US2019248756A1PendingUtilityA1
Bcl-3 inhibitors
Assignee: UNIV COLLEGE CARDIFF CONSULTANTS LTDPriority: Jul 31, 2014Filed: Apr 29, 2019Published: Aug 15, 2019
Est. expiryJul 31, 2034(~8 yrs left)· nominal 20-yr term from priority
A61P 35/02A61P 35/00C07D 295/13C07D 241/04C07C 237/42C07C 237/44C07D 295/125C07D 213/82C07D 213/81
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Claims
Abstract
The present application relates to compounds of any one of Formulae I, Ia, Ib, Ic, Id, Ie, and If. Compounds of Formula I have the structure: wherein A, B, Y, Z, R 2 , R 4 , R 5 , R 6 , R q and q are as defined herein. The compounds can be used as inhibitors of Bcl-3 and can be used for the treatment of cancer, particularly metastatic cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of Formula (Ia),
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 3 or N;
X 1 is CR 8 or N;
X 2 is CR 9 or N;
X 3 is CR 10 or N;
wherein zero or one of X 1 , X 2 , or X 3 is N;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), S(C 1 -C 6 alkyl), O(C 1 -C 6 haloalkyl), or S(C 1 -C 6 haloalkyl);
or R 2 and R 3 together with the carbon atoms to which they attach form a C 6 aryl ring, or R 5 and R 6 together with the carbon atoms to which they attach form a C 6 aryl ring, or R 3 and R 4 together with the carbon atoms to which they attach form a C 6 aryl ring, or R 4 and R 5 together with the carbon atoms to which they attach form a C 6 aryl ring;
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 8 , R 9 , R 10 , and Z are each, independently, hydrogen, halogen, OH, or O(C 1 -C 6 alkyl);
R 11 is OH, O(C 1 -C 6 alkyl), or —NH—(CH 2 ) q —R q , wherein:
q is 2 or 3;
R q is 1-piperazinyl, 1-(4-N—(R N ))piperazinyl, N-morpholino or phenyl; and
R N is C 1 -C 5 alkyl; and
R 12 is hydrogen or C 1 -C 6 alkyl;
wherein,
a) when A is CR 3 and R 2 is fluorine or chlorine, then R q is phenyl or 1-(4-N—(R N ))piperazinyl;
or
b) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 8 , R 9 , R 10 , and Z is not hydrogen and R 8 is not OCH 3 ;
or
c) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen or halogen; and at least three of R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen.
2 . The compound of claim 1 , being of Formula (Ib),
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 3 or N;
X 1 is CR 8 or N;
X 2 is CR 9 or N;
X 3 is CR 10 or N;
wherein zero or one of X 1 , X 2 , or X 3 is N;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), or O(C 1 -C 6 haloalkyl);
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 8 , R 9 , R 10 , and Z are each, independently, hydrogen, fluorine, OH, or O(C 1 -C 6 alkyl);
q is 2 or 3;
R N is C 1 -C 5 alkyl; and
R 12 is hydrogen or C 1 -C 6 alkyl.
3 . The compound of claim 1 being of Formula (Ic),
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CR 8 or N;
X 2 is CR 9 or N;
X 3 is CR 10 or N;
wherein zero or one of X 1 , X 2 , or X 3 is N;
R 2 and R 3 together with the carbon atoms to which they attach form a C 6 aryl ring, or R 5 and R 6 together with the carbon atoms to which they attach form a C 6 aryl ring, and
the remaining of R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), or O(C 1 -C 6 haloalkyl);
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 8 , R 9 , R 10 , and Z are each, independently, hydrogen, halogen, OH, or O(C 1 -C 6 alkyl);
q is 2 or 3;
R q is 1-piperazinyl, 1-(4-N—(R N ))piperazinyl, N-morpholino or phenyl;
R N is C 1 -C 5 alkyl;
R 12 is hydrogen or C 1 -C 6 alkyl; and
wherein,
a) when A is CR 3 and R 2 is fluorine or chlorine, then R q is phenyl or 1-(4-N—(R N ))piperazinyl,
or
b) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 8 , R 9 , R 10 , and Z is not hydrogen and R 8 is not OCH 3 .
4 . The compound of claim 1 , being of Formula (Ic),
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CR 8 or N;
X 2 is CR 9 or N;
X 3 is CR 10 or N;
wherein zero or one of X 1 , X 2 , or X 3 are N;
R 3 and R 4 together with the carbon atoms to which they attach form a C 6 aryl ring, or R 4 and R 5 together with the carbon atoms to which they attach form a C 6 aryl ring, and
R 2 , R 6 and the remaining of R 3 and R 5 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), or O(C 1 -C 6 haloalkyl);
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 8 , R 9 , R 10 , and Z are each, independently, hydrogen, halogen, OH, or O(C 1 -C 6 alkyl);
q is 2 or 3;
R q is 1-piperazinyl, 1-(4-N—(R N ))piperazinyl, N-morpholino or phenyl;
R N is C 1 -C 5 alkyl; and
R 12 is hydrogen or C 1 -C 6 alkyl;
wherein,
a) when A is CR 3 and R 2 is fluorine or chlorine, then R q is phenyl or 1-(4-N—(R N ))piperazinyl,
or
b) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 8 , R 9 , R 10 , and Z is not hydrogen and R 8 is not OCH 3 .
