Combination of WX001 or its derivatives for cancer treatment with KRAS G12C inhibitors

Abstract

This application provides a therapy (e.g., combination therapy) for treating cancer with an ERK 1 / 2 inhibitor and / or a KRAS G12C inhibitor. In some cases, the cancer is resistant to the KRAS G12C inhibitor (e.g., acquired resistance). In some cases, the ERK 1 / 2 inhibitor is WX001. In some embodiments, the KRAS G12C inhibitor is compound 17.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to PCT application PCT / CN2023 / 123037, filed on September 29, 2023, and PCT application PCT / CN2024 / 117234, filed on September 5, 2024, the contents of which are incorporated herein by reference in their entirety for all purposes. Invention Field

[0003] This application relates to therapies (e.g., combination therapies) for treating cancer using ERK 1 / 2 inhibitors and / or KRAS G12C inhibitors. Background Technology

[0004] The Ras / Raf / MEK / ERK pathway is a classic mitogen-activated protein kinase (MAPK) signaling cascade pathway that participates in the activation of various growth factors, cytokines, mitogens, and hormone receptors, and is one of the most important signal transduction pathways controlling cell growth, differentiation, and survival.

[0005] Studies have shown that aberrant activation of the Ras / Raf / MEK / ERK pathways due to mutations or amplifications is a determinant of the development of many cancers. For example, KRAS is a key regulator of cytokines that shape the tumor microenvironment. KRAS mutations play a role in many cancers. The incidence of KRAS mutations in human tumors is approximately 22%. KRAS G12C mutations account for approximately 44% of all KRAS mutations. G12C is a single-point mutation in which a glycine residue at codon 12 of the KRAS protein is replaced with a cysteine ​​residue, favoring an active GTP-binding conformation. This promotes constitutive activation of signaling pathways leading to tumorigenesis.

[0006] Although KRAS G12C inhibitors have recently demonstrated clinical efficacy, the overall response rate (ORR) of two clinical-stage KRAS G12C inhibitors, sotorasib and adagrasib (MRTX849), is only in the 30-40% range. These data indicate that a significant proportion of individuals with KRAS G12C mutations exhibit primary resistance to KRAS G12C inhibition. The combination of G12C inhibitors with other pathway inhibitors to further enhance the antitumor effect of KRAS G12C inhibition has been explored, representing a highly relevant strategy for overcoming primary resistance and improving overall response rates. However, the use of inhibitors at these upstream nodes can rapidly lead to resistance issues due to mutations or pathway reactivation, significantly limiting their clinical application. In particular, the adaptive feedback reactivation of the RAS-RAF-MEK-ERK signaling cascade is a key molecular mechanism driving both primary and acquired resistance to KRAS G12C inhibitors. Achieving deeper and more lasting responses in these patients remains a significant challenge.

[0007] All references cited in this article, including patent applications, patent publications, and UniProtKB / Swiss-Prot access numbers, are incorporated in full as if each individual reference were specifically and individually indicated as being incorporated by reference. Summary of the Invention

[0008] This application provides a method for treating an individual with cancer, comprising administering to the individual an effective amount of 1) an ERK 1 / 2 inhibitor; and 2) a KRAS G12C inhibitor.

[0009] In some embodiments, the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

[0011] in,

[0012] R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace;

[0013] R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents;

[0014] n is 0 or 1;

[0015] m is 1 or 2;

[0016] Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R;

[0017] R a and R c Independently selected from D, F, Cl, Br, and I;

[0018] R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one, two or three R substituents;

[0019] R is selected from F, Cl, Br and I.

[0020] In some embodiments of any of the above methods, the ERK 1 / 2 inhibitor is selected from:

[0021] .

[0022] According to some embodiments of any of the above methods, the ERK 1 / 2 inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0023] .

[0024] In some embodiments of any of the above methods, the KRAS G12C inhibitor is a small molecule. In some embodiments of any of the above methods, the KRAS G12C inhibitor is selected from the group consisting of: sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, RMC-8839, HBI-2438, and JNJ-74699157. In some embodiments of any of the above methods, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0025]

[0026] in

[0027] T1 is selected from O and N;

[0028] R1 is selected from C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a replace;

[0029] When T1 is 0, R2 does not exist;

[0030] When T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0031] R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0032] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0033] R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms;

[0034] R8 is selected from H and CH3;

[0035] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups;

[0036] R b Each is independently selected from F, Cl, Br, I, OH, and NH2;

[0037] R cEach is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups;

[0038] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0039] R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino;

[0040] The condition is that, when R1 is a naphthyl group, the naphthyl group is optionally substituted by F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

[0041] This application, in another aspect, provides a method for treating an individual with cancer, comprising administering to the individual an effective amount of 1) an ERK 1 / 2 inhibitor; and 2) a KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0042]

[0043] in

[0044] T1 is selected from O and N;

[0045] R1 is selected from C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a replace;

[0046] When T1 is 0, R2 does not exist;

[0047] When T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0048] R3 is C 1-3 Alkyl, wherein the C 1-3Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0049] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0050] R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms;

[0051] R8 is selected from H and CH3;

[0052] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups;

[0053] R b Each is independently selected from F, Cl, Br, I, OH, and NH2;

[0054] R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups;

[0055] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0056] R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino;

[0057] The condition is that, when R1 is a naphthyl group, the naphthyl group is optionally substituted by F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

[0058] According to some embodiments of any of the above methods, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof:

[0059] or .

[0060] According to some embodiments of any of the above methods, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof:

[0061] .

[0062] In some embodiments of any of the above methods, the ERK 1 / 2 inhibitor is a small molecule. In some embodiments of any of the above methods, the ERK 1 / 2 inhibitor is selected from the group consisting of: BVD-523 (Uritinib), CC-90003, GDC-0994 (Ravoxertinib), KO-947, LTT462, LY3214996 (temuterkib), WX001, SCH772984, FR180204, and MK-8353. In some embodiments of any of the above methods, the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0063]

[0064] in,

[0065] R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace;

[0066] R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents;

[0067] n is 0 or 1;

[0068] m is 1 or 2;

[0069] Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R;

[0070] R a and R c Independently selected from D, F, Cl, Br, and I;

[0071] R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one, two or three R substituents;

[0072] R is selected from F, Cl, Br and I.

[0073] According to some embodiments of any of the above methods, the KRAS G12C inhibitor is administered orally. According to some embodiments of any of the above methods, the ERK 1 / 2 inhibitor is administered orally.

[0074] In some embodiments of any of the above methods, the cancer comprises one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments of any of the above methods, the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma; optionally, the cancer is selected from the group consisting of colon cancer, lung cancer, and pancreatic cancer. In some embodiments of any of the above methods, the cancer is a solid tumor; optionally, the solid tumor is an advanced, unresectable, and / or metastatic solid tumor.

[0075] In some embodiments of any of the above methods, the cancer was previously treated with a prior KRAS G12C inhibitor, optionally, wherein the cancer was previously treated with two different prior KRAS G12C inhibitors. In some embodiments of any of the above methods, the cancer is resistant to or has acquired resistance to the prior KRAS G12C inhibitor, optionally, wherein the cancer is resistant to or has acquired resistance to a prior KRAS G12C inhibitor (e.g., MRTX849, e.g., AMG510). In some embodiments of any of the above methods, the cancer is resistant to or has acquired resistance to two different prior KRAS G12C inhibitors. According to some embodiments of any of the above methods, the individual has acquired a secondary KRAS mutation, optionally, wherein the individual acquired a secondary KRAS mutation at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 after prior KRAS inhibitor treatment, further optionally, the individual acquired a secondary mutation in G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T after prior KRAS inhibitor treatment, further optionally, wherein the secondary mutation includes Q61H. According to some embodiments of any of the above methods, the copy number of mutant KRAS in the cancer is increased compared to the cancer prior to prior KRAS G12C inhibition treatment. According to some embodiments of any of the above methods, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some embodiments of any of the above methods, the prior KRAS G12C inhibitor is or includes sotorasib or adagrasib.

[0076] In some embodiments of any of the above methods, the cancer has not been previously treated with a prior KRAS G12C inhibitor. In some embodiments of any of the above methods, the prior KRAS G12C inhibitor is or includes sotorasib or adagrasib.

[0077] In some embodiments of any of the above methods, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously or together.

[0078] According to some embodiments of any of the above methods, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered sequentially.

[0079] In some embodiments of any of the above methods, optionally, a) the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor, or b) the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor.

[0080] In some embodiments of any of the above methods, the KRAS G12C inhibitor is administered orally, intravenously, or subcutaneously. In some embodiments of any of the above methods, the ERK 1 / 2 inhibitor is administered orally, intravenously, or subcutaneously.

[0081] According to some embodiments of any of the methods described above, the ERK 1 / 2 inhibitor is administered in one or more doses, optionally, wherein the ERK 1 / 2 inhibitor is administered twice daily, daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. According to some embodiments of any of the methods described above, the dose is equivalent to a dose of about 10 mg / kg to about 100 mg / kg for mice, optionally, wherein the dose is equivalent to a dose of about 10 mg / kg to about 50 mg / kg for mice.

[0082] According to some embodiments of any of the above methods, the KRAS G12C inhibitor is administered in one or more doses, optionally, wherein the KRAS G12C inhibitor is administered twice daily, daily, or every two days for at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. According to some embodiments of any of the above methods, the dose is equivalent to a dose of about 10 mg / kg to about 100 mg / kg for mice, optionally, wherein the dose is equivalent to a dose of about 10 mg / kg to about 50 mg / kg for mice.

[0083] According to some embodiments of any of the above methods, the third therapy further includes administering an effective amount of a third therapy to the individual. According to some embodiments of any of the above methods, the third therapy comprises another anticancer agent. According to some embodiments of any of the above methods, the anticancer agent is selected from the group consisting of: immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, debulking agents, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy and antimetastatic agents; optionally, the anticancer agent is an EGFR inhibitor; further optionally, the EGFR inhibitor is an anti-EGFR antibody; further optionally, the EGFR antibody is cetuximab.

[0084] In some implementations of any of the above methods, the individual is a person.

[0085] According to some embodiments of any of the above methods, the method includes selecting an individual for treatment based on the presence of one or more cancer cells containing KRAS abnormalities (e.g., KRAS G12C, KRAS G12D, KRAS Q61H), optionally wherein the KRAS abnormality includes a) a) a mutant KRAS G12C protein, b) a mutant KRAS G12D protein, and / or c) a mutant KRAS Q61H protein.

[0086] This disclosure, in another aspect, provides the use of ERK 1 / 2 inhibitors and KRAS G12C inhibitors in the preparation of medicaments for treating cancer.

[0087] In some embodiments of any of the above methods, the cancer is selected from the group consisting of: colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma. In some embodiments of any of the above methods, the cancer is colorectal cancer (e.g., NSCLC). In some embodiments of any of the above methods, the cancer is pancreatic cancer. In some embodiments of any of the above methods, the cancer is lung cancer.

[0088] According to some embodiments of any of the above methods, the treatment includes a dose equivalent to 25 to 50 mg / kg of an ERK 1 / 2 inhibitor for mice.

[0089] According to some embodiments of any of the above methods, the treatment includes a dose equivalent to 10 to 100 mg / kg of a KRAS G12C inhibitor.

[0090] This application also provides a kit for treating individual cancers, comprising: 1) an ERK 1 / 2 inhibitor; and 2) a KRAS G12C inhibitor. Attached Figure Description

[0091] Figure 1 The percentage change in body weight (%) is displayed. The percentage change in body weight in female BALB / c nude mice loaded with NCI-H2122 tumors was established in different treatment groups. Changes were calculated based on the animals' body weight on day 1 of administration. Data points represent the group mean percentage change in body weight (BW). Error bars represent the standard error (SEM) of the mean.

[0092] Figure 2 Tumor growth curves of female BALB / c nude mice loaded with NCI-H2122 xenografts are shown in different treatment groups. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0093] Figure 3 The tumor volume of female BALB / c nude mice with established NCI-H2122-loaded tumors is shown in different treatment groups. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0094] Figure 4 The tumor weights isolated from female BALB / c nude mice with established NCI-H2122-loaded tumors are shown. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0095] Figure 5 The data shows the percentage change in body weight over time for each group of mice with tumors established using SW-837 loading. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0096] Figure 6A Tumor growth curves of mice loaded with SW-837 xenografts are shown in different treatment groups. Data points represent group means; error bars represent the standard error (SEM) of the means. Figures 6B-6C This study demonstrates the antitumor effects of various treatments on mice bearing SW837 xenografts, as well as event-free survival during and after treatment.

[0097] Figure 7 Tumor volume growth curves of mice with established tumors loaded with CR9537 are shown in different treatment groups. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0098] Figure 8 The data shows the percentage change in body weight over time for each group of mice with tumors established using CR9537. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0099] Figure 9 The data show the body weights of female BALB / c nude mice loaded with AMG510-R-xMia PaCa-2 clone #2 tumors in different groups. Data points represent group mean body weights. Error bars represent the standard error (SEM) of the mean.

[0100] Figure 10 This shows the percentage change in body weight in different groups of female BALB / c nude mice loaded with AMG510-R-xMia PaCa-2 clone #2 tumors. This change was calculated based on the animals' body weight on day one of drug administration. Data points represent the group mean percentage change in body weight. Error bars represent the standard error (SEM) of the mean.

[0101] Figure 11 Tumor growth curves of female BALB / c nude mice loaded with AMG510-R-xMia PaCa-2 clone #2 tumors are shown. Data points represent group means. Error bars represent the standard error (SEM) of the means.

[0102] Figure 12 The survival curves of BALB / c nude mice loaded with AMG510-R-xMia PaCa-2 clone #2 tumors (tumor size greater than 1,000 mm) are shown in different treatment groups. 3 As an event).

[0103] Figure 13 The overall properties of WX001 are shown.

[0104] Figure 14A The results showed that WX001 exhibited good selectivity in the Eurofins Kinome panel, which contains 430 kinases, in the overall kinase selectivity analysis. Figure 14B and Figure 14CThe results showed that potential off-target kinases were tested by dose-titration biochemistry in subsequent IC50 analysis (inhibition rate >80% at 1 μM concentration in Kinome analysis). WX001 showed more than 9.5 times higher selectivity than GSK3α and more than 10 times higher selectivity than all other potential off-target kinases.

[0105] Figure 15A This demonstrates the inhibitory effect of WX001 on downstream signaling pathways, as determined by phosphorylated RSK analysis in BRAF or KRAS mutant cancer cell lines. Figure 15B The antiproliferative effect of WX001 in BRAF or KRAS mutant cancer cell lines was demonstrated by the Cell Titer-Glo method.

[0106] Figure 16A The growth of tumors over time is shown in an NCI-H358 NSCLC cancer model treated with WX001 or BVD523 (referencing an ERK 1 / 2 inhibitor). Figure 16B The growth of tumors over time in an HCT-116 colorectal cancer model treated with WX001 or the reference ERK 1 / 2 inhibitors BVD523 and LY3214996 is shown.

[0107] Figure 17A The growth of NCI-H358 NSCLC tumors is shown after monotherapy with the KRAS G12C inhibitor MRTX849, AMG510 and compound 17 or in combination with WX001. Figure 17B The summary of complete tumor response rates is shown for each treatment group.

[0108] Figure 18 The percentage change in body weight of female BALB / c nude mice with established NCI-H1373 tumors is shown in different treatment groups. This change is calculated based on the animals' body weight on day 1 of administration. Data points represent the group mean percentage change in body weight. Error bars represent the standard error (SEM) of the mean.

[0109] Figure 19 The data show the body weight of female BALB / c nude mice with established NCI-H1373 tumors in different treatment groups. Data points represent the group mean body weight. Error bars represent the standard error (SEM) of the mean.

[0110] Figure 20 Tumor growth curves of female BALB / c nude mice with established tumors loaded with NCI-H1373 are shown in different treatment groups. Data points represent group means; error bars represent the standard error (SEM) of the means.

[0111] Figure 21 Tumor growth curves of female BALB / c nude mice with established tumors loaded with NCI-H1373 are shown in different treatment groups. Data points represent group means; error bars represent the standard error (SEM) of the means. Detailed Implementation

[0112] This application provides a combination therapy for treating KRAS-mutant cancers (e.g., KRAS G12C cancers), comprising an ERK 1 / 2 inhibitor and a KRAS inhibitor (e.g., a KRAS G12C inhibitor). As illustrated in the examples, the combination therapy provides a favorable and effective treatment for KRAS-mutant cancers (e.g., KRAS G12C cancers) while being safe and tolerable.

[0113] definition

[0114] Before describing the embodiments in detail, it should be understood that this disclosure is not limited to specific compositions or biological systems, and of course, these compositions or biological systems can vary. It should also be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting.

[0115] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless otherwise expressly specified. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and so on.

[0116] As used herein, the term "about" refers to the typical range of error for a corresponding value, as is well known to those skilled in the art. References to "about" for a value or parameter herein include (and describe) embodiments for that value or parameter itself.

[0117] It should be understood that aspects and embodiments of this disclosure include aspects and embodiments that are “comprising,” “composed of,” and “substantially composed of.”

[0118] As used herein, the term "treatment" refers to a clinical intervention in a clinicopathological process aimed at altering the natural course of the treated individual or cells. The desired effects of treatment include slowing disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. For example, an individual is successfully "treated" if one or more cancer-related symptoms are relieved or eliminated, including but not limited to reducing the proliferation of cancer cells (or destroying cancer cells), reducing symptoms caused by the disease, improving the quality of life of the patient, reducing the dosage of other medications required to treat the disease, and / or prolonging the individual's survival. In some implementations, "treating" a disease such as cancer means delaying disease progression, i.e., postponing, hindering, slowing, delaying, stabilizing, and / or postponing the development of a disease (e.g., cancer or KRAS G12C cancer). The duration of this delay varies depending on the medical history and / or the individual receiving treatment. Those skilled in the art will appreciate that a sufficient or significant delay can effectively encompass prevention, i.e., the individual does not develop the disease. For example, the occurrence of advanced cancer (such as metastatic cancer) may be delayed.

[0119] An "effective amount" is at least the minimum amount required to achieve a measurable improvement or prevention of a specific disease (e.g., cancer). Effective amounts as used herein may vary depending on a variety of factors, such as the patient's disease state, age, sex, and weight, and the ability of the therapeutic agent (or combination of therapeutic agents) to elicit the desired response in an individual. An effective amount also refers to the amount by which any toxic or adverse effects of the treatment are offset by the beneficial effects of the treatment. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as reducing one or more symptoms caused by the disease, improving the quality of life of a person with the disease, reducing the dosage of other medications required to treat the disease, enhancing the effect of another medication (e.g., by targeting), delaying disease progression, and / or prolonging survival. For cancer or tumors, an effective amount of a drug may have the effects of reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., to some extent slowing or ideally stopping) the invasion of cancer cells into peripheral organs; inhibiting (i.e., to some extent slowing and ideally stopping) tumor metastasis; inhibiting tumor growth to some extent; and / or alleviating one or more symptoms associated with the disease to some extent. An effective amount may be administered once or multiple times. For the purposes of this disclosure, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve therapeutic effects. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may be achieved in combination with another drug, compound, or pharmaceutical composition, or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, an "effective amount" may be considered in the case of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the desired result can be achieved or attained in combination with one or more other agents.

[0120] As used herein, the term "subject" for therapeutic purposes means any animal classified as a mammal, including humans, domesticated and farm animals, as well as zoo animals, sporting animals, or pet animals, such as dogs, horses, cats, cattle, etc. Preferably, the mammal is a human.

[0121] The terms “subject” and “patient” are used interchangeably and include mammals such as humans and non-human primates, as well as rabbits, rats, mice, goats, pigs, and other mammals. The term does not necessarily mean that a subject has been diagnosed with a disease, but generally refers to an individual under medical supervision.

[0122] In the context of preventing a condition, the term “prevention” generally refers to preventing or delaying the onset of a disease, or preventing a subject (whether human or animal) from developing its clinical or subclinical symptoms, for example, preventing the disease from occurring in a subject who is susceptible to the condition or disease but has not yet been diagnosed with it.

[0123] As used herein, the term "pharmaceutically acceptable" means that the solvent, diluent, excipient, and / or its salts are chemically and / or physically compatible with the other components in the formulation and physiologically compatible with the recipient.

[0124] As used herein, the term "pharmaceutically acceptable carrier and / or excipient" means a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active agent, and is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), including but not limited to pH adjusters, surfactants, adjuvants, and ionic strength enhancers. For example, pH adjusters include, but are not limited to, phosphate buffers; surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80; and ionic strength enhancers include, but are not limited to, sodium chloride.

[0125] As used in this article, the term "adjuvant" refers to a nonspecific immune enhancer that, when delivered to an organism along with or before an antigen, can enhance the organism's immune response to the antigen or alter the type of immune response. There are various types of adjuvants, including but not limited to aluminum adjuvants (e.g., aluminum hydroxide), Freund's adjuvants (e.g., complete and incomplete Freund's adjuvants), Corynebacterium, lipopolysaccharides, and cytokines. Freund's adjuvant is currently the most commonly used adjuvant in animal experiments. Aluminum hydroxide adjuvant is more commonly used in clinical trials.

[0126] The pharmaceutically acceptable salts disclosed herein can be prepared from parent compounds containing acidic or basic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof.

