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CN-122003424-A - Fused ring compound and application thereof in KRAS inhibitor

CN122003424ACN 122003424 ACN122003424 ACN 122003424ACN-122003424-A

Abstract

A fused ring compound having a structure of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopically substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, useful in the treatment of one or more cancers caused by KRAS mutations, pharmaceutical compositions comprising the same and uses thereof.

Inventors

  • REN JUNFENG
  • LIU GUANFENG
  • WU XIANCAI
  • YANG MAO
  • LI HONGBO
  • LI YINGFU

Assignees

  • 成都海博为药业有限公司
  • 深圳海博为药业有限公司

Dates

Publication Date
20260508
Application Date
20241010
Priority Date
20231010

Claims (20)

  1. A compound of formula I, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof: A 1 is selected from C or N; A 2 is selected from S, N or C, A 3 is selected from N, O or C, and A 2 、A 3 is not both C; z is independently selected from H or deuterium at each occurrence; Ra 1 is selected from H, halogen, C (CH 3 ) =ch-or -CH＝CH 2 、-CF＝CH 2 、-CN、OH、NH 2 、-CF 3 、-CHF 2 、-CH 2 F、-CF 2 CH 3 、-CF 2 CF 3 、-0CHF 2 、-0CF 3 、 aroyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclopentenyl, cyclohexyl, cycloheptyl, methyl, ethyl, propyl, butyl, pentyl, ethenyl, propenyl, allyl, butenyl, allyl, pentadienyl, dipentenyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy; n 1 is an integer from 0 to 3; ra 2 is selected from-CN, H, or none; Rb 1 、Rb 2 、Rb 3 is selected from the group consisting of no, hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonate, phosphate, wherein the substituents are each independently selected from deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonate, phosphate; n 2 is an integer from 0 to 6; ring a is selected from one of the following substituted or unsubstituted structures: X 1 、X 2 is independently selected from N or C, X 3 is selected from N, O or C, only one of X 1 、X 2 、X 3 is C, rb 4 、Rb 5 is independently selected from H, halogen, deuterium, substituted or unsubstituted alkyl, hydroxy and cyano 、-C(＝O)NRb 41 Rb 42 、-(CH 2 )m 121 C(＝O)NRb 41 Rb 42 、-(CH 2 )m 121 NRb 41 Rb 42 、-NRb 41 Rb 42 、-C(＝O)Rb 41 、-C(＝O)ORb 41 ;Rb 41 、Rb 42 is independently selected from H, substituted or unsubstituted alkyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic and phosphoric acid groups, m 11 is selected from integers of 0-3, and m 12 、m 13 、m 121 is independently selected from integers of 0-6; each occurrence of Rb 6 is independently selected from N, O or C, each occurrence of Rb 6 is independently selected from the group consisting of no, H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfo, phosphate, carbonyl, substituted or unsubstituted alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amido, aryl, heteroaryl, acylguanidine, wherein each substituent is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfo, and phosphate, m 14 is selected from the group consisting of integers from 0 to 3, and m 15 is selected from the group consisting of integers from 0 to 6; X 6 is selected from N or O, X 7 is selected from N, O or C, rb 7 is independently selected from none, H, halogen, deuterium, substituted or unsubstituted alkyl, hydroxy, cyano, carbonyl 、-C(＝O)NRb 41 Rb 42 、-(CH 2 )m 121 C(＝O)NRb 41 Rb 42 、-(CH 2 )m 121 NRb 41 Rb 42 、-NRb 41 Rb 42 、-C(＝O)Rb 41 、-C(＝O)ORb 41 ;Rb 41 、Rb 42 is independently selected from H, substituted or unsubstituted alkyl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic, phosphoric acid, m 16 is selected from integers from 0 to 6, and m 17 is selected from integers from 0 to 3; X 8 is selected from N, O or C, rb 8 is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, carbonyl, substituted or unsubstituted alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidine, wherein each substituent is independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, and m 18 is selected from an integer of 0 to 6; Each occurrence of Rb 9 is independently selected from the group consisting of H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphonic acid, carbonyl, substituted or unsubstituted alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amide, aryl, heteroaryl, acylguanidine, wherein each substituent is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, and phosphoric acid, and m 19 is selected from the integer of 0 to 6; X 11 is selected from N, O or C, rb 20 is independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, carbonyl, substituted or unsubstituted alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amido, aryl, heteroaryl, acylguanidine, wherein each substituent is independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, m 21 is selected from integers from 0 to 6, and m 20 、m 22 is selected from integers from 0 to 3; X 12 、X 13 、X 14 is independently selected from N or O, rb 21 is