5 . The compound of claim 1 , being of Formula (Id),
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 3 or N;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), or O(C 1 -C 6 haloalkyl);
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 8 , R 10 , and Z are each, independently, hydrogen, fluorine, OH, or O(C 1 -C 6 alkyl);
R 11 is OH, O(C 1 -C 6 alkyl), or —NH—(CH 2 ) q — R q , wherein:
q is 2 or 3;
R q is 1-piperazinyl, 1-(4-N—(R N ))piperazinyl, N-morpholino or phenyl; and
R N is C 1 -C 5 alkyl; and
R 12 is hydrogen or C 1 -C 6 alkyl;
wherein,
a) when A is CR 3 and R 2 is fluorine or chlorine, then R q is phenyl or 1-(4-N—(R N ))piperazinyl,
or
b) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 8 , R 10 , and Z is not hydrogen and R 8 is not OCH 3 ;
or
c) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen or halogen; and at least three of R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen.
6 . The compound of claim 1 , being of Formula (Ie),
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 3 or N;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), or O(C 1 -C 6 haloalkyl);
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 8 , R 9 , and Z are each, independently, hydrogen, fluorine, OH, or O(C 1 -C 6 alkyl);
R 11 is OH, O(C 1 -C 6 alkyl), or —NH—(CH 2 ) q —R q , wherein:
q is 2 or 3;
R q is 1-piperazinyl, 1-(4-N—(R N ))piperazinyl, N-morpholino or phenyl; and
R N is C 1 -C 5 alkyl; and
R 12 is hydrogen or C 1 -C 6 alkyl;
wherein,
a) when A is CR 3 and R 2 is fluorine or chlorine, then R q is phenyl or 1-(4-N—(R N ))piperazinyl,
or
b) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 8 , R 9 , and Z is not hydrogen and R 8 is not OCH 3 ;
or
c) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen or halogen; and at least three of R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen.
7 . The compound of claim 1 , being of Formula (If),
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 3 or N;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen, C 1 -C 6 haloalkyl, NO 2 , NR a R b , OH, O(C 1 -C 6 alkyl), or O(C 1 -C 6 haloalkyl);
R a and R b are each, independently, hydrogen or C 1 -C 6 alkyl;
R 9 , R 10 , and Z are each, independently, hydrogen, fluorine, OH, or O(C 1 -C 6 alkyl);
R 11 is OH, O(C 1 -C 6 alkyl), or —NH—(CH 2 ) q —R q , wherein:
q is 2 or 3;
R q is 1-piperazinyl, 1-(4-N—(R N ))piperazinyl, N-morpholino or phenyl; and
R N is C 1 -C 5 alkyl; and
R 12 is hydrogen or C 1 -C 6 alkyl;
wherein,
a) when A is CR 3 and R 2 is fluorine or chlorine, then R q is phenyl or 1-(4-N—(R N ))piperazinyl,
or
b) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino, then at least one of R 9 , R 10 , and Z is not hydrogen and R 8 is not OCH 3 ;
or
c) when A is CR 3 , R 2 is fluorine or chlorine, q is 2 and R q is N-morpholino at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen or halogen; and at least three of R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen.
8 . The compound of claim 1 , selected from
or a pharmaceutically acceptable salt thereof.
9 . The compound according to claim 8 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
10 . A method for the treatment of cancer, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 1 .
11 . The method of claim 10 , wherein the cancer is leukaemia or lymphoma.
12 . The method of claim 11 , wherein the cancer is anaplastic large cell lymphoma (ALCL), Classic Hodgkin lymphoma (cHL), non-Hodgkin's lymphoma; or a solid tumour cancer.
13 . The method of claim 12 , wherein the solid tumour cancer is breast cancer, melanoma, lung cancer, pancreatic cancer, oesophageal cancer, colorectal cancer, nasopharyngeal carcinoma, or hepatocarcinoma.
14 . A method according to claim 10 , wherein the treatment comprises the treatment or prevention of metastasis in cancer.
15 . A method according to claim 10 wherein the cancer is breast cancer.
16 . A method according to claim 10 wherein the cancer is triple negative breast cancer or HER2 enriched breast cancer.
17 . A method according to claim 10 wherein the compound is to be used in combination with one or more additional active agents which are useful in the treatment of cancer.
18 . A method according to claim 17 , wherein the one or more additional active agents are selected from:
anti-HER2 agents; standard adjuvant therapy regimens; and anti-angiogenic/antimetastatic agents.
19 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically or veterinarily acceptable excipient or carrier.
20 . A process for the preparation of a pharmaceutical composition according to claim 87 , the process comprising bringing the compound according to claim 1 into association with a pharmaceutically or veterinarily acceptable excipient or carrier.Join the waitlist — get patent alerts
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