Treatment of patients with cancers that have KRAS mutations

Abstract

Methods and pharmaceutical uses for treating cancer and tumor patients with KRAS mutations.

Description

[Technical field]

[0001] The present invention relates to methods of treating cancer, in particular to methods of treating cancer patients with KRAS mutations. [Background technology]

[0002] The official name of the KRAS gene is Kirsten ratsarcoma viral oncogene homolog. The protein encoded by the KRAS gene is a small GTPase that belongs to the RAS protein superfamily. There are three types of RAS genes: KRAS, NRAS, and HRAS. The proteins encoded by these genes are GTPases and act as molecular switches in pathways that regulate cell proliferation and survival. Based on current COSMIC data, KRAS is the most commonly mutated gene (22%) among the three genes, followed by NRAS (8%) and finally HRAS (3%). The KRAS gene significantly affects human cancer, with KRAS mutations found in approximately 30% of all cancer patients, including 90% of pancreatic cancers, 50% of colon cancers, and 25% of lung cancers. In non-small cell lung cancer, KRAS gene mutations account for 20-30% of cases and are found mainly in lung adenocarcinomas and rarely in lung squamous cell carcinomas. KRAS gene mutations are mainly concentrated in codons 12, 13 and 61, with codon 12 mutations accounting for more than 80% of all mutations, such as G12A, G12C, G12D, G12R, G12S and G12V. The most common way in which the KRAS gene is activated is by point mutation, with 95% of KRAS mutations occurring mainly in codon 12 (>80%) and codon 13 of exon 2. Common mutation forms include KRAS-G12C mutations (accounting for 13% of all KRAS mutations), KRAS-G12V (20%) and KRAS-G12D (29%) mutations (Loong HHF, Du N, Cheng C, Lin H, Guo J, Lin G, Li M, Jiang T, Shi Z, Cui Y, Jin X, Yao J, Xing Y, Yao M, Wang K, Mok TSK, Liu L. KRAS G12C mutations in Asia: A landscape analysis of 11,951 Chinese tumor samples. Transl Lung Cancer Res 2020. doi:10.21037 / tlcr-20-455).

[0003] The G12C mutation in the KRAS gene has been used to design covalent inhibitors with preclinical activity because the mutant contains a cysteine ​​residue (the 12th glycine is changed to cysteine). For example, AMG-510 (the first KRAS-G12C inhibitor in clinical development) and MRTX849 have shown potent antitumor activity.

[0004] On May 29, 2021, sotorasib (AMG-510, Lumakeras), known in the industry as a "game-changing anti-cancer drug" and active against KRAS mutations, was approved by the FDA for the treatment of patients with non-small cell lung cancer harboring KRAS-G12C mutations who have previously received at least one systemic therapy. AMG510 is specifically designed for the mutant subtype KRAS-G12C and has high selectivity. AMG510 can specifically bind to KRAS-G12C in over 6,000 proteins, trapping and inactivating it.

[0005] On June 24, 2021, the U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation to adagrasib (MRTX849) for the treatment of patients with KRAS-G12C mutated non-small cell lung cancer (NSCLC) who have previously received systemic therapy. The drug is an oral inhibitor optimized specifically for KRAS-G12C mutants. MRTX849 has shown promising safety and anti-cancer activity, as demonstrated in preliminary human clinical trials, in the treatment of KRAS-G12C mutated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) as well as other solid tumors by irreversibly and selectively binding to inactive KRAS-G12C, preventing KRAS-G12C from sending cell growth signals and triggering cancer cell death.

[0006] However, there are no commercially available drugs for the broader G12D subtype of KRAS mutations. Summary of the Invention

[0007] AST-3424 (OBI-3424) is a first-in-class DNA alkylating cancer therapeutic that targets overexpression of aldo-keto reductase 1C3 (AKR1C3), selectively targeting cancers that overexpress AKR1C3 and selectively releasing a potent DNA alkylating agent in the presence of the AKR1C3 enzyme. This selective mode of activation distinguishes AST-3424 from traditional alkylating agents (e.g., cyclophosphamide and ifosfamide). Overexpression of AKR1C3 is found in a wide range of treatment-resistant and refractory cancers, including hepatocellular cancer (HCC), castration-resistant prostate cancer (CRPC), and T-cell acute lymphoblastic leukemia (T-ALL). AKR1C3 is highly expressed in up to 15 types of solid and hematological tumors. Currently, the drug is in phase II clinical trials in China and the United States (US OBI-3424-NCT03592264-Phase II, castration prostate cancer and liver cancer; US OBI-3424-NCT04315324-Phase II, T-lymphoblastic acute leukemia (T-ALL); China AST-3424-CTR20191399-Phase II, solid tumors; China AST-3424-CTR20201915-Phase II, T-lymphocytic acute leukemia (T-ALL) and B-lymphocytic acute leukemia (B-ALL)).

[0008] AST-3424 and compounds [ka] (hereinafter referred to as AST) has been found to have good therapeutic efficacy against KRAS mutant G12D subtype tumor models with high expression of AKR1C3 in animal in vivo model studies of this drug and similar drugs.

[0009] Based on these experimental results, the present application provides the following cancer treatment methods and medical uses of the compounds.

[0010] A therapy using an agent containing an AKR1C3-activating DNA alkylator prodrug compound as a monotherapy or in combination with other therapeutic agents to treat patients with cancers and tumors that have KRAS mutations.

[0011] 1. A pharmaceutical use of an AKR1C3 activating DNA alkylator prodrug compound, said compound being used in the manufacture of a monotherapy drug or a drug in combination with other therapeutic agents for the treatment of cancer and tumor patients with KRAS mutations.

[0012] An AKR1C3-activating DNA alkylating agent prodrug compound means that the compound is a prodrug and that the prodrug molecule reacts with the AKR1C3 enzyme to release a cytotoxic DNA alkylating agent immediately after reaction.

[0013] Specifically, taking AST-3424 as an example, the above compound, which is a specific substrate for the aldo-keto reductase AKR1C3, can be rapidly and effectively reduced only in cancer cells with high expression of AKR1C3, thereby releasing the cytotoxic DNA alkylating agent AST-2660, which crosslinks with DNA and subsequently leads to cancer cell death.

[0014] [ka]

[0015] A method of treatment for treating cancer and tumor patients with KRAS mutations using a drug containing an AKR1C3 activating DNA alkylator prodrug compound, either as monotherapy or in combination with other therapeutic agents, wherein the compound is selected from structural formula (1) or (2), and salts, esters, solvates and isotopic isomers thereof:

[0016] [ka]

[0017] 2. A pharmaceutical use of an AKR1C3 activating DNA alkylator prodrug compound, said compound being used in the manufacture of a monotherapy drug or a drug in combination with other therapeutic agents for treating cancer and tumor patients with KRAS mutations, said pharmaceutical use of a compound selected from structural formula (1) or (2), and salts, esters, solvates and isotopic isomers thereof:

[0018] In the formula, R1, R2, R3, R4, R5, R8, R9 and R 10 The definition is set out in the claims of patent application PCT / CN2020 / 089692, International Publication No. 2020228685.

[0019] Specifically, the above groups are defined as follows:

[0020] During the ceremony, R1 is C6~C 10 aryl or Z-substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 membered heteroaryl or Z-substituted heteroaryl, 7-15 membered fused ring or Z-substituted fused ring, R2 is hydrogen, a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OMS, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 aryl or Z-substituted aryl, a 4-15 membered heterocycle or Z-substituted heterocycle, a 5-15 membered heteroaryl or Z-substituted heteroaryl, an ether having 1 to 6 carbon atoms, or a Z-substituted alkoxy having 1 to 6 carbon atoms, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6, -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , -NR 6 SO2R 7 , or -NR 6 SO2NR 6 R 7 or R 2 is the group R to which it is attached. 1 together with the atom of the formula (I) form a 7- to 15-membered fused ring or a Z-substituted fused ring, R3 is hydrogen, halogen, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OLCMS, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 aryl or Z-substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6 , -OCO-R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , or -NR 6 SO2R 7 and R4 and R5 are each independently hydrogen, a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OLCMS, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10aryl or Z-substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, -CONR 6 R 7 , -SO2NR 6 R 7 , -SO2R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 6 , -OCOR 6 , or -NR 6 SO2R 7 or R 4 and R 5 form, together with the atoms of the benzene ring to which they are attached, a 7- to 15-membered fused ring or a Z-substituted fused ring; R6 and R7 are each independently hydrogen, cyano or isocyano, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 or Z-substituted aryl, a 4-15 membered heterocycle or Z-substituted heterocycle, a 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, or R 6 and R 7 together with the atom to which they are attached form a 5- to 7-membered heterocyclyl or a 5- to 7-membered Z-substituted heterocyclyl; R8 and R 10 are each independently hydrogen, deuterium, aryl or Z-substituted aryl, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, R 8 and R 10 At least one of must be hydrogen or deuterium, R9 is a C6-C alkyl group substituted with at least one fluorine atom or nitro group. 10 a substituted aryl, a 4- to 15-membered substituted heterocycle substituted with at least one fluorine atom or nitro group, or a 5- to 15-membered substituted heteroaryl substituted with at least one fluorine atom or nitro group; the substituent Z is a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OMS, C1-C3 alkyl or substituted alkyl, C1-C3 alkoxy or substituted alkoxy, C2-C3 alkenyl or substituted alkenyl, C2-C3 alkynyl or substituted alkynyl, C3-C8 cycloalkyl or substituted cycloalkyl, aromatic ring, heterocycle, heteroaromatic ring and fused ring, or substituted aromatic ring, heterocycle, heteroaromatic ring and fused ring, the substitution pattern being mono- or di-substituted; R9 C6~C 10 The substituent of the substituted aryl, 4- to 15-membered substituted heterocycle, or 5- to 15-membered substituted heteroaryl is a halogen atom, nitro, cyano or isocyano, hydroxy, amino, C1-C3 alkyl or alkoxy, alkenyl, alkynyl, cycloalkyl or benzene ring, a substituted benzene ring, C1-C3 alkoxy or halogen atom-substituted alkoxy.

[0021] Specifically, the compounds of formula (1) and formula (2) are selected from the group consisting of:

[0022] [ka] [ka] [ka]

[0023] The specific definitions and meanings of each group, as well as the preparation methods and spectral data of each compound, are described in patent application PCT / CN2020 / 089692, International Publication No. 2020228685, which is incorporated herein by reference in its entirety.

[0024] Apparently, the compounds of structural formula (1) or (2) are prodrugs of AST-2660, similar to AST-3424 or AST, which can be activated by AKR1C3 enzyme to form AST-2660 (an alkylating agent) and exhibit anticancer efficacy.

[0025] [ka]

[0026] A method of treatment for treating cancer and tumor patients with KRAS mutations using a drug containing an AKR1C3 activating DNA alkylator prodrug compound, either as monotherapy or in combination with other therapeutic agents, wherein the compound is selected from structural formula (3), and salts, esters, solvates and isotopic isomers thereof.

[0027] [ka]

[0028] 1. A pharmaceutical use of an AKR1C3 activating DNA alkylator prodrug compound, said compound being used in the manufacture of a monotherapy drug or a drug in combination with other therapeutic agents for treating cancer and tumor patients with KRAS mutations, said compound being selected from the group consisting of structural formula (3) and salts, esters, solvates and isotopic isomers thereof: [ka] Wherein, the definitions of A, E, G, X and Y are as set forth in the claims of patent application PCT / NZ2019 / 050030, International Publication No. 2019190331 (corresponding to Chinese Patent Application No. 2019800234236, Chinese Patent Application Publication No. 111918864). The pharmaceutical use of the compound.

