JPWO2019213526A5

JPWO2019213526A5 -

Info

Publication number: JPWO2019213526A5
Application number: JP2020560752A
Authority: JP
Publication date: 2022-04-25
Anticipated expiration: 2039-05-03

Claims

Equation (I):

[During the ceremony,
E ¹ and E ² are independently N or CR ¹ ;

Is a single or double bond required to give all atoms their normal valence;
R ^p are independently H, hydroxy, -C _1-6 alkyl, halo, -C _1-4 haloalkyl, -C _1-4 alkoxy, -NH-C _1-4 alkyl, -N (C _{1- 4} Alkyl) ₂ , cyano, -C _2-3 alkoxy, -C _2-3 alkynyl, -C _3-14 cycloalkyl, -C _2-14 heterocycloalkyl, aryl or heteroaryl;
R ¹ is independently H, hydroxy, -C _{1 to 6} alkyl, -C _{1 to 6} haloalkyl, -C _{1 to 6} alkoxy, -NH-C _{1 to 6} alkyl, -N (C _{1 to 4} alkyl). ) ₂ , cyano or halo;
R ² is halo, -C _{1 to 6} alkyl, -C _{1 to 6} haloalkyl, -OR ^2a , -N (R ^2a ) ₂ , -C _{2 to 6} alkenyl, -C _{2 to 6} alkynyl, -C _{0 to.} 3alkylene-C _3-14 cycloalkyl, -C _0-3alkylene _- C _2-14 heterocycloalkyl, aryl, heteroaryl, -C _0-3alkylene- C _6-14 aryl or -C _0-3alkylene- C _2-14 heteroaryl, each R ^2a independently H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _3-14 cycloalkyl, -C _2-14 heterocycloalkyl. , -C _2-6 alkenyl, -C _2-6 alkynyl, aryl or heteroaryl, or the two R ^2a substituents form a 3-7 membered ring with the nitrogen atom to which they are attached;
R ³ is halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkoxy, C _3-6 cycloalkyl, -C _2-14 heterocycloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, aryl or heteroaryl;
^R4 is

And;
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic, cross-linked, fused, or spiro 6-11-membered ring;
L is a bond, -C _1-6 alkylene, -OC _0-6 alkylene, -SC _0-6 alkylene or -NH-C _0-6 alkylene, -C _2-6 alkylene, -O. For -C _2-6 alkylene, -SC _2-6 alkylene and NH-C _2-6 alkylene, one carbon atom of the alkylene group shall be optionally substituted with O, S or NH. Can be;
R ^4a is H, -C _{1 to 6} alkyl, C _{2 to 6} alkynyl, C _{1 to 6} alkylene-OC _{1 to 4} alkyl, C _{1 to 6} alkylene-OH, C _{1 to 6} haloalkyl, cycloalkyl, Heterocycloalkyl, C 0-3alkylene-C _3-14 cycloalkyl, C _0-3 alkylene _- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _{0-3 alkylene-} C _6-14 aryl. Or

