US2022389029A1PendingUtilityA1

Fused pyridone compound, and preparation method therefor and use thereof

Assignee: SHANGHAI JEMINCARE PHARMACEUTICALS CO LTDPriority: Sep 20, 2019Filed: Sep 21, 2020Published: Dec 8, 2022
Est. expirySep 20, 2039(~13.2 yrs left)· nominal 20-yr term from priority
C07D 498/14C07D 498/22A61P 35/00C07D 471/14C07D 471/22A61K 31/553A61K 31/5383A61K 31/4985C07D 513/22C07D 491/147A61P 1/18A61P 1/00A61P 11/00
48
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Claims

Abstract

Disclosed in the present invention are a fused pyridone compound, and a preparation method therefor and a use thereof. Specifically, the present invention discloses a compound of formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof, and the use of the compound as a KRAS inhibitor.

Claims

exact text as granted — not AI-modified
1 . A compound represented by formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein, 
         R 1 , R 2  are independently selected from H, halogen and C 1-6  alkyl, the C 1-6  alkyl is optionally substituted by 1, 2 or 3 R; 
         R 3  is selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl, C 1-6  heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl-O— and C 3-6  cycloalkyl-O—, the C 1-6  alkyl, C 1-6  heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl-O— or C 3-6  cycloalkyl-O— is optionally substituted by 1, 2 or 3 R; 
         R 4  is independently selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl, the C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         R 5  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3  alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl, the C 1-6  alkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3  alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         L 1  is selected from —C(═O)—, —S(═O)— and —S(═O) 2 —; 
         R 6  is selected from H, CN, C 1-6  alkyl, C 1-6  alkyl-S(═O) 2 —, 3-6 membered heterocycloalkyl, —C 1-6  alkyl-3-6 membered heterocycloalkyl and C 3-6  cycloalkyl-C(═O)—, the C 1-6  alkyl, C 1-6  alkyl-S(═O) 2 —, 3-6 membered heterocycloalkyl, —C 1-6  alkyl-3-6 membered heterocycloalkyl or C 3-6  cycloalkyl-C(═O)— is optionally substituted by 1, 2 or 3 R; 
         R 7  is independently selected from H, halogen, OH, NH 2 , CN, —C(═O)—OH, C 1-6  alkyl-O—C(═O)—, —C(═O)—NH 2 , C 1-6  alkyl, C 1-6  heteroalkyl and —C 1-6  alkyl-3-6 membered heterocycloalkyl, the C 1-6  alkyl, C 1-6  heteroalkyl, C 1-6  alkyl-O—C(═O)— or —C 1-6  alkyl-3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         T 1 , T 2  are independently selected from N and —C(R 8 )—; 
         R 8  is selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         R 9  is selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl and C 1-6  heteroalkyl, the C 1-6  alkyl or C 1-6  heteroalkyl is optionally substituted by 1, 2 or 3 R; 
         R 10  is selected from H, halogen, CN, C 1-6  alkyl, C 1-6  alkoxy and C 1-6  alkylamino, the C 1-6  alkyl, C 1-6  alkoxy or C 1-6  alkylamino is optionally substituted by 1, 2 or 3 R; 
         R is independently selected from H, halogen, OH, NH 2 , CN, 
       
       
         
           
           
               
               
           
         
       
       C 1-6  alkyl, C 1-6  heterocycloalkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6  cycloalkyl-O— and 5-6 membered heterocycloalkyl-O—, the C 1-6  alkyl, C 1-6  heterocycloalkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6  cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2 or 3 R′;
 R′ is selected from F, Cl, Br, I, OH, NH 2  and CH 3 ; 
 ring A is independently 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; 
 n is selected from 0, 1, 2, 3 or 4; 
 m is selected from 0, 1, 2, 3 or 4; 
 D 1  is selected from O; 
 Y is selected from N, CH or C; 
    is   or  , and when   is  , R 2 , R 10  are not existed; 
    is   or  ; 
 when in  ,   is  , X 1 , X 2  are independently selected from —N═, —C(R 7 )═ and —C(R 7 ) 2 —C(R 7 )═; 
 when in  ,   is  , X 1 , X 2  are independently selected from single bond, —O—, —S—, S(═O), S(═O) 2 , —N(R 6 )—, —C(═O)—, —C(R 7 ) 2 — and —C(R 7 ) 2 —C(R 7 ) 2 —; 
 and, Y cannot be connected to two   at the same time, when the bond between Y and R 9  is  , R 9  is not existed; 
 the above 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 1-6  heterocycloalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from —O—, —NH—, —S—, —C(═O)—, —C(═O)O—, —S(═O)—, —S(═O) 2  and N. 
 