[0029] Specifically, the above groups are defined as follows:

[0030] During the ceremony, A is H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, CFH2, CF2H, CF3, F, Cl, Br, I, OCF3, COR, or CON(R)2; E is SO or SO2; X is Cl, Br, I, or OSOR; Y is Cl, Br, I, or OSOR; each R is independently H or C1-C6 alkyl; G is a radical group selected from the group consisting of formulae (B) to (AA), [ka] During the ceremony, R1 is H, C1-C6 alkyl, CH2(CH2) n OH, CH2CH(OH)CH2OH, phenyl, pyridyl, benzyl, or pyridylmethyl, provided that when R1 is phenyl, pyridyl, benzyl, or pyridylmethyl, R1 may be substituted at any substitutable position with C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, OR6, N(R6)(R7), CFH2, CF2H, CF3, F, Cl, Br, I, OCF3, COR6, CON(R6)(R7), SOR6, SON(R6)(R7), SO2R6, SON(R6)(R7), CN, or NO2; R2 and R3 are each independently H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, OR6, N(R6)(R7), CFH2, CF2H, CF3, F, Cl, Br, I, OCF3, COR6, CON(R6)(R7), SOR6, SON(R6)(R7), SO2R6, SO2N(R6)(R7), CN, or NO2; R4 is N(R6)(R7), OH, OCH2(CH2) n N(R6)(R7), or CH2(CH2) n N(R6)(R7), R5 is hydrogen or a C1-C6 alkyl group; R6 and R7 are each independently H or C 1~6 alkyl, or R6 and R7 together form a substituted or unsubstituted 5- or 6-membered heterocycle; Z is CH or N; W is CH2, O, S, SO, or SO2; n is 0 to 6; * indicates the point of connection to formula (I).

[0031] Specifically, the compound of formula (3) is selected from the group consisting of:

[0032] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0033] The specific definitions and meanings of each group, as well as the preparation methods and spectral data of each compound are described in patent application PCT / NZ2019 / 050030, International Publication No. 2019190331 (corresponding to Chinese Patent Application No. 2019800234236, Chinese Patent Application Publication No. 111918864), which is incorporated herein by reference in its entirety.

[0034] The compound of structural formula (3), like AST-3424 or AST, is a nitrogen mustard analogue. [ka] It is a prodrug of AKR1C3 enzyme which activates it to produce nitrogen mustard analogues. [ka] (DNA alkylating agents) and may exhibit anticancer efficacy.

[0035] [ka]

[0036] A method of treatment for treating cancer and tumor patients with KRAS mutations using a drug containing an AKR1C3 activating DNA alkylator prodrug compound, either as monotherapy or in combination with other therapeutic agents, wherein the compound is selected from structural formula (4), and salts, esters, solvates and isotopic isomers thereof.

[0037] [ka]

[0038] 1. A pharmaceutical use of an AKR1C3 activating DNA alkylator prodrug compound, said compound being used in the manufacture of a monotherapy drug or a drug in combination with other therapeutic agents for treating cancer and tumor patients with KRAS mutations, said compound being selected from the group consisting of structural formula (4) and salts, esters, solvates and isotopic isomers thereof: [ka] wherein the definition of Rw is as set forth in the claims of patent application PCT / CN2020 / 120281, International Publication No. 2021068952. Specifically, the above groups are defined as follows:

[0039] Rw is [ka] and R1 is H, C 1~6 Alkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl; 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and phenyl each have one, two, or three R a may be substituted with Each R a are independently H, F, Cl, Br, I, -CN, -OH, C 1~3 Alkoxy or C1~3 is alkyl, R2 is H or C 1~6 is alkyl, or R1 and R2 together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is selected from 1, 2, or 3 R b may be substituted with Each R b are independently H, F, Cl, Br, I, -CN, -OH, -NH2, -OCH3, -OCH2CH3, -CH3, or -CH2CH3; R3 is H, F, Cl, Br, I, -OH, -NH2, C 1~3 Alkoxy or C 1~3 is alkyl, or R2 and R3 are linked together; Structural Units [ka] but [ka] or [ka] Become, T1 is -(CR c R d ) m or -(CR c R d ) n -O-, m is 1, 2 or 3; n is 1 or 2; T2 is N or CH; R c and R d are independently H, F, and C 1~3 Alkyl, or C 1~3 is an alkoxy; R4, R5 and R6 are each independently H, F, Cl, Br, I, C 1~3 Alkyl, or C 1~3is an alkoxy; T is N or CH; R7 and R8 are each independently H, F, Cl, Br, or I; R9 and R 10 are each independently H, F, Cl, Br, I, -CN, or a 4- to 6-membered heterocycloalkyl and a 5- to 6-membered heteroaryl, each containing 1, 2, 3, or 4 heteroatoms independently selected from -N, -O-, and -S-.

[0040] Specifically, the compound of formula (4) is [ka] is selected from the group consisting of:

[0041] The definitions and meanings of each group, as well as the preparation methods and spectral data of each compound, are described in patent application PCT / CN2020 / 120281, International Publication No. 2021068952, which is incorporated herein by reference in its entirety.

[0042] Apparently, the compound of structural formula (3) is a prodrug of AST-2660, similar to AST-3424 or AST, which can be activated by AKR1C3 enzyme to form AST-2660 (a DNA alkylating agent) and exhibit anti-cancer efficacy.

[0043] [ka]

[0044] A method of treatment for treating cancer and tumor patients with KRAS mutations using a drug containing an AKR1C3 activating DNA alkylator prodrug compound, either as monotherapy or in combination with other therapeutic agents, wherein the compound is selected from structural formula (5), and salts, esters, solvates and isotopic isomers thereof.

[0045] [ka]

[0046] 1. A pharmaceutical use of an AKR1C3 activating DNA alkylator prodrug compound, said compound being used in the manufacture of a monotherapy drug or a drug in combination with other therapeutic agents for treating cancer and tumor patients with KRAS mutations, said compound being selected from the group consisting of structural formula (5) and salts, esters, solvates and isotopic isomers thereof: [ka] In the formula, X, Y, Z, R, T, A and X 10 The definition is as set forth in the claims of patent application PCT / US2016 / 062114, International Publication No. 2017087428 (corresponding to Chinese Patent Application No. 2016800200132, Chinese Patent Application Publication No. 108136214), the pharmaceutical use of the compound.

[0047] Specifically, the above groups are defined as follows:

[0048] X 10 is O, S, SO, or SO2, A is C6~C 10 Aryl, 5-15 membered heteroaryl, or -N=CR 1 R 2 and R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 , or -NR 13 COR 14 and X, Y and Z are each independently hydrogen, CN, halogeno, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle, ether, -CONR 13 R14 , or -NR 13 COR 14 and R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 , or -NR 13 COR 14 and R 13 and R 14 are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4-15 membered heterocycle, or ether; T is -OP(Z 1 ) moiety. 5 -X 5 -Y 5 and a phosphoramidate alkylating agent comprising a moiety, wherein Z 5 is a heteroatom such as nitrogen, sulfur or oxygen, and X 5 is substituted or unsubstituted ethylene, Y 5 is a halogeno or other leaving group, or Z 5 -X 5 -Y 5 together form an aziridinyl (NCH2CH2) moiety, and Z 1 is O or S, In the above, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, and ether groups are substituted or unsubstituted.

[0049] Specifically, the compound of formula (5) is selected from the group consisting of:

[0050] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0051] The specific definitions and meanings of each group, as well as the preparation methods and spectral data of each compound are described in patent application PCT / US2016 / 062114, International Publication No. 2017087428 (corresponding to Chinese Patent Application No. 2016800200132, Chinese Patent Application Publication No. 108136214), which is incorporated herein by reference in its entirety.

[0052] Apparently, the compound of structural formula (5), like AST-3424 or AST, is a prodrug of a phosphoramidate alkylating agent, which can be activated by the AKR1C3 enzyme to form T (a phosphoramidate alkylating agent; AST-2660 is a phosphoramidate alkylating agent) and exert anticancer efficacy.

[0053] [ka]

[0054] A method of treatment for treating cancer and tumor patients with KRAS mutations using a drug containing an AKR1C3 activating DNA alkylator prodrug compound, either as monotherapy or in combination with other therapeutic agents, wherein the compound is selected from structural formula (6), and salts, esters, solvates and isotopic isomers thereof.

[0055] [ka]

[0056] 1. A pharmaceutical use of an AKR1C3 activating DNA alkylator prodrug compound, said compound being used in the manufacture of a monotherapy drug or a drug in combination with other therapeutic agents for treating cancer and tumor patients with KRAS mutations, said compound being selected from the group consisting of structural formula (6) and salts, esters, solvates and isotopic isomers thereof: [ka] During the ceremony, A is a substituted or unsubstituted C6-C 10 Aryl, biaryl or substituted biaryl, 5-15 membered heteroaryl, or -N=CR 1 R 2 where the substituents are halogeno, -CN, -NO2, -O-(CH2)-O-, -CO2H and salts thereof, -OR 100 , -CO2R 100 , -CONR 101 R 102 , -NR 101 R 102 , -NR 100 SO2R 100 , -SO2R 100 , -SO2NR 101 R 102 , C1-C6 alkyl and C3-C 10 heterocyclyl; In the formula, R 100 , R 101 and R 102 are each independently hydrogen, C1-C8 alkyl, or C6-C12 aryl, or R 101 and R 102 form a 5- to 7-membered heterocycle together with the nitrogen atom to which they are attached, In the above, the alkyl group and the aryl group are each substituted with 1 to 3 halogeno groups or 1 to 3 C1 to C6 alkyl groups, R 1 and R 2 are each independently phenyl or methyl; X, Y and Z are each independently hydrogen or halogen; R is hydrogen or C1-C6 alkyl or halogen-substituted alkyl; Medicinal uses of the compound.

[0057] Obviously, the term "compound" includes the compound itself as well as any solvates, salts, esters or isotopic isomers thereof.

[0058] "Cx-Cy" or "Cx-y" before a group refers to the range of the number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group having at least 1 and up to 6 carbon atoms.

[0059] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, and in some embodiments 1 to 6 carbon atoms. "C alkyl" refers to an alkyl group having x to y carbon atoms. This term includes linear and branched hydrocarbyl groups such as (by way of example) methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl ((CHC-), n-pentyl (CHCHCHCHCH-), and neopentyl ((CH)CCH-).

[0060] "Aryl" refers to aromatic groups having 6-14 carbon atoms, no ring heteroatoms, and either a single ring (e.g., phenyl) or multiple fused (condensed) rings (e.g., naphthyl or anthryl). For multiple ring systems, including fused, bridged, and spiro ring systems with aromatic and non-aromatic rings without ring heteroatoms, the term "aryl" or "Ar" applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalen-2-yl is an aryl group because the point of attachment is at the 2-position of the aromatic phenyl ring). "Arylene" refers to a divalent aryl radical with appropriate hydrogen content.

[0061] "Cycloalkyl" refers to saturated or partially saturated cyclic groups having 3 to 14 carbon atoms, no ring heteroatoms, and monocyclic or polycyclic rings, including fused, bridged, and spirocyclic systems. For polycyclic systems having aromatic and non-aromatic rings with no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8,-tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl groups. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl. "Cycloalkylene" refers to divalent cycloalkyl radicals with appropriate hydrogen content.

[0062] "Halogeno" refers to one or more of fluoro, chloro, bromo, and iodo.

[0063] "Heteroaryl" refers to an aromatic group having 1-14 carbon atoms and 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, including monocyclic (e.g., imidazolyl-2-yl and imidazol-5-yl) and polycyclic (e.g., imidazopyridyl, benzotriazolyl, benzimidazol-2-yl, and benzimidazol-6-yl) systems. For polycyclic systems, including fused, bridged, and spiro ring systems with aromatic and non-aromatic rings, the term "heteroaryl" applies when there is at least one ring heteroatom and the point of attachment is to an atom of the aromatic ring (e.g., 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group may be oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety.Included within the term heteroaryl are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzothienyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroiso Quinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazole, pyri Examples of heteroaryl groups include, but are not limited to, diaryl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, and xanthenyl. "Heteroarylene" refers to a divalent heteroaryl radical having appropriate hydrogen content.