Selected from;
R ⁵ and R ⁶ are independently H, halo, -C _{1 to 6} alkyl, -C _{2 to 6} alkynyl, -C _{1 to 6} alkylene-OC _{1 to 4} alkyl, and -C _{1 to 6} respectively. Alkylene-OH, -C _1-6 haloalkyl, -C _1-6 alkyleneamine, -C _0-6 alkylene-amide, -C _0-3 alkylene-C (O) OH, -C _{0-3 alkylene-} C ( O) OC _1-4 alkyl, -C _1-6 alkylene-O-aryl, -C _0-3 alkylene-C (O) C _1-4 alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C _{0 to} 3alkylene-C _{3 to 14} cycloalkyl, -C _{0 to 3} alkylene-C _{2 to 14} heterocycloalkyl, -C _{0 to 3} alkylene-C _{6 to 14} aryl, -C _{0 to 3} alkylene-C It is _2-14 heteroaryl or cyano, or R5 and R6 form a 4- to ⁶ - ^membered ring with the atoms to which they are attached;
R ⁷ is H or C _1-6 alkyl, or R ⁷ and R ⁵ form a 4- to 6-membered ring with the atom to which they are attached;
R ⁸ is -C _{1 to 6} alkyl, -C _{0 to 3} alkylene-C _{6 to 14} aryl, -C _{0 to 3} alkylene -C _{3 to 14} heteroaryl, -C _{0 to 3} alkylene -C _{3 to 14} cyclo. Alkyl, -C _0-3alkylene -C _2-14 heterocycloalkyl, -C _1-6 alkoxy, -OC 0-3alkylene-C _6-14 aryl, -OC _0-3alkylene _- C ₃ _-14 heteroaryl, -OC _0-3alkylene _- C _3-14 cycloalkyl, -OC 0-3alkylene-C _2-14 heterocycloalkyl, -NH-C _1-8 alkyl, -N ( C _1-8 alkyl) ₂ , -NH-C _0-3 alkylene-C _6-14 aryl, -NH-C _0-3 alkylene-C _2-14 heteroaryl, -NH-C _0-3 alkylene-C _{3 -14} cycloalkyl, -NH-C _0-3 alkylene-C _2-14 heterocycloalkyl, halo, cyano or C _1-6 alkylene-amine;
Here, the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl group of any one of the R ^p , R ² , R ^2a , R ³ , R ⁴ , R ^4a , R ⁵ , R ⁶ , R ⁷ and R ⁸ substituents. Has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups are C = O groups can be included and the spiroheterocycloalkyl and heterocycloalkyl groups may contain S ₌ O or SO2;
Here, the -C _{1 to 6} alkyl of any one of the R ^p , R ¹ , R ² , R ^2a , R ³ , R ⁴ , R ^4a , L, R ⁵ , R ⁶ , R ⁷ and R ⁸ substituents. , -C _2-6 alkenyl, -C _2-6 alkynyl and -OC _1-6 alkyl are unsubstituted or OH, -OC _1-6 alkyl, -C _1-6 alkyl-O -C _1-6 alkyl, halo, -O-halo C _1-6 alkyl, -CN, -NR ^a R ^b , -NR ^a R ^b R ^c , -OSO ₂ R ^a , -SO ₂ R ^a , -CH ₂ CH ₂ OCH ₃ ,-(= O), -C (= O),
-C (= O) R ^a , -OC (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -SiR ^a R ^b R ^c , -O- (3-10 membered heterocycloalkyl), 6-12 membered aryl or heteroaryl, 5-12 membered spirocycloalkyl or spiroheterocycloalkyl, 3-12 membered cyclo 1, 2 or 3 R ^9s independently selected from alkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups. Substituentally substituted with substituents, the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S. The cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups can contain a C = O group, and the spiroheterocycloalkyl and heterocycloalkyl groups further contain S = O or SO ₂ . It is possible;
Here, any of the aryl, heteroaryl, any of the R ^p , R ¹ , R ² , R ^2a , R ³ , R ⁴ , R ^4a , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ substituents. Cycloalkyl and heterocycloalkyl groups are unsubstituted or OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH,- C _{1 to 6} alkyl-OC 1 _{to 6} alkyl, C _{1 to 6} haloalkyl, -O-halo C _{1 to 6} alkyl, -SO ₂ R ^c , -CN, -C (= O) NR ^c R ^d , -C (= O) R ^c , -OC (= O) R ^a , -C (= O) OR ^c , 6-12 member aryl or heteroaryl, 5-12 member spirocycloalkyl or spiroheterocycloalkyl Independently selected from 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl or 3 to 12-membered monocyclic or bicyclic heterocycloalkyl groups 1 It may be substituted with 2, 3 or 4 R ¹⁰ substituents, the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of R ¹⁰ being independently selected from O, N or S 1, 2 The cycloalkyl, spirocycloalkyl and spiroheterocycloalkyl group of R10 or the heterocycloalkyl group of R10 may contain ³ or ⁴ heteroatoms and may further contain a C = O group. Spiroheterocycloalkyl and heterocycloalkyl groups can contain S ₌ O or SO2;
Here, each R ^a , R ^b , R ^c and R ^d are independently hydrogen, OH, -C _{1 to 6} alkyl, -CH ₂ CH ₂ OCH ₃ , phenyl , -C _{1 to 6} alkyl-C ( = O) OH, -C _{1 to 6} alkyl-C (= O) -OC _{1 to 6} alkyl, -C _{1 to 6} alkyl-3 to 12-membered cycloalkyl, -C _{1 to 6} alkyl-3 to 12-membered heterocycloalkyl, -C _1-6 alkyl-6-12-membered heteroaryl, 6-12-membered aryl or heteroaryl, 3-12-membered monocyclic or bicyclic cycloalkyl or 3-~ A 12-membered monocyclic or bicyclic heterocycloalkyl group, said heteroaryl group of R ^a , R ^b , R ^c and R ^d , a heterocycloalkyl group, or R ^a , R ^b , R ^c and The heterocycloalkyl group of the C1-6 alkyl-heterocycloalkyl group of R ^d has ₁ , 2, 3 or 4 heteroatoms independently selected from O, N or S and has ^Ra . The cycloalkyl and heterocycloalkyl groups of R ^b , R ^c and R ^d and the heterocycloalkyl groups of the -C _1-6 alkyl-heterocycloalkyl groups of R ^a , R ^b , R ^c and R ^d . , The cycloalkyl and heterocycloalkyl groups of R ^a , R ^b , R ^c and R ^d and the -C _1-6 of R a, R ^b , R ^c and R ^d ^. The heterocycloalkyl group of the alkyl-heterocycloalkyl group can contain a C = O group; and the alkyl, aryl, heteroaryl, cycloalkyl, hetero of R ^a , R ^b , R ^c and R ^d . The heterocycloalkyl group or the heterocycloalkyl group of the -C _1-6 alkyl-heterocycloalkyl group of R ^a , R ^b , R ^c and R ^d is unsubstituted or 1, 2, 3 or 4 It can be substituted with an ^R12 substituent, where each ^R12 is H, OH, halo, -C _1-6 alkyl, N (CH ₃ ) ₂ , -C _1-6 haloalkyl, C (= O). A compound having the structure of CH ₃ , -C (= O) OCH ₃ or -C _{1 to 6} alkyl-OC _{1 to 6} alkyl]; or its steric isomer, its atrop isomer. , The pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer or the atom thereof. A pharmaceutically acceptable salt of the isomer.

