JPWO2021023154A5

JPWO2021023154A5 -

Info

Publication number: JPWO2021023154A5
Application number: JP2022506075A
Authority: JP
Publication date: 2023-08-16

Claims

A compound of formula (I), its optical isomers, and pharmaceutically acceptable salts,
During the ceremony,
R ₁ , R ₂ , R ₁₁ are each independently selected from —H , halogen, —OH , —NH ₂ , —CN , C _1-6 alkyl, C _1-6 alkoxy, and C _1-6 alkylamino and C _1-6 alkyl, C _1-6 alkoxy, or C _1-6 alkylamino is optionally substituted with 1, 2, or 3 R,
T ₁ is selected from N and −C (R ₃ );
T ₂ is selected from N and −C (R ₄ );
R ₃ and R ₄ are each independently —H , halogen, —OH , —NH ₂ , —CN , C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, selected from C _1-6 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 cycloalkyl, or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R,
R ₅ is independently —H , halogen, —OH , —NH ₂ , —CN , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl-OC (= O)-, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl, and 5-10 membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkylamino, C _1-6 alkyl-OC(=O)-, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl, or 5-10 membered heteroaryl is optional substituted with 1, 2, or 3 R in
R ₆ is independently —H , halogen, —OH , —NH ₂ , —CN , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl-OC (= O)—, C _3-6 cycloalkyl, and 3-6 membered heterocycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkyl-OC( =O)—, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R;
Ring A is selected from C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl, and 5-10 membered heteroaryl;
Ring B is selected from C _6-10 aryl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl fused 5-6 membered heterocycloalkyl;
R ₇ is selected from H, halogen, —CN , C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino, C _1-6 alkyl, C _1-6 alkoxy or C _{1- 6alkylamino} is optionally substituted with 1, 2, or 3 R;
R ₈ and R ₉ are each independently selected from —H , halogen, —CN , C _1-6 alkyl, C _3-6 cycloalkyl, and 3-6 membered heterocycloalkyl, C _1-6 alkyl, C _1-6 heteroalkyl, C _1-6 alkylamino, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R,
teeth,
represents
but
when R ₇ and R ₉ are absent and
L ₁ is a single bond, —CH ₂ — ,
, -O- , -S- , -S (=O) - , -C (=O) - , -S (=O) ₂ , and N( _R10 );
L ₂ is selected from -CH2- , -O- , -S- _, and -C (=O) - ;
_L3 is selected from _a single bond, -C ( _R12R12 ) - , and -C (=O) - ;
_L4 is selected from -S (=O) - , -S (=O) ₂ , and -C (=O) - ;
m is selected from 1, 2, 3, and 4;
n is selected from 1, 2, 3, and 4;
R ₁₀ is selected from — H, C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R,
_R12 is independently selected from —H , —F , —Cl _, —Br , —I , —OH , —NH2 , —CN , Me, and —CF3 _;
R is independently —H , halogen, —OH , —NH ₂ , —CN ,
, C _1-6 alkyl, C _1-6 alkyl-OC(=O)-, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, and 5-6 membered heterocycloalkyl , C _1-6 alkyl, C _1-6 alkyl-OC(=O)-, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, or 5-6 membered heterocycloalkyl is optionally optionally substituted with 1, 2, or 3 R',
R' is selected from -F _, -Cl , -Br , -I , -OH , _-NH2 , and -CH3 ;
3- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C _1-6 heterocycloalkyl are independently -O- , -NH- , -S- , -C compounds containing 1, 2, or 3 heteroatoms or heteroatom groups selected from (=O)O - , -S (=O) - , -S(=O) ₂ , and N; its optical isomers, and pharmaceutically acceptable salts.