[0064] "Heterocyclic" or "heterocycle", or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group having 1-14 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen, including monocyclic and polycyclic systems, including fused, bridged, and spirocyclic systems. For polycyclic systems having aromatic and / or non-aromatic rings, the terms "heterocyclic", "heterocycle", "heterocycloalkyl", or "heterocyclyl" apply when there is at least one ring heteroatom and the point of attachment is to an atom of the non-aromatic ring (e.g., 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-6-yl, and decahydroquinolin-6-yl). In some embodiments, the heterocyclic groups herein are 3-15 membered, 4-14 membered, 5-13 membered, 7-12 membered, or 5-7 membered heterocycles. In some other embodiments, the heterocycle contains 4 heteroatoms. In some other embodiments, the heterocycle contains three heteroatoms. In some other embodiments, the heterocycle contains up to two heteroatoms. In some embodiments, the nitrogen and / or sulfur atom(s) of the heterocycle group may be oxidized to provide an N-oxide (N→O), sulfmyl, or sulfonyl moiety. Heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g., C 3~10 ) refers to the total number of carbon atoms in the heterocyclyl group, excluding the number of heteroatoms. Divalent heterocyclic radicals have the hydrogen content adjusted appropriately.

[0065] "Biaryl" refers to a structure in which two aromatic rings are linked by a single CC bond, such as biphenyl or bipyridine.

[0066] The term "optionally substituted" refers to a substituted or unsubstituted group. A group may be substituted with one or more substituents, for example, 1, 2, 3, 4, or 5 substituents. Substituents include oxo, halogeno, -CN, NO2, -N2+, -CO2R. 100 , -OR 100 , -SR 100 , -SOR 100 , -SO2R 100 , -NR 100 SO2R 100 , -NR 101 R 102 , -CONR 101 R 102 , -SO2NR 101 R 102 , C1-C6 alkyl, C1-C6 alkoxy, -CR 100 =C(R 100 )2, -CCR 100 , C3~C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 12 Aryl and C2-C 12 Preferably, R is selected from the group consisting of heteroaryl, or divalent substituents such as -O-(CH2)-O-, -O-(CH2)2-O-, and 1 to 4 methyl substituted versions thereof, 100 , R 101 and R 102 are each independently hydrogen or C1-C8 alkyl, C3-C 12 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 12 Aryl or C2-C 12 Heteroaryl, or R 100 and R 102 form a 5-7 membered heterocycle together with the nitrogen atom to which they are linked, and in the above, each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with 1 to 3 halogeno groups, 1 to 3 C1 to C6 alkyl groups, 1 to 3 C1 to C6 haloalkyl groups, or 1 to 3 C1 to C6 alkoxy groups. The substituents are chloro, fluoro, -OCH 3、Methyl, ethyl, isopropyl, cyclopropyl, -CO2H and their salts and C1-C6 alkyl esters, CONMe2, CONHMe, CONH2, -SO2Me, -SO2NH 2、 -SO2NMe 2、 It is preferably selected from the group consisting of -SO2NHMe, -NHSO2Me, -NHSO2CF3, -NHSO2CH2Cl, -NH2, -OCF3, -CF3 and -OCHF2.

[0067] Specifically, the compound of formula (6) is selected from the group consisting of:

[0068] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0069] The specific definitions and meanings of each group, as well as the preparation methods and spectral data of each compound are described in PCT / US2016 / 021581, International Publication No. 2016145092 (corresponding to Chinese Patent Application No. 2016800150788, Chinese Patent Application Publication No. 107530556), PCT / US2016 / 062114, International Publication No. 2017087428 (corresponding to Chinese Patent Application No. 2016800446081, Chinese Patent Application Publication No. 108290911), and PCT / CN2020 / 089692, International Publication No. 2020228685, which are incorporated herein by reference in their entireties.

[0070] Apparently, the compound of formula (6) is a prodrug of AST-2660, similar to AST-3424 or AST, and can be activated by the AKR1C3 enzyme to form AST-2660 and exert anti-cancer efficacy.

[0071] [ka]

[0072] AST-3424 (OBI-3424), [ka] (hereafter referred to as AST), and [ka] The preparation method and spectral data of are disclosed in the following patent applications, PCT / US2016 / 021581 (corresponding to Chinese Patent Application Publication No. 107530556, Chinese Patent Application No. 2016800150788), PCT / US2016 / 062114 (corresponding to Chinese Patent Application Publication No. 108290911, Chinese Patent Application No. 2017087428), PCT / US2016 / 062114 (corresponding to Chinese Patent Application Publication No. 108290911, Chinese Patent Application No. 20168004), PCT / US2016 / 021581 (corresponding to Chinese Patent Application Publication No. 107530556 ... The related prepared concentrated injections, as well as related formulations, preparation methods, and clinical suitability and administration methods are described and disclosed in detail in related patents WO 2021008520, WO 2021043275, which are incorporated herein by reference in their entireties.

[0073] Monotherapy refers to a single drug therapy. Combination refers to a combination drug therapy. Monotherapy refers to the use of only one anticancer drug during the course of treatment. Combination therapy refers to the use of two or more anticancer drugs simultaneously or sequentially during the course of treatment.

[0074] In general, combination therapy requires consideration of various dosages and administration cycles depending on the characteristics of the disease and the types of drugs used in combination, and only in accordance with the above circumstances can the combination therapy plan obtained from such consideration achieve better therapeutic effects than monotherapy.

[0075] For both monotherapy and combination therapy regimens, the dosage and administration cycle of the drugs should be explored through clinical trials with reference to the dosage and administration regimens of AST-3424 and its analogs, as well as the other drugs listed above.

[0076] The dosage for monotherapy can be determined with reference to the dosages for animal experiments in International Publication Nos. 2019062919, 2016145092, and 2017087428.

[0077] Further, the KRAS mutation is selected from the group consisting of a KRAS-G12D mutation, a KRAS-G12V mutation, and a KRAS-G12C mutation.

[0078] Mutations in one or both of the genes corresponding to KRAS can be detected and diagnosed using commercially available (companion) diagnostic kits, such as those approved in China: Amoy Dx, National Device Registration 20153401126, Human KRAS Gene Mutation Detection Kit (Fluorescent PCR Method), Tellgen, National Device Registration 20163401341, Human K-RAS Gene 7 Mutation Detection Kit (PCR Fluorescence Method) There is.

[0079] Apparently, next-generation sequencer (NGS) sequencing (YS 450 gene NGS large panel) can also be used to determine the specific KRAS mutation subtype.

[0080] More preferably, the KRAS mutation is selected from the KRAS-G12D mutation.

[0081] The tumor mutation load (burden) level of the described genetic alterations is intermediate.

[0082] Tumor mutation burden (TMB) can vary from high to low depending on the type of tumor. In general, a TMB with more than 20 mutations / Mb (Mb stands for bases per million bases) is considered high, a TMB with less than 10 mutations / Mb is considered low, and anything in between is considered moderate. At the 2017 World Lung Cancer Conference, Squibb presented the results of a clinical trial called CheckMate-032. This was a phase II clinical trial of 401 patients with advanced lung cancer who had failed first-line therapy and were treated with a PD-1 inhibitor alone or in combination with ipilimumab. The patients were divided into three categories according to their TMB levels: high, intermediate, and low TMB patients. In patients who received the combination therapy, the efficiencies of the three groups were 62%, 20%, and 23%, respectively, with the high TMB group being three times more efficient than the other two groups. The median overall survival for the three groups was 22.0 months, 3.6 months, and 3.4 months, respectively - a six-fold difference between 22.0 and 3.4 months! This study demonstrated that for a range of cancer drugs, differences in TMB levels can have a significant impact on drug efficacy.

[0083] In addition, the prodrug compound is [ka] It is preferably selected from the group consisting of:

[0084] The aforementioned cancers are selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer and bladder cancer.

[0085] The other therapeutic agent is selected from the group consisting of a KRAS inhibitor and an immunotherapeutic agent (immune checkpoint inhibitor).

[0086] KRAS inhibitors are substances that inhibit KRAS enzyme activity. For details, please refer to the review article Goebel, Lisa & Muller, Matthias & Goody, Roger & Rauh, Daniel. (2020). KRasG12C inhibitors in clinical trials: A short historical perspective. RSC Medicinal Chemistry. 11.10.1039 / D0MD00096E.

[0087] KRAS inhibitors that have entered clinical development or are already on the market include sotorasibe (AMG510) developed by Amgen in the United States, adagrasib (MRTX849) developed by Mirati Therapeutics, GDC6036 developed by Roche, LY3499446 developed by Lilly, JNJ74699157 (ARS3248) co-developed by Araxes and Janssen, D-1553 developed by InventisBio, JAB-3312 developed by Jacobio Pharma, JAB-3068 developed by Jacobio Pharma, GH35 developed by Gen House, and Betta Pharma. These are BPI-421286 developed by Pharma; BI17016963 developed by Boehringer Ingelheim; mRNA-5671 developed by Moderna; and AZD-4785 jointly developed by AstraZeneca and Ionis.

[0088] [ka]

[0089] Here, the KRAS inhibitor is selected from the group consisting of sotrasib (AMG510), adagrasib (MRTX849), GDC6036, LY3499446, JNJ74699157 (ARS3248), and D-1553.

[0090] Immune checkpoint molecules are regulatory molecules in the immune system that play an inhibitory role and are essential for maintaining self-tolerance, preventing autoimmune reactions, and minimizing tissue damage by controlling the timing and strength of immune responses. Immune checkpoint molecules are expressed in immune cells and inhibit the function of immune cells, thereby preventing the body from generating an effective antitumor immune response and causing immune escape of tumors. Immune checkpoint molecules associated with tumors include PD1, PD-L1, CTLA4, Tim3, and LAG3. Currently, PD1, PD-L1, and CTLA4 are more frequently studied. There are several monoclonal antibody drugs developed for immune checkpoint inhibitors that are directed against the corresponding immune checkpoints. Their main function is to block the inhibitory effect of tumor cells on immune cells by blocking the interaction between immune cells and tumor cells that express immune checkpoints. The immunotherapy drug is selected from the group consisting of PD-1 monoclonal antibodies and PD-L1 monoclonal antibodies.

[0091] Preferably, the cancer or tumor is selected from the group consisting of gastric cancer, pancreatic cancer and lung cancer.

[0092] In addition to containing the corresponding prodrug compound, the above-mentioned drug should also be added with pharmaceutically acceptable auxiliary or excipient based on the specific properties of the drug, medicine or preparation.The medicine can be any dosage form for clinical administration, such as tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, needle for injection, freeze-dried powder for injection, or infusion.Depending on the specific dosage form and mode of administration, the pharmaceutically acceptable auxiliary or excipient in the medicine may include one or more of the following: diluent, solubilizer, disintegrant, suspending agent, lubricant, adhesive, filler, flavoring agent, sweetener, antioxidant, surfactant, preservative, packaging agent and pigment, etc. [Brief description of the drawings]

[0093] [Figure 1]1 shows the tumor volume increase curves for each mouse group in the HuPrime® gastric cancer GA6201 model. [Diagram 2] 1 shows the relative tumor growth inhibition rate curves for each mouse group in the HuPrime® gastric cancer GA6201 model. [Diagram 3] 1 shows the body weight curves for each mouse group in the HuPrime® gastric cancer GA6201 model. [Figure 4] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® gastric cancer GA6201 model. [Diagram 5] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® pancreatic cancer PA1222 model. [Figure 6] 1 shows the relative tumor growth inhibition curves for each mouse group in the HuPrime® pancreatic cancer PA1222 model. [Figure 7] 1 shows the body weight curves for each mouse group in the HuPrime® pancreatic cancer PA1222 model. [Figure 8] 1 is a curve of percentage change in body weight in each mouse group in the HuPrime® pancreatic cancer PA1222 model. [Figure 9] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® lung cancer LU11693 model. [Figure 10] 1 shows the relative tumor growth inhibition curves for each mouse group in the HuPrime® lung cancer LU11693 model. [Figure 11] 1 shows the body weight curves for each mouse group in the HuPrime® lung cancer LU11693 model. [Figure 12] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® lung cancer LU11693 model. [Figure 13] This is a curve showing the increase in tumor volume in each mouse group in a human-derived pancreatic cancer HPAF-II subcutaneous xenograft model. [Figure 14]1 shows a curve of percentage change in body weight in each mouse group in a human pancreatic cancer HPAF-II subcutaneous xenograft model. [Figure 15] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® lung cancer LU5161 subcutaneous model. [Figure 16] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® lung cancer LU5161 subcutaneous model. [Figure 17] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® colon cancer CR3820 subcutaneous model. [Figure 18] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® colon cancer CR3820 subcutaneous model. [Figure 19] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® pancreatic cancer PA2637 subcutaneous model. [Figure 20] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® PA2637 subcutaneous pancreatic cancer model. [Figure 21] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® lung cancer LU11873 subcutaneous model. [Figure 22] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® lung cancer LU11873 subcutaneous model. [Diagram 23] 1 shows the tumor volume increase curves for each mouse group in the HuPrime® pancreatic cancer PA1383 subcutaneous model. [Figure 24] 1 shows the percentage change curve of body weight in each mouse group in the HuPrime® PA1383 subcutaneous pancreatic cancer model. [Diagram 25] Photographs of the IHC staining results for the GA6201 model, the LU11693 model, the PA1222 model, and the control group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0094] The present invention will be described below with specific embodiments. Those skilled in the art will understand that these examples are only used to illustrate the present invention and do not limit the scope of the present invention in any way.