The compound according to claim 1 , wherein R ^p is —C _{1 to 6} alkyl.

The compound according to claim 2 , wherein ^RP is −CH ₃ .

The compound according to any one of claims 1 to 3 , wherein R ¹ is H.

The compound according to any one of claims 1 to 4 , wherein ^R2 is an unsubstituted or substituted aryl.

The compound according to any one of claims 1 to 5 , wherein R ³ is a halo.

The compound according to claim 6 , wherein R ³ is Cl.

^R4 is

The compound according to any one of claims 1 to 7 .

The compound according to claim 8 , wherein L is a bond.

The compound according to claim 8 , wherein the ring A is a monocyclic 4- to 7-membered ring.

The compound according to claim 10 , wherein the ring A is an unsubstituted or substituted heterocycle.

^R4 is

The compound according to any one of claims 1 to 11 , which is selected from the group consisting of.

^R4 is

The compound according to claim 12 .

The compound according to claim 8 , wherein R ⁵ is H or R ⁶ is H.

The compound according to any one of claims 1 to 14 , wherein R ⁸ is -C _{1 to 6} alkyl , -C _{6 to 14} aryl, or -C _{3 to 14} heteroaryl.

R8 is i ^- Pr, t-Bu, phenyl, benzyl, OCH ₃ , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

The compound according to any one of claims 1 to 14 , selected from the group consisting of.

^R8 is

The compound according to claim 16 , which is selected from the group consisting of.

formula

A compound having a structure selected from the above, a stereoisomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereo isomer or a pharmaceutically acceptable salt thereof. Tolerable salt.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient.

An in vitro method of inhibiting KRAS G12C in a cell, comprising contacting the cell with the compound according to any one of claims 1-18 or the composition according to claim 19 .

The pharmaceutical composition according to claim 19, for treating cancer .

Claims that the cancer is non-small cell lung cancer, small intestinal cancer, wormdrop cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cancer, or bile duct cancer. 21. The pharmaceutical composition.

22. The pharmaceutical composition according to claim 22 , wherein the cancer is non-small cell lung cancer.

22. The pharmaceutical composition according to claim 22 , wherein the cancer is colorectal cancer.

22. The pharmaceutical composition according to claim 22 , wherein the cancer is pancreatic cancer.

The pharmaceutical composition according to any one of claims 21 to 25, wherein the cancer is mediated by a KRAS G12C mutation.