Alpha helix mimetic compositions for treating cancer and other CBP/catenin-mediated diseases and conditions
Alpha-helix mimetic structures and compounds represented by the formula (I) wherein the general formula and the definition of each symbol are as defined in the specification, a compound relating thereto, and methods relating thereto, are disclosed. Applications of these compounds in the treatment of medical conditions, e.g., cancer diseases, fibrotic diseases, and pharmaceutical compositions comprising the mimetics are further disclosed.
1. A compound having the following general formula (I):
wherein
A is —(CHR 7 )—;
wherein
R 7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;
B and E are the same or different and independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, and wherein B and E do not form an optionally substituted spiro ring indicated by dashed lines;
G is —NH—, —NR 6 —, —O—, —CH 2 —, —CHR 6 — or —C(R 6 ) 2 —;
wherein
each R 6 is the same or different and independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
R l is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and
R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
with the proviso that
1) when Rb is optionally substituted lower alkylene, then W 22 should be —O— or —NH—,
2) when E and B are hydrogen, then R 3 should be hydrogen,
3) when G is —NH—, —CH 2 —, —CHR 6 — or —NR 6 —, then neither B nor E should be hydrogen, and
4) when G is —O—, B and E are hydrogen and R 3 is hydrogen, then R 1 should not be 8-quinolylmethyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 ,
wherein
B and E are the same or different and independently selected from hydrogen, and optionally substituted alkyl.
3. The compound of claim 1
wherein
G is —NR 6 —, —O—, —CH 2 — or —C(R 6 ) 2 —;
wherein
each R 6 is the same or different and independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.
4. The compound of claim 1
wherein
A is —(CHR 7 )—;
wherein
R 7 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl.
5. The compound of claim 1
wherein
R 1 is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl.
6. The compound of claim 1
wherein
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
7. The compound of claim 1 ,
wherein
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted aryl or optionally substituted heteroaryl.
8. The compound of claim 7 ,
wherein
R 10 is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
9. The compound of claim 1 ,
wherein
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted aryl or optionally substituted heteroaryl.
10. The compound of claim 9 ,
wherein
R 20 is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
11. The compound of claim 1 ,
wherein
R 3 is selected from hydrogen and C 1-4 lower alkyl group.
12. The compound of claim 1 ,
wherein
R 7 of A is -Rc-R 70
wherein
Rc is bond or optionally substituted lower alkylene, and
R 70 is optionally substituted aryl or optionally substituted heteroaryl.
13. The compound of claim 12 ,
wherein
R 70 is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
14. The compound of claim 1 ,
wherein
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene, and
R 10 is optionally substituted aryl, or optionally substituted heteroaryl, and
R 3 is selected from hydrogen and C 1-4 lower alkyl group.
15. The compound of claim 1 ,
wherein
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted aryl or optionally substituted heteroaryl; and
R 3 is selected from hydrogen and C 1-4 lower alkyl group.
16. The compound of claim 1 ,
wherein
R 7 of A is -Rc-R 70
wherein
Rc is bond or optionally substituted lower alkylene, and
R 70 is optionally substituted aryl or optionally substituted heteroaryl; and
R 3 is selected from hydrogen and C 1-4 lower alkyl group.
17. The compound of claim 2 ,
wherein
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene, and
R 10 is optionally substituted allyl and
R 3 is selected from hydrogen or C 1-4 lower alkyl group.
18. The compound of claim 2 ,
wherein
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted aryl or optionally substituted heteroaryl, and
R 3 is selected from hydrogen and C 1-4 lower alkyl group.
19. The compound of claim 2 ,
wherein
R 7 of A is -Rc-R 70
wherein
Rc is bond or optionally substituted lower alkylene, and
R 70 is optionally substituted aryl or optionally substituted heteroaryl; and
R 3 is selected from hydrogen and C 1-4 lower alkyl group.
20. The compound of claim 1 ,
wherein
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene, and
R 10 is optionally substituted aryl, or optionally substituted heteroaryl,
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene;
R 20 is optionally substituted aryl or optionally substituted heteroaryl;
R 3 is selected from hydrogen and C 1-4 lower alkyl group;
R 7 of A is -Rc-R 70
wherein
Rc is bond or optionally substituted lower alkylene, and
R 70 is optionally substituted aryl or optionally substituted heteroaryl.
21. The compound of claim 14 ,
wherein
R 10 is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
22. The compound of claim 15 ,
wherein
R 20 is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
23. The compound of claim 16 ,
wherein
R 70 is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
24. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or diluent.
25. A library of compounds, comprising at least one compound according to claim 1 .
26. A process for preparing a compound having the following general formula (I):
wherein
A is —(CHR 7 )—;
wherein
R 7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;
B and E are the same or different and independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, and wherein B and E do not form an optionally substituted spiro ring indicated by dashed lines;
G is —NH—, —NR 6 —, —O—, —CH 2 —, —CHR 6 — or —C(R 6 ) 2 —;
wherein
each R 6 is the same or different and independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;
R 2 is —W 21 —W 22 —Rb—R 20 ;
wherein
W 21 is —(CO)— or —(SO 2 )—;
W 22 is bond, —O—, —NH— or optionally substituted lower alkylene;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and
R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
with the proviso that
1) when Rb is optionally substituted lower alkylene, then W 22 should be —O— or —NH—,
2) when E and B are hydrogen, then R 3 should be hydrogen,
3) when G is —NH—, —CH 2 —, —CHR 6 — or —NR 6 —, then neither B nor E should be hydrogen, and
4) when G is —O—, B and E are hydrogen and R 3 is hydrogen, then R 1 should not be 8-quinolylmethyl;
or a salt thereof, which comprises reacting a compound having the following general formula (II):
wherein
R 91 is selected from optionally substituted alkyl, linker and solid support;
R 92 is selected from optionally substituted alkyl, linker and solid support; and
the other symbols are as defined above, or a salt thereof, with an acid.