[0127] The compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure considers all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures, and other mixtures, such as mixtures rich in enantiomers or diastereomers, all of which are covered within the scope of this disclosure. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All such isomers and mixtures thereof are covered within the scope of this disclosure.

[0128] The compounds disclosed herein may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or C-14 (14C). As another example, hydrogen may be substituted with deuterium to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. Regardless of radioactivity, all variations in the isotopic composition of the compounds disclosed herein are included within the scope of this invention.

[0129] The term “optional” or “optionally” means that a subsequent event or condition may occur but is not required, and the term includes both cases where the event or condition occurs and cases where the event or condition does not occur.

[0130] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific atom by a substituent, including deuterium and hydrogen variants, provided that the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Positions on the aromatic ring cannot be oxo-substituted. The term "optional substitution" means that an atom may or may not be substituted by a substituent; unless otherwise stated, the type and number of substituents can be arbitrary, as long as it is chemically feasible.

[0131] When any variable (e.g., R) appears more than once in the composition or structure of a compound, the definition of that variable is independent each time it appears. Therefore, for example, if a group is substituted by 0-2 Rs, that group can optionally be substituted by up to two Rs, where the definition of R is independent each time it appears. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations yield a stable compound.

[0132] When the number of linking groups is 0, for example -(CRR)0-, it indicates that the linking group is a single bond.

[0133] When one of the variables is a single bond, it means that the two groups connected by the single bond are directly connected. For example, when L in ALZ represents a single bond, the structure of ALZ is actually AZ.

[0134] When the linkage direction of the listed linking groups is not specified, the linkage direction is arbitrary. For example, when When the linking group L is -MW-, -MW- can be attached to rings A and B in the same direction according to the reading order from left to right, forming... Alternatively, they can be connected to rings A and B in the opposite direction according to the reading order from left to right, forming... Combinations of linking groups, substituents, and / or their variants are permitted only if a stable compound can be obtained.

[0135] Unless otherwise stated, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups via chemical bonds. When the connection sites of chemical bonds are variable and there are hydrogen atoms at the connectable sites, when a connectable site with a hydrogen atom is connected to a chemical bond, as the number of connected chemical bonds increases, the number of hydrogen atoms at that site decreases accordingly, and the group becomes a group with the corresponding valence. The chemical bond between this site and other groups can be a straight solid line bond (…). ), straight dashed key ( ) or wavy line ( () indicates that the group is linked to other groups through the oxygen atom in the group. For example, the straight solid line bond in -OCH3 indicates that the group is linked to other groups through the oxygen atom in the group; The straight dashed bond in the figure indicates that the group is connected to other groups through the two ends of the nitrogen atom in the group; The wavy line in the diagram indicates that the group is connected to other groups through the 1-carbon and 2-carbon atoms in the phenyl group; This means that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including... , , and There are at least four connection methods; even if an H atom is drawn on -N-, Still includes The connection method is the same; however, for each chemical bond added, the number of H atoms at that position decreases by one, and the group becomes the corresponding monovalent piperidinyl group.

[0136] Unless otherwise stated, wedge solid keys ( ) and wedge-shaped dashed key ( ) indicates the absolute configuration of the solid center; straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid; wavy line ( ) indicates a wedge-shaped solid key ( ) or wedge-shaped dashed key ( ); or wavy lines ( ) indicates a solid key ( ) and dashed key ( ).For example, express and ,as well as represent and .

[0137] Unless otherwise stated, the terms “rich in one isomer,” “isomer-enriched,” “enriched in one enantiomer,” or “enantiomer-enriched” mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0138] Optically active (R)- and (S)- isomers, or D- and L- isomers, can be prepared using chiral synthesis or chiral reagents or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, the resulting diastereomeric mixture can be separated by asymmetric synthesis or derivatization with a chiral auxiliary, and the auxiliary group can be cleaved to obtain the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), the compound reacts with a suitable optically active acid or base to form a salt of the diastereomeric compound, which is then resolved by diastereomeric methods conventional in the art to obtain the pure enantiomer. Furthermore, the separation of enantiomers and diastereomeric compounds is typically performed using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0139] Unless otherwise stated, the term "C" 1-6 "Alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc. They can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0140] Unless otherwise stated, the term "C" 1-3 "Alkyl" is used to represent a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. C 1-3 Alkyl groups include C 1-2 Alkyl, C 2-3 Alkyl groups, etc. They can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0141] Unless otherwise stated, the term "C" 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms and connected to the rest of the molecule by an oxygen atom. C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0142] Unless otherwise stated, the term "C" 1-3 "Alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms and connected to the remainder of the molecule via an amino group. C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0143] Unless otherwise stated, "C 2-3"Alkenyl" is used to represent a straight-chain or branched hydrocarbon group consisting of 2 to 3 carbon atoms, containing at least one carbon-carbon double bond, which can be located at any position in the group. 2-3 Alkenes include C3 and C2 alkenes. 2-3 The alkenyl group can be monovalent, divalent, or polyvalent. C 2-3 Examples of alkenyl groups include, but are not limited to, vinyl and propenyl groups.

[0144] Unless otherwise stated, "C 2-3 "Alkyne" is used to represent a straight-chain or branched hydrocarbon group consisting of 2 to 3 carbon atoms, containing at least one carbon-carbon triple bond, which can be located at any position in the group. 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

[0145] Unless otherwise stated, the term "C" 6-10 "Aromatic ring" and "C" 6-10 The term "aryl" is used interchangeably in this disclosure. The term "C" is also used interchangeably. 6-10 "Aromatic ring" or "C" 6-10 "Aryl" refers to a cyclic hydrocarbon group with a conjugated π-electron system and consisting of 6 to 10 carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, where each ring is aromatic. It can be monovalent, divalent, or polyvalent. 6-10 Aryl groups include C 6-9 C9, C 10 And C6 aryl, etc. C 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups (including 1-naphthyl and 2-naphthyl groups).

[0146] Unless otherwise stated, the terms "5- to 10-membered heteroaryl ring" and "5- to 10-membered heteroaryl group" are used interchangeably. The term "5- to 10-membered heteroaryl group" refers to a cyclic group having a conjugated π-electron system and consisting of 5 to 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic ring system, wherein each ring is aromatic, and wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(p is 1 or 2). 5- to 10-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. 5- to 10-membered heteroaryl groups include 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, and 6-membered heteroaryl groups. Examples of 5-10 quinone heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, 3-pyrrole, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), and thiazolyl (including 2-thiazolyl, 4-thiazolyl, etc.). (e.g., azole and 5-thiazolyl), furanyl (including 2-furanyl and 3-furanyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl), benzothiazolyl (including 5-benzothiazolyl), purine, benzimidazolyl (including 2-benzimidazolyl), benzoxazolyl, indole (including 5-indole), isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl), or quinolinyl (including 3-quinolinyl, 6-quinolinyl).

[0147] Unless otherwise stated, the term "4- to 8-membered heterocyclic alkyl", alone or in combination with other terms, refers to a saturated cyclic group consisting of 4 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(p is 1 or 2). The ring includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, for "4- to 8-membered heterocyclic alkyl groups," the heteroatom can be present at the position where the heterocyclic alkyl group is attached to the rest of the molecule. 4- to 8-membered heterocyclic alkyl groups include 4-6, 5-6, 4, 5, and 6-membered heterocyclic alkyl groups, etc. Examples of 4- to 8-membered heterocyclic alkyl groups include, but are not limited to, azaheptanyl, oxacyclobutane, thioheptanyl, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxacyclohexyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or dioxacycloheptyl, etc.

[0148] Unless otherwise stated, Cn - n+m or Cn - Cn+m includes any specific case of n to n+m carbons, such as C 1-12 This includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12, as well as any range from n to n+m. For example, C1-12 includes C1-3, C1-6, C1-9, C3-6, C3-9, C3-12, C6-9, C6-12, and C9-12, etc. Similarly, n-membered to n+m-membered rings represent the number of atoms on the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, as well as any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0149] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the embodiments listed below, embodiments formed by combining the embodiments listed below with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Alternative embodiments include, but are not limited to, the embodiments disclosed herein.

[0150] The structures of the compounds disclosed herein can be confirmed using conventional methods well known to those skilled in the art. If this disclosure pertains to the absolute configuration of a compound, that absolute configuration can be confirmed using conventional techniques in the art, such as single-crystal X-ray diffraction (SXRD). In single-crystal X-ray diffraction (SXRD), a Bruker D8 venture diffractometer was used, with CuKα radiation as the light source, and the scanning mode was as follows: The diffraction intensity data of the cultured single crystals were scanned and collected. After collecting the relevant data, the crystal structure was further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0151] The solvents used in this disclosure are commercially available.

[0152] Compounds are named in accordance with general naming principles in the art or using ChemDraw® software. Commercially available compounds are named according to their supplier catalog names.

[0153] The pharmaceutically acceptable salts disclosed herein can be prepared from parent compounds containing acidic or basic moieties using conventional chemical methods. Generally, these salts can be prepared by reacting the free acidic or basic form of the compound with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture thereof.

[0154] All references cited in this article, including patent applications, patent publications, and UniProtKB / Swiss-Prot access numbers, are incorporated in full as if each individual reference were specifically and individually indicated as being incorporated by reference.

[0155] Methods of treating cancer

[0156] This article provides a method for treating a subject with cancer harboring a KRAS G12C mutation (i.e., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein), comprising administering to the subject an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor is used to prepare a medicament for treating cancer, wherein the treatment is used in combination with the KRAS G12C inhibitor.

[0157] In some embodiments, the ERK 1 / 2 inhibitor is, for example, a small molecule, peptide (e.g., antibody), antisense oligonucleotide, etc., that inhibits the activity of ERK1 and / or ERK2 proteins. Exemplary small molecule ERK 1 / 2 inhibitors that can be used in the methods provided herein include, but are not limited to, BVD-523 (Uritinib), CC-90003, GDC-0994 (Ravoxertinib), KO-947, LTT462, LY3214996 (temuterkib), WX001, SCH772984, FR180204, and MK-8353. In some embodiments, the KRAS G12C inhibitor is a small molecule. Exemplary small molecule KRAS G12C inhibitors that can be used in the methods provided herein include, but are not limited to, compounds 17, sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, HBI-2438, and JNJ-74699157. In some embodiments, the KRAS G12C inhibitor is compound 17. Further details regarding these and other exemplary small molecule KRAS G12C inhibitors will be described in further detail below.

[0158] In some embodiments, a method of treating an individual (e.g., a human patient) with cancer (e.g., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, e.g., cancer resistant to a prior KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor is a small molecule. In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is a small molecule. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer has not received KRAS G12C inhibition therapy. In some embodiments, the ERK1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK1 / 2 inhibitor. In some embodiments, the method further includes administering to the individual an effective amount of a third therapy comprising another anticancer agent, optionally said anticancer agent being selected from immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, debulking agents, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy, and antimetastatic agents. In some embodiments, the method includes selecting the individual for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein.

[0159] In some embodiments, a method of treating an individual (e.g., a human patient) with cancer (e.g., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, e.g., cancer resistant to a prior KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor is a small molecule. In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is a small molecule. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer (e.g., cancer cells) has only partially responded to prior KRAS treatment. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method further includes administering to the individual an effective amount of a third therapy comprising another anticancer agent, optionally said anticancer agent being selected from immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, debulking agents, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy, and antimetastatic agents. In some embodiments, the method includes selecting the individual for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein.

[0160] In some embodiments, a method of treating an individual (e.g., a human patient) with cancer (e.g., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, e.g., cancer resistant to a prior KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor is a small molecule. In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is a small molecule. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., has acquired resistance) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer has been previously treated with a KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations following prior KRAS inhibitor treatment. In some implementations, the cancer tissue exhibits R68M, Y96D, or A59T mutations following prior KRAS inhibitor treatment.In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method further includes administering to the individual an effective amount of a third therapy comprising another anticancer agent, optionally said anticancer agent being selected from immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, debulking agents, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy, and antimetastatic agents. In some embodiments, the method includes selecting the individual for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the cancer further comprises a KRAS Q61H mutation. In some embodiments, the KRAS Q61H mutation is acquired after prior treatment (e.g., KRAS G12C treatment).

[0161] In some embodiments, a method of treating an individual's cancer (e.g., a cancer comprising one or more cancer cells expressing a KRASG12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0162]

[0163] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibition (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary mutation of KRAS has occurred in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits KRAS mutations at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib.In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired after prior treatment (e.g., KRAS G12C treatment).

[0164] In some embodiments, a method of treating an individual cancer (e.g., a cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor is selected from the following formula or a pharmaceutically acceptable salt thereof.

[0165] .

[0166] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibition (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially.In some embodiments, the ERK 1 / 2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired following prior treatment (e.g., KRAS G12C treatment).

[0167] In some embodiments, a method of treating an individual cancer (e.g., a cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor is of the following formula or a pharmaceutically acceptable salt thereof.

[0168] .

[0169] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially.In some embodiments, the ERK 1 / 2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired following prior treatment (e.g., KRAS G12C treatment).

[0170] In some embodiments, a method of treating an individual cancer (e.g., a cancer comprising one or more cancer cells expressing a KRASG12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0171]

[0172] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein the C6-10 aryl and 5 to 10-membered heteroaryl are optionally surrounded by 1, 2, 3, 4 or 5 R1 groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3The ERK1 / 2 inhibitor is an alkylamino group; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and -C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the ERK1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibition (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, and compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary mutation of KRAS has occurred in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits KRAS mutations at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.In some embodiments, the second KRAS inhibitor is sotorasib or adagrasib. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired after prior treatment (e.g., KRAS G12C treatment).

[0173] In some embodiments, a method of treating an individual cancer (e.g., a cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0174] or .

[0175] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially.In some embodiments, the ERK 1 / 2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired following prior treatment (e.g., KRAS G12C treatment).

[0176] In some embodiments, a method of treating an individual's cancer (e.g., a cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0177] .

[0178] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially.In some embodiments, the ERK 1 / 2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired following prior treatment (e.g., KRAS G12C treatment).

[0179] In some embodiments, a method of treating an individual cancer (e.g., a cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, such as a cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0180]

[0181] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I; and wherein the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0182]

[0183] Where T1 is selected from O and N; R1 is selected from C. 6-10Aryl and 5 to 10-membered heteroaryl, wherein the C6-10 aryl and 5 to 10-membered heteroaryl are optionally surrounded by 1, 2, 3, 4 or 5 R a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3The ERK1 / 2 inhibitor is an alkylamino group; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and -C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the ERK1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibition (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary mutation of KRAS has occurred in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits KRAS mutations at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.In some embodiments, the second KRAS inhibitor is sotorasib or adagrasib. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired after prior treatment (e.g., KRAS G12C treatment).

[0184] In some embodiments, a method of treating an individual (e.g., a human patient) with cancer (e.g., cancer containing one or more cancer cells expressing a KRAS G12C mutant protein, e.g., cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0185]

[0186] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I; and the KRAS G12C inhibitors described herein comprise agents containing the following formula or pharmaceutically acceptable salts thereof.

[0187] 。

[0188] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially.In some embodiments, the ERK 1 / 2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1 / 2 inhibitor. In some embodiments, the method further includes administering to the individual an effective amount of a third therapy comprising another anticancer agent, optionally said anticancer agent being selected from immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, debulking agents, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy, and antimetastatic agents. In some embodiments, the method includes selecting the individual for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired after prior treatment (e.g., KRAS G12C treatment).

[0189] In some embodiments, a method of treating an individual (e.g., a human patient) with cancer (e.g., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, e.g., cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0190] ;

[0191] And wherein the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof,

[0192]

[0193] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3The ERK1 / 2 inhibitor is an alkylamino group; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and -C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the ERK1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibition (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary mutation of KRAS has occurred in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits KRAS mutations at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.In some embodiments, the second KRAS inhibitor is sotorasib or adagrasib. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired after prior treatment (e.g., KRAS G12C treatment).

[0194] In some embodiments, a method of treating an individual (e.g., a human patient) with cancer (e.g., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein, e.g., cancer resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0195] ;

[0196] The KRAS G12C inhibitors mentioned above include agents containing the following formula or pharmaceutically acceptable salts thereof.

[0197] .

[0198] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibition (e.g., resistance has been acquired) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some implementations, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway. In some implementations, the second KRAS inhibitor is sotorasib or adagrasib. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially.In some embodiments, the ERK 1 / 2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the KRAS Q61H mutation is acquired following prior treatment (e.g., KRAS G12C treatment).

[0199] In some embodiments, a method of treating an individual (e.g., a human patient) with lung cancer (e.g., NSCLC containing a KRAS G12C mutation, such as NSCLC cancer with a KRAS G12C mutation sensitive to EGFR therapy) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, a method of treating an individual (e.g., a human patient) with lung cancer (e.g., lung cancer resistant to KRAS G12C inhibitors) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the dose of the KRAS G12C inhibitor is equivalent to a dose of 30-100 mg / kg in mice (e.g., not exceeding 50 mg / kg, 40 mg / kg, or 30 mg / kg), optionally said KRAS G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered at a dose equivalent to 25-50 mg / kg in mice (e.g., a daily dose of about or at least about 50 mg / kg), optionally wherein the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the ERK 1 / 2 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof.

[0200] ,

[0201] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0203]

[0204] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor is selected from compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent (compound 17) having the following formula or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., has acquired resistance) (e.g., resistant to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits R68M, Y96D, or A59T mutations following prior KRAS inhibitor treatment. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.

[0206] In some embodiments, a method of treating an individual (e.g., a human patient) with colorectal cancer (e.g., colorectal cancer containing a KRAS G12C mutation, such as colorectal cancer with a KRAS G12C mutation resistant to previous KRAS G12C therapy) is provided, comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the dose of the KRAS G12C inhibitor is equivalent to a mouse dose of 10-100 mg / kg (e.g., not exceeding 30 mg / kg, 20 mg / kg, or 10 mg / kg), optionally wherein the KRAS G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered at a dose equivalent to 25-50 mg / kg in mice (e.g., a daily dose of about or at least about 50 mg / kg or 25 mg / kg), optionally wherein the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the method further includes administration of an EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab). In some embodiments, the dose of the EGFR inhibitor is equivalent to approximately 30 mg / kg in mice. In some embodiments, the EGFR inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor, KRAS G12C inhibitor, and / or EGFR inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the ERK 1 / 2 inhibitor is administered before the EGFR inhibitor. In some embodiments, the EGFR inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the EGFR inhibitor is administered before the KRAS G12C inhibitor. In some implementations, the KRAS G12C inhibitor is administered before the EGFR inhibitor.In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the ERK 1 / 2 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof.

[0207]

[0208] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0210]

[0211] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor is selected from compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the cancer has acquired resistance to KRASG12C inhibition (e.g., it has acquired resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations following prior KRAS inhibitor treatment. In some implementations, the cancer tissue exhibits R68M, Y96D, or A59T mutations following prior KRAS inhibitor treatment. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.

[0213] In some embodiments, a method of treating an individual (e.g., a human patient) with colorectal cancer (e.g., colorectal cancer containing KRAS G12C and Q61H mutations) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor (e.g., WX001); and (2) a KRAS G12C inhibitor (e.g., MRTX849, e.g., compound 17). In some embodiments, a method of treating an individual (e.g., a human patient) with colorectal cancer (e.g., colorectal cancer containing KRAS G12C and Q61H mutations) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor (e.g., WX001); and (2) MRTX849. In some embodiments, a method of treating an individual (e.g., a human patient) with colorectal cancer (e.g., colorectal cancer containing KRAS G12C and Q61H mutations) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor (e.g., WX001); and (2) compound 17. In some embodiments, the Q61H mutation is acquired after developing resistance to a prior KRAS inhibitor (e.g., a prior KRAS G12C inhibitor). In some embodiments, the dose of the KRAS G12C inhibitor is equivalent to a dose of 30-100 mg / kg in mice (e.g., not exceeding 50 mg / kg, 40 mg / kg, or 30 mg / kg), optionally said KRAS G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered at a dose equivalent to 25-50 mg / kg in mice (e.g., a daily dose of about or at least about 50 mg / kg), optionally wherein the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the ERK 1 / 2 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof.

[0214]

[0215] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0217]

[0218] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor is selected from compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the cancer has acquired resistance to KRASG12C inhibition (e.g., it has acquired resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits R68M, Y96D, or A59T mutations following prior KRAS inhibitor treatment. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.

[0220] In some embodiments, a method of treating an individual (e.g., a human patient) with pancreatic cancer (e.g., pancreatic cancer containing a KRAS G12C mutation, such as pancreatic cancer with a KRAS G12C mutation resistant to a previous KRAS G12C inhibitor) is provided, comprising administering to the individual (1) an ERK 1 / 2 inhibitor (e.g., WX001); and (2) a KRAS G12C inhibitor (e.g., MRTX849, e.g., compound 17). In some embodiments, the dose of the KRAS G12C inhibitor is equivalent to a dose of 30-100 mg / kg in mice (e.g., not exceeding 50 mg / kg, 40 mg / kg, or 30 mg / kg), optionally said KRAS G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered at a dose equivalent to 25-50 mg / kg in mice (e.g., a daily dose of about or at least about 50 mg / kg), optionally wherein the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the ERK 1 / 2 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof.

