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 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 C 6-14 aryl-alkyl, optionally substituted 5-14 membered heteroaryl-alkyl, optionally substituted C 3-10 cycloalkyl-alkyl, optionally substituted 3-10 membered heterocycloalkyl-alkyl, optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted C 3-10 cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl;
G is —NH— or —NR 6 —,
wherein
R 6 is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;
R 1 is Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted bicyclic fused aryl or optionally substituted bicyclic fused 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; and
R 20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted C 3-10 cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl; and
R 3 is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
wherein
the heteroaryl is a monocyclic or bicyclic aromatic radical wherein at least one ring atom is a heteroatom selected from the group consisting nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon; and
wherein the heterocycloalkyl is cycloalkyl provided that at least one of the atoms forming the ring is a heteroatom selected from the group consisting nitrogen, oxygen, and sulfur;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 ,
wherein
R 7 is optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-14 aryl-alkyl, optionally substituted 5-14 membered heteroaryl-alkyl, optionally substituted C 3-10 cycloalkyl-alkyl or optionally substituted 3-10 membered heterocycloalkyl-alkyl.
3. The compound of claim 1 ,
wherein
R 2 is —W 21 —W 22 —Rb—R 20 ,
wherein
W 21 is —(CO)—;
W 22 is —NH—;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted C 3-10 cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl.
4. The compound of claim 1 ,
wherein
R 3 is C 1-4 alkyl.
5. The compound of claim 1 ,
wherein
R 7 is optionally substituted C 6-14 aryl-alkyl, optionally substituted 5-14 membered heteroaryl-alkyl, optionally substituted C 3-10 cycloalkyl-alkyl or optionally substituted 3-10 membered heterocycloalkyl-alkyl.
6. The compound of claim 1 ,
wherein
G is —NH— or —NR 6 —,
wherein
R 6 is lower alkyl or lower alkenyl.
7. The compound of claim 1 ,
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted naphthyl, 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 pyrropyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
8. The compound of claim 3 ,
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted naphthyl, 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 pyrropyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.
9. The compound of claim 7 ,
wherein
R 3 is C 1-4 alkyl.
10. The compound of claim 7 ,
wherein
R 2 is —W 21 —W 22 —Rb—R 20 ,
wherein
W 21 is —(CO)—;
W 22 is —NH—;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted C 6-14 aryl or optionally substituted 5-14 membered heteroaryl.
11. The compound of claim 1 ,
wherein
R 7 is optionally substituted C 6-14 aryl-alkyl, optionally substituted 5-14 membered heteroaryl-alkyl, optionally substituted C 3-10 cycloalkyl-alkyl or optionally substituted 3-10 membered heterocycloalkyl-alkyl;
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted naphthyl, 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 pyrropyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl;
R 3 is C 1-4 alkyl;
R 2 is —W 21 —W 22 —Rb—R 20 ,
wherein
W 21 is —(CO)—;
W 22 is —NH—;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted aryl or optionally substituted 5-14 membered heteroaryl.
12. The compound of claim 6 ,
wherein
R 7 is optionally substituted C 6-14 aryl-alkyl, optionally substituted 5-14 membered heteroaryl-alkyl, optionally substituted C 3-10 cycloalkyl-alkyl or optionally substituted 3-10 membered heterocycloalkyl-alkyl;
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted naphthyl, 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 pyrropyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl;
R 3 is C 1-4 alkyl;
R 2 is —W 21 —W 22 —Rb—R 20 ,
wherein
W 21 is —(CO)—;
W 22 is —NH—;
Rb is bond or optionally substituted lower alkylene; and
R 20 is optionally substituted C 6-14 aryl or optionally substituted 5-14 membered heteroaryl.
13. The compound of claim 1 selected from
(6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxamide,
(6S,9S)-84(2-aminobenzo[d]thiazol-4-yl)methyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate,
sodium 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl phosphate,
sodium 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(naphthalen-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl phosphate,
(6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N4R)-1-phenylethyl)-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N4S)-1-phenylethyl)-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)—N-benzyl-6-(4-hydroxy-2,6-dimethylbenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)-8-(benzo[b]thiophen-3-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)-8-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-8-(isoquinolin-5-ylmethyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)—N-benzyl-8-((5-chlorothieno[3,2-b]pyridin-3-yl)methyl)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide,
(6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoxalin-5-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, and (6S,9S)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)-N-(thiophen-2-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide.
14. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
15. 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 C 6-14 aryl-alkyl, optionally substituted 5-14 membered heteroaryl-alkyl, optionally substituted C 3-10 cycloalkyl-alkyl, optionally substituted 3-10 membered heterocycloalkyl-alkyl, optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted C 3-10 cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl;
G is —NH— or —NR 6 —,
wherein
R 6 is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;
R 1 is —Ra—R 10 ;
wherein
Ra is optionally substituted lower alkylene and
R 10 is optionally substituted bicyclic fused aryl or optionally substituted bicyclic fused 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; and
R 20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted C 3-10 cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl; and
R 3 is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
wherein
the heteroaryl is a monocyclic or bicyclic aromatic radical wherein at least one ring atom is a heteroatom selected from the group consisting nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon; and
wherein the heterocycloalkyl is cycloalkyl provided that at least one of the atoms forming the ring is a heteroatom selected from the group consisting nitrogen, oxygen, and sulfur;
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 or solid support;
R 92 is selected from optionally substituted alkyl, linker or solid support; and
the other symbols are as defined above, or a salt thereof,
with an acid.