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CN-122003421-A - KRAS-PROTAC chimeric compounds and uses thereof

CN122003421ACN 122003421 ACN122003421 ACN 122003421ACN-122003421-A

Abstract

Provides a compound shown as [ B-L ] n -KRAS ligand (I), or pharmaceutically acceptable salt or stereoisomer thereof, and application thereof in treating diseases such as tumor, immunity or inflammation. Also provides a pharmaceutical preparation, a pharmaceutical composition and application of the compound.

Inventors

  • SUN WEI
  • YE JIUYONG
  • DENG TAO
  • WANG LING
  • GUO LIUBIN
  • ZHAO SHENGXING
  • ZHAI WENQIANG
  • LIU DONGZHOU

Assignees

  • 杭州中美华东制药有限公司

Dates

Publication Date
20260508
Application Date
20240919
Priority Date
20230922

Claims (18)

  1. A compound of formula (I) [ B-L ] n -KRAS ligand (I), Or a pharmaceutically acceptable salt or stereoisomer thereof, Wherein the KRAS ligand is a KRAS inhibitor, B is a degradation tag, such as an E3 ligase ligand, L is a linking group between B and the KRAS ligand, N is the number of said degradation tags attached to said KRAS ligand and is selected from 1,2 or 3, preferably 1.
  2. The compound of claim 1, wherein the KRAS ligand is a compound of formula (KI) or formula (KII): or a pharmaceutically acceptable salt or stereoisomer thereof, Wherein: x 1 is N or C; X 2 and X 3 are independently N or CR 100 ; R 100 is independently hydrogen, deuterium, halogen, hydroxy, amino, -CN, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CONR 100a R 100b , cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl or aryl, heteroaryl being optionally substituted with one or more deuterium, halogen, cyano, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups; R 100a 、R 100b is each independently hydrogen, deuterium, halogen, cyano, hydroxy or-C 1-8 alkyl; m is an integer from 0 to 3; L 1 、L 2 and L 3 are independently a single bond, -C 1-8 alkylene-, -O-, -S-, -NR 1a - -R 1b C＝CR 1c -、-C(R 1a R 1b )-、-C(＝O)-、-S(＝O)-、-S(＝O) 2 -、-PR 1a -、-P(＝O)R 1a 、-C(＝O)O-、-OC(＝O)-、-C(＝O)NR 1a -、-NR 1a C(＝O)-、S(＝O)O-、-OS(＝O)-、-OS(＝O) 2 -、-S(＝O)NR 1a -、-NR 1a S(＝O)-、-S(＝O) 2 NR 1a -、-NR 1a S(＝O) 2 -、-OC(＝O)O-、-OC(＝O)NR 1a -、-NR 1a C(＝O)O- Or-NR 1a C(＝O)NR 1b -; n is an integer from 1 to 10; R 1 is selected from hydrogen, halogen, amino, hydroxy, -C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 1a 、-SO 2 R 1a 、-COR 1a 、-CO 2 R 1a 、-CONR 1a R 1b 、-CH 2 C(＝O)NR 1a R 1b 、-C 2-8 alkynyl (NR 1a ) 2 、-C(＝NR 1a )NR 1b R 1c 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO 2 R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO 2 NR 1b R 1c 、, or-NR 1a SO 2 R 1b , said-C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl each optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxy, -C 1-8 alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 1a 、R 1b , and R 1c is independently hydrogen, deuterium, halogen, cyano, amino, hydroxy, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R 1d , or (R 1a and R 1b )、(R 1b and R 1c ), or (R 1c and R 1a ) together with the one or more atoms to which they are attached form a 3 to 9 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 1e ; Wherein R 1d and R 1e are each independently hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 1f 、-SO 2 R 1f 、-COR 1f 、-CO 2 R 1f 、-CONR 1f R 1g 、-C(＝NR 1f )NR 1g R 1h 、-NR 1f R 1g 、-NR 1f COR 1g 、-NR 1f CONR 1g R 1h 、-NR 1f CO 2 R 1g 、-NR 1f SONR 1g R 1h 、-NR 1f SO 2 NR 1g R 1h 、, OR-NR 1f SO 2 R 1g , each of said-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, OR heteroaryl being optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 1i 、-NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, OR heteroaryl; R 1f 、R 1g 、R 1h 、R 1i and R 1j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; r 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 2a ; each R 2a is independently hydrogen, halogen, amino, hydroxy, -C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 2b 、-SO 2 R 2b 、-COR 2b 、-CO 2 R 2b 、-CONR 2b R 2c 、-CH 2 C(＝O)NR 2b R 2c 、-C(＝NR 2b )NR 2c R 2d 、-NR 2b R 2c 、-NR 2b