Alpha helix mimetics and methods relating thereto
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 chemical library 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
is single bond or double bond;
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 is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G and Y are independently carbon atom or nitrogen atom;
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 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
when B is benzene, and R 2 is —W 21 —W 22 —Rb—R 20 , wherein W 21 is —(CO)—, W 22 is —NH—, and Rb is bond, then R 20 should not be optionally substituted phenyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 ,
wherein
R 3 is hydrogen or optionally substituted alkyl.
3. The compound of claim 1 , which has the following general formula (I-d):
wherein
is single bond or double bond;
A is —(CHR)—;
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 is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G is carbon atom or nitrogen atom;
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
when B is benzene, and R 2 is —W 21 —W 22 —Rb 20 , wherein W 21 is —(CO)—, W 22 is —NH—, and Rb is bond, then R 20 should not be optionally substituted phenyl.
4. The compound of claim 1 ,
wherein
B is optionally substituted 5-membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y.
5. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
6. A compound having the following general formula (II):
wherein
is single bond or double bond;
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 is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G and Y are independently carbon atom or nitrogen atom;
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 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;
R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
R 91 is selected from optionally substituted alkyl, linker and solid support; and
R 92 is selected from optionally substituted alkyl, linker and solid support;
with the proviso that
when B is benzene, and R 21 is W 21 —W 22 —Rb—R 20 , wherein W 21 is —(CO)—, W 22 is —NH—, and Rb is bond, then R 20 should not be optionally substituted phenyl;
or a salt thereof.
7. A process for preparing a compound having the following general formula (I):
wherein
is single bond or double bond;
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 is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G and Y are independently carbon atom or nitrogen atom;
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 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
when B is benzene, and R 2 is —W 21 —W 22 —Rb—R 20 , wherein W 21 is —(CO)—, W 22 is —NH—, and Rb is bond, then R 20 should not be optionally substituted phenyl;
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.