1 or 2;
R 3 and R 4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 5 and R 5 * at each occurrence is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance;
R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 )-(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:
said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)O R 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,
n is 0, 1 or 2, and
m is 0 or 1;
R 3 * and R 4 * at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance; and
R 6 is H or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(0)-NR 3 R 4 ; -(alkylene) m -0-R 5 , -(alkylene) m -S(0) n -R 5 , or -(alkylene) m -S(0) n -NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and
R 10 is (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A .
20 . The method of claim 19 , wherein the Compound is selected from the group consisting of
Structure
Reference
Structure
A
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AA
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CC
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GG
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KK
LL
MM
NN
OO
PP
QQ
RR
SS
TT
UU
VV
WW
XX
YY
ZZ
AAA
BBB
CCC
DDD
EEE
FFF
GGG
HHH
III
JJJ
KKK
LLL
MMM
NNN
OOO
PPP
QQQ
RRR
SSS
TTT
UUU
VVV
WWW
XXX
21 . The method of claim 20 , wherein the Compound is Compound Q or its pharmaceutically acceptable salt.
22 . The method of claim 20 , wherein the Compound is Compound T or its pharmaceutically acceptable salt.
23 . The method of claim 20 , wherein the Compound is Compound U or its pharmaceutically acceptable salt.
24 . The method of claim 20 , wherein the Compound is Compound GG or its pharmaceutically acceptable salt.
25 . The method of claim 20 , wherein the Compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.
26 . The method of claim 20 , wherein the Compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.
27 . The method of claim 20 , wherein the Compound is selected from the group consisting of Compound AAA through ZZZ, or its pharmaceutically acceptable salt.
28 . The method of claim 19 , wherein the autoimmune disease is arthritis.
29 . The method of claim 19 , wherein the autoimmune disease is psoriasis.
30 . The method of claim 19 , wherein the autoimmune disease is Crohn's disease.
31 . The method of claim 19 , wherein the autoimmune disease is lupus.
32 . The method of claim 19 , wherein the Compound is conjugated to a targeting agent.
33 . The method of claim 32 , wherein the targeting agent is an antibody or antibody fragment.
34 . The method of claim 19 , wherein the Compound is conjugated to a radioisotope.
35 . The method of claim 28 , wherein the host is a human.
36 . The method of claim 29 , wherein the host is a human.
37 . The method of claim 30 , wherein the host is a human.
38 . The method of claim 1 , wherein the Compound is administered in combination therapy with a second active agent.
39 . The method of claim 19 , wherein the Compound is administered in combination therapy with a second active agent.Cited by (0)
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