Imidazotriazine and pyrrolopyrimidine derivatives as KRAS G12C inhibitors

1 . A compound of Formula (I) or (II):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein

L 1 and L 2 are each independently selected from the group consisting of a single bond, —CO—NH—, —NH—CO—, —O—, —NR a —, —NR a (CH 2 ) m —, —S—, —(CH 2 ) m —, —O—(CH 2 ) m —, —O—CH(R a )—, —CH(R a )—, —CH(R a ) (CH 2 ) m —, —(CH 2 ) m —O—, —C(O)—, —SO 2 —, cycloalkylene, oxetandiyl, tetrahydrofurandiyl, tetrahydropyrandiyl, azetidindiyl, pyrrilidindiyl, piperidindiyl, and piperizindiyl;

R 1 is selected from the group consisting of phenyl, naphthalenyl, indanyl, fluorenyl, indazolyl, dihydroacenaphthylenyl, quinolinyl, isoquinolinyl, indolyl, 2,3-dihydrobenzofuranyl, benzoimidazolyl, 1,3-dihydroisobenzofuranyl, benzofuranyl, carbazolyl, benzoisoquinolinyl, benzoisoindolyl, and dihydroindenyl, wherein each of said phenyl, naphthalenyl, indanyl, fluorenyl, indazolyl, dihydroacenaphthylenyl, quinolinyl, isoquinolinyl, indolyl, 2,3-dihydrobenzofuranyl or dihydroindenyl is optionally substituted with at least one R 6 selected from the group consisting of —C 1-8 alkyl, —C 1-8 alkoxy, -haloC 1-8 alkyl, oxo, halogen, hydroxy, —NH 2 , and C 3-6 cycloalkyl, wherein each R 6 is identical or different when R 1 is substituted with more than one R 6 ;

R 2 is selected from the group consisting of —NR b R c , cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one R 6 , wherein each R 6 is identical or different when R 2 is substituted with more than one R 6 , and each R 6 is selected from the group consisting of —C 1-8 alkyl, halogen, hydroxy, oxo, —C 1-8 alkoxy, —NR b R c , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said —C 1-8 alkyl, —C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, amino, CN, cycloalkyl, heterocyclyl, aryl or heteroaryl,

or two R 6 , when on two adjacent carbon atoms of a phenyl ring, together with the two intervening carbon atoms to which they are attached, form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s);

R 3 is selected from the group consisting of hydrogen, halogen, oxo, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, —C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 3 ′ is selected from the group consisting of hydrogen, oxo, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, —C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 4 is selected from the group consisting of

R 5 is selected from the group consisting of hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, oxo, —NR b R c , —(CH 2 ) m —CO—NR d R e , cycloalkyl, heterocyclyl, aryl, heteroaryl and —(CH 2 ) m —CN;

R a , R b and R c are each independently selected from the group consisting of hydrogen, deuterium (D), cyano (CN), halogen, hydroxy, —C 1-8 alkoxy, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR d R e , and —CO—NR d R c , and each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with R f ; or

(R a and R b ), (R a and R c ) or (R b and R c ) together with the atom(s) to which they are attached, form a 4- to 6-membered ring, said ring is optionally substituted with at least one R g ;

each R f is selected from the group consisting of halogen, hydroxy, oxo, —C 1-8 alkoxy, —NR d R e , —CO—NR d R e , —NR d —CO—R e , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each said —C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy or —C 1-4 alkyl;

R d , R e and R g are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, oxo, and —C 1-8 alkyl, and each said —C 1-8 alkyl is optionally substituted with at least one halogen, oxo, —CF 3 or —COCH 3 ;

p is independently 0, 1, 2, 3 or 4; and

each m and n are independently 0, 1, 2, 3, 4, 5 or 6.

2 . The compound according to claim 1 , wherein R 1 is selected from the group consisting of

wherein R 6 is selected from the group consisting of F, Br, Cl, OH, —OCH 2 , oxo, —CH 2 CN, —NH 2 , —CF 3 , —CF 2 H,

CH 2 CH 3 , and CH 3 ; and wherein q1 is 0, 1 or 2.