[0095] "Administering" a drug to a patient refers to direct administration, which can be administration or self-administration by a medical professional to the patient, and / or indirect administration, which can be the act of prescribing a medication. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering a drug to the patient.

[0096] "Cancer" refers to leukemias, lymphomas, carcinomas, and other malignant tumors (including solid tumors) with potentially uncontrollable growth that can spread locally by invasion and throughout the body by metastasis. Examples of cancer include, but are not limited to, cancer of the adrenal gland, bone, brain, breast, bronchus, colon and / or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nervous tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid. Specific examples of other cancers include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell carcinoma, glioblastoma multiforme, hairy cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, pancreatic islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid, malignant melanoma, malignant hypercalcemia, Marfan body habitus habitus tumors, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, mycosis fungoides, osteogenic and other sarcomas, ovarian tumors, pheochromocytoma, polycythemia vera, primary brain tumors, small cell lung cancer, squamous cell carcinoma of both ulcerative and papillary types, hyperplasia, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, renal cell tumor, focal skin lesions, reticulum cell sarcoma, and Wilms' tumor.

[0097] "Patient" and "individual" are used interchangeably and refer to a mammal in need of treatment for cancer. Typically, a patient is a human. Typically, a patient is a human who has been diagnosed with cancer. In certain embodiments, a "patient" or "individual" may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, or rat, used in screening, characterizing, and evaluating drugs and therapeutics.

[0098] "Solid tumor" refers to solid tumors including, but not limited to, metastatic tumors in the bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin and soft tissue (sarcomas).

[0099] A "therapeutically effective amount" of a drug refers to the amount of drug that, when administered to a cancer patient, will have the intended therapeutic effect (e.g., reduction, remission, mitigation, or elimination of one or more clinical symptoms of the patient's cancer). The therapeutic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0100] "Treatment" or "therapy" of a condition or patient refers to taking measures to obtain a beneficial or desired result (including a clinical result). For purposes of this invention, a beneficial or desired clinical result includes, but is not limited to, reduction or amelioration of one or more symptoms of cancer, reduction in the extent of disease, delay or slowing of disease progression, remission, remission, or stabilization of the disease state, or other beneficial result. In some cases, treatment of cancer may result in a partial response or a stable condition.

[0101] "Tumor cell" refers to a tumor cell of any suitable species, eg, a mammal, such as a murine, canine, feline, equine or human.

[0102] "Patient" and "individual" are used interchangeably and refer to a mammal in need of treatment for cancer. Typically, a patient is a human. Typically, a patient is a human who has been diagnosed with cancer. In certain embodiments, a "patient" or "individual" may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, or rat, used in screening, characterizing, and evaluating drugs and therapeutics.

[0103] "Treatment" or "treatment of a patient" refers to the administration, use or administration of a therapeutically effective amount of a drug to a patient in accordance with the present invention.

[0104] "Administering" or "using" a drug to a patient refers to direct administration, which can be administration by a medical professional to the patient or self-administration, and / or indirect administration, which can be the act of prescribing a medication. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering a drug to the patient.

[0105] "Treatment" or "therapy" of a condition or patient refers to taking measures to obtain a beneficial or desired result (including a clinical result). For purposes of this invention, a beneficial or desired clinical result includes, but is not limited to, reduction or amelioration of one or more symptoms of cancer, reduction in the extent of disease, delay or slowing of disease progression, remission, remission, or stabilization of the disease state, or other beneficial result. In some cases, treatment of cancer may result in a partial response or a stable condition.

[0106] The experimental methods in the following examples are conventional methods unless otherwise specified. All medicinal materials, reagent materials, etc. used in the following examples are commercially available products unless otherwise specified.

[0107] The above description of the embodiments of the present invention is not intended to limit the present invention. Those skilled in the art can make various modifications and changes according to the present invention, and any modifications and changes within the spirit of the present invention shall be included in the scope of the claims attached to the present invention.

[0108] A specific experiment of the present invention is shown below.

[0109] 1. Pharmacodynamic evaluation of test substances AST, AST-3424 and ifosfamide in the HuPrime® gastric cancer GA6201 subcutaneous xenograft model The HuPrime® gastric cancer GA6201 patient-derived xenograft (PDX) model was used as a model of KRAS pathogenic mutation with G12D amino acid mutation (KRAS-G12D). To establish a subcutaneously transplanted tumor model of human gastric cancer, HuPrime® model GA6201 tumor blocks were subcutaneously inoculated into BALB / c nude mice. The study was divided into five groups, including a 60 mg / kg group of the test drug ifosfamide, a 5 mg / kg group of the test drug AST-3424, a 2.5 mg / kg group and a 5 mg / kg group of AST, and a physiological saline (pH 7.0-7.6) vehicle control group, with five mice in each group. Among the above, the physiological saline (pH 7.0-7.6) vehicle control group, the test drug AST-3424 5mg / kg group, and the AST 2.5mg / kg and 5mg / kg groups were administered once a week via tail vein injection for a total of 3 weeks and observed for 4 weeks. The ifosfamide 60mg / kg group was administered by intraperitoneal injection for 5 consecutive days a week with a 2-day break for a total of 2 weeks and observed for 5 weeks. The therapeutic effect was evaluated based on the relative tumor growth inhibition rate (TGI (%)), and the safety was evaluated based on the weight change and death status of the animals.

[0110] The specific dosing regimen for each group is shown in Table 1 below.

[0111] [Table 1]

[0112] The tumor volumes of the mice in the various groups were measured on various days and the average values ​​were obtained, the results of which are shown in Table 2 below.

[0113] [Table 2]

[0114] According to the data in Table 2, Figure 2 was prepared showing the tumor growth in each treatment group and the control group.

[0115] The efficacy evaluation and analytical data were prepared according to the data in Table 2. Specific data are shown in Table 3.

[0116] [Table 3]

[0117] The relative tumor growth rate (T / C%) in Table 3 was the percentage of relative tumor volume or tumor weight between the treatment group and the control group at a particular time point. The calculation formula was as follows:

[0118] T / C%=TRTV / CRTV×100% (TRTV: mean RTV of the treatment group, CRTV: mean RTV of the vehicle control group, RTV=Vt / V0, V0 is the tumor volume of the animals at the time of grouping, and Vt is the tumor volume of the animals after treatment).

[0119] Relative tumor growth inhibition (TGI(%)) was calculated as follows: TGI%=(1-T / C)×100%, where T and C were the mean relative tumor volume (RTV) of the treatment and control groups, respectively, at a particular time point.

[0120] [Table 4]

[0121] Table 4 above was graphed into Figure 2.

[0122] The body weights of the mice in the various groups were measured on various days and the average values ​​were obtained, the results of which are shown in Table 5 below.

[0123] [Table 5]

[0124] The above table was plotted as a curve to obtain FIG. 3, which shows the body weight curves for each mouse group in the HuPrime® gastric cancer GA6201 model.

[0125] Similarly, the data in Table 5 was processed to obtain Table 6 below.

[0126] [Table 6]

[0127] Group01, Group02, Group03, Group04 and Group05 in Tables 4 / 5 / 6 above correspond to the above-mentioned Groups 1, 2, 3, 4, 5 and 6. 0 / 1 / 2 / 3 / 4 / 7 / 8 / 9 / 10 / 11 / 14 / 15 / 16 / 17 / 18 / 21 / 24 / 28 / 31 / 35 / 38 are the number of days after vaccination.

[0128] The above table was plotted as a curve to obtain Figure 4.

[0129] Analysis of the experimental data reveals the following regarding the treatment effects:

[0130] The test drug AST-3424 at a dose of 5 mg / kg, and the test drug AST at doses of 2.5 mg / kg and 5 mg / kg had a significant inhibitory effect on the tumor growth of HuPrime® gastric cancer GA6201 with statistically significant difference compared to the control group.

[0131] The test drug ifosfamide at a dose of 60 mg / kg had a certain inhibitory effect on the tumor growth of HuPrime® gastric cancer GA6201, but there was no statistically significant difference compared with the control group.

[0132] Analysis of the experimental data showed that ifosfamide, AST-3424, and AST were well tolerated by tumor-bearing mice at the doses tested.

[0133] 2. Pharmacodynamic and safety evaluation of test articles AST and gemcitabine in the HuPrime® PA1222 pancreatic cancer subcutaneous xenograft model HuPrime® pancreatic cancer PA1222 PDX model was used as a model of KRAS pathogenic mutation with G12D amino acid mutation (KRAS-G12D). To establish a subcutaneously transplanted tumor model of human pancreatic cancer, HuPrime® model PA1222 tumor block was subcutaneously inoculated into BALB / c nude mice. The study was divided into three groups: 120mg / kg test drug gemcitabine group, 10mg / kg test drug AST group, and 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 85% glucose injection D5W (pH 7.4) vehicle control group, with 5 mice in each group. Among the above, the 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 85% glucose injection D5W (pH 7.4) vehicle control group and the test drug AST 10 mg / kg group were administered once a week for three consecutive weeks via tail vein injection. The test drug gemcitabine 120 mg / kg group was administered once a week for three consecutive weeks via intraperitoneal injection. The therapeutic efficacy was evaluated based on the relative tumor growth inhibition rate (TGI (%)), and the safety was evaluated based on the weight change and death status of the animals.

[0134] The specific dosing regimen for each group is shown in Table 7 below.

[0135] [Table 7] Note: 1. Dosing volume was 10 μl / g. 2. QW×3: administered once a week for 3 weeks.

[0136] Tumor volumes of mice in different groups were measured on different days and average values ​​were obtained, the results of which are shown in Table 8 below.

[0137] [Table 8]

[0138] The tumor growth in each treatment group and the control group is shown in Table 8 and FIG. 5, and the efficacy evaluation is shown in Table 9.

[0139] [Table 9]

[0140] The relative tumor growth rate (T / C%) in Table 9 was the percentage of relative tumor volume or tumor weight between the treatment group and the control group at a particular time point. The calculation formula was as follows:

[0141] T / C%=TRTV / CRTV×100% (TRTV: mean RTV of the treatment group, CRTV: mean RTV of the vehicle control group, RTV=Vt / V0, V0 is the tumor volume of the animals at the time of grouping, and Vt is the tumor volume of the animals after treatment).

[0142] Relative tumor growth inhibition (TGI(%)) was calculated as follows: TGI%=(1-T / C)×100%, where T and C were the mean relative tumor volumes (RTV) of the treatment and control groups, respectively, at a particular time point.