COR 2c 、-NR 2b CONR 2c R 2d 、-NR 2b CO 2 R 2c 、-NR 2b SONR 2c R 2d 、-NR 2b SO 2 NR 2c R 2d 、, or-NR 2b SO 2 R 2c , said-C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally substituted with deuterium, halogen, cyano, hydroxy, -NR 2e R 2f , amino, -C 1-8 alkyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 2b 、R 2c 、R 2d 、R 2e 、R 2f is independently hydrogen, deuterium, halogen, or C 1-8 alkyl; R 3 and R 4 are each independently hydrogen, halogen, hydroxy, amino, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 4a 、-SO 2 R 4a 、-SO 2 NR 4a R 4b 、-COR 4a 、-CO 2 R 4a 、-CONR 4a R 4b 、-C(＝NR 4a )NR 4b R 4c 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CONR 4b R 4c 、-NR 4a CO 2 R 4b 、-NR 4a SONR 4b R 4c 、-NR 4a SO 2 NR 4b R 4c 、, or-NR 4a SO 2 R 4b , each of which is optionally substituted with at least one substituent R 4d ; further, at least one of R 3 and R 4 is F, cl, -NO 2 , or-CN; R 4a 、R 4b , and R 4c are each independently hydrogen, hydroxy, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R 4e , or (R 4a and R 4b )、(R 4b and R 4c ), or (R 4c and R 4a ) together with the atom(s) to which they are attached form a 3 to 12 membered ring containing 0, 1,2 or 3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally being substituted with at least one substituent R 4e , or R 4d and R 4e are each independently hydrogen, deuterium, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 4f 、-SO 2 R 4f 、-SO 2 NR 4f R 4g 、-COR 4f 、-CO 2 R 4f 、-CONR 4f R 4g 、-C(＝NR 4f )NR 4g R 4h 、-NR 4f R 4g 、-NR 4f COR 4g 、-NR 4f CONR 4g R 4h 、-NR 4f CO 2 R 4f 、-NR 4f SONR 4f R 4g 、-NR 4f SO 2 NR 4g R 4h 、, OR-NR 4f SO 2 R 4g , each of which-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, OR heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 4i 、-NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, OR heteroaryl; R 4f 、R 4g 、R 4h 、R 4i , and R 4j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5 、R 6 、R 7 、R 8 is independently hydrogen, deuterium, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 5a 、-SO 2 R 5a 、-SO 2 NR 5a R 5b 、-COR 5a 、-CO 2 R 5a 、-CONR 5a R 5b 、-C(＝NR 5a )NR 5b R 5c 、-NR 5a R 5b 、-NR 5a COR 5b 、-NR 5a CONR 5b R 5c 、-NR 5a CO 2 R 5b 、-NR 5a SONR 5b R 5c 、-NR 5a SO 2 NR 5b R 5c 、 or-NR 5a SO 2 R 5b , each of which is optionally substituted with at least one substituent R 5d ; R 5a 、R 5b , and R 5c are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R 5e ; R 5d and R 5e are each independently hydrogen, hydroxy, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 5f 、-SO 2 R 5f 、-SO 2 NR 5f R 5g 、-COR 5f 、-CO 2 R 5f 、-CONR 5f R 5g 、-C(＝NR 5f )NR 5g R 5h 、-NR 5f R 5g 、-NR 5f COR 5g 、-NR 5f CONR 5g R 5h 、-NR 5f CO 2 R 5f 、-NR 5f SONR 5f R 5g 、-NR 5f SO 2 NR 5g R 5h 、, OR-NR 5f SO 2 R 5g , each of which is optionally substituted with at least one substituent selected from halogen, hydroxy, amino, cyano, -C 1-8 alkyl, -C 1-8 alkyl-OH, -OR 5i 、-NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, OR heteroaryl; R 5f 、R 5g 、R 5h 、R 5i , and R 5j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is independently an integer from 1 to 5; q is independently an integer from 1 to 5; Z is selected from hydrogen, amino, hydroxy, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-NO 2 、-OR 9 、-SR 9 、-SO 2 R 9 、-COR 9 、-CO 2 R 9 、-CONR 9 R 10 、-C(＝NR 9 )NR 10 R 11 、-NR 9 R 10 、-NR 9 COR 10 、-NR 9 CONR 10 R 11 、-NR 9 CO 2 R 10 、-NR 9 SONR 10 R 11 、-NR 9 SO 2 NR 10 R 11 、, OR-NR 9 SO 2 R 10 , each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxy, amino, -C 1-8 alkyl, -OR 9a 、-NR 9a R 9b 、-NR 9a COR 9b 、-C 1-8 alkoxy, -C 1-8 alkyl-OR 9a , cycloalkyl, heterocyclyl, aryl, OR heteroaryl; r 9 、R 10 , and R 11 are each independently hydrogen, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R 9a , or (R 9 and R 10 )、(R 10 and R 11 ), or (R 11 and R 9 ) together with the one or more atoms to which they are attached form a 3 to 12 membered ring comprising 1,2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b ; Or alternatively When q is 1, (R 8 and Z) together with the