[0221]

[0222] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs cSubstituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0224]

[0225] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor is selected from compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the cancer has acquired resistance to KRASG12C inhibition (e.g., it has acquired resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits R68M, Y96D, or A59T mutations following prior KRAS inhibitor treatment. In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the individual develops resistance to KRAS inhibitors, which is independent of the MAPK pathway.

[0227] In some embodiments, a method is provided for treating cancer carrying a KRAS G12C mutation in an individual (e.g., a human patient), comprising administering to the individual (1) an ERK 1 / 2 inhibitor; (2) a KRAS G12C inhibitor; and (3) an EGFR inhibitor. In some embodiments, the cancer does not have any other KRAS mutations or abnormalities. In some embodiments, the cancer does not have any acquired secondary KRAS mutations. In some embodiments, the EGFR inhibitor is an EGFR antibody (e.g., cetuximab). In some embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the dose of the KRAS G12C inhibitor is equivalent to a dose of 30-100 mg / kg in mice (e.g., not exceeding 50 mg / kg, 40 mg / kg, or 30 mg / kg), optionally said KRAS G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered at a dose equivalent to 25-50 mg / kg in mice (e.g., a daily dose of about or at least about 50 mg / kg), optionally wherein the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the ERK 1 / 2 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof.

[0228]

[0229] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0231]

[0232] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor is selected from compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0233] .

[0234] In some embodiments, a method is provided for treating cancer carrying a KRAS G12C mutation in an individual (e.g., a human patient), comprising administering to the individual an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the cancer has at least one additional KRAS aberration in addition to the G12C mutation. In some embodiments, the additional KRAS aberration is a secondary aberration acquired following prior treatment (e.g., a prior KRAS G12C inhibitor described herein). In some embodiments, the additional KRAS aberration is a germline aberration or mutation. In some embodiments, the additional KRAS aberration is selected from high-level amplifications of the G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, and KRASG12C alleles. In some embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the dose of the KRAS G12C inhibitor is equivalent to a mouse dose of 30-100 mg / kg (e.g., not exceeding 50 mg / kg, 40 mg / kg, or 30 mg / kg), optionally, wherein the KRAS G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered at a dose equivalent to 25-50 mg / kg in mice (e.g., a daily dose of about or at least about 50 mg / kg), optionally wherein the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method includes selecting individuals for treatment based on the presence of one or more cancer cells expressing the KRAS G12C mutant protein. In some embodiments, the ERK 1 / 2 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof.

[0235]

[0236] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0238]

[0239] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor is selected from compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0240] .

[0241] In some embodiments, the subject is a human (e.g., a human patient). The cancers described herein include any type of cancer with a KRAS G12C mutation. A cancer (or population of cancer cells) comprising one or more cancer cells expressing the KRAS G12C mutant protein is optionally referred to herein as "KRAS G12C mutant cancer". In some embodiments, cancers (such as KRAS G12C mutant cancers, etc.) are colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor.

[0242] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRASG12C inhibitor is administered orally.

[0243] In some embodiments, the construct and the KRAS G12C inhibitor are administered simultaneously. In some embodiments, "simultaneous administration" means administering the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor at intervals not exceeding approximately 15 minutes, such as any one of 10, 5, or 1 minute. In some embodiments, simultaneous administration of the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor may be used in combination with a supplemental dose of the ERK 1 / 2 inhibitor and / or the KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered sequentially. In some embodiments, "sequential administration" means administering the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor at intervals exceeding approximately 15 minutes, such as any one of 20, 30, 40, 50, 60, or longer. For example, in some embodiments, the ERK 1 / 2 inhibitor is administered before the small molecule KRAS G12C inhibitor. In some embodiments, the small molecule KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, meaning their administration periods overlap. In other implementations, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are not administered simultaneously.

[0244] In some implementations, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor.

[0245] In some embodiments, the methods disclosed herein further include administering an effective amount of a third therapy. In some embodiments, the third therapy is another anticancer agent. The term "anticancer agent" or "antiproliferative agent" refers to any agent that can be used to treat cell-proliferating diseases such as cancer, including but not limited to cytotoxic agents, cell inhibitors, anti-angiogenic agents, tumor-reducing agents, chemotherapy agents, radiotherapy and radiotherapy agents, targeted anticancer agents, BRMs, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy, antimetastatic agents, and immunotherapy agents. It should be understood that, in the selected embodiments as described above, such anticancer agents may include conjugates and may be associated with the disclosed antibody prior to administration. More specifically, in some embodiments, the selected anticancer agent will be linked to an unpaired cysteine ​​residue of an engineered antibody to provide the engineered conjugate described herein. Thus, such engineered conjugates are explicitly considered to be within the scope of this disclosure. In other embodiments, the disclosed anticancer agent will be administered in combination with a site-specific conjugate comprising the different therapeutic agents described above.

[0246] This document also provides the use of an effective amount of (1) an ERK 1 / 2 inhibitor and (2) a KRAS G12C inhibitor for treating a subject with cancer harboring a KRAS G12C mutation (i.e., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein), including administering an effective amount of the (1) ERK 1 / 2 inhibitor and (2) a KRAS G12C inhibitor to the subject. In some embodiments, the ERK 1 / 2 inhibitor is used to prepare a medicament for treating cancer, wherein the treatment is used in combination with a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are used to prepare a medicament for treating cancer, wherein the treatment is used in combination with a KRAS G12C inhibitor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

[0247] This document also provides the use of any of the methods described herein for treating a subject with cancer harboring a KRAS G12C mutation (i.e., cancer comprising one or more cancer cells expressing the KRAS G12C mutant protein), including administering to the subject an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. ERK 1 / 2 and ERK 1 / 2 inhibitor.

[0248] In some embodiments, the methods and uses of this disclosure can be combined with additional therapeutic agents, including, for example, anticancer agents, including small molecule inhibitors of cancer. The additional therapeutic agents can also be kinase antagonists or inhibitors. In some embodiments, the kinase is involved in the RAS / RAF / MEK / ERK pathway. In some embodiments, the kinase is an extracellular signal-regulated kinase (ERK). In some embodiments, the ERK is ERK1. In some embodiments, the ERK kinase is ERK2 (also known as MAPK1). ERK kinases are terminal kinases in phosphate relay signaling pathways that regulate growth and mitotic signaling. ERK kinases phosphorylate substrates involved in regulating cell proliferation, survival, growth, metabolism, migration, and differentiation.

[0249] In some embodiments, the treatment results in at least more than about 70%, 75%, 80%, 85%, 90%, 95%, or 97% tumor growth inhibition. In some embodiments, the treatment results in tumor regression. In some embodiments, compared to monotherapy with a G12C inhibitor or monotherapy with an ERK 1 / 2 inhibitor, the treatment results in prolonged or sustained tumor suppression, regression, or radiation effects for more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, or 140 days. In some embodiments, the treatment produces sustained tumor suppression, regression, or radiation effects for more than 5, 10, 15, 20, 25, or 30 days after treatment cessation.

[0250] This application also provides for the use of any ERK 1 / 2 inhibitor described herein for the treatment of cancers with BRAF abnormalities (e.g., V600E) or KRAS abnormalities (e.g., any mutant KRAS described in the “Mutated KRAS” section, such as KRASG12C, or KRAS G12D). See, for example, Figure 15A and 15B In some implementations, ERK 1 / 2 inhibitors comprise a reagent of formula (I) or a pharmaceutically acceptable salt thereof.

[0251]

[0252] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl H and C 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents are used; n is 0 or 1; m is 1 or 2; ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl groups are optionally replaced by 1, 2 or 3 R groups. d Replace; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3The alkoxy group is optionally substituted with one, two, or three R substituents; R is selected from F, Cl, Br, and I. In some embodiments, the ERK 1 / 2 inhibitor comprises a molecule having the following formula or a pharmaceutically acceptable salt thereof.

[0253] .

[0254] This application also provides for the use of any of the G12C inhibitors described herein in combination with an EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab) for the treatment of cancers with KRAS G12C mutations. In some embodiments, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In some embodiments, the KRAS G12C inhibitor comprises a reagent of formula (III) or a pharmaceutically acceptable salt thereof.

[0255]

[0256] Wherein T1 is selected from O and N; R1 is selected from C6-10 aryl and 5 to 10-membered heteroaryl, wherein C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and —C≡CH, and R5, R6, and R7 are each independently H. In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0257] .

[0258] This application also provides a composition (e.g., a pharmaceutical composition) comprising a KRAS G12C inhibitor (e.g., compound 17) and an ERK 1 / 2 inhibitor (e.g., WX001). In some embodiments, the composition further comprises a drug carrier.

[0259] KRAS and KRAS inhibitors

[0260] A. KRAS

[0261] The Kirsten rat sarcoma (KRAS) gene belongs to the RAS family, and its mutations are a genetic driver of various cancer types, particularly colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC). KRAS-G12 mutations (89%) are predominant in human cancers, followed by G13 (9%) and Q61 (1%) mutations. Furthermore, G12D mutations are the most common among the three most common G12C (14%), G12D (36%), and G12V (23%) mutations. Compared to G12D, which plays a major role in PDAC, G12C is the most common mutation subtype in NSCLC (13%). Identifying specific types of KRAS mutations in combination with other gene mutations can provide information about disease aggressiveness or drug sensitivity, which is fundamental to precision medicine or personalized care. See, for example, Liu et al., Cancer Gene Ther 29, 875–878 (2022).

[0262] KRAS protein is a signaling GTPase that switches between active GTP-binding and inactive GDP-binding conformations. Guanine nucleotide exchange factor (GEF) promotes the exchange of GDP for GTP on KRAS, while GTP-activating protein (GAP) facilitates the exchange of GTP for GDP. Activation of plasma membrane receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) family initiates KRAS activation and subsequent multiple effector pathways, particularly the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Downstream of RTKs, SOS-Ras / Rac guanine nucleotide exchange factor 1 (SOS1) and protein tyrosine phosphatase non-receptor type 11 (PTPN11, preferably referred to as SHP2) promote the ratio of GDP-GTP exchange, leading to KRAS activation. Comparison of the GTP and GDP-binding structures of KRAS identified two regions, termed switch I and switch II. A mutant cysteine ​​residue 12 is located adjacent to the pocket (P2) in switch II. Compared to wild-type, KRAS mutations disrupt the guanine exchange cycle, thereby locking it into an inactive GDP-binding form that drives pro-tumor signals. Oncogenic KRAS signaling establishes a major signaling axis for tumor cell proliferation and survival, providing a key target for cancer therapy. See, for example, Liu et al., Cancer Gene Ther 29, 875–878 (2022).

[0263] B. KRAS G12C inhibitors

[0264] Despite long being considered "untreatable," promising progress has recently been made in clinical trials of drugs that directly inhibit oncogenic RAS, thanks to the development of drugs that specifically bind to the KRAS-G12C mutant protein. In particular, the covalently valent KRAS-G12C inhibitors sotorasib and adagrasib are being used to treat patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS-G13C mutations. Unfortunately, the vast majority of patients do not fully respond to KRAS-G12C inhibitor therapy, primarily due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improved understanding of drug responses in the tumor microenvironment is likely to continue to advance the design, testing, and clinical application of KRAS-G12C inhibitors. See Liu et al., Cancer Gene Ther 29, 875–878 (2022).

[0265] In some embodiments, a KRAS inhibitor is an inhibitor of the G12C variant of KRAS (i.e., KRAS G12C). In some embodiments, the term "KRAS G12C inhibitor" refers to any agent that inhibits the activity of the KRAS G12C mutant protein, such as a peptide, fusion peptide, antibody, peptide, antisense oligonucleotide, or small molecule drug. In some embodiments, the KRAS G12C inhibitor interacts directly with the KRAS G12C mutant protein to inhibit its activity.

[0266] In some embodiments, the KRAS G12C inhibitor is a small molecule drug. In some embodiments, the KRAS G12C inhibitor is a small molecule (e.g., an irreversible small molecule inhibitor) that inhibits KRAS activity by forming an irreversible covalent bond with cysteine ​​residues of the KRAS G12C mutant protein.

[0267] a) Exemplary KRAS G12C inhibitors

[0268] The exemplary KRAS G12C inhibitors discussed herein (e.g., compound 17) include, but are not limited to, a class of KRAS G12C inhibitors. The molecular mode of action (MOA) of this class of KRAS G12C inhibitors is allosteric binding to the Switch II pocket of the GDP-binding form of the KRAS G12C protein and a covalent bond at cysteine-12. This irreversible binding traps KRAS G12C in its GDP-binding inactive state. This class of KRAS G12C inhibitors with the same mechanism of action (MOA) includes sotorasib, adgrasib, JDQ443, GDC-6036, etc. Therefore, ERK 1 / 2 inhibitors (e.g., WX001) and exemplary KRAS G12C inhibitors are expected to expand to all KRAS G12C inhibitors of the same class.

[0269] In some embodiments, the KRAS G12C inhibitor comprises or is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0270]

[0271] in

[0272] T1 is selected from O and N;

[0273] R1 is selected from C6-10 aryl and 5 to 10 heteroaryl groups, wherein the C6-10 aryl and 5 to 10 heteroaryl groups are optionally represented by 1, 2, 3, 4 or 5 R1 groups. a replace;

[0274] When T1 is 0, R2 does not exist;

[0275] When T1 is N, R2 is selected from H and C. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl, wherein the C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0276] R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0277] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's.d replace;

[0278] R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms;

[0279] R8 is selected from H and CH3;

[0280] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups;

[0281] R b Each is independently selected from F, Cl, Br, I, OH, and NH2;

[0282] R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups;

[0283] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0284] R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O-CO-C 1-3 Alkylamino;

[0285] The condition is that, when R1 is a naphthyl group, the naphthyl group may optionally be converted by F, Cl, Br, OH, NH2, CF3, CH2CH3, and Replace, and R5, R6 and R7 are each independently H.

[0286] In some embodiments of this disclosure, the aforementioned R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2 and The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2 and The variable can be optionally replaced by 1, 2 or 3 Fs, and other variables are as defined in this disclosure.

[0287] In some embodiments of this disclosure, the aforementioned Ra is independently selected from F, OH, NH2, CH3, CF3, CH2CH3, and Other variables are as defined in this disclosure.

[0288] In some embodiments of this disclosure, R1 is selected from phenyl, naphthyl, indole, and indazole, wherein the phenyl, naphthyl, indole, and indazole are optionally surrounded by one, two, or three R1 groups. a Instead, other variables are as defined in this disclosure.

[0289] In some embodiments of this disclosure, R1 is selected from... , , and Other variables are as defined in this disclosure.

[0290] In some embodiments of this disclosure, the R2 is selected from H, CH3, CH2CH3, and CH(CH3)2, wherein the CH3, CH2CH3, and CH(CH3)2 are optionally represented by one, two, or three R2 molecules. b Instead, other variables are as defined in this disclosure.

[0291] In some embodiments of this disclosure, R2 is selected from H and CH3, and other variables are as defined in this disclosure.

[0292] In some embodiments of this disclosure, each of the above R is independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and Other variables are as defined in this disclosure.

[0293] In some embodiments of this disclosure, the aforementioned R c The radicals are selected from tetrahydropyrrolidinyl and hexahydro-1H-pyrrolidinyl, wherein the tetrahydropyrrolidinyl and hexahydro-1H-pyrrolidinyl are optionally substituted with one, two or three Rs, and other variables are as defined in this disclosure.

[0294] In some embodiments of this disclosure, the aforementioned R c Selected from , , and Other variables are as defined in this disclosure.

[0295] In some embodiments of this disclosure, the aforementioned R c Selected from , , and Other variables are as defined in this disclosure.

[0296] In some embodiments of this disclosure, R3 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... c Instead, other variables are as defined in this disclosure.

[0297] In some embodiments of this disclosure, R3 is selected from... , , ,and Other variables are as defined in this disclosure.

[0298] In some embodiments of this disclosure, R3 is selected from... , , ,and Other variables are as defined in this disclosure.

[0299] In some embodiments of this disclosure, the R4 is selected from H and CH3, wherein the CH3 is optionally surrounded by one, two, or three R4 molecules. d Instead, other variables are as defined in this disclosure.

[0300] In some embodiments of this disclosure, R4 is selected from H, CH3 and CH2CN, and other variables are as defined in this disclosure.

[0301] This disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0302]

[0303] in

[0304] T1 is selected from O and N;

[0305] R1 is selected from phenyl, naphthyl, and indazole, wherein the phenyl, naphthyl, and indazole are optionally surrounded by one, two, three, four, or five R1 groups. a replace;

[0306] When T1 is 0, R2 does not exist;

[0307] When T1 is N, R2 is selected from H and C. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3Alkyl, wherein the C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0308] R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0309] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0310] R5, R6 and R7 are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0311] R8 is selected from H and CH3;

[0312] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, and OCH3;

[0313] R b Each is independently selected from F, Cl, Br, I, OH, and NH2;

[0314] R c Each is independently selected from tetrahydropyrrolidinyl and hexahydro-1H-pyrrolidinyl, wherein the tetrahydropyrrolidinyl and hexahydro-1H-pyrrolidinyl are substituted with one, two or three Rs;

[0315] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0316] R is independently selected from H, F, Cl, Br and CH3.

[0317] In some embodiments of this disclosure, the above-described compounds or pharmaceutically acceptable salts thereof are disclosed, wherein said compounds are selected from:

[0318]

[0319] in

[0320] R4 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0321] T1, R1, R2, R3, R5, R6, R7 and R d As defined in this disclosure;

[0322] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S), or rich in one enantiomer.

[0323] In some embodiments of this disclosure, R1 is selected from phenyl, naphthyl, and... The phenyl, naphthyl and Optionally by 1, 2 or 3 R a Instead, other variables are as defined in this disclosure.

[0324] In some embodiments of this disclosure, R1 is selected from... , , and Other variables are as defined in this disclosure.

[0325] In some embodiments of this disclosure, the R2 is selected from H, CH3, CH2CH3, and CH(CH3)2, wherein the CH3, CH2CH3, and CH(CH3)2 are optionally represented by one, two, or three R2 molecules. b Instead, other variables are as defined in this disclosure.

[0326] In some embodiments of this disclosure, R2 is selected from H and CH3, and other variables are as defined in this disclosure.

[0327] In some embodiments of this disclosure, the aforementioned R c Selected from , , and Other variables are as defined in this disclosure.

[0328] In some embodiments of this disclosure, the aforementioned R c Selected from , , and Other variables are as defined in this disclosure.

[0329] In some embodiments of this disclosure, R3 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... c Instead, other variables are as defined in this disclosure.

[0330] In some embodiments of this disclosure, R3 is selected from... , , and Other variables are as defined in this disclosure.

[0331] In some embodiments of this disclosure, R3 is selected from... , , and Other variables are as defined in this disclosure.

[0332] In some embodiments of this disclosure, the R4 is selected from H and CH3, wherein the CH3 is optionally surrounded by one, two, or three R4 molecules. d Instead, other variables are as defined in this disclosure.

[0333] In some embodiments of this disclosure, R4 is selected from H, CH3 and CH2CN, and other variables are as defined in this disclosure.

[0334] This disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0335]

[0336] in

[0337] T1 is selected from O and N;

[0338] R1 is selected from phenyl, naphthyl, and indazole, wherein the phenyl, naphthyl, and indazole are optionally surrounded by one, two, three, four, or five R1 groups. a replace;

[0339] When T1 is 0, R2 does not exist;

[0340] When T1 is N, R2 is selected from H and C. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl, wherein the C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0341] R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0342] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0343] R5, R6 and R7 are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0344] R8 is selected from H and CH3;

[0345] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, and OCH3;

[0346] R b Each is independently selected from F, Cl, Br, I, OH, NH2, and CH3;

[0347] R c Each is independently a tetrahydropyrrole group, wherein the tetrahydropyrrole group is substituted with 1, 2 or 3 R groups;

[0348] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0349] R is independently selected from F, Cl, Br and CH3.

[0350] In some embodiments of this disclosure, the above-described compounds or pharmaceutically acceptable salts thereof are disclosed, wherein said compounds are selected from:

[0351]

[0352] T1, R1, R2, R3, R4, R5, R6 and R7 are as defined in this disclosure; carbon atoms marked with "*" are chiral carbon atoms, existing as a single enantiomer (R) or (S), or rich in one enantiomer.

[0353] In some embodiments of this disclosure, R1 is selected from phenyl, naphthyl, and... The phenyl, naphthyl and Optionally by 1, 2 or 3 R a Instead, other variables are as defined in this disclosure.

[0354] In some embodiments of this disclosure, R1 is selected from... , , and Other variables are as defined in this disclosure.

[0355] In some embodiments of this disclosure, the R2 is selected from H, CH3, CH2CH3, and CH(CH3)2, wherein the CH3, CH2CH3, and CH(CH3)2 are optionally represented by one, two, or three R2 molecules. b Instead, other variables are as defined in this disclosure.

[0356] In some embodiments of this disclosure, R2 is selected from H and CH3, and other variables are as defined in this disclosure.

[0357] In some embodiments of this disclosure, the aforementioned R c for Other variables are as defined in this disclosure.

[0358] In some embodiments of this disclosure, R3 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... c Instead, other variables are as defined in this disclosure.

[0359] In some embodiments of this disclosure, R3 is... Other variables are as defined in this disclosure.

