Optically active azabicyclo ring derivative
The compound of formula (1a) wherein p is 1 or 2, R 1 -R 4 are hydrogen atom or the like, and a-d are 1 or 2, or a pharmaceutically acceptable salt thereof, which has an antitumor effect by inhibiting the binding between a MLL fusion protein that is infused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.
1. A compound of formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, a halogen atom, —OR 7 , or M-Q; or R 1 and R 2 and/or R 3 and R 4 may be combined to form each independently ═O or ═CR 12A R 13A ;
M is, each independently if there are plural, C 1-6 alkylene, which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, chlorine atom, bromine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano) C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, 3- to 10-membered saturated heterocyclyl, C 6-10 arylene, or 5- to 12-membered heteroarylene, wherein the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclyl, the arylene, and the heteroarylene may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, chlorine atom, bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
Q is, each independently if there are plural, a hydrogen atom, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 7 is, each independently if there are plural, a hydrogen atom, C 1-6 alkyl, which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, phenyl, 5- to 6-membered heteroaryl, C 2-4 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 12A and R 13A are each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, and if there are plural R 12A or R 13A , each R 12A or R 13A may be the same or different, or when R 12A and R 13A are both C 1-6 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 8-membered saturated carbocycle;
R 35A is, each independently if there are plural, C 1-6 alkyl;
R 36A and R 37A are each independently a hydrogen atom or C 1-6 alkyl, and if there are plural R 36A or R 37A , each R 36A or R 37A may be the same or different, or when R 36A and R 37A are both C 1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
a, b, c, and d are each independently 1 or 2;
P 0 is each independently a hydrogen atom or P 1 ; and
P 1 is each independently an amino-protecting group.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, a halogen atom, —OR 7 , or M-Q; or R 1 and R 2 and/or R 3 and R 4 may be combined together to form each independently ═O or ═CR 12A R 13A ;
M is, each independently if there are plural, C 1-6 alkylene, which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
Q is, each independently if there are plural, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 7 is, each independently if there are plural, a hydrogen atom, C 1-6 alkyl, or C 2-6 alkenyl, wherein the alkyl and the alkenyl may be substituted with one phenyl;
R 12A and R 13A are each independently hydrogen atom, C 1-6 alkyl, which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 37A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 37A R 37A , and cyano, and if there are plural R 12A or R 13A , each R 12A or R 13A are the same or different, or when R 12A and R 13A are both C 1-6 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 8-membered saturated carbocycle;
R 35A is, each independently if there are plural, C 1-6 alkyl;
R 36A and R 37A are each independently hydrogen atom or C 1-6 alkyl, and if there are plural R 36A or R 37A , each R 36A or R 37A may be the same or different, or when R 36A and R 37A are both C 1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle; and
a, b, c, and d are each independently 1 or 2;
P 0 is each independently a hydrogen atom or P 1 ; and
P 1 is each independently an amino-protecting group.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, a fluorine atom, or M-Q;
or R 1 and R 2 and/or R 3 and R 4 may be combined together to form each independently ═O or ═CR 12A R 13A ;
M is, each independently if there are plural, C 1-3 alkylene;
Q is, each independently if there are plural, C 3-6 cycloalkyl which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, C 1-3 alkyl, —NR 36A SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 12A and R 13A are each independently hydrogen atom, C 3-6 cycloalkyl which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, C 1-3 alkyl, —NR 36A SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, and if there are plural R 12A or R 13A , each R 12A or R 13A may be the same or different;
R 35A is, each independently if there are plural, C 1-6 alkyl;
R 36A and R 37A are each independently hydrogen atom or C 1-6 alkyl, and if there are plural R 36A or R 37A , each R 36A or R 37A may be the same or different, or when R 36A and R 37A are both C 1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
a and c are 1;
both b and d are either 1 or 2;
P 0 is each independently a hydrogen atom or P 1 ; and
P 1 is each independently an amino-protecting group.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 12A and R 13A are a hydrogen atom.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, fluorine atom, or M-Q; or
R 1 and R 2 and/or R 3 and R 4 may be combined together to form ═CH 2 ;
M is, each independently if there are plural, methylene;
Q is, each independently if there are plural, C 3-6 cycloalkyl;
a and c are 1;
both b and d are either 1 or 2;
P 0 is each independently a hydrogen atom or P 1 ; and
P 1 is each independently an amino-protecting group.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are a hydrogen atom; and
R 3 and R 4 are each independently a hydrogen atom or a fluorine atom;
provided that both R 3 and R 4 are not a hydrogen atom.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are each independently a hydrogen atom or M-Q; and
R 3 and R 4 are each independently a hydrogen atom or a fluorine atom;
provided that both R 1 and R 2 are not a hydrogen atom.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is a hydrogen atom;
R 2 is -M-Q;
R 3 is a hydrogen atom; and
R 4 is a hydrogen atom or a fluorine atom.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is -M-Q;
R 2 is a hydrogen atom;
R 3 is a hydrogen atom or a fluorine atom; and
R 4 is a hydrogen atom.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom; or R 1 and R 2 and/or R 3 and R 4 may be combined together to form ═CH 2 ;
provided that all of R 1 , R 2 , R 3 , and R 4 are not a hydrogen atom.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are combined together to form ═CH 2 ; and
R 3 and R 4 are a hydrogen atom.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are a hydrogen atom; and
R 3 and R 4 are combined together to form ═CH 2 .
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
a, b, c, and d are 1.
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
a and c are 1; and
b and d are 2.
15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 1.
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 2.
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
P 1 is benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl.
18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
P 1 is tert-butoxycarbonyl.
19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
tert-butyl 7-[(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo [2.2.2] octane-3-carbonyl]-2,7-diazaspiro [3.5] nonane-2-carboxylate,
tert-butyl 7-[(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo [2.2.2] octane-3-carbonyl]-2,7-diazaspiro [3.5] nonane-2-carboxylate,
tert-butyl 7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo [2.2.2] octane-3-carbonyl]-2,7-diazaspiro [3.5] nonane-2-carboxylate, and
(2,7-diazaspiro [3.5] nonan-7-yl)[(1S,3S,4R)-5-methylidene-2-azabicyclo [2.2.2] octan-3-yl] methanone.