atom(s) to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally being substituted with at least one substituent R 9b ; Wherein R 9a and R 9b are each independently hydrogen, deuterium, halogen, hydroxy, amino, carbonyl-C 1-8 alkyl, -C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR 9c 、-SO 2 R 9c 、-C 1-8 alkyl -OR 9c 、-COR 9c 、-CO 2 R 9c 、-CONR 9c R 9d 、-C(＝NR 9c )NR 9d R 9e 、-NR 9c R 9d 、-NR 9c COR 9d 、-NR 9c CONR 9d R 9e 、-NR 9c CO 2 R 9d 、-NR 9c SONR 9d R 9e 、-NR 9c SO 2 NR 9d R 9e 、, OR-NR 9c SO 2 R 9d , each of said-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, OR heteroaryl being optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 9f 、-NR 9f R 9g , cycloalkyl, heterocyclyl, aryl, OR heteroaryl, and R 9c 、R 9d 、R 9e 、R 9f and R 9g are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  3. The compound of claim 1 or 2, wherein the B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from vonHippel-Lindau (VHL), cereblon (CRBN), XIAP, E3A, MDM2, post-promotion complex (APC)、UBR5(EDD1)、SOCS/BC-box/eloBC/CUL5/RING、LNXp80、CBX4、CBLL1、HACE1、HECTD1、HECTD2、HECTD3、HECW1、HECW2、HERC1、HERC2、HERC3、HERC4、HUWE1、ITCH、NEDD4、NEDD4L、PPIL2、PRPF19、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、A20/TNFAIP3、AMFR/gp78、ARA54、β-TrCP1/BTRC、BRCA1、CBL、CHIP/STUB1、E6、E6AP/UBE3A、F-box protein 15/FBXO15、FBXW7/Cdc4、GRAIL/RNF128、HOIP/RNF31、cIAP-1/HIAP-2、cIAP-2/HIAP-1、cIAP(pan)、ITCH/AIP4、KAP1、MARCH8、MindBomb1/MIB1、MindBomb2/MIB2、MuRF1/TRIM63、NDFIP1、NEDD4、NleL、Parkin、RNF2、RNF4、RNF8、RNF168、RNF43、SART1、Skp2、SMURF2、TRAF-1、TRAF-2、TRAF-3、TRAF-4、TRAF-5、TRAF-6、TRIM5、TRIM21、TRIM32、UBR5, or ZNRF3; preferably, B is a group binding to an E3 ligase selected from VHL, CRBN, MDM or cIAP, Preferably, said B is a CRBN binding group.
  4. A compound according to any one of claims 1-3, wherein B is selected from structures represented by the general formula: Wherein: each G is independently selected from CR C2 R C3 、NR C2 , CO, or SO 2 ; Y is selected from bond, NR C2 CO、CONR C2 or NH; p1 is selected from 0, 1 or 2; Each W 1 、W 2 、W 3 、W 4 、W 5 and W 6 is independently selected from N or CR C4 ; Each X 5 is independently selected from O or S; Each V 1 is independently absent or selected from NH、O、S、SO、SO 2 、SO 2 NR C2 、CO、CO 2 、C(O)NR C2 、C(S)NR C2 、NR C2 、NR C2 CO、NR C2 CONR C3 、-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R C4 , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, preferably each V 1 is independently absent, -O-, -CH 2 -, -CH=CH-, or-NH-; Each V 2 is independently selected from CR C2 R C3 、NR C2 , O, or S; Each Z 1 is independently selected from hydrogen, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R C5 ; R C1 、R C2 、R C3 、R C4 and R C5 are selected from hydrogen, carboxyl, cyano, nitro, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR C6 、-SO 2 R C6 、-SO 2 NR C6 R C7 、-COR C6 、-CO 2 R C6 、-CONR C6 R C7 、-POR C6 R C7 、-NR C6 R C7 、-NR C6 COR C7 、-NR C6 CONR C7 R C8 、-NR C6 CO 2 R C7 、-NR C6 SO 2 NR C7 R C8 、, or-NR C6 SO 2 R C7 , each of which is optionally substituted with at least one substituent R C9 ; R C6 、R C7 、R C8 and R C9 are selected from hydrogen, deuterium, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Further, the method comprises the steps of, Each G is independently selected from CH 2 、CO、SO 2 , NH, or N-C 1-6 alkyl; x 5 is selected from O or S; V 1 is absent, NH, O, -C 1-8 alkyl, or-C 2-8 alkenyl, preferably absent, -O-, -CH 2 -, -ch=ch-, or-NH-. V 2 is selected from NH, N-C 1-6 alkyl, N-C 6-10 aryl, N-3-10 membered heterocyclyl, N-5-10 membered heteroaryl, N-C 3-10 cycloalkyl, O or S; Z 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, halogen or hydrogen; R C1 is selected from hydrogen, C 1-3 alkyl, hydroxy or-CH 2 -3-10 membered heterocyclyl; W 1 、W 2 、W 3 、W 4 、W 5 and W 6 are independently optionally selected at each occurrence from N or-CR C4 ,R C4 independently from hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy, deuterated C 1-3 alkyl, or-OC 1-3 alkyl, preferably W 1 、W 2 、W 3 、W 4 and W 5 are selected from-CR C4 , and R C4 is selected from hydrogen, halogen (fluoro, chloro), methyl, or