3 . The compound according to claim 1 , wherein R 1 is selected from the group consisting of

4 . The compound according to claim 1 , wherein L 1 is selected from the group consisting of a single bond, —CO—NH—, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —C(O)—, and —CH(CH 3 )—.

5 . The compound according to claim 1 , wherein L 2 is selected from the group consisting of a single bond, —O—, —O—(CH 2 ) m —, —O—CH(R a )—, —O—CH(R a )—(CH 2 ) m —, cyclopropylene, azetidindiyl, and —NR a (CH 2 ) m —, wherein m is 1 or 2; and R a is selected from the group consisting of hydrogen, methyl, and deuterium(D).

6 . The compound according to claim 1 , wherein L 2 is selected from the group consisting of a single bond, —O—CH 2 —, —O—CH 2 CH 2 —, —O—CH 2 CH 2 CH 2 —, —O—, —O—CH(CH 3 )—, —NH—CH 2 —, —NH—CH 2 CH 2 —, —O—CH(CH 3 )CH 2 —,

and wherein the asterisks * refer to the linking positions.

7 . The compound according to claim 1 , wherein R 2 is selected from the group consisting of

—NR b R c ,

wherein each R 6 is selected from the group consisting of halogen, hydroxy, —C 1-8 alkyl, —C 1-8 alkoxy and heterocyclyl, wherein the —C 1-8 alkyl is optionally substituted with hydroxy or halogen; each q2 is 0, 1, 2 or 3; R b and R c are independently hydrogen, deuterium(D), halogen, or —C 1-8 alkyl.

8 . The compound according to claim 7 , wherein R 6 is selected from the group consisting of CH 3 , OH, CH 2 OH, F, —CHF 2 , —OCH 3 , Cl, Br, and

9 . The compound according to claim 1 , wherein R 2 is selected from the group consisting of

10 . The compound according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, halogen, oxo, and —C 1-8 alkyl.

11 . The compound according to claim 1 , wherein R 4 is

wherein R a is selected from the group consisting of hydrogen, deuterium(D), halogen, —C 1-8 alkyl and —C 1-8 alkoxy, said —C 1-8 alkyl or —C 1-8 alkoxy is optionally substituted with at least one halogen, hydroxy, —C 1-8 alkoxy, or —NR d COR e ;

R b is selected from the group consisting of hydrogen and —C 1-8 alkyl;

R c is selected from the group consisting of hydrogen, halogen, —C 1-8 alkyl, —CN, —NR d R e , —CO—NR d R e , and heteroaryl, wherein said —C 1-8 alkyl is optionally substituted with at least one R f ;

each R f is selected from the group consisting of halogen, hydroxy, —NR d R e , —C 1-8 alkoxy, and 4- to 7-membered heterocyclyl, wherein each said —C 1-8 alkoxy or 4- to 7-membered heterocyclyl is optionally substituted with halogen, hydroxy or —C 1-4 alkyl; and

R d and R e are each independently hydrogen, deuterium(D), halogen or —C 1-8 alkyl, wherein said —C 1-8 alkyl is optionally substituted with at least one halogen or —COCH 3 .

12 . The compound according to claim 1 , wherein R 4 is selected from the group consisting of

13 . The compound according to claim 1 , wherein R 5 is selected from the group consisting of hydrogen, halogen, —C 1-8 alkyl, —NR b R c , —(CH 2 ) m —C(O)—NR d R e , and —(CH 2 ) m —CN, each R b and R c are independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R b and R c ) together with the atom(s) to which they are attached form a 4- to 6-membered ring, said ring is optionally substituted with at least one R g ;

R d , R e and R g are each independently hydrogen, deuterium (D), halogen, oxo, or —C 1-8 alkyl; and

each m is independently 0, 1, 2, or 3.

14 . The compound according to claim 1 , wherein R 5 is selected from the group consisting of —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —(CH 2 ) m —C(O)—NR d R c , —(CH 2 ) m —CN, and hydrogen, wherein each m is 0 or 1; and p is 1.

15 . A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

16 . A pharmaceutical composition comprising the compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

17 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

18 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 16 .