[0143] [Table 10]

[0144] The above table was plotted as a curve to obtain Figure 6.

[0145] The body weights of the mice in the various groups were measured on various days and the average values ​​were obtained, the results of which are shown in Table 11 below.

[0146] [Table 11]

[0147] The above table was plotted as a curve to obtain FIG. 7, which shows the body weight curves for each mouse group in the HuPrime® pancreatic cancer PA1222 model.

[0148] Similarly, the data in Table 11 was processed to obtain Table 12 below.

[0149] [Table 12]

[0150] The above table was plotted as a curve to obtain Figure 8.

[0151] Analysis of the experimental data reveals the following regarding the treatment effects:

[0152] The test drug gemcitabine at a dose of 120 mg / kg (group 2) had a certain inhibitory effect on the tumor growth of HuPrime® pancreatic cancer PA1222 with a statistically significant difference compared to the control group. The test drug AST at a dose of 10 mg / kg (group 3) had a significant inhibitory effect on the tumor growth of HuPrime® pancreatic cancer PA1222 with a statistically significant difference compared to the control group. Two mice in this group were cured of tumors, with a cure rate of 40% each. The tumor inhibitory effect of the test drug AST at 10 mg / kg (group 3) was significantly better than that of the test drug gemcitabine (120 mg / kg, group 2) (p=0.000778).

[0153] Analysis of the experimental data showed that mice treated with the test drug gemcitabine (120 mg / kg, group 2), AST at 10 mg / kg (group 3) and the control group (group 1) did not experience any obvious weight loss during the treatment period and were well tolerated.

[0154] 3. Pharmacodynamic and safety evaluation of test substances AST and cisplatin in HuPrime® lung cancer LU11693 subcutaneous xenograft model HuPrime® lung cancer LU11693 PDX model was used as a model of KRAS pathogenic mutation with G12C amino acid mutation. To establish a subcutaneously transplanted tumor model of human lung cancer, HuPrime® model LU11693 tumor block was subcutaneously inoculated into BALB / c nude mice. The study was divided into three groups, including a 4mg / kg group of test drug cisplatin, a 10mg / kg group of test drug AST, and a 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 85% glucose injection D5W (pH 7.4) vehicle control group, with six mice in each group. Mice in each group were administered once a week via tail vein injection for three consecutive weeks. The therapeutic efficacy was evaluated based on the relative tumor growth inhibition rate (TGI (%)), and the safety was evaluated based on the weight change and death status of the animals.

[0155] The specific dosing regimen for each group is shown in Table 13 below.

[0156] [Table 13] Note: 1. Dosing volume was 10 μl / g. 2. QW×3: administered once a week for 3 weeks.

[0157] Tumor volumes of mice in different groups were measured on different days and average values ​​were obtained, the results of which are shown in Table 14 below.

[0158] [Table 14]

[0159] The tumor growth in each treatment group and the control group is shown in Table 14 and FIG. 9, and the efficacy evaluation is shown in Table 15.

[0160] [Table 15]

[0161] The relative tumor growth rate (T / C%) in Table 15 was the percentage of relative tumor volume or tumor weight between the treatment group and the control group at a particular time point. The calculation formula was as follows:

[0162] T / C%=TRTV / CRTV×100% (TRTV: mean RTV of the treatment group, CRTV: mean RTV of the vehicle control group, RTV=Vt / V0, V0 is the tumor volume of the animals at the time of grouping, and Vt is the tumor volume of the animals after treatment).

[0163] Relative tumor growth inhibition (TGI(%)) was calculated as follows: TGI%=(1-T / C)×100%, where T and C were the mean relative tumor volumes (RTV) of the treatment and control groups, respectively, at a particular time point.

[0164] [Table 16]

[0165] The above table was plotted as a curve to obtain Figure 10.

[0166] The body weights of the mice in the various groups were measured on various days and the average values ​​were obtained, the results of which are shown in Table 17 below.

[0167] [Table 17]

[0168] The above table was plotted as a curve to obtain FIG. 11, which shows the body weight curves for each mouse group in the HuPrime® lung cancer LU11693 model.

[0169] Similarly, the data in Table 17 was processed to obtain Table 18 below.

[0170] [Table 18]

[0171] The above table was plotted as a curve to obtain Figure 12.

[0172] Analysis of the experimental data reveals the following regarding the treatment effects:

[0173] The test drug cisplatin (4 mg / kg) treatment group showed a certain tumor inhibition effect with statistical significance (p=0.0152) compared to the control group on the 28th day after the first administration, with a relative tumor growth inhibition rate (TGI) of 23.98%.

[0174] The test drug AST (10 mg / kg) treatment group showed a certain tumor inhibition effect with statistical significance (p<0.001) compared with the control group on the 28th day after the first administration, and the relative tumor growth inhibition rate TGI (%) was 54.64%, but the TGI was less than 60%, indicating no obvious tumor inhibition effect.

[0175] Analysis of the experimental data showed that some mice in the treatment groups with the test drugs AST (10 mg / kg) and cisplatin (4 mg / kg) experienced severe weight loss, which may be related to the potential toxicity of the high dose drugs.

[0176] From the above three sets of experimental data, the following conclusions can be drawn.

[0177] 1.Both AST-3424 and AST had significant efficacy in the GA6021 gastric cancer and PA1222 pancreatic cancer PDX models, which are KRAS pathogenic mutation models harboring the G12D amino acid mutation, with TGI% exceeding 90%.

[0178] 2. The tumor inhibitory effect of AST in lung cancer LU11693, a model of KRAS pathogenic mutations with the G12C amino acid mutation, was unclear, with the TGI% being less than 60%.

[0179] 3. Both AST-3424 and AST were relatively well tolerated in each model.

[0180] Through further research, the present inventors have found that in KRAS pathogenic mutation models with G12D amino acid mutation, AST-3424 and AST have generally significant therapeutic effects on various cancer indications. In KRAS pathogenic mutation models with G12C amino acid mutation, the therapeutic effect of AST is related not only to the type of cancer but also to other factors.

[0181] 4. Antitumor effects and safety evaluation of test substances AST, AST-3424 and ifosfamide in human pancreatic cancer HPAF-II subcutaneous xenograft model The human-derived pancreatic cancer HPAF-II subcutaneous xenograft model was used as a CDX model harboring the KRAS G12D pathogenic mutation.

[0182] To establish a subcutaneous transplant model of human pancreatic cancer, human pancreatic cancer HPAF-II cells were subcutaneously inoculated into BALB / c nude female mice. The study was divided into the following groups: Test drug treatment groups Ifosfamide 60mg / kg monotherapy group (group 2) was intraperitoneally administered once a day for 5 consecutive days, rested for 2 days, and then administered once a day for 5 consecutive days; AST 4mg / kg monotherapy group (group 3) was administered via tail vein once a day for 5 consecutive days, rested for 2 days, then rested for 2 weeks, and then administered once a day for 5 consecutive days; AST 8mg / kg monotherapy group (group 4) was administered via tail vein once a week for a total of 3 weeks. the AST-3424 1 mg / kg monotherapy group (Group 5) was administered once daily through the tail vein for 5 consecutive days, rested for 2 days, then rested for 2 weeks, and then administered again once daily for 5 consecutive days; and the glucose injection (pH 7.7-8.0) vehicle control group (Group 1) was administered once daily through the tail vein for 5 consecutive days, rested for 2 days, then rested for 2 weeks, and then administered again once daily for 5 consecutive days. There were a total of 5 groups in this study, with 6 mice in each group. The route, amount, and regimen of administration for the experimental design are shown in Table 19.

[0183] [Table 19]

[0184] In this application, the abbreviations for the administration route are: iv: tail vein injection, ip: intraperitoneal injection, the abbreviations for the dosing cycle are: QW: once a week, QD: once a day, and "QD*5, 2 days rest, 2 weeks rest, QD*5" means administration once a day for 5 consecutive days, followed by 2 days of rest, then 2 weeks of rest, followed by administration again once a day for 5 consecutive days.

[0185] Tumor growth was recorded for each treatment group and control group on various days of the study, as shown in Table 20. The corresponding growth curves of tumor volume in each mouse group were shown in Figure 13. The therapeutic effect was evaluated based on the relative tumor growth rate and the relative tumor growth inhibition rate. The efficacy analysis of each group was shown in Table 21. The body weight change of the treatment group and the control group after administration was recorded, and the safety of each group in the human-derived pancreatic cancer HPAF-II subcutaneous xenograft model was investigated. The results of the body weight change of the mice were shown in Table 22. The curve graph of the body weight change percentage over time in each treatment group was shown in Figure 14.

[0186] [Table 20]

[0187] [Table 21]

[0188] [Table 22]

[0189] The mean tumor volume in mice in the vehicle control group was 2212.64 mm3 at 31 days after the first dose. 3 The mean tumor volume at day 31 in the ifosfamide 60 mg / kg treatment group (group 2) was 2678.00 mm 3 The relative tumor growth inhibition rate (TGI) (%) was -14.65%, which was not statistically significant compared to the control group (p>0.05).

[0190] The mean tumor volumes at day 31 for the study drug AST treatment groups at doses of 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) and 8 mg / kg (QW x 3) (Groups 3 and 4) and the AST-3424 group at dose of 1 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) (Group 5) were 457.66, 170.65, and 685.85 mm, respectively. 3 There was a statistically significant difference compared to the control group (p<0.05), and the relative tumor growth inhibition rates (TGI) (%) were 79.55%, 92.64%, and 69.46%, respectively.

[0191] The above experimental results showed that AST-3424 and AST, i.e., AST at a dose of 8 mg / kg (QW×3), AST at a dose of 4 mg / kg (QD×5, 2 days off, 2 weeks off, QD×5), and AST-3424 at a dose of 1 mg / kg (QD×5, 2 days off, 2 weeks off, QD×5), had significant antitumor effects on the human-derived pancreatic cancer HPAF-II subcutaneous model in the model harboring the KRAS G12D pathogenic mutation. Furthermore, mice in each test drug treatment group did not lose weight during the treatment period and the treatment was well tolerated.

[0192] 5. Antitumor efficacy and safety evaluation of test substances AST, AST-3424 and ifosfamide monotherapy in HuPrime® lung cancer LU5161 subcutaneous model The HuPrime® lung cancer LU5161 subcutaneous model was a PDX model harboring a KRAS G12D pathogenic mutation.

[0193] To establish a subcutaneously transplanted tumor model of human lung cancer, HuPrime® lung cancer LU5161 tumor blocks were subcutaneously inoculated into Balb / nude female mice. The study was divided into the following groups: The test drug ifosfamide 60mg / kg monotherapy group (group 2) was administered once daily for 5 consecutive days, rested for 2 days, and then administered once daily again for 5 consecutive days; AST 4mg / kg monotherapy group (group 3), and AST 8mg / kg monotherapy group (group 4) were administered once a week for a total of 3 weeks; AST 4mg / kg monotherapy group (group 5), and AST-3424 1mg / kg monotherapy group (group 6) were administered once daily for 5 consecutive days, rested for 2 days, then rested for 2 weeks, then administered once daily again for 5 consecutive days; and glucose injection (pH 7.7-8.0) vehicle control group (group 1) was administered once daily for 5 consecutive days, rested for 2 days, then rested for 2 weeks, then administered once daily again for 5 consecutive days. In this study, there were a total of 6 groups, with 6 mice in each group. Among them, the test drug ifosfamide was administered intraperitoneally, and the vehicle control group, AST, and AST-3424 were all administered by tail vein injection. The route of administration, dose, and regimen of the experimental design are shown in Table 23.