  5. A compound according to any one of claims 1-3, wherein B is selected from structures represented by the general formula: Wherein: each G is independently selected from CR C2 R C3 、NR C2 , CO, or SO 2 ; Y is selected from a bond, or NH; p1 is selected from 0, 1 or 2; Each W 1 、W 2 、W 3 、W 4 and W 5 is independently selected from N or CR C4 ; Each X 5 is independently selected from O or S; Each V 1 is independently absent, or selected from NH、O、S、SO、SO 2 、SO 2 NR C2 、CO、CO 2 、C(O)NR C2 、C(S)NR C2 、NR C2 、NR C2 CO、NR C2 CONR C3 、-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R C4 , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, preferably each V 1 is independently absent, -O-, -CH 2 -, -ch=ch-, or-NH-; Each V 2 is independently selected from CR C2 R C3 、NR C2 , O, or S; Each Z 1 is independently selected from hydrogen, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R C5 ; r C1 、R C2 、R C3 、R C4 and R C5 are selected from hydrogen, carboxyl, cyano, nitro, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR C6 、-SO 2 R C6 、-SO 2 NR C6 R C7 、-COR C6 、-CO 2 R C6 、-CONR C6 R C7 、-POR C6 R C7 、-NR C6 R C7 、-NR C6 COR C7 、-NR C6 CONR C7 R C8 、-NR C6 CO 2 R C7 、-NR C6 SO 2 NR C7 R C8 、, or-NR C6 SO 2 R C7 , each of said-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one substituent R C9 ; R C6 、R C7 、R C8 and R C9 are selected from hydrogen, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Further, the method comprises the steps of, G is selected from CH 2 、CO、SO 2 , NH or N-C 1-6 alkyl; x 5 is selected from O or S; V 1 is absent, NH, O, -C 1-8 alkyl, or-C 2-8 alkenyl, preferably absent, -O-, -CH 2 -, -ch=ch-, or-NH-. V 2 is selected from NH, N-C 1-6 alkyl, N-C 6-10 aryl, N-3-10 membered heterocyclyl, N-5-10 membered heteroaryl, N-C 3-10 cycloalkyl, O or S; Z 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, halogen or hydrogen; R C1 is selected from hydrogen, C 1-3 alkyl, hydroxy or-CH 2 -3-10 membered heterocyclyl; W 1 、W 2 、W 3 、W 4 and W 5 are independently optionally selected from N or-CR C4 , each R C4 is independently selected from hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy, deuterated C 1-3 alkyl, or Preferably, W 1 、W 2 、W 3 、W 4 and W 5 are selected from-CR C4 , and R C4 is selected from hydrogen, halogen (fluorine, chlorine), methyl, or
  6. A compound according to any one of claims 1-5, wherein L is (LNK) u , Wherein: u is 1, 2, 3, 4, 5 or 6; Each LNK is independently absent, or selected from: (1) C 1-8 alkylene, C 2-8 alkenylene, and C 2-8 alkynylene, wherein the C 1-8 alkylene, C 2-8 alkenylene, and C 2-8 alkynylene are optionally substituted with 1 or more substituents independently selected from halogen, OH, and-OC 1-4 alkyl; -N (C 1-8 alkyl) -, -CON (C 1-8 alkyl) -, -N (C 1-8 alkyl) CO-; Preferably C 1-8 alkylene, C 2-8 alkenylene, and C 2-8 alkynylene, wherein the C 1-8 alkylene, C 2-8 alkenylene, and C 2-8 alkynylene are optionally substituted with 1 or more substituents independently selected from F, cl, OH, and-OC 1-3 alkyl; -N (C 1-8 alkyl) -, -CON (C 1-8 alkyl) -, -N (C 1-8 alkyl) CO-; More preferably C 1-8 alkylene (preferably C 1-3 alkylene, more preferably ) C 2-8 alkenylene (preferably C 2-3 alkenylene), C 2-8 alkynylene (preferably C 2-3 alkynylene), halogenated C 1-8 alkylene (preferably halogenated C 1-3 alkylene, more preferably) ) C 1-3 Alkoxy-substituted C 1-8 alkylene (preferably C 1-3 Alkoxy-substituted C 1-3 alkylene, more preferably) )、 Or alternatively (2) 4-8 Membered heteromonocyclic group, 4-10 membered heterobicyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclic group, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocyclic group, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl optionally substituted by 1 or more halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylhydroxy, cyano, amino, oxo, C 1-4 alkylhydroxy, C 1-4 alkoxy groups, and the heteroaryl, heteromonocyclic group, heterospirocyclic group, heterobridged cyclic group contains 1-4 heteroatoms independently selected from O, S, N, wherein the plurality of halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylhydroxy, cyano, amino, oxo, C 1-4 alkoxy groups for substitution is preferably The heteromonocyclic group is preferably The heterospiro group is preferably The spirocycloalkyl group is preferably The heterobicyclic group is preferably The heterocyclic ring group is preferably The heteroaryl group is preferably The aryl group is preferably