[0360] In some embodiments of this disclosure, R4 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... d Instead, other variables are as defined in this disclosure.

[0361] In some embodiments of this disclosure, R4 is CH2CN, and other variables are as defined in this disclosure.

[0362] This disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0363]

[0364] in

[0365] T1 is selected from O and N;

[0366] R1 is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are optionally surrounded by one, two or three R1 groups. a replace;

[0367] When T1 is 0, R2 does not exist;

[0368] When T1 is N, R2 is selected from C. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl, wherein the C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0369] R3 is C 1-3 Alkyl, wherein the C1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0370] R4 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0371] R5, R6 and R7 are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0372] R a Each of them is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3 and OCH3;

[0373] R b Each is independently selected from F, Cl, Br, I, OH, NH2, and CH3;

[0374] R c Each is independently a tetrahydropyrrole group, wherein the tetrahydropyrrole group is substituted with 1, 2 or 3 R groups;

[0375] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0376] R are each independently selected from F, Cl, Br and CH3; carbon atoms marked with "*" are chiral carbon atoms, existing as a single enantiomer (R) or (S), or rich in one enantiomer.

[0377] In some embodiments of this disclosure, R1 is a naphthyl group, wherein the naphthyl group is optionally surrounded by one, two, or three R groups. a Instead, other variables are as defined in this disclosure.

[0378] In some embodiments of this disclosure, R1 is selected from... and Other variables are as defined in this disclosure.

[0379] In some embodiments of this disclosure, the R2 is selected from CH3, CH2CH3, and CH(CH3)2, wherein the CH3, CH2CH3, and CH(CH3)2 are optionally represented by one, two, or three R2 molecules. b Instead, other variables are as defined in this disclosure.

[0380] In some embodiments of this disclosure, R2 is CH3, and other variables are as defined in this disclosure.

[0381] In some embodiments of this disclosure, the aforementioned R c for Other variables are as defined in this disclosure.

[0382] In some embodiments of this disclosure, R3 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... c Instead, other variables are as defined in this disclosure.

[0383] In some embodiments of this disclosure, R3 is... Other variables are as defined in this disclosure.

[0384] In some embodiments of this disclosure, R4 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... d Instead, other variables are as defined in this disclosure.

[0385] In some embodiments of this disclosure, R4 is CH2CN, and other variables are as defined in this disclosure.

[0386] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0387]

[0388] R1 is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are optionally surrounded by one, two or three R1 groups. a replace;

[0389] R2 is selected from C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl, wherein the C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0390] R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0391] R4 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0392] R5, R6 and R7 are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0393] Ra and R b Each is independently selected from F, Cl, Br, I, OH, NH2, and CH3;

[0394] R c Each is independently a tetrahydropyrrole group, wherein the tetrahydropyrrole group is substituted with 1, 2 or 3 R groups;

[0395] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0396] R is independently selected from F, Cl, Br and CH3;

[0397] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S), or rich in one enantiomer.

[0398] In some embodiments of this disclosure, R1 is a naphthyl group, and other variables are as defined in this disclosure.

[0399] In some embodiments of this disclosure, R1 is... Other variables are as defined in this disclosure.

[0400] In some embodiments of this disclosure, the R2 is selected from CH3, CH2CH3, and CH(CH3)2, wherein the CH3, CH2CH3, and CH(CH3)2 are optionally represented by one, two, or three R2 molecules. b Instead, other variables are as defined in this disclosure.

[0401] In some embodiments of this disclosure, R2 is CH3, and other variables are as defined in this disclosure.

[0402] In some embodiments of this disclosure, the aforementioned R c for Other variables are as defined in this disclosure.

[0403] In some embodiments of this disclosure, R3 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... c Instead, other variables are as defined in this disclosure.

[0404] In some embodiments of this disclosure, R3 is... Other variables are as defined in this disclosure.

[0405] In some embodiments of this disclosure, R4 is CH3, wherein the CH3 is optionally surrounded by one, two, or three R... d Instead, other variables are as defined in this disclosure.

[0406] In some embodiments of this disclosure, R4 is CH2CN, and other variables are as defined in this disclosure.

[0407] In some embodiments of this disclosure, the above-described compounds or pharmaceutically acceptable salts thereof are disclosed, wherein said compounds are selected from:

[0408]

[0409] Among them, R1, R5 and R c As defined in this disclosure;

[0410] R4 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0411] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0412] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S), or rich in one enantiomer.

[0413] In some embodiments of this disclosure, the above-described compounds or pharmaceutically acceptable salts thereof are disclosed, wherein said compounds are selected from:

[0414]

[0415] in

[0416] R1, R2, R4, R5, R6, R7, R8 and R are as defined in this disclosure.

[0417] This disclosure also includes some implementation schemes obtained through any combination of the above variables.

[0418] This disclosure provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0419]

[0420] .

[0421] In some embodiments of this disclosure, the above-described compounds or pharmaceutically acceptable salts thereof are disclosed, wherein said compounds are selected from:

[0422]

[0423] .

[0424] In some embodiments of this disclosure, the above-described compounds or pharmaceutically acceptable salts thereof are disclosed, wherein said compounds are selected from:

[0425]

[0426] .

[0427] In some embodiments, the KRAS G12C compound is compound 17 having the following structure, or a pharmaceutically acceptable salt thereof.

[0428]

[0429] The above-mentioned compounds exhibit good cell proliferation inhibitory activity against the KRASG12C-mutant MIA-PA-CA-2 cell line and NCI-H358 cells. The disclosed compounds demonstrate good stability in liver microsomes, hepatocytes, plasma, and whole blood, as well as good PK properties and significant antitumor activity. See, for example, US20230151004A1 and WO2023 / 036282, which are incorporated herein by reference in their entirety. The manufacture and / or synthesis of the above-mentioned compounds can be found in US20230151004A1 and / or WO2023 / 036282.

[0430] b) Other exemplary KRAS G12C inhibitors

[0431] Exemplary KRAS G12C inhibitors that can be used in the methods provided herein include, but are not limited to, sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, LY3537982, RMC-6291, RMC-8839, HBI-2438, compound 17, JNJ-74699157, BI 1823911, MK-1084, HS-10370, JMKX001899, YL-15293, ZG19018, XNW14010, HJ891, BEBT-607, GEC-255, and JS116. Other exemplary small molecule KRAS G12C inhibitors are described, for example, Hillig et al. (2019) Proc Natl Acad Sci US A. 116(7): 2551–2560 and Sun et al. (2012) Angew Chem Int Ed Engl. 51(25): 6140–6143, and described in WO 2020 / 233592, WO2021 / 023247, WO 2021 / 083167, WO 2020 / 238791, WO 2021 / 000885, CN 112585129, CN112552295, CN 112390818, CN 112390796, WO 2019 / 141250, CN 111592528, WO 2020 / 259432, CN 112300153, CN 112552294, WO 2020 / 239123, CN 110698378, CN 111377918, CN111205286, CN 112047939, WO 2020 / 259513, WO 2021 / 023154, CN 112430234, WO 2021 / 063346, WO 2021 / 058018, CN 112225734, WO 2021 / 155716, CN112159405, CN 112778302, CN112830928, WO 2020 / 1027943、CN 112574199、WO 2021 / 037018、CN 110172089、WO 2020 / 156285、CN 111499634、WO 2020 / 177629、WO 2020 / 216190、WO 2020 / 221239、WO 2020 / 233592、WO 2020 / 238791、WO2020 / 239077, WO 2020 / 239123, CN 112047933, CN112047937, CN 112047948, WO 2020 / 259513, WO 2020 / 259573, WO 2020 / 259432, WO 2021 / 000885, CN 112174950, CN 112300153, WO 2021 / 023154, WO 2021 / 023247, CN 112390818, WO 2021 / 027943, WO 2021 / 027911, WO 2021 / 031952, C.N. 112390796, WO 2021 / 037018, CN112442029, WO 2021 / 043322, WO 2021 / 052499, CN 112538084, CN 112552295, WO 2021 / 058018, WO 2021 / 063346, WO 2021 / 068898, WO 2021 / 078285, CN 112225734, CN112707905, CN 112745335, WO 2021 / 083167, CN 112778284, WO 2021 / 088458, CN112851663, WO 2021 / 093758, WO 2021 / 098859, CN 112830928, CN 111377918, WO 2021 / 104431, WO 2021 / 109737, WO 2021 / 113595, CN 112920183, WO 2021 / 121371, WO 2021 / 121367, CN 113004269, WO 2021 / 129824, WO 2021 / 129820, CN 113061132, WO 2021 / 139678, WO 2021 / 139748, CN 111205286, W.O. 2021 / 143693, CN 113135924, WO 2021 / 147965, WO 2021 / 155716, WO 2021 / 168193, WO 2021 / 169990, WO 2021 / 169963, CN113321654, WO 2021 / 175199, WO 2021 / 180181, WO 2021 / 185233, WO 2021 / 190467, WO2021 / 197499, CN 112574199, CN 112300269, US20230151004 and above, WO2023 / 036282, the above-mentioned literature content is included in the full text.

[0432] In some embodiments, the KRAS G12C inhibitor is AMG 510, also known as sotorasib, LUMAKRAS™, and LUMYKRAS™, as described above. AMG 510 is currently developed by Amgen / Beigene. AMG 510 can exist in two transtransfer-inhibiting isomers, one with higher activity than the other (see, for example, https: / / cen.acs.org / pharmaceuticals / drug-discovery / Amgen-unveils-KRas-inhibitor-human / 97 / i14). AMG 510 selectively forms an irreversible covalent bond with a sulfur atom in the cysteine ​​residue present in the G12C mutant form of the KRAS protein but not in the wild-type form. The covalent binding of AMG 510 to KRAS G12C locks the protein in its inactive GDP-binding conformation, thereby inhibiting KRAS-dependent signal transduction. AMG 150 has the chemical formula C30HF2N6O3 and a molecular weight of 560.606 g / mol. Chemically, AMG 150 is described as 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-m90cFv90ine-(propyl-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(propyl-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one, and has the following chemical structure:

[0433] .

[0434] The CAS registry number for AMG 510 is 2252403-56-6. The efficacy of AMG 510 has been demonstrated in a cohort of patients enrolled in a single-arm, open-label, multicenter trial (NCT03600883), and is currently under investigation in further clinical trials. Complete information on the preparation, dispensing, dosage, and administration schedule of AMG 510 can be found in the local package insert (for the United States, see, for example, www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 214665s000lbl.pdf). Further details on the structure and synthesis of AMG 510 are provided in WO 2018 / 217651, the contents of which are incorporated herein by reference in their entirety.

[0435] In some embodiments, the KRAS G12C inhibitor is MRTX849 (also known as adagrasib). MRTX849 is currently being developed by Mirati / Zai Lab. Similar to AMG 510, MRTX849 selectively forms an irreversible covalent bond with a sulfur atom in a cysteine ​​residue present in the G12C mutant form of the KRAS protein but not in the wild-type form. Like AMG 510, the covalent binding of MRTX849 to KRAS G12C locks the protein in its inactive GDP-binding conformation, thereby inhibiting KRAS-dependent signal transduction. The chemical formula of MRTX849 is C1. 32 H 35 ClFN7O2 has a molecular weight of 604.13 g / mol. MRTX849 is chemically described as 2-[(2S)-4-[7-(8-chloronaphthyl-1-yl)-2-[[(2S)-1-methylpyrrolidone-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, and has the following chemical structure:

[0436]

[0437] The CAS registry number for MRTX849 is 2326521-71-3. MRTX849 is currently being evaluated in several clinical trials, including NCT04613596, NCT04685135, NCT03785249, and NCT04330664. Further details regarding the structure and synthesis of MRTX849 are provided in Fell et al. (2020) J. Med. Chem. 63, 6679-6693 and WO 2017 / 201161, the contents of which are incorporated herein by reference in their entirety.

[0438] In some embodiments, the KRAS G12C inhibitor is JAB-21822. JAB-21822 was developed by Jacobio Pharmaceuticals Group Co., LTD (see, for example, en.jacobiopharma.com / blank3.html?introId=23 and www.jacobiopharma.com / news / 207.html). JAB-21822 is currently being evaluated in several clinical trials, including NCT05009329 and NCT05002270. Further details regarding the structure and synthesis of JAB-21822 are provided in WO 2021 / 057832, the contents of which are incorporated herein by reference in their entirety.

[0439] In some embodiments, the KRAS G12C inhibitor is GDC-6036. GDC-6036 was developed by Genentech, Inc. (see, for example, www.genentechoncology.com / pipeline-molecules / kras-g12c.html) and is currently being evaluated in the clinical trial NCT04449874. Further details regarding the structure and synthesis of GDC-6036 are provided in WO 2020 / 097537, the contents of which are incorporated herein by reference in their entirety.

[0440] In some embodiments, the KRAS G12C inhibitor is JDQ443. JDQ443 is a KRAS G12C inhibitor being developed by Novartis. The structure of JDQ443 is as follows:

[0441]

[0442] JDQ443 is currently being evaluated in the clinical trial NCT04699188. Further details regarding the synthesis of JDQ443 are provided in WO 2021 / 124222, the contents of which are incorporated herein by reference in their entirety.

[0443] In some embodiments, the KRAS G12C inhibitor is D-1553. D-1553 was developed by InventisBio Co., Ltd. (see, e.g., www.inventisbio.com / %e4%b8%b4%e5%ba%8a%e8%af%95%e9%aa%8c / ) and is currently being evaluated in the clinical trial NCT04585035 in collaboration with Merck Sharp & Dohme. Further details regarding the structure and synthesis of D-1553 are provided in WO 2020 / 233592, the contents of which are incorporated herein by reference in their entirety.

[0444] In some embodiments, the KRAS G12C inhibitor is GH35. GH35, developed by Suzhou Genhouse BioCo., Ltd. (see, for example, www.genhousebio.com / en / product / index.html), is being evaluated in the clinical trial NCT05010694. Further details regarding the structure and synthesis of GH35 are provided in WO2020 / 177653, the contents of which are incorporated herein by reference in their entirety.

[0445] In some embodiments, the KRAS G12C inhibitor is GFH925. GFH925 was developed by GenFleet Therapeutics (Zhejiang) (see, for example, www.genfleet.com / en / science) and is being evaluated in the clinical trial NCT05005234. Further details regarding the structure and synthesis of GFH925 are provided in WO 2020 / 177629, WO2020 / 221239 and WO 2021 / 031952, the contents of which are incorporated herein by reference in their entirety.

[0446] In some embodiments, the KRAS G12C inhibitor is BPI-421286. BPI-421286 was developed by Betta Pharmaceutical Co., Ltd. (see, for example, www.bettapharma.com / News / show / id / 2380), and the China National Medical Products Administration has accepted clinical trial applications for BPI-421286 (CXHL2100046 and CXHL2100047). Further details regarding the structure and synthesis of BPI-421286 are provided in CN112390796, the contents of which are incorporated herein by reference in their entirety.

[0447] In some embodiments, the KRAS G12C inhibitor is LY3537982. LY3537982 was developed by Eli Lilly and Company and Loxo Oncology, Inc. (see, for example, www.lillyloxooncologypipeline.com / molecule / kras-g12c-inhibitor / ) and is being investigated in the clinical trial NCT04956640. Further details regarding the structure and synthesis of LY3537982 are provided in WO2021 / 118877, the contents of which are incorporated herein by reference in their entirety.

[0448] In some implementations, the KRAS G12C inhibitor is RMC-6291. RMC-6291 was developed by Revolution Medicines.

[0449] In some implementations, the KRAS G12C inhibitor is RMC-8839. RMC-8839 was developed by Revolution Medicines.

[0450] In some implementations, the KRAS G12C inhibitor is HBI-2438. HBI-2438 was developed by Huya Bioscience and Jemin Biocare and is being investigated in the clinical trial NCT05485974.

[0451] In some implementations, the KRAS G12C inhibitor is JNJ-74699157 (ARS-3248). JNJ-74699157 was developed by Johnson and Johnson and Wellspring Biosciences and investigated in the clinical trial NCT04006301.

[0452] C. ERK 1 / 2

[0453] Extracellular regulated protein kinases (ERK) 1 and ERK2 are key players and terminal signaling kinases in the Ras / Raf / MEK / ERK pathway. ERK 1 / 2 act as crucial signaling nodules downstream of the Ras-Raf-MEK-ERK pathway and have been shown to be overactivated in human cancers driven by RAS or RAF mutations. Innate resistance to RAF or MEK inhibitors is partly due to loss of regulation through negative feedback loops and pathway reactivation.

[0454] Dysregulation of the RAS / RAF / MAP / ERK kinase cascade is associated with many human cancers. Any mutation leading to cascade signaling dysregulation results in aberrant activation of ERK 1 / 2 and tumorigenesis. Therefore, due to the importance of ERKs as key pathway regulators, they are highly controlled by a variety of spatial and temporal mechanisms. ERK 1 / 2 is directly phosphorylated by MEK1 and MEK2. Phosphorylated (e.g., activated) ERK 1 / 2 kinases subsequently phosphorylate a variety of substrates that regulate cell cycle progression, differentiation, and survival (Sugiura et al., Cells, 10(10): 2509 (2021)). For example, ERK 1 / 2-regulated transcription factors control genes that play important roles in key cellular processes such as cell proliferation and cell cycle progression.

[0455] The ERK signaling cascade is also involved in several aspects of tumor development (Sugiura et al., Cells, 10(10):2509 (2021)). For example, ERK 1 / 2-mediated phosphorylation of certain protein substrates (such as focal adhesion kinase) promotes cancer cell migration.

[0456] D. ERK 1 / 2 inhibitors

[0457] Because ERK kinases are a link between several important signaling pathways in normal cells, progress with ERK inhibitors has been limited due to their low therapeutic index. However, tumors with altered upstream proteins of ERK 1 / 2 have been observed to be sensitive to ERK inhibitors (Chin et al. Jour. Imm. Pres. Onc., 2(1):10-16, (2020)). ERK 1 / 2 inhibitors are known to inhibit ERK kinases through one of two main mechanisms. ERK inhibitors can inhibit ERK catalytic activity by competing for ATP binding sites. These inhibitors, known as catalytic ERKi or catERKi, are reversible inhibitors that primarily lead to the accumulation of phosphorylated ERK 1 / 2 in the cell nucleus (Kidger et al., Mol. Cancer Ther. 19(2): 525-539 (2020)). Dual-mechanism ERK inhibitors (dmERKi) prevent ERK activation by blocking MEK1 / 2-mediated phosphorylation of the TEY motif (Kidger et al., 2020).

[0458] In some embodiments, an ERK 1 / 2 inhibitor is an inhibitor of ERK 1 / 2. In some embodiments, the term "ERK 1 / 2" refers to any agent that inhibits the activity of ERK 1 / 2 proteins (e.g., ERK 1 / 2 kinases), such as peptides, fusion peptides, antibodies, peptides, antisense oligonucleotides, or small molecule drugs. In some embodiments, an ERK 1 / 2 inhibitor interacts directly with the ERK 1 / 2 protein to inhibit its activity.

[0459] In some embodiments, the ERK 1 / 2 inhibitor is a small molecule drug. In some embodiments, the ERK 1 / 2 inhibitor is a small molecule (e.g., a reversible small molecule catalytic ERK 1 / 2 inhibitor) that inhibits ERK 1 / 2 catalytic activity by competitively binding to the ERK 1 / 2 protein with ATP. In some embodiments, the ERK 1 / 2 inhibitor is a small molecule (e.g., a dual-mechanism ERK 1 / 2 inhibitor) that inhibits ERK 1 / 2 activity, thereby preventing the formation of the active ERK 1 / 2 conformation. In some embodiments, the ERK 1 / 2 inhibitor prevents the phosphorylation of ERK 1 / 2. In some embodiments, the ERK 1 / 2 inhibitor is a thiazolactam spiroheterocyclic compound, such as the ERK 1 / 2 inhibitor disclosed in WO2023274256, which is incorporated herein by reference. Preparation and / or synthesis of ERK 1 / 2 inhibitors can be found in WO2023274256.

[0460] a) Exemplary ERK 1 / 2 inhibitors

[0461] In some embodiments, the ERK 1 / 2 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0462]

[0463] in,

[0464] R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace;

[0465] R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents;

[0466] n is 0 or 1;

[0467] m is 1 or 2;

[0468] Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R;

[0469] R a and R c Independently selected from D, F, Cl, Br, and I;

[0470] R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two, or three R substituents;

[0471] R is selected from F, Cl, Br and I.

[0472] In some embodiments of this disclosure, R1 and R2 are independently selected from H, CH3, and CH2CH3, and the CH3 and CH2CH3 are optionally separated by 1, 2, or 3 Rs. a replace.

[0473] In some embodiments of this disclosure, R1 and R2 are independently selected from H, CH3, CHF2, CD3, and CH2CH3.

[0474] In some embodiments of this disclosure, R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and CH3, and CH3 is optionally surrounded by 1, 2, or 3 R groups. c replace.

[0475] In some embodiments of this disclosure, R4, R5, R6 and R7 are independently selected from H, F, Cl, Br, I and CH3.

[0476] In some embodiments of this disclosure, R is selected from F, Cl, Br, I, CH3 and OCH3, and said CH3 and OCH3 are optionally substituted by 1, 2 or 3 R substituents.

[0477] In some embodiments of this disclosure, the R d Selected from CH3 and OCH3.