independently selected from H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, carbonyl, substituted or unsubstituted alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amido, aryl, heteroaryl, acylguanidine, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid, phosphoric acid, m 23 is selected from integers of 1-3, and m 24 is selected from integers of 0-6; rb 22 is independently selected from H, deuterium, halogen, hydroxy, cyano, amino, alkoxy, sulfonyl, phosphoryl, sulfonic, phosphoric, carbonyl, substituted or unsubstituted alkyl or cycloalkyl, heteroalkyl or heterocycloalkyl, ester, acyl, amido, aryl, heteroaryl, acylguanidine, wherein each substituent is independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic, phosphoric, and m 25 is selected from an integer of 0 to 6; m 26 、m 27 is an integer from 0 to 3; x 15 、X 16 is independently selected from O and NH; X 17 is selected from O or N, rb 10 、Rb 11 is independently selected from-OH, -CH 3 and H; ring B has the following structure: Wherein X 1 、X 2 is independently selected from hydrogen, deuterium, halogen, Y is selected from hydrogen or deuterium, rd 1 is ring C; Ring C is selected from one of the following: Re 1 、Re 2 、Re 3 is independently selected from the group consisting of-H, -OH, halogen, -NO 2 、-CN、-CF 3 、-C 2 F 5 、-OCF 3 、-OCHF 2 、-OCH 2 F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, alkynyl, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonate, phosphate, wherein each of said substituents is independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonate, phosphate; n 3 is independently selected from an integer of 0 to 5 at each occurrence, n 4 is independently selected from 0 or 1 at each occurrence; Or, when n 3 is 2 or more, two adjacent Re 1 、Re 2 or Re 3 may also form a 4-to 7-membered ring with the atom connected therebetween; A 4 ～A 8 is independently selected from hetero atoms or C, and is not completely C, the number of hetero atoms in A 4 ～A 8 is 1,2 or 3, and the hetero atoms are selected from N or/and O; A 9 ～A 14 is independently selected from hetero atoms or C, and is not completely C, the number of hetero atoms in A 9 ～A 14 is 1 or 2, and the hetero atoms are selected from N or/and O; The substituents of the ring A, the ring B and the ring C are selected from-OH, halogen, -NO 2 、-CN、-CF 3 、-C 2 F 5 、-OCF 3 、-OCHF 2 、-OCH 2 F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester group, amido, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonic acid group and phosphoric acid group; The aforementioned alkyl is selected from the group consisting of C 0-10 alkyl.
  2. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 1, wherein substituted alkyl is selected from-CF 3 、-C 2 F 5 .
  3. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 1, wherein X 4 、X 5 is independently selected from N, O or C, respectively, and is not simultaneously O; X 6 is selected from N or O, X 7 is selected from N, O or C, and X 6 、X 7 is not simultaneously O; X 12 、X 13 、X 14 is independently selected from N or O, and X 12 、X 13 is not simultaneously O.
  4. The compound of claim 1, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, wherein Re 1 、Re 2 、Re 3 is independently selected from the group consisting of-H, -OH, halogen, -NO 2 、-CN、-CF 3 、-C 2 F 5 、-OCF 3 、-OCHF 2 、-OCH 2 F, phosphate, monomethyl phosphate, dimethylphosphate, C 1-5 straight or branched alkyl, C 1-5 alkoxy, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -S (C 0-10 alkyl), -OCON (C 0-10 alkyl) (C 0-10 alkyl), C 5-6 aryl, heteroaryl, a six membered heteroaryl, each occurrence; Or when n 3 is greater than or equal to 2, two adjacent Re 1 、Re 2 or Re 3 can also form saturated or unsaturated C 3-8 cycloalkyl, saturated or unsaturated C 3-8 heterocycloalkyl, saturated or unsaturated cyclic lactone, C 5-6 aryl, bridged cycloalkyl and spirocycloalkyl with the atomic composition connected between them, wherein H in the groups can be substituted by-D, -OH, -F, -NO 2 、-CN、-CF 3 、-C 2 F 5 、C 1-3 alkyl and amido.
  5. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 1, wherein ring C is selected from the group consisting of: Re 1 is independently selected from the group consisting of-H-OH, -F, -Cl, -CN, -CF 3 、-C 2 F 5 、-OCF 3 mono-methylphosphoryl, dimethylphosphoryl, C 1-5 linear or branched alkyl C 1-5 alkoxy, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, -S (C 0-10 alkyl), -OCON (C 0-10 alkyl) (C 0-10 alkyl), C 5-6 aryl, five membered heteroaryl, six membered heteroaryl; Or when n 3 is more than or equal to 2, two adjacent Re 1 and a carbon atom between the two Re 1 form saturated or unsaturated C 3-8 cycloalkyl, saturated or unsaturated C 3-8 heterocycloalkyl, five-membered ring lactone, C 5-6 aryl, bridged cycloalkyl and spirocycloalkyl, wherein H in the groups can be substituted by-D, -OH, -F, -NO 2 、-CN、-CF 3 、-C 2 F 5 、C 1-3 alkyl and amido.