  7. The compound of any one of claim 2-6, wherein in the KRAS ligand of formula (KI) or formula (KII), X 1 is N, CH or C, X 2 is N, and X 3 is N; And/or R 100 is selected from hydrogen, halogen, hydroxy, amino, cyano, -OC 1-8 alkyl or C 3-8 cycloalkyl, preferably hydrogen, halogen, cyano, -OC 1-8 alkyl or C 3-8 cycloalkyl, more preferably H, F, cl and cyclopropyl; And/or R 3 and R 4 are each independently hydrogen, halogen, cyano, -OC 1-8 alkyl, C 1-8 alkyl or cycloalkyl, said-C 1-8 alkyl, -OC 1-8 alkyl and cycloalkyl each optionally being substituted with deuterium, halogen, cyano, hydroxy, amino, -OC 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that at least one of R 3 or R 4 is F, cl, -NO 2 , or-CN, further that R 3 and R 4 are independently selected from halogen, hydrogen, C 1-6 alkyl, cyano, -NO 2 , provided that at least one of R 3 or R 4 is F, cl, -NO 2 , or-CN; And/or, L 1 、L 2 and L 3 are independently a single bond, -C 1-6 alkylene-, -O-, -S-, -NR 1a - -R 1b C＝CR 1c -、-C(R 1a R 1b )-、-C(＝O)-、-S(＝O)-、-S(＝O) 2 -、-PR 1a -、-P(＝O)R 1a 、-C(＝O)O-、-OC(＝O)-、-C(＝O)NR 1a -、-NR 1a C(＝O)-、S(＝O)O-、-OS(＝O)-、-OS(＝O) 2 -、-S(＝O)NR 1a -、-NR 1a S(＝O)-、-S(＝O) 2 NR 1a -、-NR 1a S(＝O) 2 -、-OC(＝O)O-、-OC(＝O)NR 1a -、-NR 1a C(＝O)O-、-NR 1a C(＝O)NR 1b -; Further, L 3 is selected from single bonds; And/or L 2 is selected from single bond, -NH-, -CH 2 -, -O-, -S-; and/or L 1 is selected from a single bond, -NH-, -O-, -S-, -NHC (=o) -, -CH 2 -、-(CH 2 ) 2 -, n=1 or 2; and/or- (L 1 ) n -selected from the group consisting of single bond, -NH-, -O-, -S- -OCH 2 -、-S-CH 2 -、 -NHC(=O)-、-CH 2 -、-(CH 2 ) 2 -; And/or R 1 is selected from C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, C 6-10 heteroaryl, each of which is optionally substituted with deuterium, halogen, cyano, hydroxy, -C 1-8 alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and/or R 1 is selected from C 3-10 heterocyclyl, preferably N-containing C 3-10 heterocyclyl, more preferably N-containing 7-10 membered heteroaikanyl, more preferably And/or R 1 is selected from C 4-10 heterocyclyl or C 4-10 heteroaryl, said heterocyclyl or heteroaryl comprising 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, preferably R 1 is Wherein M is N or CH and Cy3 is a 4-10 membered heterocyclyl or heteroaryl group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said heterocyclyl or heteroaryl group being optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxy, -C 1-8 alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl, more preferably R 1 is Wherein M is N, cy3 is a 7-10 membered bridged heteroalkyl ring group and the heterocyclic group comprises 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, even more preferably R 1 is And/or- (L 1 ) n -R 1 is selected from-R 1 , i.e. L 1 is a single bond, and R 1 is selected from C 4-10 heterocyclyl or C 4-10 heteroaryl comprising 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, preferably R 1 is Wherein M is N or CH and Cy3 is a 4-10 membered heterocyclyl or heteroaryl group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said heterocyclyl or heteroaryl group being optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxy, -C 1-8 alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl, more preferably R 1 is Wherein M is N, cy3 is a 7-10 membered bridged heterocycloalkyl and said bridged heterocycloalkyl comprises 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, even more preferably R 1 is And/or the number of the groups of groups, - (L 1 ) n is selected from the group consisting of-NH-, -O-, -S-, and, -OCH 2 -、-S-CH 2 -、 -NHC (=o) -, -CH 2 -、-(CH 2 ) 2 -, and/or R 1 is selected from-NR 1a R 1b 