[0478] In some embodiments of this disclosure, ring A is selected from... , and And the stated , and Choose 1, 2, or 3 Rs d replace.

[0479] In some embodiments of this disclosure, ring A is selected from... , and .

[0480] In some embodiments of this disclosure, the structural unit for .

[0481] In some embodiments of this disclosure, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0482] ,

[0483] in,

[0484] R2 is defined as in any one of claims 1 to 3;

[0485] R6 and R7 are as defined in any one of claims 1, 4 and 5.

[0486] In some embodiments of this disclosure, the ERK 1 / 2 inhibitor comprises WX001 or a pharmaceutically acceptable salt thereof as shown in the formula below.

[0487] .

[0488] In some embodiments of this disclosure, the compound is crystal form A of WX001, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.2080 ± 0.2000°, 18.8429 ± 0.2000°, and 20.6217 ± 0.2000°;

[0489] .

[0490] In some embodiments of this disclosure, the X-ray powder diffraction pattern of the ERK 1 / 2 inhibitor has characteristic diffraction peaks at the following 2θ angles: 10.2080 ± 0.2000°, 18.8429 ± 0.2000°, 20.6217 ± 0.2000°, 25.0767 ± 0.2000°, and 25.4797 ± 0.2000°.

[0491] In some embodiments of this disclosure, the X-ray powder diffraction pattern of the ERK 1 / 2 inhibitor has characteristic diffraction peaks at the following 2θ angles: 10.2080 ± 0.2000°, 15.2687 ± 0.2000°, 17.6747 ± 0.2000°, 18.8429 ± 0.2000°, 20.6217 ± 0.2000°, 21.0531 ± 0.2000°, 25.0767 ± 0.2000°, and 25.4797 ± 0.2000°.

[0492] In some embodiments of this disclosure, the X-ray powder diffraction pattern of the ERK 1 / 2 inhibitor has characteristic diffraction peaks at the following 2θ angles: 10.2080 ± 0.2000°, 14.4684 ± 0.2000°, 15.2687 ± 0.2000°, 17.6747 ± 0.2000°, 18.8429 ± 0.2000°, 20.6217 ± 0.2000°, 21.0531 ± 0.2000°, 21.5713 ± 0.2000°, 22.0420 ± 0.2000°, 22.4540 ± 0.2000°, 25.0767 ± 0.2000°, and 25.4797 ± 0.2000°.

[0493] In some embodiments of this disclosure, the X-ray powder diffraction pattern of the ERK 1 / 2 inhibitor has characteristic diffraction peaks at the following 2θ angles: 10.2080°, 10.4856°, 14.4684°, 15.0133°, 15.2687°, 15.9518°, 16.6214°, 17.6747°, 17.9514°, 18.4703°, 18.8429°, 19.1531°, 20.6217°, 21.0531°, 21.2894°, 21.5713°, 22.0420°, 22.4540°, 25.0767°, 25.4797°, 26.3255°, and 26.9544°.

[0494] In some embodiments of this disclosure, the ERK 1 / 2 inhibitor has a differential scanning calorimetry curve with an endothermic onset point of 241.0 ± 3.0 °C.

[0495] In some embodiments, the ERK 1 / 2 inhibitor has a thermogravimetric analysis curve showing a weight loss of 0.83% at 150.0 ± 3.0 °C.

[0496] b) Other exemplary ERK 1 / 2 inhibitors

[0497] Exemplary small molecule ERK 1 / 2 inhibitors that can be used in the methods provided herein include, but are not limited to, BVD-523 (Uritinib), CC-90003, GDC-0994 (Ravoxertinib), KO-947, LTT462, LY3214996 (temuterkib), SCH772984, ERA007, ASN007, FR180204, and MK-8353.

[0498] In some embodiments, the ERK 1 / 2 inhibitor is BVD-523, also known as ulixertinib and VRT752271. BVD-523 is currently being developed by BioMed Valley. BVD-523 is a reversible, ATP-competitive, orally administered inhibitor. The chemical formula of BVD-523 is C21H22Cl2N4O2, and its molecular weight is 433.33 g / mol. BVD-523 is chemically described as (S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide hydrochloride, with the following chemical structure:

[0499]

[0500] The CAS registry number for BVD-523 is 869886-67-9. The efficacy of BVD-523 has been demonstrated in a cohort of patients recruited in a multicenter dose-escalation trial (NCT01781429) and is currently being investigated in further clinical trials.

[0501] In some embodiments, the ERK 1 / 2 inhibitor is CC-90003. CC-90003 is a covalent ERK 1 / 2 inhibitor developed by Celgene.

[0502] In some implementations, the ERK 1 / 2 inhibitor is GDC-0994, also known as ravoxertinib. GDC-0994 was developed by Array and Genentech. GDC-0994 has the CAS number 1453848-26-4 and is also known as 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one. Its molecular formula is C21H18ClFN6O2, and its molecular weight is 440.863 g / mol. The efficacy of GDC-0994 was demonstrated in a cohort of patients enrolled in an open-label, multicenter, dose-escalation trial (NCT01875705). Further details regarding the structure and synthesis of GDC-0994 are provided in WO2013 / 130976, the contents of which are incorporated herein by reference in their entirety.

[0503] In some embodiments, the ERK 1 / 2 inhibitor is KO-947, developed by ArcexesPharma and KuraOncology. Further details regarding the structure and synthesis of KO-947 are provided in WO2015 / 051341, the contents of which are incorporated herein by reference in their entirety.

[0504] In some embodiments, the ERK 1 / 2 inhibitor is LTT462, also known as rineterkib, developed by Novartis. LTT462 has the chemical formula C1. 26 H 27 BrF3N5O2.

[0505] In some implementations, the ERK 1 / 2 inhibitor is LY3214996, also known as temuterkib. LY3214996 was developed by Eli Lilly. The efficacy of temuterkib is currently being investigated in clinical trials.

[0506] In some embodiments, the ERK 1 / 2 inhibitor is SCH772984. SCH772984 was developed by Merck. The CAS number for SCH772984 is 942183-80-4, and its molecular formula is C2. 33 H 33 N9O2 has a molecular weight of 587.67 g / mol.

[0507] In some embodiments, the ERK 1 / 2 inhibitor is FR180204. FR180204 is also known as 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-amine. Its CAS number is 865362-74-9, its molecular formula is C18H13N7, and its molecular weight is 327.3 g / mol.

[0508] In some embodiments, the ERK 1 / 2 inhibitor is MK-8353 (SCH900353). MK-8353 was developed by Merck. MK-8353 has the CAS number 1184173-73-6, a molecular weight of 691.84 g / mol, and the molecular formula C37H41N9O3S.

[0509] E. KRAS-G12C resistance

[0510] In some embodiments, the cancer is resistant to prior KRAS treatment (e.g., treatment involving a KRAS-G12C inhibitor, or the cancer has acquired resistance to KRAS G12C inhibition, such as resistance to KRAS inhibitors like MRTX849, AMG510, or compound 17, or has acquired resistance). In some embodiments, the cancer (e.g., cancer cells) responds only partially to prior KRAS treatment. In some embodiments, a partial response is determined by the lack of tumor regression. In some embodiments, a partial response is determined by tumor growth inhibition of no more than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% (e.g., calculated using the methods described herein).

[0511] A range of strategies have attempted to indirectly target KRAS, such as by inhibiting farnesyltransferases through blocking KRAS post-translational modifications or suppressing downstream KRAS effectors. Amgen and Mirati Therapeutics have developed two direct KRAS-G12C inhibitors, sotorasib (also known as AMG 510 or Lumakras) and adagrasib (also known as MRTX849), which lock KRAS in an inactive state to prevent cell proliferation by selectively forming a covalent bond with cysteine ​​12 within the switch II pocket of the KRAS-G12C protein. Preclinical studies have shown that sotorasib and adagrasib selectively attenuate the viability of KRAS-G12C mutant cell lines without affecting cell lines with other KRAS mutations in vitro and in vivo. Both sotorasib and adagrasib have long half-lives (5.5–24 hours) and wide tissue distribution in humans. Surprisingly, neither sotorasib nor adagrasib affects PI3K signaling, indicating that upstream pathways independent of KRAS-G12C promote PI3K activation, which explains the development of resistance to KRAS-G12C inhibitors.

[0512] Emerging preclinical and clinical evidence suggests that the most significant obstacle to KRAS-G12C inhibitor therapy is the inevitable development of resistance. While the problem of resistance to treatment is multifaceted, intercellular variability or intratumoral heterogeneity is considered a major contributing factor to KRAS-G12C inhibitor resistance. Single-cell RNA sequencing analysis of KRAS-G12C mutant NSCLC cell lines treated with the KRAS-G12C inhibitor ARS1620 revealed that a subpopulation of cells synthesizing novel KRAS-G12C protein instead of wild-type KRAS protein was the cause of adaptive resistance. See, for example, Nature. 2020 Jan; 577(7790):421-425. Further analysis suggests that EGFR or Aurora kinase A (AURKA) signaling can maintain newly expressed KRAS-G12C protein in an active GTP-binding form, thereby evading KRAS-G12C inhibitor therapy. However, another study showed that wild-type RAS activation mediated by multiple RTKs, rather than a single RTK, is the cause of acquired resistance to KRAS-G12C inhibitors (ARS-1620 and sotorasib) in various cancer cell lines. See Clin Cancer Res. 2020; 26:1633–43. In any case, numerous independent studies have demonstrated the importance of PTPN11 / SHP2 as a common downstream of RTKs in activating wild-type or mutant KRAS proteins to mediate acquired resistance. A clinical trial (NCT04330664) is underway to test the combination of TNO155 (an SHP2 inhibitor) and adagrasib in patients with advanced solid tumors harboring KRAS-G12C mutations. Furthermore, activation of the PI3K-AKT-mTOR pathway contributes to the development of sotorasib resistance in human PDAC cell lines in vitro and in xenograft mouse models. Gene set enrichment analysis and mass spectrometry-based phosphorylation proteomics analysis revealed that the induction of epithelial-mesenchymal transition (EMT) promotes resistance to sotorasib or ARS-1620 in NSCLC cells through cell type-dependent activation of the PI3K or ERK pathway. Nuclear factor, erythrocyte-like 2 (NFE2L2, best known as NRF2), regulated by kelch-like ECH-associated protein 1 (KEAP1), is a key transcription factor in cellular antioxidant responses. KEAP1 or NFE2L2 mutations predicted to be poorly responsive to checkpoint inhibitor immunotherapy may also be associated with resistance to adagrasib. These findings provide a therapeutic approach targeting kinases or transcription factors to overcome resistance to KRAS-G12C inhibitors.See, for example, CancerGene Ther 29, 875–878 (2022).

[0513] Furthermore, intrinsic or adaptive resistance may be caused by concurrent genetic alterations, such as secondary KRAS mutations and other gene mutations that are not targeted by KRAS-G12C inhibitors. In fact, a recent clinical study used next-generation sequencing and deep mutation scanning to characterize genetic variations in tissue samples or circulating tumor DNA from patients resistant to adagrasib. In 38 patients with KRAS-G12C-mutant cancers (27 with NSCLC, 10 with colorectal cancer, and 1 with appendiceal cancer) who received adagrasib monotherapy, 45% were found to have a presumed mechanism of resistance to adagrasib. Furthermore, 18% of these patients exhibited multiple overlapping genetic mechanisms: acquired KRAS mutations G12D / R / V / W, G13D, Q61H, R68S, H95D / Q / R, and Y96C; high-level amplification of the KRAS-G12C allele; acquired bypass resistance mechanisms including MET amplification; activating mutations in NRAS, BRAF, MAP2K1, RETALK, RET, RAF1, FGFR3, NF1, and PTEN; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. This information can ultimately be synthesized at any decision point for each tumor cell and used to adjust treatment. Similarly, one NSCLC patient was reported to have acquired resistance to adagrasib, which was associated with the reactivation of RAS-MAPK signaling by mutations in 10 secondary genes along the RAS-RAF-MEK-ERK pathway. The KRAS-Y96D mutation directly affects the binding of adagrasib to the P2 pocket, leading to resistance in multiple cancer cell lines (H358, MIAPaCa2, and BaF3) to sotorasib, adagrasib, or ARS-1620. In contrast, Revolution Medicines' novel RAS(ON) inhibitor, the representative KRAS-G12C selective inhibitor RM-018, maintains potent inhibitory activity against tumor cells carrying the KRAS-G12C / Y92D double mutation. Besides KRAS-Y96D, KRAS-Y96S and KRAS-Y96C are also contributing factors to BaF3 cell resistance to sotorasib or adagrasib, a process that can be reversed by combining with the SOS1 inhibitor (BI-3406). In summary, these results highlight the complexity of the genetic mechanisms underlying resistance to KRAS-G12C inhibitors.See, for example, Cancer Gene Ther 29, 875–878 (2022).

[0514] In some implementations, a secondary mutation of KRAS occurs in the cancer tissue following prior KRAS inhibitor treatment.

[0515] In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits KRAS mutations at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations. In some embodiments, following prior KRAS inhibitor treatment, the cancer tissue exhibits R68M, Y96D, or A59T mutations.

[0516] In some embodiments, the individual includes a secondary mutation in KRAS. In some embodiments, the secondary mutation includes R68, Y96, or A59 mutations in KRAS. In some embodiments, the individual includes R68M, Y96D, or A59T mutations.

[0517] In some embodiments, the cancer includes copy number variations in KRAS. In some embodiments, the cancer includes a copy number in KRAS (e.g., mutant KRAS, such as wild-type KRAS) that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than a reference copy number. In some embodiments, the cancer contains a KRAS copy number (e.g., mutant KRAS, such as wild-type KRAS) that is at least about one, two, three, four, five, six, seven, eight, nine, or ten times higher than a reference copy number of KRAS. In some embodiments, the reference copy number of KRAS is the corresponding copy number of KRAS in a reference individual (or a group of reference individuals) who does not have the disease (e.g., cancer). In some embodiments, the reference copy number of KRAS is the corresponding copy number of KRAS in the same individual prior to previous treatment (e.g., previous KRAS G12C inhibitor treatment).

[0518] In some embodiments, the cancer includes upregulated KRAS mRNA levels and / or KRAS protein levels relative to a reference individual's corresponding tissue or organ, a non-cancerous tissue or organ of the same individual, or the same cancer prior to previous treatment. In some embodiments, the cancer contains KRAS mRNA and / or KRAS protein levels (e.g., mutant KRAS, such as wild-type KRAS) that are at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than reference KRAS mRNA and / or KRAS protein levels. In some embodiments, the cancer contains KRAS mRNA and / or KRAS protein levels (e.g., mutant KRAS, such as wild-type KRAS) that are at least about one, two, three, four, five, six, seven, eight, nine, or ten times higher than reference KRAS mRNA and / or KRAS protein levels. In some embodiments, the reference KRAS mRNA level and / or KRAS protein level is the corresponding KRAS mRNA level and / or KRAS protein level of a reference individual (or a group of reference individuals) who is disease-free (e.g., cancer). In some embodiments, the reference KRAS mRNA level and / or KRAS protein level is the corresponding KRAS mRNA level and / or KRAS protein level of the same individual prior to previous treatment (e.g., previous KRASG12C inhibitor treatment).

[0519] In some implementations, the cancer includes a KRAS promoter mutation that increases the strength of the promoter.

[0520] In some embodiments, the cancer includes increased wild-type RAS signaling relative to a corresponding tissue or organ in a reference individual, non-cancerous tissue or organ in the same individual, or the same cancer prior to previous treatment. In some embodiments, the cancer has increased levels of active GTP-binding wild-type RAS. In some embodiments, wild-type RAS includes H-RAS and / or N-RAS.

[0521] In some implementations, the individual develops resistance to KRAS inhibitors that is independent of the MAPK pathway (e.g., when there are no significant changes in the mRNA or protein levels of molecules involved in the MAPK pathway, see, for example, Microbiol Mol Biol Rev. 2011 Mar; 75(1): 50–83).

[0522] Previous KRAS inhibitor treatment

[0523] In some implementations, the aforementioned KRAS inhibitor is an inhibitor that specifically targets codon 12 mutations.

[0524] In some embodiments, the KRAS inhibitor is a G12C inhibitor. Exemplary G12C inhibitors can be found, for example, in J Exp Clin Cancer Res 41, 27 (2022), the full text of which is incorporated herein by reference. In some embodiments, the KRAS inhibitor is ARS-1620, RM-018, sotorasib, or adagrasib.

[0525] In some embodiments, the KRAS inhibitor is a G12D inhibitor. Exemplary G12D inhibitors can be found, for example, in Cell Discov 8, 5 (2022), the full text of which is incorporated herein by reference. In some embodiments, the aforementioned G12D inhibitor is MRTX1133 or RMC-9805.

[0526] In some implementations, the KRAS inhibitor is a G12V inhibitor. Exemplary G12V inhibitors can be found, for example, in Cancer Res (2021) 81 (13_Supplement): 1260, the full text of which is incorporated herein by reference.

[0527] In some embodiments, the complex is administered at least approximately 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, or 24 months after treatment with the KRAS inhibitor.

[0528] In some embodiments, the complex is administered no more than about 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 or 24 months after treatment with the KRAS inhibitor.

[0529] Mutant KRAS (e.g., mutations at codon 12, such as secondary mutations following previous KRAS inhibitor treatment).

[0530] In some embodiments, the cancerous tissue has a KRAS aberration. In some embodiments, the KRAS aberration includes a mutation at codon 12. In some embodiments, the mutation at codon 12 is a somatic mutation. In some embodiments, the mutation at codon 12 is a germline mutation. In some embodiments, the KRAS aberration is G12C.

[0531] In some embodiments, the cancerous tissue has a KRAS mutation at codons 13, 59, 61, 68, 95, or 96. In some embodiments, the cancerous tissue has a high level of amplification of the G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, or KRASG12C allele. In some embodiments, any mutation at codons 13, 59, 61, 68, 95, and / or 96 is a germline mutation. In some embodiments, any mutation at codons 13, 59, 61, 68, 95, and / or 96 is a somatic mutation.

[0532] In some embodiments, the cancerous tissue has a secondary KRAS mutation following prior KRAS inhibitor treatment. In some embodiments, the cancerous tissue has a KRAS mutation at codons 12, 13, 59, 61, 68, 95, or 96 following prior KRAS inhibitor treatment. In some embodiments, the cancerous tissue has an acquired KRAS aberration with high-level amplification of the alleles selected from G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, and KRASG12C, optionally, the acquired KRAS aberration occurred following prior KRAS inhibitor treatment. In some embodiments, the cancerous tissue has a Q61H mutation following prior treatment (e.g., prior KRAS inhibitor treatment).

[0533] In some embodiments, the cancerous tissue has at least one (or at least two, three, four, or five) additional KRAS aberrations (e.g., an additional mutation) in addition to G12C. In some embodiments, the at least one (or at least two, three, four, or five) additional KRAS aberrations are selected from the group consisting of high-level amplifications of the G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, and KRASG12C alleles. In some embodiments, the additional KRAS aberration is Q61H.

[0534] Genetic aberrations in KRAS can be assessed based on samples (e.g., samples from an individual and / or reference samples). In some embodiments, the sample is a tissue sample or nucleic acid extracted from a tissue sample. In some embodiments, the sample is a cell sample (e.g., a CTC sample) or nucleic acid extracted from a cell sample. In some embodiments, the sample is a tumor biopsy. In some embodiments, the sample is a tumor sample or nucleic acid extracted from a tumor sample. In some embodiments, the sample is a biopsy sample or nucleic acid extracted from a biopsy sample. In some embodiments, the sample is a formaldehyde-fixed paraffin-embedded (FFPE) sample or nucleic acid extracted from an FFPE sample. In some embodiments, the sample is a blood sample. In some embodiments, cell-free DNA is isolated from a blood sample. In some embodiments, the biological sample is a plasma sample or nucleic acid extracted from a plasma sample.

[0535] Genetic aberrations in KRAS can be determined by any method known in the art. See, for example, Dickson et al. Int. J. Cancer, 2013, 132(7): 1711-1717; Wagle N. Cancer Discovery, 2014, 4: 546-553; and Cancer Genome Atlas Research Network. Nature 2013, 499: 43-49. Exemplary methods include, but are not limited to, genomic DNA sequencing, sulfite sequencing, or other DNA sequencing-based methods using Sanger sequencing or next-generation sequencing platforms; polymerase chain reaction assays; in situ hybridization assays; and DNA microarrays. Epigenetic characteristics (e.g., DNA methylation, histone binding, or chromatin modification) of one or more genes in a sample isolated from an individual can be compared with epigenetic characteristics of one or more genes from a control sample. Nucleic acid molecules extracted from a sample can be sequenced or analyzed to determine whether genetic aberrations exist relative to a reference sequence (e.g., a wild-type sequence of KRAS).

[0536] In some embodiments, cell-free DNA sequencing methods are used to assess genetic aberrations in KRAS. In some embodiments, next-generation sequencing is used to assess genetic aberrations in KRAS. In some embodiments, next-generation sequencing is used to assess genetic aberrations in KRAS isolated from blood samples. In some embodiments, exome sequencing is used to assess genetic aberrations in KRAS. In some embodiments, fluorescence in situ hybridization analysis is used to assess genetic aberrations in KRAS. In some embodiments, genetic aberrations in KRAS are assessed before initiating the treatment method described herein. In some embodiments, genetic aberrations in KRAS are assessed after initiating the treatment method described herein. In some embodiments, genetic aberrations in KRAS are assessed both before and after initiating the treatment method described herein. The level of KRAS abnormality may refer to abnormal expression levels or abnormal activity levels.