  6. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 5, wherein when n 3 is 2 or more, adjacent two Re 1 may further constitute one of the following structures with its associated benzene ring: Wherein, K 2 、K 3 、K 4 and benzene ring are condensed to form saturated or unsaturated five-membered ring, K 2 、K 3 、K 4 is independently selected from C, N, O, S, K 5 、K 6 、K 7 is independently selected from C, N, O, S, K 8 is independently selected from C, N, O, S, R 50 、R 51 、R 52 、R 53 is independently selected from-H, -D, -OH, -F, -NO 2 、-CN、-CF 3 、-C 2 F 5 、C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, and m 6 、m 7 、m 8 、m 9 is selected from integers of 0-6.
  7. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 1, wherein ring C is selected from the group consisting of: Re 1 is independently selected from halogen, -CF 3 、-C 2 F 5 、-OCF 3 、-OCHF 2 、-OCH 2 F for each occurrence.
  8. The compound of claim 1, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, Selected from the group consisting of Selected from the group consisting of
  9. The compound of claim 1, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, Wherein, X 4 and X 5 are selected from one of the following combinations: (1) X 4 is O, X 5 and C; (2) X 4 、X 5 is C; (3) X 4 is N, X 5 and C; (4) X 4 is O, X 5 and N; m 14 is selected from 0, 1 or 2; Wherein X 15 、X 16 is independently selected from O and NH, and the two are different; Wherein X 17 is selected from O, rb 10 、Rb 11 is selected from one of the following combinations: (1) Rb 10 、Rb 11 is independently selected from-OH and-CH 3 , and the two are different; (2) Rb 10 、Rb 11 is selected from H.
  10. The compound of claim 9, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, Wherein m 14 is selected from 2 and X 4 is O, X 5 is C; m 15 is selected from 2, rb 6 is independently selected from hydroxy, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted amido, and each substituent is independently selected from halogen, alkyl, and hydroxy.
  11. The compound of claim 10, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, The structure is as follows:
  12. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 11, wherein Rb 6 is independently selected from hydroxy, substituted or unsubstituted C 1-3 alkyl at each occurrence, and wherein said substituents are independently selected from halogen, hydroxy.
  13. A compound according to claim 1, in the form of a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, characterized in that a 1 is selected from C, a 2 is selected from S, a 3 is selected from C, rb 1 is selected from halogen, substituted or unsubstituted alkyl or cycloalkyl, -CN, phosphoryl, said substituents being independently selected from deuterium, halogen, respectively, rb 2 is selected from halogen, ra 1 is selected from H, halogen, ra 2 is selected from-CN.
  14. A compound according to claim 1, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, characterized in that Rb 1 is selected from Cl, br, I, -CF 3 , cyclopropyl, -CN, rb 2 is selected from F and Ra 1 is selected from H, F, cl, br.
  15. A compound according to claim 1, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, wherein n 1 is selected from 1 or 2;n 2 is selected from 0;n 3 is selected from 1, 2, 3, 4 or 5.
  16. The compound, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof according to claim 1, wherein formula I is selected from one of the following:
  17. A pharmaceutical composition, characterized in that the active compound of the pharmaceutical composition comprises one or more selected from the group consisting of a compound according to any one of claims 1-16, a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, a metabolite, a metabolic precursor, an isotopically substituted form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal.
  18. Use of a compound of any one of claims 1-16, a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopically substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, for the manufacture of a medicament for inhibiting KRAS.
  19. The use of claim 18, wherein the KRAS-inhibiting agent is a KRAS G12D, KRAS G12V, KRAS G12S, KRAS G12C, KRAS G12R, KRAS G12A or KRAS G13D-inhibiting agent.
  20. The use of claim 18, wherein the compound, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotopic substitution, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof, is for the manufacture of a medicament for treating, alleviating or preventing noonan syndrome, leopard syndrome, leukemia, neuroblastoma, lymphoma, melanoma, esophageal cancer, head and neck cancer, breast cancer, lung cancer, bone cancer, biliary tract cancer, glioma, nasopharyngeal cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, bladder cancer, prostate cancer, testicular cancer, endometrial cancer, pancreatic ductal adenocarcinoma, ovarian cancer, rectal and colon cancer related diseases or conditions.