、C 3-10 cycloalkyl, said cycloalkyl optionally substituted by-NR 1d R 1e ; and/or R 2 is naphthyl or heteroaryl (preferably ) Wherein said naphthyl or said heteroaryl is optionally substituted with one or more (e.g. 2 or 3) R 2a , preferably selected from And/or R 5 、R 6 、R 7 、R 8 is independently hydrogen, deuterium, or C 1-8 alkyl; and/or R 5 is hydrogen; And/or R 6 is hydrogen; And/or R 7 is hydrogen; And/or R 8 is hydrogen; And/or p is selected from 1, 2; and/or q is selected from 1, 2; and/or Z is selected from-NR 9 R 10 , wherein R 9 、R 10 is independently hydrogen, methyl, ethyl substituted with-OCH 3 , further Z is selected from And/or Z is selected from-NR 9 R 10 wherein R 9 and R 10 are 3 to 12 membered heterocyclyl selected from And/OR Z is selected from-OR 9 , wherein R 9 is selected from hydrogen, methyl, ethyl substituted with hydroxy, C 3 cycloalkyl, further Z is selected from And/or Z is selected from
  8. The compound of any one of claims 2-7, wherein: the KRAS ligand of the formula (KI) or the formula (KII) is selected from compounds shown in the formula (KIA) or the formula (KIB): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein ,R 100 、m、L 1 、n、R 1 、L 3 、R 2 、L 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、Z、p、q is each as defined in any one of claims 2 to 7, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; And/or, the KRAS ligand of formula (KI) or formula (KII) is selected from compounds of formula (KIIA) or formula (KIIB): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein ,R 100 、m、L 1 、n、R 1 、L 3 、R 2 、L 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、p、q is each as defined in any one of claims 2 to 7, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; and/or, the KRAS ligand of formula (KI) or formula (KII) is selected from compounds represented by formula (KIC-1), (KIC-2), (KIC-3): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein L 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, Z are each as defined in any one of claims 2 to 7, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; And/or, the KRAS ligand of formula (KI) or formula (KII) is selected from compounds represented by formulas (KIIC-1), (KIIC-2), (KIIC-3), (KIIC-4): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein L 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q are each as defined in any one of claims 2 to 7, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; and/or, the KRAS ligand of formula (KI) or formula (KII) is selected from compounds of formula (KIF): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein R 100 、m、Z、X 1 、L 3 、R 2 、R 3 、R 4 is each as defined in any one of claims 2 to 7, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; And/or, the KRAS ligand of formula (KI) or formula (KII) is selected from compounds of formula (KIIF): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 100 、m、X 1 、L 3 、R 2 、R 3 、R 4 is each as defined in any one of claims 2 to 7, and at least one of R 3 and R 4 is F, cl, -NO 2 , or-CN.
  9. The compound of any one of claims 2-8, wherein the KRAS ligand of formula (KI) or formula (KII) is selected from:
  10. the compound of any one of claims 1-9, wherein B is selected from: Wherein V 1 is selected from a single bond, -O-, -CH 2 -, -CH=CH-, -C (O) -NH-, or-NH-; And/or, the B is selected from: Wherein V 1 is selected from the group consisting of a single bond, -O-, -CH 2 -, -C (O) -NH-, or-NH-, preferably a single bond; And/or, the B is selected from: preferably, it is:
  11. The compound of any one of claims 1-10, wherein the L is (LNK) u , wherein: u is 1, 2, 3, 4, 5 or 6, and Each LNK is independently absent, or is selected from C 1-8 alkylene (preferably C 1-3 alkylene, more preferably ) C 2-8 alkenylene, C 2-8 alkynylene, halogenated C 1-8 alkylene (preferably halogenated C 1-3 alkylene, more preferably) ) C 1-3 Alkoxy-substituted C 1-3 alkylene (preferably )、 And/or, L is selected from: And/or, L is selected from: L is optionally substituted 1-4 times with-F, -Cl, -CF 3 、-CH 3 、-NH 2 、-CN、-COOH、-OH、-CH 2 OH, =O.