[0537] In some implementations, individuals do not develop secondary KRAS mutations in exon 1 and / or exon 2 after KRAS treatment.

[0538] cancer

[0539] In some embodiments, the cancer is leukemia or lymphoma. In some embodiments, the cancer is a solid tumor.

[0540] In some embodiments, the solid tumor includes, but is not limited to, sarcomas and carcinomas, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterine sarcoma, synovial sarcoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, and sweat gland carcinoma. Sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0541] In some implementations, the disease is selected from myelodysplastic syndromes, lung cancer (e.g., NSCLC, small cell lung cancer, squamous cell lung cancer), colorectal cancer, acute myeloid leukemia, pancreatic cancer, rectal cancer, esophageal squamous cell carcinoma, gastrointestinal stromal tumor, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, multiple myeloma, and glioma.

[0542] In some implementations, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).

[0543] In some implementations, the cancer is colorectal cancer.

[0544] In some implementations, the cancer is lung cancer (e.g., NSCLC).

[0545] In some implementations, the cancer is malignant and / or advanced cancer.

[0546] dose

[0547] The dosage of ERK 1 / 2 inhibitors, KRAS G12C inhibitors, and / or EGFR inhibitors (e.g., anti-EGFR antibodies, such as cetuximab) that will effectively treat, inhibit, and prevent cancers carrying KRAS G12C mutations (i.e., cancers containing one or more cancer cells expressing the KRAS G12C mutant protein) can be determined using standard clinical techniques. The dosage of the inhibitor also depends on the concentration of each inhibitor, the route of administration, the severity of the cancer, the patient's condition, and should be determined based on the physician's judgment and each patient's individual circumstances. Effective dosages can be deduced from dose-response curves derived from in vitro or animal model testing systems.

[0548] In some embodiments, this document provides methods and / or uses for treating a subject with cancer harboring a KRAS G12C mutation (i.e., cancer comprising one or more cancer cells expressing a KRAS G12C mutant protein), including administering to the subject an effective amount of (1) an ERK 1 / 2 inhibitor; and (2) a KRAS G12C inhibitor. In some embodiments, the method further includes administering an effective amount of an EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab). In some embodiments, the effective amount (e.g., a dose) may produce the function described below and herein.

[0549] In some embodiments, the ERK 1 / 2 inhibitor is of the following formula or a pharmaceutically acceptable salt thereof.

[0550]

[0551] In some implementations, the amount of ERK 1 / 2 inhibitor administered to the subject is equivalent to a mouse dose contained in any of the following ranges: about 10 mg / kg to about 100 mg / kg, about 10 to about 25 mg / kg, about 10 to about 30 mg / kg, about 10 mg / kg to about 50 mg / kg, about 20 to about 25 mg / kg, about 20 to about 50 mg / kg, about 25 to about 50 mg / kg, about 25 to about 55 mg / kg, about 20 to about 25 mg / kg, about 40 to about 50 mg / kg, about 30 mg / kg to about 50 mg / kg, about 20 mg / kg to about 60 mg / kg, about 10 mg / kg to about 25 mg / kg, or about 45 mg / kg to about 55 mg / kg. In some implementations, the amount of ERK 1 / 2 inhibitor administered to the subject for cancer treatment is equivalent to a mouse dose comprising, for example, approximately 20 mg / kg, approximately 21 mg / kg, approximately 22 mg / kg, approximately 23 mg / kg, approximately 24 mg / kg, approximately 25 mg / kg, approximately 26 mg / kg, approximately 27 mg / kg, approximately 28 mg / kg, approximately 29 mg / kg, approximately 30 mg / kg, approximately 31 mg / kg, approximately 32 mg / kg, approximately 33 mg / kg, approximately 34 mg / kg, approximately 35 mg / kg, approximately 36 mg / kg, approximately 37 mg / kg, approximately 38 mg / kg, approximately 39 mg / kg, approximately 40 mg / kg, approximately 41 mg / kg, approximately 42 mg / kg, approximately 43 mg / kg, approximately 44 mg / kg, approximately 45 mg / kg, approximately 46 mg / kg, approximately 47 mg / kg, approximately 48 mg / kg, approximately 49 mg / kg, approximately 50 mg / kg, approximately 4 ...0 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg / kg, approximately 40 mg mg / kg, approximately 51 mg / kg, approximately 52 mg / kg, approximately 53 mg / kg, approximately 54 mg / kg, approximately 55 mg / kg, or approximately 60 mg / kg. In some embodiments, the ERK 1 / 2 inhibitor is administered to the subject twice daily, once daily, or every two days. In some embodiments, the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1 / 2 inhibitor is administered twice daily, once daily, or every two days for at least approximately 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or 52 weeks.

[0552] In some embodiments, the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0553]

[0554] In some implementations, the amount of KRAS G12C inhibitor administered to the subject is equivalent to a mouse dose contained in any of the following ranges: about 1 to about 10 mg / kg, about 10 to about 100 mg / kg, about 10 to about 25 mg / kg, about 10 to about 30 mg / kg, about 10 mg / kg to about 50 mg / kg, about 20 to about 25 mg / kg, about 20 to about 50 mg / kg, about 25 to about 50 mg / kg, about 25 to about 55 mg / kg, about 20 to about 25 mg / kg, about 40 to about 50 mg / kg, about 30 mg / kg to about 50 mg / kg, about 20 mg / kg to about 60 mg / kg, about 10 mg / kg to about 25 mg / kg, about 40 mg / kg to about 80 mg / kg, about 5 mg / kg to about 30 mg / kg, about 50 mg / kg to about 100 mg / kg, about 75 mg / kg to about 100 mg / kg, about 80 mg / kg to about 100 mg / kg. mg / kg, 90 mg / kg to about 100 mg / kg, or about 40 mg / kg to about 100 mg / kg.In some implementations, the dose of the KRAS G12C inhibitor used to treat the cancer in the subject is equivalent to, for example, the following mouse doses: about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 ... The recommended doses are approximately 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, or approximately 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, or 100 mg / kg. In some embodiments, the G12C inhibitor is administered to the subject twice daily, once daily, or every two days. In some embodiments, the G12C inhibitor is administered twice daily, once daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the G12C inhibitor is administered twice daily, once daily, or every two days for at least approximately 5, 6, 7, 8, 9, 10, or 52 weeks.

[0555] In some embodiments, the ERK 1 / 2 inhibitor is administered orally. In some embodiments, the KRASG12C inhibitor is administered orally. In some embodiments, one or more inhibitors are administered twice daily, daily, or every two days. In some embodiments, one or more inhibitors are administered twice daily, daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, one or more inhibitors are administered twice daily, daily, or every two days for at least about 5, 6, 7, 8, 9, 10, or 52 weeks. In some embodiments, one or more inhibitors are administered twice daily. In some embodiments, one or more inhibitors are administered twice daily for 28 days. In some embodiments, the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, myeloma, and sarcoma. In some embodiments, the cancer is an advanced, unresectable, and / or metastatic solid tumor. In some embodiments, the cancer is resistant to KRAS G12C inhibitors (e.g., acquired resistance) (e.g., resistance to KRAS inhibitors, such as MRTX849, AMG510, or compound 17). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer has been previously treated with a second KRAS G12C inhibitor. In some embodiments, a secondary KRAS mutation occurs in the cancer tissue following prior KRAS inhibitor treatment. In some embodiments, a KRAS mutation occurs in the cancer tissue at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T mutations following prior KRAS inhibitor treatment. In some embodiments, the cancer tissue exhibits R68M, Y96D, or A59T mutations following prior KRAS inhibitor treatment.In some embodiments, 1) the individual contains a secondary mutation in KRAS, optionally including an R68, Y96, or A59 mutation in KRAS, optionally including an R68M, Y96D, or A59T mutation; 2) the cancer contains a copy number variation in KRAS; 3) relative to a corresponding tissue or organ of a reference individual, a non-cancer tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains upregulated KRAS mRNA levels and / or KRAS protein; 4) the cancer contains a mutation in the KRAS promoter that increases promoter strength; and / or 5) relative to a corresponding tissue or organ of a reference individual, a non-cancer tissue or organ of the same individual, or the same cancer prior to prior treatment, the cancer contains increased wild-type RAS signaling, optionally including increased levels of active GTP-binding wild-type RAS, optionally including H-RAS and / or N-RAS. In some embodiments, the second KRAS inhibitor is sotorasib or adagrasib. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, together, or sequentially. In some embodiments, the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor. In some embodiments, the method further includes administering to the individual an effective amount of a third therapy comprising another anticancer agent, optionally said anticancer agent being selected from immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, debulking agents, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy, and antimetastatic agents.

[0556] In some embodiments, the ERK 1 / 2 inhibitor is used to prepare a medicament for treating cancer, wherein the treatment is used in combination with a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are used to prepare a medicament for treating cancer, wherein the treatment is used in combination with a KRAS G12C inhibitor. The treatment comprises administering (1) the ERK 1 / 2 inhibitor and (2) the KRAS G12C inhibitor in an amount (e.g., a dose) capable of producing the function described herein.

[0557] In some embodiments, the dose of the EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab) administered to the subject is equivalent to a mouse dose, i.e., about 30 mg / kg or at least about 30 mg / kg. In some embodiments, the EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab) is administered intravenously or subcutaneously. In some embodiments, the EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab) is administered at a frequency of twice daily, once daily, or once every two days. In some embodiments, the EGFR inhibitor (e.g., an anti-EGFR antibody, such as cetuximab) is administered at a frequency not exceeding twice daily, once daily, or once every two days.

[0558] In some implementations, treatment according to any method or use disclosed herein results in a reduction of tumor size (e.g., tumor volume) of at least about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 12, about 15, about 18, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 times compared to tumors not treated according to any method or use disclosed herein (e.g., monotherapy or solvent control).

[0559] In some implementations, treatment according to any method or use disclosed herein results in a reduction of tumor growth inhibition of at least about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 33.3%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% compared to tumors not treated according to any method or use disclosed herein. %, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0560] In some implementations, treatment according to any of the methods or uses disclosed herein results in a reduction of tumor weight of at least about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 12, about 14, about 16, about 18, or about 20 times compared to a tumor not treated according to any of the methods or uses disclosed herein.

[0561] In some implementations, treatment according to any of the methods or uses disclosed herein results in a reduction of tumor weight of at least about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, or about 8.5 times compared to a tumor not treated according to any of the methods or uses disclosed herein.

[0562] In some implementations, treatment according to any method or use disclosed herein results in a survival rate that is at least about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, or about 8.5-fold higher than that of subjects (e.g., individuals) who were not treated according to any method or use disclosed herein (e.g., monotherapy or solvent control).

[0563] Kits for treating cancer

[0564] A kit is provided comprising materials that can be used to treat KRAS G12C-mutant cancers, such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma. In some embodiments, the kit includes a container containing an ERK 1 / 2 inhibitor as described herein, and a second container containing a KRAS G12C inhibitor.

[0565] A kit is provided comprising materials that can be used to treat KRAS G12C-mutant cancers, such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma. In some embodiments, the kit includes a container containing an ERK 1 / 2 inhibitor as described herein, and a second container containing a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor comprises an agent containing a pharmaceutically acceptable salt of formula (I) or thereof.

[0566]

[0567] Among them, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a Substitution; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents; n is 0 or 1; m is 1 or 2; ring A is selected from those arbitrarily replaced by 1, 2 or 3 R groups. d Substituted pyrazolyl and tetrahydropyranyl groups; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with one, two or three R substituents; R is selected from F, Cl, Br and I.

[0568] A kit is provided comprising materials for treating KRAS G12C-mutant cancers, such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma. In some embodiments, the kit comprises a container containing an ERK 1 / 2 inhibitor as described herein, and a second container containing a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof:

[0569] .

[0570] A kit is provided comprising materials that can be used to treat KRAS G12C-mutant cancers, such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma. In some embodiments, the kit includes a container containing an ERK 1 / 2 inhibitor described herein, and a second container containing a KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0571]

[0572] Where T1 is selected from O and N; R1 is selected from C. 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a Replacement; when T1 is 0, R2 does not exist; when T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b Replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c Replacement; R4 is selected from H and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d Substitution; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be optionally substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with one, two, or three R groups; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; provided that, when R1 is naphthyl, the naphthyl group may optionally be substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

[0573] A kit is provided comprising materials for treating KRAS G12C-mutant cancers, such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma. In some embodiments, the kit includes a container containing an ERK 1 / 2 inhibitor as described herein, and a second container containing a KRAS G12C inhibitor; and wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof:

[0574] .

[0575] A kit is provided comprising materials that can be used to treat KRAS G12C-mutant cancers, such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma. In some embodiments, the kit includes a container containing an ERK 1 / 2 inhibitor as described herein, and a second container containing a KRAS G12C inhibitor. In some embodiments, the ERK 1 / 2 inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0576] ; and the KRAS G12C inhibitors described herein comprise agents containing the following formula or pharmaceutically acceptable salts thereof:

[0577] .

[0578] In some embodiments, the kit includes a container and a label or packaging instructions on or attached to the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, test tubes, etc. Containers can be formed from a variety of materials, such as glass or plastic. A first container contains a composition (e.g., a composition containing an ERK 1 / 2 inhibitor as described herein), which, alone or in combination with another composition, is effective in treating (e.g., delaying progression) KRAS G12C-mutant cancers (e.g., lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma). The container may have a sterile inlet (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). At least one agent in the composition is an ERK 1 / 2 inhibitor as described herein. In some embodiments, at least one agent in the composition is an ERK 1 / 2 inhibitor described herein. In some embodiments, the label or instruction manual indicates that the composition is used in combination with a KRAS G12C inhibitor for the treatment of KRAS G12C-mutant cancers (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, bile duct cancer, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML), uterine cancer, gastroesophageal cancer, or rectal adenocarcinoma). In some embodiments, the KRAS G12C inhibitor is compound 17.

[0579] In addition, the kit may include (a) a first container containing a composition comprising an ERK 1 / 2 inhibitor as described herein, and (b) a second container containing a composition comprising a KRAS G12C inhibitor (e.g., a peptide, antibody, fusion peptide, antisense oligonucleotide, or small molecule drug capable of inhibiting the activity of a KRAS G12C mutant protein). In some embodiments, the second container contains a small molecule KRAS G12C inhibitor.

[0580] Exemplary small molecule KRAS G12C inhibitors that can be packaged with the kit provided herein include, but are not limited to, sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, RMC-8839, HBI-2438, JNJ-74699157, and compound 17. In some embodiments, the KRAS G12C inhibitor is compound 17. Additionally, the kit may include an extra container containing pharmaceutically acceptable buffers, such as water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may also contain other materials required from a commercial and user perspective, including additional buffers, diluents, filters, needles, and syringes.

[0581] All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0582] Exemplary Implementation

[0583] Implementation Scheme 1. A method for treating an individual with cancer, comprising administering to the individual an effective amount of 1) an ERK 1 / 2 inhibitor; and 2) a KRAS G12C inhibitor, wherein the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0584]

[0585] in,

[0586] R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace;

[0587] R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents;

[0588] n is 0 or 1;

[0589] m is 1 or 2;

[0590] Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R;

[0591] R a and R c Independently selected from D, F, Cl, Br, and I;

[0592] R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one, two or three R substituents;

[0593] R is selected from F, Cl, Br and I.

[0594] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein the ERK 1 / 2 inhibitor is selected from:

[0595] .

[0596] Implementation Scheme 3. The method according to Implementation Scheme 2, wherein the ERK 1 / 2 inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof.

[0597] .

[0598] Implementation Scheme 4. The method according to any one of Implementation Schemes 1-3, wherein the KRAS G12C inhibitor is a small molecule.

[0599] Implementation Scheme 5. The method according to Implementation Scheme 4, wherein the KRAS G12C inhibitor is selected from the group consisting of: sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, LY3537982, RMC-6291, RMC-8839, HBI-2438, and JNJ-74699157.

[0600] Implementation Scheme 6. The method according to Implementation Scheme 5, wherein the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0601]

[0602] in

[0603] T1 is selected from O and N;

[0604] R1 is selected from C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a replace;

[0605] When T1 is 0, R2 does not exist;

[0606] When T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0607] R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0608] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0609] R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms;

[0610] R8 is selected from H and CH3;

[0611] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups;

[0612] R b Each is independently selected from F, Cl, Br, I, OH, and NH2;

[0613] R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups;

[0614] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0615] R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino;

[0616] The condition is that, when R1 is a naphthyl group, the naphthyl group may optionally be replaced by F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

[0617] Implementation Scheme 7. A method of treating an individual with cancer, comprising administering to the individual an effective amount of 1) an ERK 1 / 2 inhibitor; and 2) a KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent containing formula (III) or a pharmaceutically acceptable salt thereof.

[0618]

[0619] in

[0620] T1 is selected from O and N;

[0621] R1 is selected from C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a replace;

[0622] When T1 is 0, R2 does not exist;

[0623] When T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace;

[0624] R3 is C 1-3Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace;

[0625] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace;

[0626] R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms;

[0627] R8 is selected from H and CH3;

[0628] R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups;

[0629] R b Each is independently selected from F, Cl, Br, I, OH, and NH2;

[0630] R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups;

[0631] R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0632] R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino;

[0633] The condition is that, when R1 is a naphthyl group, the naphthyl group is optionally substituted by F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

[0634] Implementation Scheme 8. The method according to Implementation Scheme 7, wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof:

[0635] or .

[0636] Implementation Scheme 9. The method according to Implementation Scheme 8, wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof:

[0637] .

[0638] Implementation Scheme 10. The method according to any one of Implementation Schemes 7-9, wherein the ERK 1 / 2 inhibitor is a small molecule.

[0639] Implementation Scheme 11. The method according to Implementation Scheme 10, wherein the ERK 1 / 2 inhibitor is selected from the group consisting of: BVD-523 (Uritinib), CC-90003, GDC-0994 (Ravoxertinib), KO-947, LTT462, LY3214996 (temuterkib), WX001, SCH772984, FR180204, and MK-8353.

[0640] Implementation Scheme 12. The method according to Implementation Scheme 10, wherein the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof.

[0641]

[0642] in,

[0643] R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace;

[0644] R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents;

[0645] n is 0 or 1;

[0646] m is 1 or 2;

[0647] Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R;

[0648] R a and R c Independently selected from D, F, Cl, Br, and I;

[0649] R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 alkoxy, and C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one, two or three R substituents;

[0650] R is selected from F, Cl, Br and I.

[0651] Implementation Scheme 13. The method according to any one of Implementation Schemes 1-12, wherein the KRAS G12C inhibitor is administered orally.

[0652] Implementation Scheme 14. The method according to any one of Implementation Schemes 1-13, wherein the ERK 1 / 2 inhibitor is administered orally.

[0653] Implementation Scheme 15. The method according to any one of Implementation Schemes 1-14, wherein the cancer comprises one or more cancer cells expressing the KRAS G12C mutant protein.

[0654] Implementation Scheme 16. The method according to any one of Implementation Schemes 1-15, wherein the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cancer, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.

[0655] Implementation Scheme 17. The method according to any one of Implementation Schemes 1-16, wherein the cancer is a solid tumor, optionally wherein the solid tumor is an advanced, unresectable and / or metastatic solid tumor.

[0656] Implementation Scheme 18. The method according to any one of Implementation Schemes 1-17, wherein the cancer is resistant to KRAS G12C inhibitors, optionally wherein the cancer is resistant to KRAS G12C inhibitors (e.g., MRTX849, e.g., AMG510).

[0657] Implementation Scheme 19. The method according to any one of Implementation Schemes 1-18, wherein the cancer has previously been treated with a KRAS G12C inhibitor.

[0658] Implementation Scheme 20. The method according to Implementation Scheme 19, wherein the KRAS12C inhibitor is sotorasib.

[0659] Implementation Scheme 21. The method according to any one of Implementation Schemes 1-20, wherein the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered simultaneously.

[0660] Implementation Scheme 22. The method according to any one of Implementation Schemes 1-21, wherein the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered together.

[0661] Implementation Scheme 23. The method according to any one of Implementation Schemes 1-20, wherein the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered sequentially.

[0662] Implementation Scheme 24. The method according to Implementation Scheme 23, wherein the ERK 1 / 2 inhibitor is administered prior to the KRASG12C inhibitor.

[0663] Implementation Scheme 25. The method according to Implementation Scheme 23, wherein the KRAS G12C inhibitor is administered prior to the ERK1 / 2 inhibitor.

[0664] Implementation Scheme 26. The method according to any one of Implementation Schemes 1-25, wherein the ERK 1 / 2 inhibitor is administered in one or more doses.

[0665] Implementation Scheme 27. The method according to Implementation Scheme 26, wherein the dose is equivalent to a dose of about 10 mg / kg to about 100 mg / kg for mice.

[0666] Implementation Scheme 28. The method according to any one of Implementation Schemes 1-27, wherein the KRAS inhibitor is administered in one or more doses.

[0667] Implementation Scheme 29. The method according to Implementation Scheme 28, wherein the dose is equivalent to a dose of about 10 mg / kg to about 50 mg / kg for mice.

