Krasg12c mutant protein inhibitor, prearation and use thereof

A compound with general formula (I), its stereoisomer, pharmaceutically acceptable salt, polymorph or isomer. The structure of the compound shown in general formula (I) is as follows:

• Wherein,
• Each L1 is independently selected from bond, O, NH, CH2, CO or S at each occurrence;
• Each R1 at each occurrence is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl at each occurrence independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, or S;
• each R1 at each occurrence independently and optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R20;
• Each R20 at each occurrence is independently selected from deuterium, halogen, oxo, —C1-6 alkyl, —C1-6 alkylene-(halogen)1-3, C1-6 hetero alkyl, —CN, —OR6, —C1-6 alkylene-(OR6)1-3, —O—C1-6 alkylene-(halogen)1-3, —SR6, —S—C1-6 alkylene-(Halogen)1-3, —NR6R7, —C1-6 alkylene —NR6R7, —C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NR6R7, —NR6C(═O)R7, —S(O)2NR6R7 or —C3-6 carbocyclyl;
• each R12 is independently and optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 Substituents selected from deuterium, halogen, —C1-6 alkyl, —C1-6 alkoxy, oxo, —OR6, —NR6R7, —CN, —C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NR6R7, —NR6 C(═O)R7 or —S(O)2NR6R7;
• Each X1, X2 is independently selected from N, CR21 at each occurrence;
• Each R18 is independently selected from H, D, cyano, halogen, C1-6 alkyl, COOH, NHCOH, CONH2, OH or —NH2;
• Each R21 is independently selected from H, D, cyano, halogen, C1-6 alkyl, COOH, NHCOH, CONH2, OH or —NH2;
• Each L2 at each occurrence is independently selected from bond, O, NH, C1-6 alkyl, CO, OC1-6 alkyl, NHC1-6 alkyl or S at each occurrence;
• Each R19 is independently selected from
• Each Ring A is a C3-10 carbocyclic ring,
• can be attached to the same or to a different atom of ring A;
• Each R2 is —OR6, —NR6R7, —SR6, —S(═O)R6, —S(═O)2R6, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each heterocyclyl and heteroaryl at each occurrence independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S═O or S(═O)2. Each R2 at each occurrence independently and optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R22;
• Each R3 and R4 at each occurrence is independently selected from deuterium, hydrogen, halogen, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, oxo, —OR6, —NR6R7, —CN, —C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NR6R7, —NR6C(═O)R7 or —S(O)2NR6R7 or —C3-10 carbocyclyl, each heterocyclyl and heteroaryl at each occurrence is independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S═O or S(═O)2, each R3 and R4 at each occurrence is independently and optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 subsituents selected from deuterium, halogen, oxo, —C1-6 alkyl, —C1-6 alkoxy, oxo, —OR6, —NR6R7, —CN, —C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NR6R7, —NR6 C(═O)R7 or —S(O)2NR6R7.
• Each R5 at each occurrence is independently selected from deuterium, halogen, oxo, —C1-6 alkyl, —C1-6 alkylene-(halogen)1-3, C1-6 heteroalkyl, —CN, —OR6, —C1-6 alkylene-(OR6)1-3, —O—C1-6 alkylene-(halogen)1-3, —SR6, —S—C1-6 alkylene-(Halogen)1-3, —NR6R7, —C1-6 alkylene —NR6R7, —C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NR6R7, —NR6C(═O)R7, —S(O)2NR6R7 or —C3-6 carbocyclyl, each heterocyclyl and heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S═O or S(═O)2;
• each R3 and R4 at each occurrence independently and optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, —C1-6 alkyl, —C1-6 alkoxy, oxo, —OR6, —NR6R7, —CN, —C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NR6R7, —NR6C(═O)R7 or —S(O)2NR6R7;
• Each R6 and R7 at each occurrence is independently selected from hydrogen or —C1-6 alkyl, each R6 and R7 is independently and optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 R22 or R7 and R7 together with the N atom to which they are connected together form a 3-10-membered heterocycle, and the 3-10-membered heterocycle may further comprise 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(═O) or S(═O)2, and the 3-10 membered heterocycle is independently and optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 R22;
• Each R22 at each occurrence is independently selected from deuterium, halogen, oxo, —C1-6 alkyl, —C1-6 alkylene-(halogen)1-3, C1-6hetero alkyl, —CN , —C1-6 alkyl, —C1-6 alkylene-(O—C1-6alky)1-3, —O—C1-6 alkylene-(halogen)1-3, —S—C1-6 alkyl, —S—C1-6 alkylene-(halogen)1-3, N—C1-6alkyl-C1-6alkyl, —C1-6alkylene-NC1-6alkylC1-6alkyl,—C(═O)C1-6 alkyl, —C(═O)OC1-6 alkyl, —OC(═O)C1-6alkyl, —C(═O)NC1-6 alkylC1-6 alkyl, —NC1-6alkylC(═O)C1-6alkyl,—S(O)2NC1-6alkyl, C1-6alkyl or —C3-6 carboncyclyl;
• s is selected from 0, 1, 2, 3, 4, 5 or 6;
• p is selected from 0, 1, 2, 3, 4, 5 or 6;
• q is selected from 0, 1, 2, 3, 4, 5 or 6.
• m is selected from 1, 2, 3
• n is selected from 1, 2, 3
• U is independently selected from —C0-4 alkyl-, —CR8R9—, —C1-2 alkyl(R8)(OH)—, —C(O)—, —CR8R90—, —OCR8R9—, —SCR8R9—, —CR8R9S—, —NR8—, —NR8C(O)—, —C(O)NR8—, —NR8C(O)NR9—, —CF2—, —O—, —S—, —S(O)m—, —NR8S(O)m—, —S(O)mNR8—;
• Y is absent or selects from C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is optionally replaced by one or more G1;
• Z is independently selected from cyano, —NR10CN,
• The bond c is a double bond or a triple bond;
• When c is a double bond, Ra, Rb and Rc are each independently selected from H, deuterium, cyano, halogen, C1-6 alkyl, C3-6 cycloalkyl or 3-6 membered heterocyclyl. wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more G2s;
• Ra and Rb or Rb and Rc optionally together with the carbon atoms to which they are attached form a 3-6 membered ring optionally containing heteroatoms;
• When the bond c is a triple bond, Ra and Rc are absent, and Rb independently selected from H, deuterium, cyano, halogen, C1-6 alkyl, C3-6 cycloalkyl or 3-6 membered heterocyclyl is substituted with one or more G3s;
• R10 is independently selected from H, deuterium, C1-6 alkyl, C3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more G4s;
• G1, G2, G3 and G4 are each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —OR11, —OC(O)NR11R12, —C(O)OR1, —C(O)NR11R12, —C(O)R11R12, —NR11C(O)R12, —NR11C(O)NR12R13, —S(O)mR11 or —NR11S(O)mR12, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, Heteroaryl is optionally replaced by 1 or more deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —OR14, —OC(O)NR14R15, —C(O)OR14, —C(O)NR14R15, —C(O)R14, —NR14R15, —NR14C(O)R15, —NR14C(O)NR15R16, —S(O)mR14 or —NR14S(O)nR15 substituent;
• R8, R9, R11, R12, R13, R14 and R15 is independently selected from Hydrogen, deuterium, cyano, halogen, C1-6 alkyl, C3-8 cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl;
• and m is 1 or 2.