  12. The compound of any one of claims 6-11, wherein u is 5 and the (LNK) u is-LNKa-LNKb-LNKc-LNKd-LNKe-, Wherein: LNKa, LNKb, LNKc, LNKd and LNKe are each independently LNK as defined in any one of claims 6 to 11; Preferably LNKa is selected from the group consisting of-N (C 1-8 alkyl) -, and 4-8 membered heteromonocyclic group, 4-10 membered heteromonocyclic group and 5-12 membered heterospirocyclic group optionally substituted with 1 or more halogens, said plurality of halogens for substitution may form together with the ring atom a 3-5 membered carbocycle or heterocycle, and said heteromonocyclic group, heterobicyclic group and heterospirocyclic group contain 1 or 2 heteroatoms independently selected from O, S, N, wherein said heteromonocyclic group is preferably The heterospiro group is preferably The heterobicyclic group is preferably Preferably LNKa is selected from And/or LNKb is absent or selected from C 1-3 alkylene, And a 4-8 membered heteromonocyclic group optionally substituted with 1 or more halogens, and the heteromonocyclic group contains 1 or 2 heteroatoms independently selected from O, S, N, wherein the heteromonocyclic group is preferably Preferably LNKb is absent or selected from CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 , And/or LNKc is absent or selected from C 1-3 alkylene, C 2-3 alkynylene, And 4-8 membered heteromonocyclic group, 5-12 membered heterospirocyclic group, 3-7 membered monocycloalkyl group or 6-10 membered aryl group, said heteromonocyclic group or heterospirocyclic group containing 1 or 2 heteroatoms independently selected from O, S, N, wherein said monocycloalkyl group is preferably The heteromonocyclic group is preferably The heterospiro group is preferably The aryl group is preferably Preferably LNKc is absent or selected from CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 , And/or LNKd is absent, or selected from C 1-3 alkylene and Preferably LNKd is absent, or selected from CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 and And/or LNKe is absent, or selected from And 4-8 membered heteromonocyclic group, 4-10 membered heteromonocyclic group, 5-12 membered heterospirocyclic group, 5-10 membered heteroaryl group or 6-10 membered aryl group optionally substituted with 1 or more halogen, oxo, wherein the plurality of halogen or oxo groups for substitution may form together with the ring atom a 3-5 membered carbocyclic or heterocyclic ring and the heteroaryl, heteromonocyclic group, heterobicyclic group or heterospirocyclic group contains 1 or 2 heteroatoms independently selected from O, S, N, wherein the heteromonocyclic group is preferably The heterospiro group is preferably The heterobicyclic group is preferably The heteroaryl group is preferably The aryl group is preferably Preferably LNKe is absent, or selected from More preferably, L is selected from: Even more preferably, L is selected from:
  13. A compound of formula (I) according to any one of claims 1 to 12, which is a compound of formula (V): or a pharmaceutically acceptable salt or stereoisomer thereof, Wherein ,X 1 、R 100 、m、L 2 、L 3 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、p、q、LNK、u、B is as defined in any one of claims 1 to 12, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; And/or it is a compound as shown in formula (KVC), formula (KVD) or formula (kce): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein L 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, LNK, u, B are as defined in any one of claims 1 to 12, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; And/or it is a compound represented by formula (KVF): Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Wherein R 100 、m、X 1 、L 3 、R 2 、R 3 、R 4 , LNK, u, B are as defined in any one of claims 1 to 12, at least one of R 3 and R 4 is F, cl, -NO 2 or-CN; preferably, in said compound of formula (KVC), formula (KVD) or formula (kce): L 2 is O, one of R 3 and R 4 is H, the other is F or Cl, preferably F, R 5 、R 6 、R 7 、R 8 is each H, and p and q are each 1; u is 5, and the (LNK) u is-LNKa-LNKb-LNKc-LNKd-LNKe-, Wherein: preferably, the LNKa is selected from 4-6 membered heteromonocycloalkyl and 7-10 membered heterospirocycloalkyl, the heteromonocycloalkyl and heterospirocycloalkyl containing 1 or 2N heteroatoms, wherein the heteromonocycloalkyl is preferably The heterospirocycloalkyl group is preferably Preferably, said LNKb is absent, or is Preferably, the LNKc is absent or selected from 4-6 membered heteromonocycloalkyl and 7-10 membered heterospirocycloalkyl, the heteromonocycloalkyl and heterospirocycloalkyl containing 1 or 2N heteroatoms, wherein the heteromonocycloalkyl is preferably The heterospirocycloalkyl group is preferably Preferably, the LNKd is absent, and Preferably, the LNKe is a 4-to 6-membered heteromonocyclic alkyl group containing 1 or 2N heteroatoms, preferably More preferably, the (LNK) u is selected from Preferably, said B is selected from: (1) As defined in claim 4 More preferably as defined in claim 10 Further more preferably Even more preferably And (2) As defined in claim 4 More preferably as defined in claim 10 Further more preferably Even more preferably
  14. A compound of formula (I) according to claim 1, selected from: (e.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. )、 (E.g. (E.g. )、 (E.g. )、 (E.g. )、 (E.g. (E.g. )、 (E.g. (E.g. )、 (E.g. (E.g. ) Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  16. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or stereoisomer thereof, for the preparation of a medicament associated with KRas G12D inhibition or degradation.
