4-aminobut-2-enamide derivatives and salt thereof
The present invention provides an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRASG12C as an active ingredient.
1 . An antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C as an active ingredient, wherein the compound has the formula:
A-L1-L2-G-J
wherein,
A is a chemical moiety capable of interacting with a region between Switch 2 and α3-Helix;
L1 is a linker;
L2 is a linker;
G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine 12 of GTP-bound KRAS G12C; and
J is a chemical moiety capable of interacting with GTP;
wherein, G is represented by the following formula:
wherein L1 is represented by D with —C(═O)—, L2 is represented by E with —NR 1 — and J is represented by —CHR 2 ′—NR 2 R 3 in the formula A-L1-L2-G-J; and
wherein the compound is represented by Formula (x):
wherein:
R 1 is hydrogen or C1-C6 alkyl;
R 2 and R 2 ′ join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
R 2 , R 2 ′ and R 3 are independently represented, and R 2 is hydrogen, or C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
R 2 ′ is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; and
R 3 is hydrogen;
Ra represents independently halogen, hydroxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 haloalkyl, C1-C10 monoalkylamino, C1-C10 dialkylamino, C1-C10 alkoxy, C1-C10 haloalkoxy, C1-C10 alkylsulfonyl, C1-C10 acyl, C1-C10 alkoxycarbonyl or a 4- to 10-membered saturated heterocyclic group;
wherein E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 ,
wherein E 1 , E 2 , E 3 and E 4 represent independently C, CH, CH 2 , N or NH;
R 4 is halogen or cyano;
wherein A is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
wherein when A is a single ring, A′ and A″ are absent, and the single ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 5 , wherein A 1 , A 2 , A 3 , A 4 and As represent independently C, CH, or CH 2 ;
wherein when A is a fused ring, the fused ring is represented by ring A and ring A′ or ring A and ring A″, wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with R 5 , wherein A 1 , A 2 , A 3 , A 4 and As represent independently C, CH, CH 2 , N or NH, and ring A′ or A″ is a saturated or unsaturated ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A 4 or A 4 and A 5 ;
R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C10 alkoxy, C1-C10 acyl, C1-C10 alkoxycarbonyl, or C1-C10 alkylsulfonyl;
two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A′ or ring A″ when the number of R 6 is two or more; or
each R 6 may independently represent halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, C1-C10 acyl, C1-C10 alkoxycarbonyl or C1-C10 alkylsulfonyl;
D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring may be additionally substituted with a substituent other than said amino, or D is a substituted or unsubstituted fused ring;
wherein when D is a single ring, D′ is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein D 1 represents N or NH, and D 2 , D 3 , D 4 , D 5 , D 6 and D 7 represent independently C, CH, CH 2 , N or NH;
wherein when D is a fused ring, the fused ring is represented by ring D and ring D′, wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Di, D 2 , D 3 , D 4 , D 5 , D 6 and D 7 represent independently C, CH, CH 2 , N or NH, and ring D′ is a saturated or unsaturated ring which is unsubstituted or substituted with R 8 and forms a fused ring with ring D containing D 1 , D 2 and D 7 ;
R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
R 8 is halogen or C1-C10 alkyl;
q and r represent independently 0, 1, or 2;
n is an integer of 0 to 5;
p is 0, 1, or 2; and
m is an integer of 0 to 4; or a pharmaceutically acceptable salt thereof.
2 . The antitumor agent according to claim 1 , wherein ring A′ forms a fused ring with ring A containing A 3 and A 4 , and A 1 and As are C, CH, or CH 2 .
3 . The antitumor agent according to claim 1 , wherein the compound is represented by Formula (xi):
wherein ring A′ is a saturated or unsaturated 5-membered ring forming a fused ring containing A 3 and A 4 with ring A, wherein A 1 ′, A 2 ′, A 3 ′ represent independently C, CH, CH 2 , N, NH, O or S, two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring when the number of R 6 is two or more; or
each R 6 may be independently halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy.
4 . The antitumor agent according to claim 3 , wherein the compound is represented by Formula (xii):
wherein R 2 and R 2 ′ join together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
R 2 , and R 2 ′ are independently represented, and R 2 is C1-C10 alkyl which is unsubstituted or substituted with Ra, C3-C10 cycloalkyl which is unsubstituted or substituted with Ra, or a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted with Ra;
wherein R 5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl or C1-C10 alkoxy;
wherein two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring when the number of R 6 is two or more; or
each R 6 may be independently substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C1-C10 alkoxy;
D is a fused ring represented by ring D and ring D′, and ring D′ is a saturated or unsaturated 5-membered ring forming a fused ring containing D 1 , D 2 and D 7 with ring D, and D 1 ′ and D 2 ′ represent independently C, CH, CH 2 , N, NH or S, and
R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy.