[0194] [Table 23]

[0195] Tumor growth was recorded for each treatment group and control group on various days of the study, as shown in Table 24. The corresponding growth curves of tumor volume in each mouse group were shown in Figure 15. The therapeutic effect was evaluated based on the relative tumor growth rate and the relative tumor growth inhibition rate. The efficacy analysis of each group was shown in Table 25. The body weight change of the treatment group and the control group after administration was recorded, and the safety of each group in the HuPrime® lung cancer LU5161 subcutaneous xenograft model was investigated. The results of the body weight change of the mice were shown in Table 26. The curve graph of the body weight change percentage over time in each treatment group was shown in Figure 16.

[0196] [Table 24]

[0197] [Table 25]

[0198] [Table 26]

[0199] The mean tumor volume in mice in the vehicle control group was 2238.97 mm at 28 days after the first dose. 3 The mean tumor volume at day 28 in the group treated with the test drug ifosfamide at a dose of 60 mg / kg (group 2) was 1636.39 mm 3 The relative tumor growth inhibition rate (TGI) (%) was 27.39%, which was not statistically significant compared to the control group (p>0.05).

[0200] The mean tumor volumes at day 28 for the AST-treated group at a dose of 4 mg / kg (QW x 3, group 3), the AST-treated group at a dose of 8 mg / kg (QW x 3, group 4), the AST-treated group at a dose of 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5, group 5), and the AST-3424-treated group at a dose of 1 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) (group 6) were 71.72 mm 3 , 68.18mm 3 , 37.14mm 3 and 94.42 mm 3 There was a statistically significant difference (p<0.001) compared to the control group, and the relative tumor growth inhibition rates (TGI) (%) were 96.92%, 97.05%, 98.38% and 95.62%, respectively. In all treatment groups for the test drugs AST and AST-3424, one mouse each had tumor elimination, with a elimination rate of 16.7%.

[0201] The above experimental results showed that in models with KRAS G12D pathogenic mutations, AST-3424 and AST, i.e., AST treatment groups at a dose of 4 mg / kg (QW x 3), 8 mg / kg (QW x 3), 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) (Groups 3, 4, and 5), and AST-3424 group at a dose of 1 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) (Group 6), had significant antitumor effects on the HuPrime® lung cancer LU5161 subcutaneous model at the dosages and dosing frequencies tested in this study. There was no tumor inhibition effect in the ifosfamide-treated group. Mice in each test drug treatment group tolerated the treatment well throughout the treatment period.

[0202] 6. Antitumor efficacy and safety evaluation of test substance AST and ifosfamide monotherapy in HuPrime® colon cancer CR3820 subcutaneous model The HuPrime® colon cancer CR3820 subcutaneous model was a PDX model harboring a KRAS G12D pathogenic mutation.

[0203] To establish a subcutaneously transplanted tumor model of human intestinal cancer, HuPrime® intestinal cancer CR3820 tumor blocks were subcutaneously inoculated into NOD.SCID female mice. The study was divided into the following groups: The test drug ifosfamide 60mg / kg monotherapy group (QD×5 / week×2 weeks, group 2) was administered intraperitoneally once a day for 5 consecutive days, followed by 2 days of rest, then once a day again for 5 days; AST 8mg / kg monotherapy group (QW×3, group 3) was administered once a week through the tail vein for a total of 3 weeks; AST 4mg / kg monotherapy group (QD×5, 2 days off, 2 weeks off, QD×5, group 4) and the vehicle control group glucose injection (pH 7.7-8.0, group 1) were both administered through the tail vein, all with the same dosing cycle of once a day for 5 consecutive days, 2 days of rest, then 2 weeks of rest, then once a day again for 5 consecutive days. In this experiment, there were a total of 4 groups, with 6 mice in each group. The route, amount and regimen of administration of the experimental design are shown in Table 27.

[0204] [Table 27]

[0205] Tumor growth was recorded for each treatment group and control group on various days of the study, as shown in Table 28. The corresponding growth curves of tumor volume in each mouse group were shown in Figure 17. The therapeutic effect was evaluated based on the relative tumor growth rate and the relative tumor growth inhibition rate. The efficacy analysis of each group was shown in Table 29. The body weight change of the treatment group and the control group after administration was recorded, and the safety of each group in the HuPrime® colon cancer CR3820 subcutaneous xenograft model was investigated. The results of the body weight change of the mice were shown in Table 30. Correspondingly, the curve graph of the body weight change percentage over time in each treatment group was shown in Figure 18.

[0206] [Table 28]

[0207] [Table 29]

[0208] [Table 30]

[0209] The mean tumor volume in mice in the vehicle control group was 1792.37 mm at 24 days after the first dose. 3 The mean tumor volume at day 24 in the study drug ifosfamide treatment group (Group 2) was 1199.09 mm at a dose of 60 mg / kg. 3 The relative tumor growth inhibition rate (TGI) (%) was 37.73%, which was not statistically significant compared to the control group (p>0.05).

[0210] The mean tumor volume at day 24 in the 8 mg / kg AST treatment group (QW x 3, group 3) and the 4 mg / kg AST treatment group (QD x 5, 2 days off, 2 weeks off, QD x 5, group 4) was 110.59 mm 3 and 146.58 mm 3 The relative tumor growth inhibition rates (TGI) (%) were 94.08% and 92.44%, respectively, which showed statistically significant differences compared with the control group (p<0.05).

[0211] The above experimental results showed that in models with KRAS G12D pathogenic mutations, AST, i.e., test drug AST at 8mg / kg (QWx3, group 3), 4mg / kg (QDx5, 2 days off, 2 weeks off, QDx5, group 4) had a statistically significant antitumor effect against the HuPrime® colon cancer CR3820 subcutaneous model at the doses and dosing frequencies tested in this experiment. Test drugs ifosfamide and AST were well tolerated at the doses tested in this study.

[0212] 7. Antitumor efficacy and safety evaluation of test substances AST, AST-3424 and ifosfamide monotherapy in the HuPrime® PA2637 subcutaneous pancreatic cancer model The HuPrime® pancreatic cancer PA2637 subcutaneous model was a PDX model harboring a KRAS G12D pathogenic mutation.

[0213] To establish a subcutaneously transplanted tumor model of human pancreatic cancer, HuPrime® pancreatic cancer PA2637 tumor blocks were subcutaneously inoculated into NOD.SCID female mice. The study was divided into the following groups: the test drug ifosfamide 60mg / kg monotherapy treatment group (QD×5 / week×2 weeks, group 2) was intraperitoneally administered once daily for 5 consecutive days, rested for 2 days, and then administered once daily again for 5 consecutive days; AST 8mg / kg monotherapy group (QW×3, group 3) was administered once a week via the tail vein for a total of 3 weeks; AST 4mg / kg monotherapy group (QD×5, rest for 2 days, rest for 2 weeks, QD×5, group 4), AST-3424 1 mg / kg monotherapy group (QD×5, 2 days rest, 2 weeks rest, QD×5, group 5), and vehicle control glucose injection (pH 7.7-8.0, group 1), all administered through the tail vein, all with the same dosing cycle of once daily for 5 consecutive days, 2 days rest, then 2 weeks rest, then again once daily for 5 consecutive days. In this experiment, there were a total of 5 groups, with 6 mice in each group. The route of administration, amount, and regimen of the experimental design are shown in Table 31.

[0214] [Table 31]

[0215] Tumor growth was recorded for each treatment group and control group on various days of the study, as shown in Table 32. The corresponding growth curves of tumor volume in each mouse group were shown in Figure 19. The therapeutic effect was evaluated based on the relative tumor growth rate and the relative tumor growth inhibition rate. The efficacy analysis of each group was shown in Table 33. The body weight change of the treatment group and control group after administration was recorded, and the safety of each group in the HuPrime® pancreatic cancer PA2637 subcutaneous xenograft model was investigated. The results of the body weight change of the mice were shown in Table 34. Correspondingly, the curve graph of the body weight change percentage over time in each treatment group was shown in Figure 20.

[0216] [Table 32]

[0217] [Table 33]

[0218] [Table 34]

[0219] The mean tumor volume in mice in the vehicle control group was 977.46 mm3 at 35 days after the first dose. 3 The mean tumor volume at day 35 in the 60 mg / kg ifosfamide treatment group (group 2) was 938.33 mm 3 The relative tumor growth inhibition rate (TGI) (%) was 2.74%, which was not statistically significant compared to the control group (p>0.05).

[0220] The mean tumor volume at day 35 for the AST treatment group at a dose of 8 mg / kg (QW x 3, group 3), the AST treatment group at a dose of 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5, group 4), and the AST treatment group at a dose of 1 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5, group 5) was 123.47 mm 3 , 141.48mm 3 and 186.08 mm 3 The relative tumor growth inhibition rates (TGI) (%) were 87.28%, 85.46% and 80.78%, respectively, which showed statistically significant differences compared to the control group (p<0.001).

[0221] The above experimental results showed that in models with KRAS G12D pathogenic mutations, AST and AST-3424, i.e., AST at 8mg / kg (QWx3, group 3), 4mg / kg (QDx5, 2 days off, 2 weeks off, QDx5, group 4), and AST-3424 at 1mg / kg (QDx5, 2 days off, 2 weeks off, QDx5, group 5), had statistically significant antitumor effects against the HuPrime® pancreatic cancer PA2637 subcutaneous model at the dosages and dosing frequencies tested in this experiment. During the experiment, mice in each test drug treatment group were well tolerated throughout the treatment period.

[0222] 8. Antitumor efficacy and safety evaluation of test substances AST and ifosfamide monotherapy in HuPrime® lung cancer LU11873 subcutaneous model The HuPrime® lung cancer LU11873 subcutaneous model was a PDX model harboring the KRAS G12C pathogenic mutation.

[0223] To establish a subcutaneously transplanted tumor model of human lung cancer, HuPrime® lung cancer LU11873 tumor blocks were subcutaneously inoculated into NOD.SCID female mice. The study was divided into the following groups: the test drug ifosfamide 60mg / kg monotherapy group (group 2) was administered once daily for 5 consecutive days, rested for 2 days, and then administered once daily for 5 consecutive days again; the AST 4mg / kg monotherapy group (group 5) was administered once daily for 5 consecutive days, rested for 2 days, then rested for 2 weeks, and then administered once daily for 5 consecutive days again; and the glucose injection (pH 7.7-8.0) vehicle control group (group 1) was administered once daily for 5 consecutive days, rested for 2 days, then rested for 2 weeks, and then administered once daily for 5 consecutive days again. In this experiment, there were a total of 3 groups, with 6 mice in each group. The test drug ifosfamide was administered intraperitoneally. The vehicle control group and each AST group were administered by tail vein injection. The route of administration, dose and regimen of the experimental design are shown in Table 35.

[0224] [Table 35]

[0225] Tumor growth was recorded for each treatment group and control group on various days of the study, as shown in Table 36. The corresponding growth curves of tumor volume in each mouse group were shown in Figure 21. The therapeutic effect was evaluated based on the relative tumor growth rate and the relative tumor growth inhibition rate. The efficacy analysis of each group was shown in Table 37. The body weight change of the treatment group and control group after administration was recorded to investigate the safety of each group in the HuPrime® lung cancer LU11873 subcutaneous xenograft model. The results of the body weight change of the mice were shown in Table 38. Correspondingly, the curve graph of the body weight change percentage over time in each treatment group was shown in Figure 22.

[0226] [Table 36]

[0227] [Table 37]

[0228] [Table 38]

[0229] The mean tumor volume in mice in the vehicle control group was 1677.89 mm3 at 31 days after the first dose. 3 The mean tumor volume at day 31 in the 60 mg / kg ifosfamide treatment group (group 2) was 1866.37 mm 3 The relative tumor growth inhibition (TGI) (%) was -10.08%, which was not statistically significant compared to the control group (p>0.05). The mean tumor volume at day 31 in the test drug AST treatment group (Group 5) at a dose of 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) was 406.40 mm 3 There was a statistically significant difference compared to the control group (p>0.05), and the relative tumor growth inhibition rate (TGI) (%) was 75.16%.