R is independently —H , halogen, —OH , —NH ₂ , —CN ,
, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, and 5-6 membered heterocycloalkyl, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, or 5-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R′ , or
R is independently —H, —F, —Cl, —Br, —I, —OH, —NH ₂ , —CN, Me,
is selected from Me,
is optionally substituted with 1, 2, or 3 R', or
R is independently H, F, Cl, Br, I, OH, NH2 _, CN, Me,
3. The compound of claim 1, optical isomers, and pharmaceutically acceptable salts thereof, selected from:

R. _１1 , R _２2 , R _１１11 are each independently -H, halogen, -OH, -NH _２2 , -CN, C _１－３1-3 alkyl, C _１－３1-3 alkoxy, and C _１－３1-3 is selected from alkylamino, C _１－３1-3 alkyl, C _１－３1-3 alkoxy, or C _１－３1-3 Alkylamino is optionally substituted with 1, 2, or 3 R, or R _１1 , R _２2 , and R _１１11 are each independently -H, -F, -Cl, -Br, -I, -OH, -NH _２2 , -CN, Me, -CF _３3 ,
3. The compound of claim 1, optical isomers, and pharmaceutically acceptable salts thereof, selected from:

R. _３3 and R _４4 are each independently -H, -F, -Cl, -Br, -I, -OH, -NH _２2 , -CN, Me, -CF _３3 ,
is selected from R _５5 is, -H, -F, -Cl, -Br, -I, -OH, -NH _２2 , -CN, -Me, -CF _３3 ,
is selected from R _６6 is, -H, -F, -Cl, -Br, -I, -OH, -NH _２2 , -CN, Me, -CF _３3 , -N(CH _３3 ) _２2 ,
3. The compound of claim 1, optical isomers, and pharmaceutically acceptable salts thereof, selected from:

Ring A is C _３－６3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, naphthyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indazolyl, and indolyl, wherein ring B is phenyl, naphthyl, thienyl, pyrazolyl, pyrimidinyl, indazolyl; , indolyl, 1H-benzo[d][1,2,3]triazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, benzo[d]oxazol-2(3H)-onyl, 1H -pyrazolo[3,4-b]pyridyl, isoquinolin-1(2H)-onyl, and 1H-benzo[d]imidazolyl, an optical isomer thereof, and a pharmaceutically acceptable salt.

part
but,
selected from the part
but,
6. The compound of claim 4 or 5, optical isomers and pharmaceutically acceptable salts thereof, selected from:

part
but,
7. The compound of any one of claims 1 to 6, optical isomers and pharmaceutically acceptable salts thereof, selected from:

part
but,
8. The compound of claim 7, optical isomers and pharmaceutically acceptable salts thereof, selected from:

R. _７7 is, -H, -F, -Cl, -Br, -I, -CN, Me, -CF _３3 ,
is selected from R _８8 and R _９9 are each independently -H, -F, -Cl, -Br, -I, -CN, -Me, -CF _３3 ,
3. The compound of claim 1, optical isomers, and pharmaceutically acceptable salts thereof, selected from:

part
but,
10. The compound of any one of Claims 1 or 9, optical isomers and pharmaceutically acceptable salts thereof, selected from:

is selected from
During the ceremony,
R. _１1 and R _２2 is as defined in claims 1 and 3;
L. _１1 and L _２2 is as defined in claim 1,
T and T _２2 is as defined in claim 1,
R. _５5 is as defined in claims 1 and 4;
R. _６6 is as defined in claims 1 and 4;
Ring A is as defined in claims 1, 5 and 6;
Ring B is as defined in claims 1, 7 and 8;
R. _７7 is as defined in claims 1 and 11;
R. _８8 and R _９9 11. The compound, optical isomers and pharmaceutically acceptable salts thereof according to any one of claims 1 to 10, wherein is as defined in claims 1 and 11.

A compound of the above formula selected from: and optical isomers and pharmaceutically acceptable salts thereof.

13. A therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients A pharmaceutical composition comprising

14. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the preparation of a medicament, wherein said medicament comprises KRAS - A use that can be used to prevent and/or treat G12C-related diseases.

15. Use according to claim 14, wherein said KRAS-G12C-related disease is selected from non-small cell lung cancer, colon cancer and pancreatic cancer.