5 . A compound represented by Formula (x):
wherein:
R 1 is hydrogen or C1-C6 alkyl;
R 2 and R 2 ′ join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
R 2 , R 2 ′ and R 3 are independently represented, and R 2 is hydrogen, or C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
R 2 ′ is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; and
R 3 is hydrogen;
Ra represents independently halogen, hydroxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 haloalkyl, C1-C10 monoalkylamino, C1-C10 dialkylamino, C1-C10 alkoxy, C1-C10 haloalkoxy, C1-C10 alkylsulfonyl, C1-C10 acyl, C1-C10 alkoxycarbonyl or a 4- to 10-membered saturated heterocyclic group;
wherein E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 ,
wherein E 1 , E 2 , E 3 and E 4 represent independently C, CH, CH 2 , N or NH;
R 4 is halogen or cyano;
wherein A is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
wherein when A is a single ring, A′ and A″ are absent, and the single ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 5 , wherein A 1 , A 2 , A 3 , A 4 and As represent independently C, CH, or CH 2 ;
wherein when A is a fused ring, the fused ring is represented by ring A and ring A′ or ring A and ring A″, wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with R 5 , wherein A 1 , A 2 , A 3 , A 4 and As represent independently C, CH, CH 2 , N or NH, and ring A′ or A″ is a saturated or unsaturated ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A 4 or A 4 and A 5 ;
R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C10 alkoxy, C1-C10 acyl, C1-C10 alkoxycarbonyl, or C1-C10 alkylsulfonyl;
two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A′ or ring A″ when the number of R 6 is two or more; or
each R 6 may independently represent halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, C1-C10 acyl, C1-C10 alkoxycarbonyl or C1-C10 alkylsulfonyl;
D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring may be additionally substituted with a substituent other than said amino, or D is a substituted or unsubstituted fused ring;
wherein when D is a single ring, D′ is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein D 1 represents N or NH, and D 2 , D 3 , D 4 , D 5 , D 6 and D 7 represent independently C, CH, CH 2 , N or NH;
wherein when D is a fused ring, the fused ring is represented by ring D and ring D′, wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Di, D 2 , D 3 , D 4 , D 5 , D 6 and D 7 represent independently C, CH, CH 2 , N or NH, and ring D′ is a saturated or unsaturated ring which is unsubstituted or substituted with R 8 and forms a fused ring with ring D containing D 1 , D 2 and D 7 ;
R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
R 8 is halogen or C1-C10 alkyl;
q and r represent independently 0, 1, or 2;
n is an integer of 0 to 5;
p is 0, 1, or 2; and
m is an integer of 0 to 4; or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 5 , wherein the compound is represented by Formula (xi):
wherein ring A′ is a saturated or unsaturated 5-membered ring forming a fused ring containing A 3 and A 4 with ring A, wherein A 1 ′, A 2 ′, A 3 ′ represent independently C, CH, CH 2 , N, NH, O or S, two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring when the number of R 6 is two or more; or
each R 6 may be independently halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;
or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 6 , wherein the compound is represented by Formula (xii) or a salt thereof:
wherein R 2 and R 2 ′ join together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
R 2 , and R 2 ′ are independently represented, and R 2 is C1-C10 alkyl which is unsubstituted or substituted with Ra, C3-C10 cycloalkyl which is unsubstituted or substituted with Ra, or a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted with Ra;
wherein R 5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl or C1-C10 alkoxy;
wherein two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring when the number of R 6 is two or more; or
each R 6 may be independently substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C1-C10 alkoxy;
D is a fused ring represented by ring D and ring D′, and ring D′ is a saturated or an unsaturated 5-membered ring forming a fused ring containing D 1 , D 2 and D 7 with ring D, and Di′ and D 2 ′ represents independently C, CH, CH 2 , N, NH or S, and
R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;
or a pharmaceutically acceptable salt thereof.
8 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 5 and a pharmaceutically acceptable carrier.
9 . The antitumor agent of claim 1 , wherein the antitumor agent is suitable for oral administration.
10 . A method for treating a tumor, comprising administering a therapeutically effective amount of the compound of claim 5 or pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the tumor is KRAS G12C mutation-positive.
11 . An antitumor agent comprising a compound of claim 5 or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents as an active ingredient.
12 . A method for treating a tumor, the method comprising administering a therapeutically effective amount of the compound of claim 5 or pharmaceutically acceptable salt thereof, and one or more other antitumor agents to a subject in need thereof, wherein the tumor is KRAS G12C mutation-positive.
13 . A method for treating a tumor, the method comprising administering a therapeutically effective amount of the compound of claim 5 or pharmaceutically acceptable salt thereof in combination with one or more other antitumor agents to a subject in need thereof, wherein the tumor is KRAS G12C mutation-positive.
14 . The antitumor agent of claim 1 , wherein the tumor is a cancer and wherein the tumor is KRAS G12C mutation-positive.
15 . The antitumor agent of claim 14 , wherein the cancer is one or more selected from the group consisting of a carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.
16 . The antitumor agent of claim 15 , wherein the squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.
17 . The antitumor agent of claim 15 , wherein the adenocarcinoma is a cancer of prostate, small intestine, endometrium, uterine cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.
18 . The antitumor agent of claim 14 , wherein the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer or leukemia.
19 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.