[0230] The above experimental results showed that in models with KRAS G12C pathogenic mutation, the test drug AST treatment group (group 5) with AST, i.e., a dose of 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) had a significant antitumor effect on the HuPrime® lung cancer LU11873 subcutaneous model at the dosage and dosing frequency tested in this study. There was no tumor inhibition effect in the ifosfamide treatment group. During the experiment, mice in each test drug treatment group did not lose any weight during the treatment period and were well tolerated.

[0231] Specifically, the applicant found in Example 3 that the AST in the KRAS pathogenic mutation model lung cancer LU11693 having a G12C amino acid mutation had a TGI% of 54.64% at a dose of 10 mg / kg, and had no significant antitumor effect. On the other hand, in this Example, the AST in the KRAS pathogenic mutation model lung cancer LU11873 having a G12C amino acid mutation had a TGI% of 75.16% at a dose of 4 mg / kg, and had a significant antitumor effect. The difference between these two models was significant, indicating that there may be some differences between these two PDX models. This can be seen from the data on the origin of these models.

[0232] LU11693 was derived from a 58-year-old female patient who presented clinically with cachexia and mild ulcers. LU11873 was derived from a 51-year-old male patient who presented clinically with minimal weight loss and mild ulcers.

[0233] 9. Antitumor efficacy and safety evaluation of test substances AST and ifosfamide monotherapy in the HuPrime® PA1383 subcutaneous pancreatic cancer model The HuPrime® pancreatic cancer PA1383 subcutaneous model was a PDX model harboring the KRAS G12C pathogenic mutation.

[0234] To establish a subcutaneously transplanted tumor model of human pancreatic cancer, HuPrime® pancreatic cancer PA1383 tumor blocks were subcutaneously inoculated into Balb / nude female mice. The study was divided into the following groups: The 60 mg / kg monotherapy group (group 2) of the test drug ifosfamide was administered once daily for 5 consecutive days, rested for 2 days, and then administered once daily again for 5 consecutive days; the 8 mg / kg monotherapy group (group 4) of AST was administered once a week for a total of 3 weeks; the 4 mg / kg monotherapy group (group 5) of AST was administered once daily for 5 consecutive days, rested for 2 days, then rested for 2 weeks, then administered once daily again for 5 consecutive days; and the glucose injection (pH 7.7-8.0) vehicle control group (group 1) was administered once daily for 5 consecutive days, rested for 2 days, then rested for 2 weeks, then administered once daily again for 5 consecutive days. In this study, there were a total of 4 groups, with 6 mice in each group. Of the above, the test drug ifosfamide was administered intraperitoneally. The vehicle control group and each AST group were administered by tail vein injection. The route of administration, dose and regimen of the experimental design are shown in Table 39.

[0235] [Table 39]

[0236] Tumor growth was recorded for each treatment group and control group on various days of the study, as shown in Table 40. The corresponding growth curves of tumor volume in each mouse group were shown in Figure 23. The therapeutic effect was evaluated based on the relative tumor growth rate and the relative tumor growth inhibition rate. The efficacy analysis of each group was shown in Table 41. The body weight change of the treatment group and control group after administration was recorded, and the safety of each group in HuPrime® pancreatic cancer PA1383 subcutaneous xenograft model was investigated. The results of the body weight change of the mice were shown in Table 42. Correspondingly, the curve graph of the body weight change percentage over time in each treatment group was shown in Figure 24.

[0237] [Table 40]

[0238] [Table 41]

[0239] [Table 42]

[0240] The mean tumor volume in mice in the vehicle control group was 1536.48 mm3 at 31 days after the first dose. 3 The mean tumor volume at day 31 in the group treated with the test drug ifosfamide at a dose of 60 mg / kg (group 2) was 1202.01 mm 3 The relative tumor growth inhibition (TGI) (%) was 21.84%, which was not statistically significant compared with the control group (p>0.05).

[0241] The mean tumor volume at day 31 in the study drug AST treatment groups (Groups 4 and 5) at a dose of 8 mg / kg (QW x 3) and at a dose of 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5), respectively, was 18.57 mm 3 and 39.94 mm 3 There was a statistically significant difference (p<0.05) compared with the control group, with the relative tumor growth inhibition rates (TGI) (%) of 98.72% and 97.46%, respectively. Two mice in each group had completely eliminated tumors, with an elimination rate of 33.3%.

[0242] The above experimental results showed that in models with KRAS G12C pathogenic mutation, AST treatment groups (Groups 4 and 5) at a dose of 8 mg / kg (QD x 3) and 4 mg / kg (QD x 5, 2 days off, 2 weeks off, QD x 5) had significant antitumor effects on the HuPrime® pancreatic cancer PA1383 subcutaneous model at the doses and dosing frequencies tested in this study. Ifosfamide treatment groups had no tumor-inhibiting effect. Mice in each test drug treatment group did not lose any weight during the treatment period and were well tolerated.

[0243] 10. Detection of AKR1C3 RNA expression level and enzyme content in tissues A. FPKM detection of AKR1C3 RNA expression levels According to the method described in the literature (Meng, F., Li, WF, Jung, D., Wang, CC, Qi, T., Shia, CS, Hsu, RY, Hsieh, YC, & Duan, J. (2021). A novel selective AKR1C3-activated prodrug AST-3424 / OBI-3424 exhibits broad anti-tumor activity. American journal of cancer research, 11(7), 3645-3659), the AKR1C3 RNA expression levels in the above gastric cancer GA6021, pancreatic cancer PA1222 and lung cancer LU11693 tissues were analyzed using RNA-Seq and quantified by Log2 FPKM. The results were as follows.

[0244] AKR1C3 LOG2(FPKM) was detected as 6.78 in GA6201, 11.14 in LU11693, 7.39 in PA1222, 8.31 in HPAF-II, 11.56 in LU5161, 8.34 in CR3820, 9.12 in PA2637, 10.26 in LU11873, and 9.57 in PA1383 (see Table 43).

[0245] In accordance with the above literature, AKR1C3 RNA was expressed at high levels in all nine of these tumor tissues.

[0246] B. IHC detection of AKR1C3 protein content and H score The AKR1C3 protein content of the three tissues was determined according to routine immunohistochemistry (IHC) staining (using commercially available IHC reagents, the first antibody was rabbit IgG monoclonal antibody (mAb) from Abcam, and the second antibody was Bond Polymer Refine Detection from Leica. Staining conditions: antigen retrieval 100°C, EDTA buffer pH 9.0 20 min, dilution ratio: 1:800), and the staining results were evaluated for H score.

[0247] Immunohistochemical staining intensity was divided into 0 (negative), 1+ (weak staining), 2+ (moderate staining), and 3+ (strong staining). Thresholds for weak, moderate, and strong staining were manually set on the scoring instrument, and then color recognition was performed on the stained sample photographs using image processing software. When all sample photographs were stained, the staining corresponding to a specific cell was scored according to the uniform criteria of 0 / 1 / 2 / 3 by the scoring software. The percentage of positive cells of various staining intensities relative to the total cells of the section was then counted. The following formula was used to calculate the H score as a score of the IHC results for each sample. The H score ranges from 0 to 300, and the higher the score, the higher the expression level of the target (AKR1C3 enzyme protein) corresponding to the antibody in the sample. The calculation formula is as follows:

[0248] H score = (% of 0) x 0 + (% of 1) x 1 + (% of 2) x 2 + (% of 3) x 3 The staining results for GA6201, LU11693, PA1222 and the two control groups are shown in FIG. 25, and the scoring results are shown in Table 43 below.

[0249] [Table 43]

[0250] Specific staining statistics for models GA6201, LU11693, PA1222 and the control group are shown in Table 44 below.

[0251] [Table 44]

[0252] In the above staining results, the results of the positive and negative controls within the control ranges indicated that the H-score results of this IHC staining were reliable.

[0253] According to the above results, the corresponding AKR1C3 protein was expressed at high levels in all nine tissues.

[0254] The comprehensive pharmacodynamic experimental results in the above nine models, together with the fact that the tissues used in the nine models were all tumor tissues with high expression of human AKR1C3, show that: AST-3424 and AST generally have significant therapeutic effects on cancers with high expression of AKR1C3 and KRAS pathogenic mutations of G12D amino acid mutations. AST may generally have significant therapeutic effects on cancers with high expression of AKR1C3 and KRAS pathogenic mutations of G12C amino acid mutations. This means that high expression of AKR1C3 in certain tumors may be associated with KRAS (pathogenic) mutation subtypes. In other words, in certain tumors, high or overexpression of AKR1C3 often coexists with certain subtypes of KRAS (pathogenic) mutations, resulting in high sensitivity of tumor models with these properties to AST-3424 or AST.

[0255] A Novel Selective AKR1C3-Activated Prodrug AST-3424 / OBI-3424 Exhibits Broad Anti-Tumor Activity.American Journal of Cancer research,11(7),3645~3659;Evans,K.,Duan,J.,Pritchard,T.,Jones,CD,McDermott,L.,Gu,Z.,Toscan,CE,El-Zein,N.,Mayoh,11(7),3645~3659; C.,Erickson,SW,Guo,Y.,Meng,F.,Jung,D.,Rathi,KS,Roberts,KG,Mullighan,CG,Shia,CS,Pearce,T,Teicher,BA,Smith,MA,. Lock, RB(2019).OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL Wang, Ning Zhang, Donglin Cao, Qing Li & Zhong Wang (2020) An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL, leukemia & Lymphoma,61(7),1660~1668); PCT / US2016 / 021581, International Publication No. 2016145092 (corresponding to Chinese Patent Application No. 2016800150788, Chinese Patent Application Publication No. 107530556); PCT / US2016 / 062114, International Publication No. 2017087428 (corresponding to Chinese Patent Application No. 2016800200132, Chinese Patent Application Publication No. 108136214); PCT / CN2020 / 089692, International Publication No. 2020228685; PCT / NZ2019 / 050030, International Publication No. 2019190331 (corresponding to Chinese Patent Application No. 2019800234236, Chinese Patent Application Publication No. 111918864); International Publication No. PCT / CN2020 / 120281 According to The compounds in these patent applications are AKR1C3-activating anticancer prodrugs, similar to the compounds AST-3424 and AST, and are cleaved after AKR1C3 activation to produce DNA alkylating agents. [ka] Or it becomes a nitrogen mustard structure.

[0256] Therefore, combined with the above experimental results of AST-3424 and AST, it can be speculated that AKR1C3-activating DNA alkylating agent prodrugs, either as monotherapy or in combination with other therapeutic agents, may have significant therapeutic effects on cancer and tumor patients with KRAS mutations, especially those with KRAS-G12D subtype mutations.

Claims

1. A drug for monotherapy or in combination with other therapeutic agents, comprising an AKR1C3-activating DNA alkylator prodrug compound for use in treating cancer and tumor patients with KRAS mutations.