[0668] Implementation Scheme 30. The method according to any one of Implementation Schemes 1-29 further includes administering an effective amount of a third therapy to the individual.

[0669] Implementation Scheme 31. The method according to Implementation Scheme 30, wherein the third therapy comprises another anticancer agent.

[0670] Implementation Scheme 32. The method according to Implementation Scheme 31, wherein the anticancer agent is selected from the group consisting of: immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, depressants, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy and antimetastatic agents, optionally the anticancer agent is an EGFR inhibitor, and further optionally, wherein the EGFR inhibitor is an anti-EGFR antibody (e.g., cetuximab).

[0671] Implementation Scheme 33. The method according to any one of Implementation Schemes 1-32, wherein the individual is a person.

[0672] Implementation Scheme 34. The method according to any one of Implementation Schemes 1-33, wherein the method comprises selecting an individual for treatment based on the presence of one or more cancer cells containing KRAS abnormalities (e.g., KRAS G12C, e.g., KRAS G12D, e.g., KRAS Q61H), optionally wherein the KRAS abnormality includes a) a) a mutant KRAS G12C protein, b) a mutant KRAS G12D protein, and / or c) a mutant KRAS Q61H protein.

[0673] Implementation scheme 35. Use of ERK 1 / 2 inhibitors and KRAS G12C inhibitors in the preparation of medicaments for treating cancer.

[0674] Implementation Scheme 36. According to the use described in Implementation Scheme 35, the cancer is selected from colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cancer, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.

[0675] Implementation Scheme 37. The method according to Implementation Scheme 16 or the use described in Implementation Scheme 36, wherein the cancer is colorectal cancer (e.g., NSCLC).

[0676] Implementation Scheme 38. The method according to Implementation Scheme 16 or the use described in Implementation Scheme 36, wherein the cancer is pancreatic cancer.

[0677] Implementation Scheme 39. The method according to Implementation Scheme 16 or the use described in Implementation Scheme 36, wherein the cancer is lung cancer.

[0678] Implementation Scheme 40. The method or use according to any one of Implementation Schemes 1-39, wherein the dose included in the treatment is equivalent to the dose of an ERK 1 / 2 inhibitor for mice at a dose of 25 to 50 mg / kg.

[0679] Implementation Scheme 41. The method or use according to any one of Implementation Schemes 1-40, wherein the treatment comprises a dose equivalent to 10 to 100 mg / kg of a KRAS G12C inhibitor.

[0680] Implementation Scheme 42. A kit for treating individual cancers, comprising: 1) an ERK 1 / 2 inhibitor; and 2) a KRAS G12C inhibitor.

[0681] Example

[0682] The following embodiments are provided to provide a complete disclosure and description of how the invention can be made and used to those skilled in the art, and are not intended to limit the scope of the invention as the inventors believe, nor are they intended to represent all or only the experiments conducted. Every effort has been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account. Unless otherwise stated, parts are parts by weight, molecular weights are weight-average molecular weights, temperatures are in degrees Celsius, and pressures are at atmospheres or near atmospheres.

[0683] Example 1. Evaluation of the antitumor efficacy of ERK 1 / 2 inhibitors combined with KRAS G12C inhibitors in the NCI-H2122 human lung cancer xenograft mouse model.

[0684] The aim was to evaluate the in vivo antitumor efficacy of WX001 (i.e., WX001; an ERK 1 / 2 inhibitor) in combination with compound 17 (a KRAS G12C inhibitor) in subcutaneous NCI-H2122 human lung cancer xenografts implanted in female BALB / c nude mice.

[0685] Unlike other ERK 1 / 2 inhibitors (such as Erasca's ERAS-007m, which requires a complex BID-QW dosing regimen), WX001 is administered using a simple continuous QD regimen without the dosing holidays described below, thus providing a convenient and simple option for patients.

[0686] (Compound 17)

[0687] (WX001)

[0688] While several potent ERK inhibitors (such as AZD0364, ERAS007, and MK-8353) have relatively long target protein residence times (ranging from 190 to 550 minutes), WX001 has an ERK protein residence time of approximately 40 minutes. The inventors have uniquely observed that WX001's moderate protein residence time is more advantageous because it is long enough to allow for adequate target blockade while being short enough to allow for pulsed inhibition, which helps mitigate target toxicity in normal tissues. The clinical pharmacokinetic (PK) of WX001 is approximately 3–6 hours, further supporting its intermittent target-inhibiting properties when administered once daily, twice daily, or every two days.

[0689] Materials and methods:

[0690] NCI-H2122 tumor cells (ATCC, cat# CRL-5985) were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% PS at an incubator temperature of 37°C. o C, CO2 5%. Tumor cells were routinely passaged twice a week. Cells in the exponential growth phase were harvested, counted, and used for tumor inoculation.

[0691] Female BALB / c nude mice were subcutaneously inoculated on the right side with NCI-H2122 tumor cells (5 × 10⁻⁶). 6 The tumor was treated with 0.2 mL PBS + Matrigel (1:1) to promote tumor growth. Treatment began on day 6 post-inoculation, at which time the average tumor volume reached 159 mm. 3 Animals were stratified and randomly assigned to multiple groups based on tumor volume using Excel-based randomization software. Each group consisted of 6 tumor-bearing mice. The test sample was prepared and administered to the mice according to the predetermined administration protocol shown in the experimental design table (Table E1).

[0692] Table E1: Experimental Design and Dosage of the NCI-H2122 Xenograft Model

[0693]

[0694] QD: Once a day, BID: Twice a day.

[0695] The tumor volume was measured twice a week using calipers in two dimensions, and the volume was expressed in mm using the following formula. 3 This means: V = 0.5 axb 2 , where a and b are the long and short diameters of the tumor, respectively. The T / C (%) value for each group is calculated using the following formula: T / C % = T / C × 100 % (T: treatment group; C: control group, where T and C are the average tumor weights of the treatment group and control group on a given day, respectively).

[0696] The tumor growth inhibition rate (TGI) for each group was calculated using the following formula: TGI (%) = [1 - (T i - T0) / (V i - V0)] × 100;T i T0 represents the average tumor volume of the treatment group on a specific day, and V represents the average tumor volume of the treatment group on the first day of treatment. i To be with T i The average tumor volume of the solvent group on the same day, V0 is the average tumor volume of the solvent group on the first day of treatment.

[0697] Statistical analysis was performed on the differences in tumor volume and tumor weight between groups based on data obtained on day 28 after the start of treatment.

[0698] One-way ANOVA was used to compare tumor volumes among the groups, followed by Dunnet multiple comparisons. All data were analyzed using Graphpad Prism software. p < 0.05 was considered statistically significant.

[0699] Animal weight was monitored regularly as an indirect measure of toxicity. Historical data showed that mice carrying the NCI-H2122 xenograft typically lost more than 15% of their body weight as the tumor progressed; therefore, all mice were fed nutritional gels and sunflower seeds.

[0700] result:

[0701] NCI-H2122 is a non-small cell lung cancer (NSCLC) cell line carrying a KRAS G12C mutation. Previous studies (Cancer Discov. 2020 Jan;10(1):54-71) have shown that the NCI-H2122 model represents a cancer phenotype that is partially sensitive to KRAS G12C inhibitors (e.g., MRTX849). In this study, the antitumor effect of WX001 in combination with compound 17 was evaluated in an NCI-H2122 cell line-derived xenograft model. Two clinical-stage KRAS G12C inhibitors, AMG510 and MRTX849, were included in the monotherapy control group. The efficacy of two different dose levels of WX001 monotherapy was also evaluated.

[0702] On average, the treatment was well tolerated, as indicated by the average percentage of weight loss. Figure 1 Notably, mice treated with the combination of compound 17 and WX001 did not experience a greater weight loss than the solvent control group. Figure 1 ).

[0703] Table E3: Tumor volume changes over time

[0704]

[0705]

[0706] Note:

[0707] 1. Data is presented as mean ± SEM;

[0708] 2. Number of days refers to the number of days after the start of treatment.

[0709] Table E4: Tumor growth inhibition analysis for each treatment in the NCI-H2122 xenograft model, calculated based on tumor volume measurements on day 28.

[0710]

[0711] Note:

[0712] 1. Mean ± SEM;

[0713] 2. The formula for calculating T / C is: T / C % = T / C × 100 % (T: treatment group; C: control group, where T and C are the average tumor weight of the treatment group and control group on a certain day, respectively).

[0714] 3. TGI (%) = [1-(T 28 -T0) / (V 28 -V0)] ×100%;

[0715] 4. The p-value is calculated based on the tumor volume (TV).

[0716] Table E5: Statistical analysis of differences between monotherapy with compound 17 and combination therapy with compound 17 and WX001

[0717]

[0718] Note:

[0719] Calculated based on tumor volume measurements on day 28.

[0720] Table E6: Average weight of isolated tumors in each group on day 28

[0721]

[0722] Note:

[0723] 1. Mean ± SEM;

[0724] 2. T / C % = T / C × 100 % (T: treatment group; C: control group, T and C are the average tumor weight of the treatment group and control group on a certain day, respectively);

[0725] 3. The p-value is calculated based on tumor weight.

[0726] In this study, the therapeutic effects of compound 17 and WX001 as monotherapy and in combination were evaluated in the NCI-H2122 human lung cancer subcutaneous xenograft model. Tumor volume at different time points after tumor inoculation in different groups is shown in Tables E3 and E4. Figure 2 , Figure 3 As shown, the tumor weight results are presented in Table E5 and... Figure 4 As shown.

[0727] On day 28 after administration, the mean tumor volume in the solvent control group reached 2,359 mm. 3 Treatment with the reference compound MRTX849 at 100 mg / kg (QD) and AMG510 at 100 mg / kg (QD) produced significant antitumor activity, with mean tumor volumes of 556 mm. 3 (T / C = 23.56%, TGI =81.97%, p<0.001) and 615 mm 3(T / C = 26.09%, TGI = 79.25%, p < 0.001). While tumor regression was frequently observed with AMG510 and MRTX849 at this dose level (100 mg / kg) in other KRAS G12C models, only significant tumor growth inhibition was observed in the NCI-H2122 model, with no effect on tumor regression. These data are consistent with published results (Cancer Discov. 2020 Jan;10(1):54-71), indicating partial resistance to KRAS G12C inhibitors in NCI-H2122.

[0728] Consistently, treatment with compound 17 (a potent and selective KRAS G12C inhibitor currently in clinical trials, NCT05410145) only resulted in tumor growth inhibition. No tumor regression was observed at either 30 mg / kg (QD) or 100 mg / kg (QD) doses. Compared to the solvent control group, treatment with compound 17 at doses of 30 mg / kg (QD) and 100 mg / kg (QD) produced antitumor activity with mean tumor volumes of 527 mm. 3 (T / C = 22.36%, TGI =83.25%, p<0.001), 548 mm 3 (T / C = 23.23%, TGI = 82.31%, p < 0.001). There was no difference between the group treated with compound 17 at 30 mg / kg and the group treated with compound 17 at 100 mg / kg, indicating that in this partial resistance model, the tumor-suppressive effect of compound 17 as monotherapy does not increase further with increasing dose.

[0729] Compared with the solvent control group, the ERK 1 / 2 inhibitor WX001, administered as monotherapy at doses of 25 mg / kg (BID), 25 mg / kg (QD), and 50 mg / kg (QD), all demonstrated significant antitumor activity, with mean tumor volumes of 778 mm. 3 (T / C =33.00%, TGI =71.84%, p<0.001), 1182 mm 3 (T / C = 50.13%, TGI =53.47%, p<0.001) and 777 mm 3 (T / C = 32.94%, TGI = 71.91%, p < 0.001). These data indicate that WX001 has moderate antitumor activity in the NCI-H2122 xenograft model.

[0730] When compound 17 was combined with WX001 at 30 mg / kg QD, 25 mg / kg (QD), or 50 mg / kg (QD), its antitumor activity was stronger than that of the corresponding doses of the single drug, with an average tumor volume of 262 mm. 3 (T / C= 11.11%, TGI =95.31%), 420 mm 3 (T / C = 17.81%, TGI = 88.14%) and 184 mm 3 (T / C = 7.79%, TGI = 98.88%). Compared with monotherapy with compound 17 at 30 mg / kg, the combination of compound 17 at 30 mg / kg QD and WX001 at 50 mg / kg QD significantly enhanced the antitumor effect (p = 0.0339). These results indicate that the combination of WX001 with a KRAS G12C inhibitor (such as compound 17) can almost completely inhibit tumor growth in KRAS G12C mutant tumor models that are partially resistant to KRAS G12C inhibitors.

[0731] Animal body weight was monitored regularly as an indirect measure of toxicity. Historical data showed that mice carrying NCI-H2122 xenografts typically experienced weight loss of more than 15% as the tumor progressed; therefore, all mice were fed nutritional gels and sunflower seeds. In the solvent group, 2, 1, and 2 mice, respectively, experienced weight loss >15% at PG-D14, PG-D21, and PG-D28. One mouse in group 5 (compound 17, 100 mg / kg, QD), one mouse in group 6 (WX001, 25 mg / kg, BID), and one mouse in group 9 (compound 17 + WX001, 30 mg / kg + 25 mg / kg, QD + BID) experienced weight loss >15% at PG-D11. Three mice in group 6 (WX001, 25 mg / kg, BID), three mice in group 7 (WX001, 25 mg / kg, QD), one mouse in group 8 (WX001, 50 mg / kg, QD), and two mice in group 9 (compound 17 + WX001, 30 mg / kg + 25 mg / kg, QD + BID) experienced a weight loss of >15% at PG-D18. The overall weight changes in all treatment groups were similar to those in the solvent control group, indicating good treatment tolerability in this study.

[0732] Example 2: Evaluation of the antitumor efficacy of ERK 1 / 2 inhibitors combined with KRAS G12C inhibitors in SW-837 human colorectal cancer xenograft mouse model.

[0733] The aim of this study was to evaluate, in preclinical, the in vivo efficacy of WX001 in combination with compound 17, a KRAS G12C inhibitor currently in clinical development, for the treatment of the human colorectal cancer xenograft model SW-837 (a cell line-derived xenograft model carrying a KRAS G12C mutation). The antitumor efficacy of compound 17 or WX001 as monotherapy in this model was also evaluated and compared with combination therapy.

[0734] Materials and methods:

[0735] The group design is shown in Table E7, and the dosage form and dosage are also shown in Table E7. The application volume is adjusted according to body weight (application amount = 5 μL / g).

[0736] Table E7: Study Design of the SW-837 Xenograft Model

[0737]

[0738] SW-837 tumor cells were cultured in vitro at 37ºC in air containing 5% CO2 in L-15 (100% air) medium supplemented with 10% fetal bovine serum. Cells in the exponential growth phase were harvested and quantified using a cell counter before inoculation into tumor cells. Each mouse was subcutaneously inoculated with 5 × 10⁻⁶ SW-837 tumor cells in the right lower quadrant. 6 A mixture of 0.1 ml PBS and Matrigel (1:1) was administered to each mouse cell to promote tumor growth.

[0739] When the average tumor size reaches approximately 144 mm 3 At that time, randomization began. A total of 48 mice were included in this study. All animals were randomly assigned to 6 study groups, with 8 mice in each group. Randomization was based on the "matched distribution" method (StudyDirector). TM Software, version 3.1.399.19). Dosing was administered immediately after randomization on day 0. Treatment began on the day of randomization (day 0), according to the study design (Table E7).

[0740] When the average tumor volume reaches approximately 144 mm 3 Treatment began on [date]. After randomization, the trial lasted 41 days (day 0 to day 40), including efficacy studies from day 0 to day 39. Plasma samples were taken on day 40 after the last administration. Tumor growth inhibition (TGI) was calculated from day 39, the end of the efficacy study.

[0741] Weight was measured twice a week. After randomization, tumor volume was also measured twice a week in two dimensions using calipers, with the volume expressed in mm. 3The formula is: "V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (longest tumor size), and W is the tumor width (longest tumor size perpendicular to L). Drug administration and tumor and weight measurements were performed in a laminar flow hood. StudyDirector was used." TM The software (version 3.1.399.19) measured body weight and tumor volume. The body weight of all animals was monitored throughout the study, and animals were euthanized if their body weight decreased by more than 20% relative to their weight on day one of treatment. Tumors exceeding 3000 mm in mice were also euthanized. 3 In this case, euthanasia is performed on a single mouse.

[0742] Randomization begins on day 0, and the study termination date is determined by the sponsor or until a single mouse's tumor size exceeds 3000 mm. 3 When the tumor volume of a single mouse reaches the humane endpoint and the sponsor requests, the study will terminate on the date specified after randomization. Treatment will last for 41 days from the start of grouping (day 0 to day 40), and mice will be sacrificed on day 41.

[0743] To compare tumor volumes across different groups on predetermined dates, the Bartlett test was first used to check the hypothesis of homogeneity of variance among all groups. When the p-value of the Bartlett test was ≥ 0.05, a one-way ANOVA was performed to test the overall equality of means among all groups. If the p-value of the one-way ANOVA was < 0.05, further post-hoc tests were performed by running the Tukey HSD (honest significance test) for all pairwise comparisons and by running the Dunnett test to compare each treatment group with the solvent group. When the p-value of the Bartlett test was < 0.05, the Kruskal-Wallis test was performed to test the overall equality of medians among all groups. If the p-value of the Kruskal-Wallis test was < 0.05, further post-hoc tests were performed by running the Conover nonparametric test for all pairwise comparisons or for comparing each treatment group with the solvent group, all with one-step p-adjustment.

[0744] In addition, pairwise comparisons without multiple comparison correction were performed, and the nominal / uncorrected p-values ​​were reported directly from the Welch t test or the Mann-Whitney U test. Specifically, the Bartlett test was first used to test the hypothesis of homogeneity of variance between the two groups. When the p-value of the Bartlett test was ≥0.05, the Welch t test or the Mann-Whitney U test was performed to obtain the nominal p-value.

[0745] All statistical analyses were performed using Ra language and the Statistical Computing and Graphics Environment (version 3.3.1). Unless otherwise stated, all tests were two-tailed, and a p-value < 0.05 was considered statistically significant.

[0746] result:

[0747] In this study, the in vivo efficacy of investigational compound 17 (a KRAS G12C inhibitor) and WX001 (an ERK 1 / 2 inhibitor) as monotherapy or in combination therapy in the treatment of SW-837, a subcutaneous human colorectal cancer xenograft model carrying the KRAS G12C mutation, was evaluated.

[0748] During administration, only a small number of animals in the compound treatment group showed minimal to moderate treatment-related weight loss. Figure 5 Mice in the treatment group were not given a dosing holiday due to weight loss exceeding 15%. No animal deaths were observed throughout the dosing period. No mice developed tumors exceeding 3000 mm² before the study was terminated. 3 They were then euthanized. The tumor-bearing mice in this study generally tolerated the test drug.

[0749] Bartlett's test was used to determine homogeneity of variance and normality, and nonparametric tests were used to compare differences between groups. P < 0.05 was considered statistically significant. Compound 17, administered as a single agent at 10 mg / kg, produced statistically significant antitumor efficacy in the subcutaneous xenograft model SW-837, with a TGI of 100.92% (p < 0.001 compared to the solvent control). Treatment with WX001 at 25 mg / kg and 50 mg / kg as single agents produced antitumor efficacy, with TGI values ​​of 29.43% and 53.64%, respectively (p < 0.05 compared to the solvent control) (Table E9). Figure 6A ).

[0750] Table E9: Antitumor activity of tested compounds in the SW-837 model

[0751]

[0752] Combination therapy of 25 mg / kg or 50 mg / kg WX001 with 10 mg / kg compound 17 showed stronger antitumor efficacy than compound 17 alone (p<0.001 compared with compound 17 monotherapy), with TGI values ​​of 104.58% and 105.11%, respectively (Table E9). Figure 6AIn the analysis of mean tumor volume change relative to baseline, the combination of 25 mg / kg or 50 mg / kg WX001 with 10 mg / kg compound 17 showed a significantly deeper antitumor response, with tumor regression of -77.45% and -86.64% relative to baseline, respectively, while the use of 10 mg / kg compound 17 alone resulted in a tumor regression of -15.02% relative to baseline.

[0753] Overall, these data suggest that the ERK 1 / 2 inhibitor WX001 can significantly enhance the antitumor effect of the KRAS G12C inhibitor compound 17 in a SW837 colorectal cancer xenograft model with KRAS G12C mutation.

[0754] Throughout the experiment, the animals exhibited minimal treatment-related weight loss. See also Figure 5 In this study, test compound 17 and WX001, as single agents or in combination, were well tolerated in tumor-bearing mice.

[0755] Furthermore, the addition of WX001 to the compound 17 and cetuximab dual therapy resulted in a curative antitumor effect in the SW837 colorectal cancer model. Specifically, mice were treated with a suboptimal dose of compound 17 (3 mg / kg), a combination of WX001 (25 mg / kg BID) and compound 17 (3 mg / kg), a combination of cetuximab and compound 17 (3 mg / kg), or a triple therapy. In this study, the dual therapy of WX001 (25 mg / kg BID) + compound 17 (3 mg / kg) significantly prolonged the antitumor effect, indicating a synergistic effect between compound 17 and WX001. In addition, the triple therapy of cetuximab + compound 17, or cetuximab + compound 17 + WX001, both improved event-free survival. Surprisingly, the triple therapy of cetuximab + compound 17 (30 mg / kg) + WX001 (25 mg / kg BID) achieved 100% complete tumor remission, with no tumor recurrence even 30 days after treatment cessation, demonstrating the durable anti-tumor efficacy of the triple therapy. See also Figure 6C -6D.