     
     
         2 . A compound represented by formula (I-A), an optical isomer thereof and a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein, 
         R 1 , R 2  are independently selected from H, halogen and C 1-6  alkyl, the C 1-6  alkyl is optionally substituted by 1, 2 or 3 R; 
         R 3  is selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl, C 1-6  heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl-O— and C 3-6  cycloalkyl-O—, the C 1-6  alkyl, C 1-6  heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl-O— or C 3-6  cycloalkyl-O— is optionally substituted by 1, 2 or 3 R; 
         R 4  is independently selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl, the C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         R 5  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3  alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl, the C 1-6  alkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3  alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         L 1  is selected from —C(═O)—, —S(═O)— and —S(═O) 2 —; 
         R 6  is selected from H, CN, C 1-6  alkyl, C 1-6  alkyl-S(═O) 2 —, 3-6 membered heterocycloalkyl, —C 1-6  alkyl-3-6 membered heterocycloalkyl and C 3-6  cycloalkyl-C(═O)—, the C 1-6  alkyl, C 1-6  alkyl-S(═O) 2 —, 3-6 membered heterocycloalkyl, —C 1-6  alkyl-3-6 membered heterocycloalkyl or C 3-6  cycloalkyl-C(═O)— is optionally substituted by 1, 2 or 3 R; 
         R 7  is independently selected from H, halogen, OH, NH 2 , CN, —C(═O)OH, C 1-6  alkyl-O—C(═O)—, —C(═O)—NH 2 , C 1-6  alkyl, C 1-6  heteroalkyl and —C 1-6  alkyl-3-6 membered heterocycloalkyl, the C 1-6  alkyl, C 1-6  heteroalkyl, C 1-6  alkyl-O—C(═O)— or —C 1-6  alkyl-3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         T 1 , T 2  are independently selected from N and —C(R 8 )—; 
         R 8  is selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6  alkyl, C 1-6  heteroalkyl, C 3-6  cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; 
         R is independently selected from H, halogen, OH, NH 2 , CN 
       
       
         
           
           
               
               
           
         
       
       C 1-6  alkyl, C 1-6  heterocycloalkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6  cycloalkyl-O— and 5-6 membered heterocycloalkyl-O—, the C 1-6  alkyl, C 1-6  heterocycloalkyl, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6  cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2 or 3 R′;
 R′ is selected from F, Cl, Br, I, OH, NH 2  and CH 3 ; 
 ring A is independently 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; 
 n is selected from 0, 1, 2, 3 or 4; 
    is   or  , and when   is  , R 2  is not existed; 
    is   or  ; 
 when in  ,   is  , X 1 , X 2  are independently selected from —N═, —C(R 7 )═ and —C(R 7 ) 2 —C(R 7 )═; 
 when in  ,   is  , X 1 , X 2  are independently selected from single bond, —O—, —S—, S(═O), S(═O) 2 , —N(R 6 )—, —C(═O)—, —C(R 7 ) 2 — and —C(R 7 ) 2 —C(R 7 ) 2 —; 
 the above 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 1-6  heterocycloalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from —O—, —NH—, —S—, —C(═O)—, —C(═O)O—, —S(═O)—, —S(═O) 2  and N. 
 
     
     
         3 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , selecting from 
       
         
           
           
               
               
           
         
         wherein, 
         X 1 , X 2  are independently selected from single bond, —O—, —S—, S(═O), S(═O) 2 , —N(R 6 )—, —C(═O)—, —C(R 7 ) 2 — and —C(R 7 ) 2 —C(R 7 ) 2 —, 
         R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , R 6 , R 7 , T 1 , T 2 , ring A and n are as defined in  claim 1  or  2 . 
       
     
     
         4 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 3 , wherein, R is independently selected from H, halogen, OH, NH 2 , CN, 
       
         
           
           
               
               
           
         
       
       C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, C 1-3  alkylamino, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6  cycloalkyl-O— and -5-6 membered heterocycloalkyl-O—, the C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, C 1-3  alkylamino, C 3-6  cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6  cycloalkyl-O— or 5-6 membered heterocycloalkyl-O— is optionally substituted by 1, 2 or 3 R′. 
     