  17. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment and/or prophylaxis of KRas G12D mutein-related diseases, preferably including but not limited to lung cancer, breast cancer, multiple myeloma, bladder cancer, endometrial cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, large intestine cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung cancer, squamous cell carcinoma, lung cancer, gliosis, synovial sarcoma, testicular cancer or liposarcoma, preferably pancreatic cancer, colorectal cancer, or carcinoma, preferably wherein the small cell carcinoma is selected from the group consisting of small cell and small cell carcinoma.
  18. A method of treating or preventing a KRas G12D mutein-associated disease comprising administering to a patient in need thereof an effective amount of a compound of claims 1-14 or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 15.

Description

KRAS-PROTAC chimeric compounds and uses thereof Technical Field The invention belongs to the field of medicines, and particularly relates to PROTAC chimeric compounds and application thereof in preparation of medicines for treating or preventing diseases such as tumors. Background The protein degradation targeting chimera (PROTAC) technology resulted from scientists' discovery of Ubiquitin (Ub) mediated protein degradation processes. Efforts have been made in eukaryotic cells to maintain appropriate protein levels, which are producing and degrading thousands of proteins at each time. A key factor in maintaining protein balance is a small protein molecule called ubiquitin. When linked to proteins, this results in the proteins being transported to the proteasome for degradation. Protein targeted degradation (Targeted protein degradation) is an emerging direction in the field of drug development. Protein targeted degradation drugs strive to design small molecules as a new drug, the role of traditional small molecules is to block the function of proteins, while protein targeted degradation agents act to degrade these proteins by feeding them into the proteasome (proteasome). CRAIG CREWS and Raymond Deshaies doctor polypeptide-based compounds designed a series of bifunctional chimeric molecules to induce the degradation of methionyl aminopeptidase 2 (MetAP-2) and formally proposed the PROTAC concept, applying for the related patent WO2002020740A3. However, the first PROTACs failed because these compounds, which acted as links based on large and bulky peptides, were difficult to enter cells. The Crews team designed the second generation PROTACs for the use in the Jie Xiong hormone receptor (AR) lowering based on the ubiquitin protein ligase MDM2 of E3 in 2008. In 2015, crews team designed a new generation PROTACs based on novel E3 ubiquitin ligase VHL and CRBN ligands. The KRAS (KIRSTEN RAT Sarcoma Viral Oncogene Homolog) gene is one of the most common mutant oncogenes, with KRAS gene mutations occurring in nearly 30% of cancer patients. KRAS G12D is the most common KRAS mutation, and KRAS G12D mutations are present in about 34% of pancreatic cancers, 10-12% of colorectal cancers, 4% of lung adenocarcinomas, 11% of cholangiocarcinomas, 5% of endometrial cancers, and several other cancers. It is clearly a well-established cancer target, however, a number of challenges need to be overcome to effectively target other KRAS mutants. Drug development targeting KRAS mutants is one of the important means to intervene or treat such cancers. For a long time, KRAS is covered with a "non-patent" and "non-drug targetable" spells due to its extremely high affinity for guanosine triphosphate GTP, and the "smooth" surface of KRAS proteins, which is difficult to target. One of the greatest advantages of PROTACs technology is the ability to change the target from "non-patent" (undruggable) to "drug-forming". Most traditional small molecule drugs or monoclonal antibodies require an active site for binding to an enzyme or receptor to function, however PROTACs can grasp the target protein through any corner, slit. Therefore, a small molecule therapeutic that can selectively bind to and inhibit the function of Kras G12D would be very useful. The KRAS-PROTAC chimeric compounds of the present invention are attractive agents for such mutated cancers. Disclosure of Invention It is an object of the present invention to provide protein degradation targeting chimeric compounds and pharmaceutically acceptable salts or stereoisomers thereof which have good KRAS G12D inhibitory/degradation activity and are capable of inducing KRAS degradation, and their use in the treatment of diseases such as tumors, immune or inflammatory disorders. The present invention provides compounds of the general formula (I): [ B-L ] n -KRAS ligand (I), Or a pharmaceutically acceptable salt, stereoisomer thereof, Wherein the KRAS ligand is, for example, a KRAS inhibitor, further a KRAS G12D inhibitor, B is a degradation tag, such as an E3 ligase ligand, L is a linking group between B and the KRAS ligand, N is the number of said degradation tags attached to said KRAS ligand selected from 1,2 or 3. The choice of the attachment site of the group that binds to the E3 ligase, the number of attachments, and the attachment site on the KRAS inhibitor all affect the activity of the compound. Detailed Description S1.KRAS ligand In some embodiments, KRAS ligands according to the invention are compounds of formula (KI) or formula (KII): Or a pharmaceutically acceptable salt, or stereoisomer thereof, Wherein: x 1 is N or C; X 2 and X 3 are independently N or CR 100; R 100 is independently hydrogen, deuterium, halogen, hydroxy, amino, -CN, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CONR 100aR100b, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl or aryl, heteroaryl bein