[0756] Example 3: Evaluation of the antitumor efficacy of ERK 1 / 2 inhibitors combined with KRAS G12C inhibitors in a CR9537 HuPrime® colorectal cancer xenograft mouse model.

[0757] The aim of this study was to evaluate the in vivo efficacy of test compound 17, WX001, and reference compound MRTX849 (adagrasib) as monotherapy and / or in combination with cetuximab in the HuPrime® xenograft model CR9537 derived from colorectal cancer patients.

[0758] Patient-derived xenograft (PDX) models are established from patient tumor tissue. PDX models preserve the original histopathological features and genetic background of the patient's tumor and can be passaged in immunodeficient mice. For these reasons, PDX models are widely used in discovery and translational research, serving as a valuable tool for evaluating the preclinical efficacy of new therapies and providing translational insights into treatment sensitivity.

[0759] Materials and methods:

[0760] The CR9537 PDX model (Crown Biosciences) was established from a biopsy sample of a patient with colorectal cancer exhibiting a KRAS G12C mutation. This patient's disease progressed after first- and second-line chemotherapy, and subsequently participated in a clinical trial of MRTX849. The patient eventually developed resistance to MRTX849 treatment. Genetic analysis of the patient's tumor biopsy revealed an acquired KRAS Q61H mutation, indicating that the resistance mechanism was due to a secondary KRAS mutation. This represents a patient population with limited treatment options and a high level of unmet medical needs. To discover new treatment strategies for this patient population, a patient-led xenograft (PDX) model was established by dissecting tumor biopsy tissue into small tumor fragments with a diameter of 2-3 mm and subcutaneously implanting them into BALB / c nude immunodeficient mice. Tumors that successfully grew in vivo were further passaged and cryopreserved. NGS analysis of this model confirmed both KRAS G12C and KRAS Q61H mutations.

[0761] The table below summarizes the study design, including mouse groups, number of mice in each group, and treatment regimens. Tumor growth was monitored over time after treatment.

[0762] Table E10: Experimental Design and Dosage of the CR9537 Patient-Derived Xenograft (PDX) Model

[0763]

[0764] A total of 66 mice were included in the study. All animals were randomly assigned to 11 study groups, with 6 mice in each group. Randomization was based on the "matched distribution" method (StudyDirector). TMSoftware, version 3.1.399.19). Randomization was performed on day 0. Treatment (Table E10) began on the same day as randomization (day 0). Treatment was initiated when the mean tumor volume reached approximately 145 mm. 3 Treatment began at that time. Tumor growth inhibition (TGI) calculations were based on the first mouse in the solvent group whose tumor volume exceeded 3000 mm². 3 The date on which euthanasia must be performed is a predefined humane endpoint. Treatment lasted for 64 days from the start of grouping (from day 0 to day 63), and the remaining mice were sacrificed on day 63.

[0765] After randomization, the two-dimensional tumor volume was measured twice a week using calipers, and the volume was expressed in mm. 3 The formula is: "V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (longest tumor size), and W is the tumor width (longest tumor size perpendicular to L). Administration and tumor and weight measurements were performed in a laminar flow hood. Weight and tumor volume were measured using StudyDirector." TM The software (version 3.1.399.19) is used for measurement.

[0766] To compare tumor volumes in different groups on the scheduled date, the Bartlett test was first used to check the hypothesis of homogeneity of variance among all groups.

[0767] When the p-value of Bartlett's test is ≥ 0.05, a one-way ANOVA is performed to test the overall equality of means among all groups. If the p-value of the one-way ANOVA is < 0.05, further post-hoc tests are performed by running the Tukey HSD (honest significance test) for all pairwise comparisons and by running the Dunnett test to compare each treatment group with the solvent group. When the p-value of Bartlett's test is < 0.05, the Kruskal-Wallis test is performed to test the overall equality of medians among all groups. If the p-value of the Kruskal-Wallis test is < 0.05, further post-hoc tests are performed by running the Conover nonparametric test for all pairwise comparisons or for comparing each treatment group with the solvent group, all with one-step p-adjustment.

[0768] For TGI calculations, day 32 was considered the endpoint because, in tumor measurements on day 32, there was one tumor in each of the solvent control group and the cetuximab treatment group with a volume exceeding 3000 mm. 3 This is the predetermined humanitarian endpoint. Tumor volume growth curves from day 0 to day 63 were plotted using Prism GraphPad software, as shown... Figure 7 As shown.

[0769] In addition, pairwise comparisons without multiple comparison correction were performed, and the nominal / uncorrected p-values ​​were reported directly from the Welch t test or the Mann-Whitney U test. Specifically, the Bartlett test was first used to test the hypothesis of homogeneity of variance between the two groups. When the p-value of the Bartlett test was ≥ 0.05, the Welch t test or the Mann-Whitney U test was performed to obtain the nominal p-value.

[0770] All statistical analyses were performed using Ra language and the Statistical Computing and Graphics Environment (version 3.3.1). Unless otherwise stated, all tests were two-tailed, and a p-value < 0.05 was considered statistically significant.

[0771] result:

[0772] This study evaluated the in vivo efficacy of test compound 17 (a KRAS G12C inhibitor from D3 Bio), WX001 (an ERK 1 / 2 inhibitor from D3 Bio), and reference compound MRTX849 (a KRAS G12C inhibitor currently in clinical trials for the treatment of KRAS G12C-mutant colorectal cancer) as monotherapy and / or in combination with cetuximab in the CR9537 colorectal cancer PDX model.

[0773] Reference compound MRTX849 at a dose of 50 mg / kg and test compound 17 at a dose of 50 mg / kg, as single agents, produced statistically significant antitumor efficacy in the subcutaneous xenograft model CR9537, with TGI values ​​of 56.94% and 67.29%, respectively (P<0.05 compared with the solvent control) (Table E12). Figure 7 WX001 at a dose of 50 mg / kg and cetuximab at a dose of 30 mg / kg as monotherapy did not produce significant antitumor efficacy, with TGI values ​​of 51.28% and 17.11%, respectively (P>0.05, relative to solvent control).

[0774] Table E12: Antitumor activity of tested compounds in the CR9537 model

[0775]

[0776]

[0777] In the combination therapy group, WX001, in combination with a) MRTX849 and b) compound 17, produced statistically significant antitumor effects in the subcutaneous xenograft model CR9537, with TGI values ​​of 86.56% and 74.19%, respectively (P<0.001, relative to the solvent control) (Table E12). Figure 7 This study showed consistently better efficacy than a) cetuximab and MRTX849 (TGI value of 70.26%) and b) cetuximab in combination with compound 17 (TGI value of 72.82%). Specifically, the TGI achieved by the combination of MRTX849 and compound 17 was 23% higher than that achieved by the combination of MRTX849 and cetuximab.

[0778] These results indicate that in patients with acquired secondary KRAS mutations (e.g., KRAS Q61H), the combination of an ERK 1 / 2 inhibitor (e.g., WX001) with a KRAS G12C inhibitor (MRTX849 or compound 17) is more effective than the combination of cetuximab with a KRAS G12C inhibitor. These data provide previously unknown evidence supporting clinical studies of the combination of WX001 and a KRAS G12C inhibitor in patients who previously received KRAS G12C inhibitor therapy and have developed resistance to KRAS G12C inhibitors due to acquired secondary KRAS mutations. Other acquired secondary KRAS mutations may also yield similar beneficial effects.

[0779] Animals exhibited mild to moderate weight loss during treatment. Figure 8 In this study, test compounds 17 and WX001 were well tolerated in mice with tumors.

[0780] Example 4: Evaluation of the antitumor efficacy of ERK 1 / 2 inhibitors combined with KRAS G12C inhibitors in an AMG510-resistant Mia PaCa-2 human pancreatic cancer xenograft mouse model.

[0781] The aim of this study was to evaluate the in vivo antitumor effects of MRTX849, compound 17, and WX001 in a subcutaneous AMG510-R-xMia PaCa-2 clone #2 xenograft model in female BALB / c nude mice. AMG510-R-xMIA PaCa-2 clone #2 is a monoclonal cell line selected from the AMG510-R-xMiaPaCa-2 (CP2) cell population. This cell line originated from AMG510-R-MIA PaCa-2 (CP2) resistant tumors induced by continuous AMG-510 administration in a MIA PaCa-2 human pancreatic cancer xenograft model. KRAS gene amplification was identified in AMG510-R-xMIA PaCa-2 clone #2 by RNA-seq and WES analysis.

[0782] Materials and methods:

[0783] AMG510-R-xMia PaCa-2 (CP2) clone #2 tumor cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum, 1% antibiotic antifungal agent, and 1 µM AMG510 at an incubator temperature of 37°C. o C, with an atmospheric CO2 concentration of 5%. Tumor cells were routinely passaged twice a week using trypsin-EDTA treatment. Cells in the exponential growth phase were harvested, counted, and used for tumor inoculation.

[0784] Female BALB / c nude mice were subcutaneously inoculated on the right side with tumor cells containing AMG510-R-xMia PaCa-2 (CP2) clone #2 (1 x 10⁻⁶ cells). 6 0.2 mL of PBS and Matrigel were administered to promote tumor growth. When the average tumor size reached approximately 128 mm... 3 Treatment began at the designated time. Animals were randomly assigned to eight groups using Excel-based randomization software, stratified according to tumor volume. Each group consisted of eight tumor-bearing mice. The test product was administered to mice according to the predetermined protocol shown in Table E13. The dosage was adjusted according to body weight (10 µL / g).

[0785] Table E13: Experimental Design and Dosage of AMG510-R-xMIA PaCa-2 Xenograft Model

[0786]

[0787] The primary endpoint was to observe whether tumor growth could be slowed or whether the mice could be cured. The two-dimensional dimensions of the tumor were measured twice weekly using calipers and expressed in mm using a formula. 3 Volume: V = 0.5 axb2 Where a and b are the long and short diameters of the tumor, respectively. Then, the tumor size is used to calculate the T / C and TGI values. The T / C value is then calculated using the tumor size. T / C (%) = T RTV / C RTV x 100%; T RTV It is the average relative tumor volume in the treatment group, C RTV This is the average relative tumor volume of the control group. The formula for calculating RTV is RTV = V0 n / V0, V0 is the tumor volume on the day treatment begins, V n This refers to the tumor volume on a specific day. For calculating the T / C (%), the T value from the same day should be used. RTV and C RTV .

[0788] The formula for calculating TGI for each group is: TGI (%) = [1-(T i -T0) / (V i -V0)] ×100;T i V represents the average tumor volume of the treatment group on a certain day, T0 represents the average tumor volume of the treatment group on day 1 of treatment, and V i To be with T i The average tumor volume of the solvent control group on the same day, V0 is the average tumor volume of the solvent group on day 1 of treatment.

[0789] Another endpoint of the study was animal survival. Animals whose condition deteriorated and were dying (weight loss >20%), as well as those unable to consume sufficient food or water, were euthanized. In addition to euthanasia and death, survival time was de...

Claims

1. A method of treating an individual with cancer, comprising administering to the individual an effective amount of 1) an ERK 1 / 2 inhibitor; and 2) a KRASG12C inhibitor, wherein the ERK 1 / 2 inhibitor comprises an agent containing formula (I) or a pharmaceutically acceptable salt thereof. in, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents; n is 0 or 1; m is 1 or 2; Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one, two or three R substituents; R is selected from F, Cl, Br and I.

2. The method according to claim 1, wherein, The ERK 1 / 2 inhibitors are selected from: 。 3. The method according to claim 2, wherein, The ERK 1 / 2 inhibitors include agents containing the following formula or pharmaceutically acceptable salts thereof. 。 4. The method according to any one of claims 1-3, wherein, The KRAS G12C inhibitor is a small molecule.

5. The method according to claim 4, wherein, The KRAS G12C inhibitors are selected from the group consisting of: sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, LY3537982, RMC-6291, RMC-8839, HBI-2438, and JNJ-74699157.

6. The method according to claim 4, wherein, The KRAS G12C inhibitors include agents containing formula (III) or a pharmaceutically acceptable salt thereof. in T1 is selected from O and N; R1 is selected from C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a replace; When T1 is 0, R2 does not exist; When T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace; R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups; R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; The condition is that, when R1 is a naphthyl group, the naphthyl group is optionally substituted by F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

7. A method of treating an individual with cancer, comprising administering to said individual an effective amount of 1) an ERK 1 / 2 inhibitor; and 2) a KRASG12C inhibitor, wherein, The KRAS G12C inhibitors include agents containing formula (III) or a pharmaceutically acceptable salt thereof. in T1 is selected from O and N; R1 is selected from C 6-10 aryl and 5 to 10-membered heteroaryl, wherein the C 6-10 Aryl groups and 5 to 10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. a replace; When T1 is 0, R2 does not exist; When T1 is N, R2 is selected from H and C. 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl, wherein the C 1-3 Alkyl group, —C(═O)—C 1-3 Alkyl groups and —S(═O)2—C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. b replace; R3 is C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. c replace; R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. d replace; R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one, two, or three F atoms; R8 is selected from H and CH3; R a Each is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 alkenyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group and C 2-3 The alkenyl group may be substituted by one, two, or three F groups; R b Each is independently selected from F, Cl, Br, I, OH, and NH2; R c Each is independently selected from 4- to 8-membered heterocyclic alkyl groups, wherein the 4- to 8-membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups; R d Each is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O—C(═O)—C 1-3 Alkylamino; The condition is that, when R1 is a naphthyl group, the naphthyl group is optionally substituted by F, Cl, Br, OH, NH2, CF3, CH2CH3 and —C≡CH, and R5, R6 and R7 are each independently H.

8. The method of claim 7, wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof: or .

9. The method of claim 8, wherein the KRAS G12C inhibitor comprises an agent containing the following formula or a pharmaceutically acceptable salt thereof: 。 10. The method according to any one of claims 7-9, wherein the ERK 1 / 2 inhibitor is a small molecule.

11. The method of claim 10, wherein the ERK 1 / 2 inhibitor is selected from the group consisting of: BVD-523 (Uritinib), CC-90003, GDC-0994 (Ravoxertinib), KO-947, LTT462, LY3214996 (temuterkib), WX001, SCH772984, FR180204, and MK-8353.

12. The method according to claim 10, wherein, The ERK 1 / 2 inhibitors include agents containing formula (I) or a pharmaceutically acceptable salt thereof. in, R1 and R2 are independently selected from H and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by one, two, or three R's. a replace; R4, R5, R6, and R7 are independently selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, and the C 1-3 Alkyl groups are optionally surrounded by 1, 2 or 3 Rs c Substituents; n is 0 or 1; m is 1 or 2; Ring A is selected from pyrazolyl and tetrahydropyranyl, wherein the pyrazolyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 R; R a and R c Independently selected from D, F, Cl, Br, and I; R d Selected from F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one, two or three R substituents; R is selected from F, Cl, Br and I.

13. The method according to any one of claims 1-12, wherein the KRAS G12C inhibitor is administered orally.

14. The method according to any one of claims 1-13, wherein the ERK 1 / 2 inhibitor is administered orally.

15. The method according to any one of claims 1-14, wherein the cancer comprises one or more cancer cells expressing the KRASG12C mutant protein.

16. The method according to any one of claims 1-15, wherein the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cancer, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma; optionally, wherein the cancer is selected from the group consisting of colon cancer, lung cancer, and pancreatic cancer.

17. The method according to any one of claims 1-16, wherein the cancer is a solid tumor, optionally wherein the solid tumor is an advanced, unresectable, and / or metastatic solid tumor.

18. The method according to any one of claims 1-17, wherein the cancer was previously treated with a prior KRAS G12C inhibitor, optionally wherein the cancer was previously treated with two different prior KRAS G12C inhibitors.

19. The method according to any one of claims 1-18, wherein the cancer is resistant to or has acquired resistance to a prior KRAS G12C inhibitor, optionally wherein the cancer is resistant to or has acquired resistance to a prior KRAS G12C inhibitor (e.g., MRTX849, e.g., AMG510).

20. The method of claim 19, wherein the cancer is resistant to or has acquired resistance to two different prior KRAS G12C inhibitors.

21. The method of claim 19 or claim 20, wherein the individual has acquired a secondary KRAS mutation, optionally, wherein the individual has acquired a secondary KRAS mutation at codons 13, 18, 59, 61, 68, 95, 96, 117, or 146 after prior KRAS inhibitor treatment, further optionally, wherein the individual has acquired a secondary mutation of G13C / D, A18D, Q61H / L, A59T, R68S / M, H95D / Q / R, Y96C / D, K117N, and / or A146T after prior KRAS inhibitor treatment, further optionally, wherein the secondary mutation includes Q61H.

22. The method according to any one of claims 19-21, wherein, Compared to the cancer prior to the previous treatment with KRAS G12C inhibition, the copy number of mutant KRAS in the cancer was increased.

23. The method according to any one of claims 19-22, wherein the individual develops resistance to a KRAS inhibitor, the resistance being independent of the MAPK pathway.

24. The method according to any one of claims 1-17, wherein the cancer has not been previously treated with a prior KRAS G12C inhibitor.

25. The method according to any one of claims 18-24, wherein the prior KRAS G12C inhibitor is or includes sotorasib or adagrasib.

26. The method according to any one of claims 1-25, wherein the ERK 1 / 2 inhibitor and the KRASG12C inhibitor are administered simultaneously or together.

27. The method according to any one of claims 1-25, wherein the ERK 1 / 2 inhibitor and the KRAS G12C inhibitor are administered sequentially, optionally wherein a) the ERK 1 / 2 inhibitor is administered before the KRAS G12C inhibitor, or b) the KRAS G12C inhibitor is administered before the ERK 1 / 2 inhibitor.

28. The method according to any one of claims 1-27, wherein the KRAS G12C inhibitor is administered orally, intravenously, or subcutaneously.

29. The method according to any one of claims 1-28, wherein the ERK 1 / 2 inhibitor is administered orally, intravenously, or subcutaneously.

30. The method according to any one of claims 1-29, wherein the ERK 1 / 2 inhibitor is administered in one or more doses, optionally, wherein the ERK 1 / 2 inhibitor is administered twice daily, daily, or every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.

31. The method of claim 30, wherein the dose is equivalent to a dose of about 10 mg / kg to about 100 mg / kg for mice, optionally wherein the dose is equivalent to a dose of about 10 mg / kg to about 50 mg / kg for mice.

32. The method according to any one of claims 1-31, wherein the KRAS G12C inhibitor is administered in one or more doses, optionally, wherein the KRAS G12C inhibitor is administered twice daily, daily, or every two days for at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.

33. The method of claim 32, wherein the dose is equivalent to a dose of about 10 mg / kg to about 100 mg / kg for mice, optionally wherein the dose is equivalent to a dose of about 10 mg / kg to about 50 mg / kg for mice.

34. The method according to any one of claims 1-33, further comprising administering an effective amount of a third therapy to the individual.

35. The method of claim 34, wherein the third therapy comprises another anticancer agent.

36. The method of claim 35, wherein the anticancer agent is selected from the group consisting of: immune checkpoint inhibitors, cytotoxic agents, cell inhibitors, anti-angiogenic agents, depressants, chemotherapeutic agents, antibody-drug conjugates, radiotherapy and radiotherapy agents, targeted anticancer agents, BRM, therapeutic antibodies, cancer vaccines, cytokines, hormone therapy, radiotherapy and antimetastatic agents, optionally, the anticancer agent is an EGFR inhibitor, further optionally, wherein the EGFR inhibitor is an anti-EGFR antibody, further optionally, wherein the EGFR antibody is cetuximab.

37. The method according to any one of claims 1-36, wherein the individual is a person.

38. The method according to any one of claims 1-37, wherein the method comprises selecting an individual for treatment based on the presence of one or more cancer cells containing a KRAS abnormality (e.g., KRAS G12C, e.g., KRAS G12D, e.g., KRAS Q61H), optionally wherein the KRAS abnormality includes a) a) a mutant KRAS G12C protein, b) a mutant KRAS G12D protein, and / or c) a mutant KRAS Q61H protein.

39. Use of ERK 1 / 2 inhibitors and KRAS G12C inhibitors in the preparation of drugs for treating cancer.

40. The use according to claim 39, wherein the cancer is selected from the group consisting of: colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal cancer, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, central nervous system tumors, mesothelioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.

41. The method of claim 16 or the use of claim 40, wherein the cancer is colorectal cancer (e.g., NSCLC).

42. The method of claim 16 or the use of claim 40, wherein the cancer is pancreatic cancer.

43. The method of claim 16 or the use of claim 40, wherein the cancer is lung cancer.

44. The method or use according to any one of claims 1-43, wherein the dose included in the treatment is equivalent to a dose of 25 to 50 mg / kg of an ERK 1 / 2 inhibitor for mice.

45. The method or use according to any one of claims 1-44, wherein the dose included in the treatment is equivalent to a dose of 10 to 100 mg / kg of a KRAS G12C inhibitor.

46. ​​A kit for treating an individual cancer, comprising: 1) ERK 1 / 2 inhibitors; And 2) KRAS G12C inhibitors.