Description

Fused ring compound and application thereof in KRAS inhibitor Technical Field The application relates to the technical field of medicines, in particular to a fused ring compound, a pharmaceutical composition containing the fused ring compound and application of the fused ring compound. Background The KRAS (KIRSTEN RAT Sarcoma ViralOncogene Homolog) gene belongs to RAS family, and the other two genes of the family are HRAS and NRAS respectively, and the homology between the genes can reach 85%. The KRAS is a single-polymer G protein which is positioned at two sides of a cell membrane and has GTPase activity, and the coded protein consists of 188-189 amino acids and has the molecular weight of 21KD. KRAS plays an important role in regulating and controlling the growth path of tumor cells and the signal transmission path of angiogenesis and other processes, and can control and regulate the growth path of the cells under normal conditions, and when abnormal conditions occur, the KRAS leads the cells to continuously grow and prevent the cells from self-destruction. When KRAS gene is mutated, the gene is permanently activated, and the cell growth is continuously stimulated, so that intracellular signal transduction is disordered, and cell proliferation is out of control and is cancerous. KRAS is the most common cancer mutant gene in humans, and about 30% of all cancers are associated with activation of KRAS mutations, including 95% Pancreatic Ductal Adenocarcinoma (PDAC), 45% Colon and Rectal Cancers (CRC), and 35% non-small cell lung cancer (NSCLC), among others. Due to the protein structure problem, KRAS is once considered as a "non-patentable" target in the field of tumor drug development. However, as the research goes deep, researchers find that some specific mutant KRAS proteins form a site which can act with drugs, and after being combined with small molecule drugs, the KRAS can be locked in the inactive KRAS protein-GDP state to play a role in inhibiting activation of KRAS channels, so that an anti-tumor effect is started. In recent years, several KRAS G12C candidate drugs have entered the clinic, with the fastest progression of MRTX 849 at AMG 510 and Mirati Therapeutics of amben, the former having been FDA approved for marketing, however, inhibition of these drugs requires an active cysteine residue that makes it unavailable for the treatment of non-G12C mutants (e.g., G12D, G12V, G12R, G12S, G12A, G13D, etc.), the latter constituting most KRAS alterations in cancer. Accordingly, efforts to find therapeutic regimens capable of inhibiting various mutants of KRAS continue. There are many patents currently reporting on pan-KRAS inhibitor compounds, such as KUMQUAT BIOSCOENCES inc. And chinese gancosis, respectively, reporting on a class of pan-KRAS inhibitor compounds (WO 2022173870) and (WO 2023020519). However, the reported problems of low exposure, low bioavailability and the like of various pan-KRAS inhibitors exist, so that the searching and developing of novel and efficient pan-KRAS inhibitors have important clinical significance. Disclosure of Invention In view of the above, the application provides a fused ring compound, a pharmaceutical composition containing the same and application thereof, and the provided compound can be used for treating one or more cancers caused by KRAS mutation, has good pharmacokinetic properties, can be used for preparing medicines for preventing and/or treating diseases mediated by various KRAS mutants, and has good application prospects. The present invention provides a compound of formula I, a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, a metabolite, metabolic precursor, isotopically substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or co-crystal thereof: A 1 is selected from C or N; A 2 is selected from S, N or C, A 3 is selected from N, O or C, and A 2、A3 is not both C; z is independently selected from H or deuterium at each occurrence; Ra 1 is selected from H, halogen, C (CH 3) =ch-or -CH＝CH2、-CF＝CH2、-CN、OH、NH2、-CF3、-CHF2、-CH2F、-CF2CH3、-CF2CF3、-0CHF2、-0CF3、 aroyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclopentenyl, cyclohexyl, cycloheptyl, methyl, ethyl, propyl, butyl, pentyl, ethenyl, propenyl, allyl, butenyl, allyl, pentadienyl, dipentenyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy; n 1 is an integer from 0 to 3, for example 0, 1,2 or 3; ra 2 is selected from-CN, H, or none; Rb 1、Rb2、Rb3 is selected from the group consisting of no, hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted alkoxy, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, acylguanidine, sulfonyl, phosphoryl, sulfonate, phosphate, wherein the substituents are each independently selected from deuterium, halogen, alkyl, cycloalkyl, hete