     
         5 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 4 , wherein, R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 1 , R 2  are independently selected from H, F, Me, CF 3 , 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 6 , wherein, the structural moiety 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 3  is selected from H, halogen, OH, NH 2 , CN, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, 3-6 membered heterocycloalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl-O— and C 3-6  cycloalkyl-O—, the C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, 3-6 membered heterocycloalkyl, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl-O— or C 3-6  cycloalkyl-O— is optionally substituted by 1, 2 or 3 R. 
     
     
         9 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 8 , wherein, R 3  is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 4  is independently selected from H, halogen, OH, NH 2 , CN, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridinyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl and indolyl, the C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridinyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl or indolyl is optionally substituted by 1, 2 or 3 R. 
     
     
         11 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 10 , wherein, R 4  is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, ring A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzoimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one, benzo[d]oxazol-2(3H)-one, H-benzo[d] [1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl and 1,3-dihydro-2H-benzo[d]imidazolyl-2-one, the phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzoimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one, benzo[d]oxazol-2(3H)-one, H-benzo[d] [1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl or 1,3-dihydro-2H-benzo[d]imidazolyl-2-one is optionally substituted by 1, 2 or 3 R. 
     
     
         13 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 12 , wherein, the structural moiety 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 5  is selected from H, C 1-3  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C 1-3  alkyl-, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzoimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one and 1,3-dihydro-2H-benzo[d]imidazolyl-2-one, the C 1-3  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C 1-3  alkyl-, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzoimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one or 1,3-dihydro-2H-benzo[d]imidazolyl-2-one is optionally substituted by 1, 2 or 3 R. 
     
     
         15 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 14 , wherein, R 5  is selected from H, Me, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 7  is independently selected from H, halogen, OH, NH 2 , CN, C 1-3  alkyl, C 1-3  alkyl-O—C(═O)—, —C(═O)—NH 2 , C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio and —C 1-3  alkyl-3-6 membered heterocycloalkyl, the C 1-3  alkyl, C 1-3  alkyl-O—C(═O)—, —C(═O)—NH 2 , C 1-3  alkoxy, C 1-3  alkylamino, C 1-3  alkylthio or —C 1-3  alkyl-3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R. 
     
     
         17 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 16 , wherein, R 7  is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 6  is independently selected from H, CN, C 1-3  alkyl, C 1-3  alkyl-S(═O) 2 —, 3-6 membered heterocycloalkyl, —C 1-3  alkyl-3-6 membered heterocycloalkyl and C 3-6  cycloalkyl-C(═O)—, the C 1-3  alkyl, C 1-3  alkyl-S(═O) 2 —, 3-6 membered heterocycloalkyl, —C 1-3  alkyl3-6 membered heterocycloalkyl or C 3-6  cycloalkyl-C(═O)— is optionally substituted by 1, 2 or 3 R. 
     
     
         19 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 18 , wherein, R 6  is independently selected from H, CN, Me, CF 3 , 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 18 , wherein, X 1 , X 2  are independently selected from single bond, CH 2 , CH 2 CH 2 , C(═O), O, S, NH, N(CH 3 ), S(═O), S(═O) 2 , 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1  or  2 , wherein, R 8  is selected from H, halogen, OH, NH 2 , CN, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino and C 1-3  alkylthio, the C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino or C 1-3  alkylthio is optionally substituted by 1, 2 or 3 R. 
     
     
         22 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 21 , wherein, R 8  is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, the structural moiety 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . Compounds of the following formula, optical isomers thereof and pharmaceutically acceptable salts thereof, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . A pharmaceutical composition, comprising the compound, the optical isomer and the pharmaceutically acceptable salt thereof as defined in  claims 1  or  2 , and one or more pharmaceutically acceptable carriers, diluents or excipients. 
     
     
         26 . A method of preventing and/or treating diseases related to KRAS-G12C, comprising administering to a patient in need thereof a pharmaceutically effective amount of compound of  claim 1  or  claim 2  or a pharmaceutical composition of  claim 25 . 
     
     
         27 . The method according to  claim 26 , wherein the diseases related to KRAS-G12C are selected from non-small cell lung cancer, colon cancer and pancreatic cancer.

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