2. the compound is selected from structural formulas 1 / 2 / 3 / 4 / 5 / 6, and salts, esters, solvates, and isotopic isomers thereof; 【Chemical 1】 During the ceremony, R 1 is a C 6 -C 10 aryl or Z-substituted aryl, a 4-15 membered heterocycle or Z-substituted heterocycle, a 5-15 membered heteroaryl or Z-substituted heteroaryl, a 7-15 membered fused ring or Z-substituted fused ring; R 2 is hydrogen, a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OMS, C 1 to C 6 alkyl or Z-substituted alkyl, C 2 to C 6 alkenyl or Z-substituted alkenyl, C 2 to C 6 alkynyl or Z-substituted alkynyl, C 3 to C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 to C 10 aryl or Z-substituted aryl, 4 to 15 membered heterocycle or Z-substituted heterocycle, 5 to 15 membered heteroaryl or Z-substituted heteroaryl, ether having 1 to 6 carbon atoms, or Z-substituted alkoxy having 1 to 6 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , —SO 2 R 6 , —OCOO-R 6 , —COOR 6 , —NR 6 COR 7 , —OCOR 6 , —NR 6 SO 2 R 7 , or —NR 6 SO 2 NR 6 R 7 , or R 2 together with the atom of the group R 1 to which it is attached forms a 7-15 membered fused ring or Z-substituted fused ring; R 3 is hydrogen, halogen, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OLCMS, C 1 to C 6 alkyl or Z-substituted alkyl, C 2 to C 6 alkenyl or Z-substituted alkenyl, C 2 to C 6 alkynyl or Z-substituted alkynyl, C 3 to C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 to C 10 aryl or Z-substituted aryl, 4 to 15-membered heterocycle or Z-substituted heterocycle, 5 to 15-membered heteroaryl or Z-substituted heteroaryl, C 1 to C 6 alkoxy or Z-substituted C 1 to C 6 alkoxy, —CONR 6 R 7 , —SO 2 NR 6 R 7 , —SO 2 R 6 , —OCO—R 6 , —OCOO—R 6 , —COOR 6 , —NR 6 COR 7 , —OCOR 6 , or —NR 6 SO 2 R 7 ; R 4 and R 5 are each independently hydrogen, a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OLCMS, C 1 to C 6 alkyl or Z-substituted alkyl, C 2 to C 6 alkenyl or Z-substituted alkenyl, C 2 to C 6 alkynyl or Z-substituted alkynyl, C 3 to C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 to C 10 aryl or Z-substituted aryl, 4 to 15-membered heterocycle or Z-substituted heterocycle, 5 to 15-membered heteroaryl or Z-substituted heteroaryl, C 1 to C 6 alkoxy or Z-substituted C 1 to C 6 alkoxy, —CONR 6 R 7 , —SO 2 NR 6 R 7 , —SO 2 R 6 , —OCOO-R 6 , —COOR 6 , —NR 6 COR 6 , —OCOR 6 , or —NR 6 SO 2 R 7 , or R 4 and R 5 together with the atoms of the benzene ring to which they are attached form a 7-15 membered fused ring or Z-substituted fused ring; R 6 and R 7 are each independently hydrogen, cyano or isocyano, C 1 -C 6 alkyl or Z-substituted alkyl, C 2 -C 6 alkenyl or Z-substituted alkenyl, C 2 -C 6 alkynyl or Z-substituted alkynyl, C 3 -C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 -C 10 aryl or Z-substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 membered heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z-substituted C 1 -C 6 alkoxy, or R 6 and R 7 together with the atom to which they are attached form a 5-7 membered heterocyclyl or 5-7 membered Z-substituted heterocyclyl; R 8 and R 10 are each independently hydrogen, deuterium, aryl or Z-substituted aryl, C 1 -C 6 alkyl or Z-substituted alkyl, C 2 -C 6 alkenyl or Z-substituted alkenyl, C 2 -C 6 alkynyl or Z-substituted alkynyl, C 3 -C 8 cycloalkyl or Z-substituted cycloalkyl, and at least one of R 8 and R 10 must be hydrogen or deuterium; R 9 is a C 6 -C 10 substituted aryl substituted with at least one fluorine atom or nitro group, a 4- to 15-membered substituted heterocycle substituted with at least one fluorine atom or nitro group, or a 5- to 15-membered substituted heteroaryl substituted with at least one fluorine atom or nitro group; the substituent Z is a halogen atom, cyano or isocyano, hydroxy, sulfhydryl, amino, OTs, OMS, C 1 -C 3 alkyl or substituted alkyl, C 1 -C 3 alkoxy or substituted alkoxy, C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted cycloalkyl, aromatic ring, heterocyclic ring, heteroaromatic ring and fused ring, or substituted aromatic ring, heterocyclic ring, heteroaromatic ring and fused ring, and the substitution pattern is mono- or di-substituted; Substituents of the C 6 -C 10 substituted aryl, 4- to 15-membered substituted heterocycle or 5- to 15-membered substituted heteroaryl of R 9 are halogen atoms, nitro, cyano or isocyano, hydroxy, amino, C 1 -C 3 alkyl or alkoxy, alkenyl, alkynyl, cycloalkyl or benzene ring, substituted benzene ring, C 1 -C 3 alkoxy or halogen atom-substituted alkoxy; 【Chemistry 2】 During the ceremony, A is H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, CFH 2 , CF 2 H, CF 3 , F, Cl, Br, I, OCF 3 , COR, or CON(R) 2 ; E is SO or SO 2 ; X is Cl, Br, I, or OSO2R; Y is Cl, Br, I, or OSO2R; each R is independently H or C 1 -C 6 alkyl; G is a radical group selected from the group consisting of formulas (B) to (AA), 【Chemistry 3】 During the ceremony, R 1 is H, C 1 -C 6 alkyl, CH 2 (CH 2 ) n OH, CH 2 CH(OH)CH 2 OH, phenyl, pyridyl, benzyl, or pyridylmethyl, provided that when R 1 is phenyl, pyridyl, benzyl, or pyridylmethyl, R 1 may be C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, OR 6 , N(R 6 )(R 7 ), CFH 2 , CF 2 H, CF 3 , F, Cl, Br, I, OCF 3 , COR 6 , CON(R 6 )(R 7 ), SOR 6 , SON(R 6 )(R 7 ), SO 2 R 6 , SO 2 N(R 6 )(R 7 ), CN, or NO 2 ; R 2 and R 3 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, OR 6 , N(R 6 )(R 7 ), CFH 2 , CF 2 H, CF 3 , F, Cl, Br, I, OCF 3 , COR 6 , CON(R 6 )(R 7 ), SOR 6 , SON(R 6 )(R 7 ), SO 2 R 6 , SO 2 N(R 6 )(R 7 ), CN, or NO 2 ; R4 is N(R6)(R7), OH, OCH2(CH2)nN(R6)(R7), or CH2(CH2)nN(R6)(R7); R 5 is hydrogen or a C 1 -C 6 alkyl group; R 6 and R 7 are each independently H or C 1-6 alkyl, or R 6 and R 7 together form a substituted or unsubstituted 5- or 6-membered heterocycle; Z is CH or N; W is CH2, O, S, SO, or SO2; n is 0 to 6; * represents the point of connection to formula (I), 【Chemistry 4】 During the ceremony, Rw is 【Chemistry 5】 and R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and phenyl are optionally substituted with 1, 2, or 3 R a ; each R a is independently H, F, Cl, Br, I, —CN, —OH, C 1-3 alkoxy, or C 1-3 alkyl; R 2 is H or C 1-6 alkyl; or R 1 and R 2 together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R b ; each R b is independently H, F, Cl, Br, I, —CN, —OH, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —CH 3 , or —CH 2 CH 3 ; R 3 is H, F, Cl, Br, I, —OH, —NH 2 , C 1-3 alkoxy, or C 1-3 alkyl; or R 2 and R 3 taken together represent: Structural Unit 【Chemistry 6】 but 【Chemistry 7】 or 【Chemistry 8】 and T 1 is —(CR c R d ) m or —(CR c R d ) n —O—; m is 1, 2 or 3; n is 1 or 2; T 2 is N or CH; R c and R d are each independently H, F, C 1-3 alkyl, or C 1-3 alkoxy; R 4 , R 5 and R 6 are each independently H, F, Cl, Br, I, C 1-3 alkyl, or C 1-3 alkoxy; T is N or CH; R 7 and R 8 are each independently H, F, Cl, Br, or I; R 9 and R 10 are each independently H, F, Cl, Br, I, —CN, or 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms, respectively, independently selected from N, —O—, and —S—; 【Chemistry 9】 During the ceremony, X 10 is O, S, SO, or SO 2 ; A is C 6 -C 10 aryl, 5- to 15-membered heteroaryl, or —N═CR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, a 4- to 15-membered heterocycle, an ether, —CONR 13 R 14 , or —NR 13 COR 14 ; X, Y and Z are each independently hydrogen, CN, halogeno, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, a 4-15 membered heterocycle, an ether, —CONR 13 R 14 , or —NR 13 COR 14 ; R is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, a 4-15 membered heterocycle, an ether, —CONR 13 R 14 , or —NR 13 COR 14 ; R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, a 4-15 membered heterocycle, or an ether; T comprises a phosphoramidate alkylating agent comprising one or more Z 5 -X 5 -Y 5 moieties attached to an —O—P(Z 1 ) moiety, where Z 5 is a heteroatom such as nitrogen, sulfur, or oxygen, X 5 is substituted or unsubstituted ethylene, and Y 5 is halogeno or another leaving group, or Z 5 -X 5 -Y 5 together form an aziridinyl (NCH 2 CH 2 ) moiety and Z 1 is O or S; wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocyclic group, heteroaryl group, and ether group are substituted or unsubstituted; 【Chemistry 10】 During the ceremony, A is a substituted or unsubstituted C ６ ~C １０ aryl, biaryl or substituted biaryl, 5- to 15-membered heteroaryl, or —N═CR １ R ２ where the substituents are halogeno, —CN, —NO ２ , —O—(CH ２ ) —O—, —CO ２ H and salts thereof, -OR １００ , CO ２ R １００ , -CONR １０１ R １０２ , -NR １０１ R １０２ , -NR １００ SO ２ R １００ , -SO ２ R １００ , -SO ２ NR １０１ R １０２ , C １ ~C ６ Alkyl, and C ３ ~C １０ heterocyclyl; In the formula, R １００ , R １０１ and R １０２ are each independently hydrogen, C １ ~C ８ Alkyl or C ６ ~C １２ aryl, or R １０１ and R １０２ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle; In the above, the alkyl group and the aryl group each have 1 to 3 halogen groups or 1 to 3 C １ ~C ６ is substituted with an alkyl group, R １ and R ２ are each independently phenyl or methyl; X, Y, and Z are each independently hydrogen or halogen; R is hydrogen or C １ ~C ６ is an alkyl or halogen-substituted alkyl of the formula 10. A monotherapy drug or a drug in combination with other therapeutic agents, comprising an AKR1C3-activating DNA alkylating agent prodrug compound, for use in treating cancer patients and tumor patients with KRAS mutations, as described in claim 1.

3. 2. A monotherapy drug or a drug in combination with other therapeutic agents containing an AKR1C3-activating DNA alkylating agent prodrug compound for use in treating cancer patients and tumor patients with KRAS mutations, as described in claim 1, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer and bladder cancer.

4. the KRAS mutation is selected from the group consisting of a KRAS-G12D mutation, a KRAS-G12V mutation, and a KRAS-G12C mutation; Preferably, the KRAS mutation is selected from the KRAS-G12D mutation. A monotherapy drug or a drug in combination with other therapeutic agents, comprising an AKR1C3-activating DNA alkylating agent prodrug compound, for use in treating cancer patients and tumor patients with KRAS mutations according to claim 1 or 2.

5. 5. The monotherapy drug or drug in combination with other therapeutic agents containing an AKR1C3-activating DNA alkylating agent prodrug compound for use in treating cancer patients and tumor patients with KRAS mutations according to claim 4, wherein the mutation has a moderate Tumor Mutation Load (burden): TMB level.

6. 3. The method of claim 1, wherein the other therapeutic agent is selected from the group consisting of a KRAS inhibitor and an immunotherapeutic agent, wherein the KRAS inhibitor is selected from the group consisting of sotorasib (AMG510), adagrasib (MRTX849), GDC6036, LY3499446, JNJ74699157 (ARS3248), and D-1553, and the immunotherapeutic agent is selected from the group consisting of a PD-1 monoclonal antibody and a PD-L1 monoclonal antibody.

7. The compounds of the formula (1) and the formula (2) are 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 is selected from the group consisting of The compound of formula (3) 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 is selected from the group consisting of The compound of formula (4) 【Chemical 27】 is selected from the group consisting of The compound of formula (5) 【Chemical Formula 28】 【Chemical 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 is selected from the group consisting of The compound of formula (6) 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical Formula 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 selected from the group consisting of 3. A monotherapy drug or a drug in combination with other therapeutic agents, comprising an AKR1C3-activating DNA alkylating agent prodrug compound, for use in treating cancer patients and tumor patients with KRAS mutations, as described in claim 2.

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